The information contained in these guidelines is a statement of consensus of Leukemia/BMT Program of BC professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. Use of these guidelines and documents is at your own risk and is subject to the Leukemia/BMT Program of BC’s terms of use available at Terms of Use.

Diagnosis

Definition – What is ALL?
ALL is the most common type of cancer in children, though it also occurs at any age. In ALL, too many stem cells develop into lymphoblasts, which would ordinarily develop into mature lymphocytes. However, in ALL, these blasts do not ever fully develop. These abnormal cells are known as leukemic cells, and are not able to fight infection. As the number of leukemic cells increases in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells and platelets. This may cause infection, anemia and easy bleeding. The cancerous leukemic cells can also spread to the central nervous system (brain and spinal cord), lymph nodes, spleen and liver. ALL is an aggressive, acute leukemia, and progresses rapidly without treatment. Modern combination chemotherapy protocols have made ALL highly treatable, with remission achieved in the majority of patients.

Symptoms
The early signs of ALL may be similar to the flu or other common diseases. Symptoms include:

  • Weakness or feeling tired
  • Fever
  • Easy bruising or bleeding
  • Petechiae
  • Shortness of breath
  • Weight loss or loss of appetite
  • Bone or joint pain
  • Painless lumps in the neck, underarm, stomach, or groin

Diagnosis

Many tests are used to establish ALL diagnosis. Tests include:

  • Complete blood count: This basic test obtains an accurate count of all the different types of blood cells. The hallmark of leukemia is an overabundance of white blood cells (leukocytes), and in some cases, this may be the first sign that alerts the doctor to the presence of leukemia. Leukocytes may also be normal or low in number too. In acute lymphocytic leukemia, characteristic cells called “lymphoblasts” or simply ‘blasts’ appear in significant numbers.
  • Bone marrow aspirate and biopsy: A needle is inserted into the hipbone to obtain a small piece of bone and sample of bone marrow. A pathologist examines the samples under a microscope and performs special studies to classify the leukemia according to cell type and other parameters.
  • Cytochemistry and immunocytochemistry: Cytochemistry refers to using special stains and chemical reactions to differentiate between types of leukemia. Immunocytochemistry uses the same principle, employing antibodies to produce distinct color changes in the cell sample that allow the pathologist to identify the type of leukemia present.
  • Immunophenotyping: Immunophenotyping classifies cells according to their immunologic characteristics. This test uses monoclonal antibodies to more accurately determine the type of leukemia. The presence or absence of certain antigens, called CD antigens, cell surface markers expressed by leukocytes, is very useful in determining cell lineage (whether the leukemia derives from T cells or B cells).
  • Cytogenetics (chromosome analysis): In adult ALL, the role of cytogenetics in patient management has largely been centered on the presence of the Philadelphia (Ph) chromosome which usually arises from t(9;22) and results in BCR-ABL fusion. Other recurrent chromosomal abnormalities have been described in adult ALL, however, their frequency has been low and their prognostic relevance is not clear. Getting a complete chromosome analysis at ALL diagnosis provides important diagnostic and prognostic information.
  • Molecular testing, including polymerase chain reaction testing: This test examines genes in the leukemia cell. The presence of certain genes, called oncogenes, can help diagnose precisely what form of leukemia is present. For example, in Ph positive ALL, an oncogene called BCR-ABL is often the determining factor in making a diagnosis.
  • Lumbar puncture (spinal tap): In ALL, doctors need to look for leukemia cells in cerebrospinal fluid surrounding the brain and spinal cord. After part of the lower back is numbed, some of the spinal cord fluid is withdrawn using a needle, and examined microscopically for blast cells.

Risk Stratification
Risk stratification in ALL has played an important role in predicting outcome and searching for alternative therapy to high risk patients. Although the definition of high-risk is not uniform in different studies, in general it includes:

  • Age older than 35 years
  • White blood cell (WBC) count exceeding 50 X 109/L (and in some studies 30 X 109/L) for B-lineage and 100 X 109/L for T-lineage ALL
  • Poor-risk cytogenetic abnormalities including t(9;22), t(4;11), t(1;19), complex karyotype with 5 or more chromosomal abnormalities, low hypodiploid/ near triploidy
  • Failure to achieve complete remission (CR) post first induction chemotherapy
    Any one of the above adverse factors put patients at higher risk of relapse with 5-year disease-free survival (DFS) ranging from 11-33%.

Any one of the above adverse factors put patients at higher risk of relapse with 5-year disease-free survival (DFS) ranging from 11-33%.

Treatment

Patients with acute lymphoblastic leukemia usually require urgent treatment to reduce symptoms and return blood counts to normal. This is called complete remission. Once a remission is achieved, additional treatment is given to consolidate remission and help prevent recurrence.

Chemotherapy

Chemotherapy is the main treatment for all forms of leukemia. Chemotherapy targets fast-dividing cells by disrupting critical parts of the cell cycle. Since cancer cells divide faster than normal cells, more cancer cells than normal cells are killed. Of course, a significant number of normal cells are damaged, which causes the many familiar side effects of chemotherapy. Chemotherapy may be given by mouth (pills), intravenously through an IV or catheter, or into the cerebrospinal fluid (intrathecally). Most often, combinations of chemotherapy drugs are used to achieve the optimal therapeutic outcome.

Chemotherapy is usually given in cycles, sometimes starting with intensive induction treatment, which takes several weeks. This is followed by a few weeks without treatment, allowing the patient to recover from side effects, mostly related to lower blood counts. The sequence is then repeated. Patients who achieve initial remission require additional treatment, usually given over a period of years (in acute lymphoblastic leukemia) in order to prevent recurrence. Treatment for acute leukemia is intensive and usually requires hospitalization.

Chemotherapy for ALL usually is intensive, involves a number of agents given in repeated cycles over 2-3 years and requires hospitalization initially for induction chemotherapy.

The following is a common induction combination protocol:

  • L-asparaginase or PEG-L-asparaginase, daunorubicin , vincristine and prednisone

Other drugs that may be used include:

  • Doxorubicin, cytarabine, also known as cytosine arabinoside or ara-C, etoposide, teniposide, 6-mercaptopurine, Methotrexate, cyclophosphamide, dexamethasone

Other drugs that may be used include:

  • 6-thioguanine, also known as 6-TG, 6-mercaptopurine, also known as 6-MP (Purinethol)

Beyond Chemotherapy: Advances in Treating Leukemia

Stem Cell Transplantation

Hematopoietic cell transplantation (HCT) and peripheral blood stem cell transplantation are therapeutic treatments that use stem cells (immature blood cells) to treat a patient’s malignancy, or to repair diseased or defective bone marrow. Transplants are sometimes performed early in the course of treatment to improve outcomes. In some patients, they are utilized when other treatments are not working.

These transplant procedures include intensive chemotherapy with or without radiation to destroy the cancerous cells. This is followed by an infusion of healthy new stem cells, which have the ability to grow back into the bone marrow and begin making normal blood cells again.

If a patient receives stem cells from a matched donor (using related, unrelated or cord blood), the transplant is called allogeneic. Like other tissue transplants, allogeneic stem cell transplants require a genetic match between the donor and recipient.

In allogeneic transplants, the donor is preferably a sibling. Alternatively, a matched unrelated donor who has a similar genetic type may be used. In some cases, a patient’s own stem cells may be used. This is called an autologous (self) transplant. Autologous transplant has no role in the management of ALL and is not indicated anymore for this disease.

Non-myeloablative HCT
A new transplant procedure has been developed to treat patients with leukemia and myelodysplasia who are older or have underlying medical problems. Reduced-Intensity Conditioning Transplant (RICT) or Non-myeloablative HCT, also called “mini-HCT or “mini transplant,” involves less intensive chemotherapy and radiation treatments.

Researchers now understand that the immune cells created by the transplanted donor stem cells may recognize any remaining cancer cells in the patient as “foreign,” and kill them – thus helping to fight the cancer. This RICT /mini-HCT strategy is showing great promise for leukemia and many other cancers, and is being used to treat patients who are not eligible for full myeloablative allo-transplantation. The role of RICT and/or Non-myeloablative HCT for ALL is still experimental.

Radiation Therapy
Radiation therapy uses high-energy X-rays or other types of radiation to kill cancer cells. Radiation therapy is used for prophylaxis whole brain irradiation in ALL in combination with intrathecal chemotherapy. Also it has an important role as part of the conditioning regimens before allogeneic transplantation. In addition as for many other types of cancer, radiation therapy plays a role in palliation for end stage symptomatic patients with bulky disease causing discomfort, compression or pain.

Prognosis
Acute lymphoblastic leukemia (ALL) in adults is characterized by its high response rate to induction chemotherapy: multiagent chemotherapy induces remission in 74%-92% of ALL patients; however the majority will relapse and succumb to their disease leaving only 27%-40% of adult patients younger than 60 years to enjoy long-term disease-free survival (DFS). Research is still ongoing to improve the results of patients with adult ALL, this includes using new agents, applying pediatric protocols (same agents, same dose intensity), and using allogeneic stem cell transplantation.

Algorithms
Open image in new tab to enlarge.

Outcomes

Outcome by Treatment Type 1989-2005

Outcome by Karyotype

Chemotherapy in Elderly ALL Patients

Elderly ALL Patients Treated Aggressively

T-Cell ALL

 

Publications

Please check back for associated publications.

Diagnosis

The diagnosis of AML is a medical emergency that requires referral of the patient to a tertiary referral center with expertise in the management of this disease and its complications. In British Columbia adult patients with an established or probable diagnosis of AML should be referred to the Leukemia/BMT Program at the Vancouver General Hospital (1). Children should be referred to the BC Children’s hospital.

Required Tests

  • CBC and differential
  • Electrolytes, BUN, creatinine, uric acid, liver function tests
  • INR, PTT and fibrinogen
  • Bone marrow aspirate and biopsy with aspirate sample sent for cytogenetic analysis, flow cytometry for blast cell immunophenotyping. For patients eligible for treatment (non-intensive and intensive) a portion of the diagnostic aspirate marrow is sent to the BCC Cancer Genetics laboratory for Myeloid Panel and rapid-turn-around FLT3 mutation testing. The requisition for this testing is found here.

The diagnosis of AML requires:

  • More than 20% blasts in the bone marrow or peripheral blood differential
  • Further refinement of the diagnosis to allow classification of the subtype of AML by WHO criteria requires the results of immunophenotyping and genetics (2).

At diagnosis the most important subtype recognition is acute promyelocytic leukemia (APL). Although this is a highly curable AML subtype it carries with it a high risk of hemorrhagic complications and requires specific therapy. See specific Cancer Management Guidelines for APL.

Prognosis

At diagnosis, the average age of patients with AML is 68 years. Survival and likelihood of cure with conventional therapy decreases with age such that although ~40% of adults under 60 years old can be cured that proportion is lower in patients over 60. Patients with an antecedent hematologic disease (e.g. myelodysplastic or myeloproliferative disorder) or treatment-related AML also have a less favorable prognosis than patients with de novo AML.

Genetic and cytogenetic changes in the bone marrow are generally the strongest prognostic indicators. Using the classification developed by the European Leukemia Network (ELN) (4) chromosome abnormalities classify cases as favorable, intermediate or adverse risk which is shown in Table 1. The proportion of patients with intermediate and adverse genetic changes increases with age. Almost half of AML patients have normal bone marrow cytogenetics at diagnosis. These are classified as intermediate risk. However, there are a growing number of submicroscopic mutations and rearrangements that may also affect prognosis. Recently, the availability of the Myeloid Panel for detection of mutations in multiple genes of prognostic relevance in myeloid malignancies including AML has become available through the BCCA Cancer Genetics Laboratory. We have begun to use this routinely to aid in risk stratification for AML patients who are potentially eligible for allogeneic stem cell transplantation. The current risk stratification system used by the L/BMT program is based on the 2017 ELN risk stratification system, which is used to guide decision making around stem cell transplant.

Risk Categories

Table 1. AML Risk Groups, ELN 2017

Risk Category
Genetic Abnormality
Favorablet(8;21)(q22;q22.1); RUNX1-RUNX1T1
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow*
Biallelic mutated CEBPA
IntermediateMutated NPM1 and FLT3-ITDhigh*
Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow (without adverse-risk genetic lesions)
t(9;11)(p21.3;q23.3); MLLT3-KMT2A
Cytogenetic abnormalities not classified as favorable or adverse
Adverset(6;9)(p23;q34.1); DEK-NUP214
t(v;11q23.3); KMT2A rearranged
t(9;22)(q34.1;q11.2); BCR-ABL1
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1)
-5 or del(5q); -7; -17/abn(17p)
Complex karyotype**, monosomal karyotype***
Wild-type NPM1 and FLT3-ITDhigh*
Mutated RUNX1****
Mutated ASXL1****
Mutated TP53
*FLT3-ITDlow refers to an allelic ratio (AR) <0.5, FLT3-ITDhigh refers to AR ≥ 0.5
**Complex karyotype refers to three or more unrelated chromosome abnormalities in the absence of 1 of the WHO-designated recurring translocations or inversions
***Defined by the presence of 1 single monosomy (excluding loss of X or Y) in association with at least 1 additional monosomy or structural chromosome abnormality (excluding core-binding factor AML
****These markers should not be used as an adverse prognostic marker if they co-occur with favorable-risk AML subtypes
Treatment

The goals of therapy and the likelihood of success vary greatly in AML according to disease and patient characteristics. Thus, the treatment varies depending on the ‘Risk Categories’ described under Diagnosis as well as patient age and co-morbidities. For the purpose of clinical trials and Consensus Guidelines such as those developed by the National Comprehensive Cancer Network (NCCN) (www.nccn.org) in the USA treatment strategies are usually stratified by age and fitness to undergo allogeneic stem cell transplantation. This is a high risk procedure which often cannot be recommended for patients older than 70 years or those with significant co-morbid illness.

The Leukemia/BMT Program participates in a variety of Phase 1 through Phase 4 clinical trials for which AML patients in different categories may be eligible. Clinical trial in the L/BMT Program are usually run by the Hematology Research Program. Our program believes that conducting clinical trials is essential to develop new treatments and improve outcomes for patients with AML and other blood cancers. Below are the current treatment guidelines for patients not treated on such trials.

AML – transplant eligible

A. Induction chemotherapy

The first goal of therapy is achievement of ‘complete remission’ (CR) which is defined as less than 5% blasts in a post treatment marrow with an absolute neutrophil count >1.0 x109/L, platelets ≥ 100 x109/L and absence of transfusion requirements. Recommended remission induction chemotherapy includes cytarabine and an anthracycline. The Leukemia/BMT Program currently uses conventional ‘7+3’ chemotherapy which includes cytarabine 100 mg/m2/d by continuous IV infusion for 7 days and daunorubicin 60 mg/m2/d for 3 days. The probability of achieving CR with 7+3 is approximately ~70% although it varies with risk status and age. In patients that have a documented FLT3-ITD or TKD mutation, midostaurin an oral FLT3 inhibitor should also be added following 7+3, usually starting on day +8 of therapy at a dose of 50 mg orally twice daily for 14 days. For patients with favorable or intermediate cytogenetic changes gemtuzumab-ozogamicin a CD33-directed antibody drug conjugate can be added on days 1, 4 and 7 of induction therapy. This drug is given as an infusion at a dose of 3 mg/m2 capped at a maximum dose of 4.5 mg. In patients with unknown cytogenetics at the time of starting induction, gemtuzumab-ozogamicin can be started but should be stopped if cytogenetics are discovered to be adverse or a FLT3 mutation is detected and treatment with midostaurin is planned. Details around induction and consolidation treatment are shown in the algorithm below.

If CR is documented the patient proceeds to consolidation therapy as determined by their prognostic risk assessment. If CR is not obtained the patient receives salvage chemotherapy. There is no standard salvage regimen in this circumstance. In general, the well-known MEC (mitoxantrone, etoposide and cytarabine) protocol is considered in patients that do not achieve CR or relapse following chemotherapy(6). The probability of achieving CR with MEC therapy is ~50%. For a number of years the Leukemia/BMT Program has used a salvage regimen consisting of etoposide (2.4 g/m2 by CIVI over 34h) and cyclophosphamide (2 g/m2/d on days 3-5) and this is sometimes considered in patients relapsing early on have high-dose cytarabine treatment. There is a recent phase 3 RCT showing that patients with mutated FLT3 AML with relapsed or refractory (R/R) disease have a higher response rate and OS with gilteritinib (an oral FLT3 inhibitor) compared to intensive salvage regimens such as MEC. Patients with R/R FLT3-mutated AML may be able to access gilteritinib though a compassionate access program arranged by Astellas. Alternatively, patients with a FLT3-ITD mutation with R/R AML may be treated with azacitidine and sorafenib which is funded through the compassionate access program at the BCC. The overall probability of achieving CR for AML patients who are fit to receive induction and (if necessary) salvage chemotherapy is ~80%. Patients who fail to achieve CR after salvage chemotherapy may be offered participation in a clinical trial, if available. If a trial is not available or the patient refuses participation they generally receive palliative/best supportive care.

B. Post remission therapy

The goal of post remission therapy is the prevention of relapse. If such therapy is not given most AML patients will relapse within a few months of achieving CR. There are 2 broad categories of post remission therapy; chemotherapy consolidation or stem cell transplantation, usually using cells from a healthy donor. Chemotherapy consolidation is well-tolerated but has a high risk of relapse, particularly in patients with AML with adverse risk prognostic features. The relapse risk is lower with donor stem cell transplant but the risk of treatment related death is higher, varying between 15 and ~40 or more% depending on the type of donor and the degree of matching between the donor and recipient as well as patient-specific risk factors. Thus, the risk must be weighed against the benefit for post remission strategies.

Patients with favorable risk prognostic features as defined under Diagnosis and Table 1 receive consolidation chemotherapy with 3 cycles of high-dose cytarabine at a dose of 3 g/m2/d for 6 days. For patients beyond age 60 the cytarabine dose is reduced to 1.0 g/m2/d for 5 days (INDAC) to reduce the risk of CNS toxicity. The probability of cure for such patients is ≥ 60%, thus the risk of donor stem cell transplant in CR1 is difficult to justify. Midostaurin is also given during consolidation for patients with a FLT3-mutation. In addition, gemtuzumab-ozogamicin is given as a single dose of 3 mg/m2 on day 1 of consolidation in patients with favorable or intermediate risk cytogenetics for up to 2 cycles.

Patients with intermediate or adverse risk features are considered for an allogeneic stem cell transplant is a suitable donor is available. Generally, potential donors can include: a matched related or unrelated donor, a 9/10 antigen mismatched donor, a haploidentical donor or an umbilical cord blood donor. For younger, fitter patients without significant comorbidities a myeloablative conditioning regimen is preferred to reduce the risk of relapse. Reduced intensity conditioning is used for patients > age 65 or those with significant co-morbid issues. In the absence of an available donor 3 cycles of cytarabine-based consolidation is administered.

The probability of long-term disease free survival with an allogeneic stem cell transplant performed in CR1 overall is approximately 50%. Donor stem cell transplantation appears to overcome some of the negative prognosis associated with poor risk AML, risk of relapse post-transplant is still dependent on the prognostic features of the leukemia. Reduced intensity conditioning regimens are used for elderly AML patients who are considered otherwise fit. However, it is the minority of older patients who are stem cell candidates due to lack of a suitable donor or comorbid issues (10). In addition, AML in the elderly often has poor risk features that increase the risk of relapse following reduced intensity regimens.

C. Therapy of relapsed disease

AML patients frequently develop relapsed disease after the completion of all planned therapy. There is no standard ‘best’ therapy in this situation and the prognosis is generally poor. Currently, the Leukemia/BMT program offers clinical trial participation to all such patients if a trial is available. If the patient refuses participation or a suitable trial is not available, some patients may receive re-induction chemotherapy such as MEC or another regimen. The probability of achieving a second CR is ~30-50% overall but varies with the length of CR1 (longer CR1 predicts greater likelihood of CR2). If CR2 is obtained and the patient has not previously received a donor transplant, the patient would receive a transplant if a donor can be identified. The risk of treatment-related complications and relapse post transplant is higher when a donor transplant is done beyond CR1. If CR2 is not obtained the patient would receive palliative/supportive care.

AML, elderly and/or unfit

A. Induction chemotherapy for the ‘fit’ elderly

Outcomes are generally worse for with elderly AML patients, which is related to a higher incidence of adverse risk prognostic genetic features, secondary AML as well as a poorer tolerance of intensive chemotherapy. Thus, it is appropriate to consider entry into clinical trials at diagnosis for such patients. If an appropriate clinical trial is not available or the patient refuses participation conventional therapy can be offered. The Leukemia/BMT Program currently uses conventional ‘7+3’ chemotherapy as described above for younger AML patients for the ‘fit’ elderly up to age 70. In patients, over age 70 induction with favorable cytogenetics (e.g. t(8;21) or inv(16)) is considered in fit patients who are assessed to have the ability to tolerate intensive chemotherapy. In some patients over age 70 with AML and intermediate risk genetics, intensive induction is considered in fit patients without significant comorbidities that might be considered candidates for stem cell transplantation. Older patients with adverse risk genetics changes are generally treated with non-intensive approaches such as azacitidine.

B. Post remission therapy

The goal of post remission therapy is the prevention of relapse. Unfortunately, this is an elusive goal in the elderly with AML, and ~80-90% of elderly AML patients who achieve CR1 will eventually relapse. Thus, the benefit of any post remission therapy must be carefully weighed against the risk of morbidity and occasional mortality associated with the treatment. Chemotherapy consolidation is generally offered to elderly AML patients who achieve CR1 and who tolerate induction therapy well. Outside of a clinical trial protocol this usually consists of 2-3 cycles of intermediate dose cytarabine consolidation as outlined above. Rarely fit, elderly patients in CR1 may be candidates for consolidation using a reduced intensity conditioning transplant.

C. Therapy of relapsed disease

The duration of CR1 for most elderly AML patients is less than one year. Since second remissions are typically more difficult to achieve and, when achieved, are much shorter than the first, re-induction therapy is rarely offered to elderly AML patients. Selected patients may be appropriate candidates for clinical trials, if available. Most patients receive palliative/best supportive care.

D. Therapy for the AML in the ‘unfit’ elderly.

Patients ≥70 years of age or younger patients with serious co-morbidity are rarely treated with standard induction chemotherapy and often the most appropriate management non-intensive chemotherapy. Funded non-intensive chemotherapy in BC currently include treatment with azacitidine or low-dose cytarabine (LDAC) and these treatments are associated with a modest improvement in OS compared to best-supportive care alone. Azacitidine (AZA) is the preferred treatment in many patients, particularly with adverse risk genetic changes or secondary AML, as there is limited efficacy of LDAC in this situation. In addition, LDAC requires the patient or a caregiver to administer this subcutaneously at home and pick-up the medication from a BCC pharmacy. Goals of non-intensive therapy are to reduce transfusion requirements, slow progression of the disease and maintain quality of life and improve survivial. BCC compassionate Access Program (CAP) approval is required for both low dose cytarabine and AZA therapy. Treatment of patients with non-intensive chemotherapy or best-supportive care also often includes palliative care referral, homecare as well as other best supportive measures such as transfusion support and hydroxyurea.
Patients wishing more active treatment may be eligible for clinical trials of novel agents. Most of these trials are currently run through the L/BMT program in Vancouver and treatment is usually given as an outpatient. Venetoclax is an oral BCL2 inhibitor that has demonstrated promising activity in older patients combined with azacitidine with improved response rate and longer OS compared to azacitidine alone. Funding is not yet available for this combination, however a funding proposal has been submitted to the BC Cancer PEC committee.

Outcomes

Publications

Chalandon Y, Barnett MJ, Horsman DE, Conneally E, Nantel SH, Nevill TJ, Nitta J, Shepherd JD, Sutherland HJ, Toze CL, Hogge DE. Influence of Cytogenetic Abnormalities on Outcome after Allogeneic Bone Marrow Transplantation for Acute Myeloid Leukemia in First Complete Remission. Biol Blood Marrow Transplant 8:435-443, 2002.

Song S, Christova R, Perusini S, Alizadeh S, Bao R-Y, Miller BW, Hurren R, Jitkova Y, Gronda M, Isaac M, Joseph B, Subramaniam R, Aman, A, Chau A, Hogge DE, Weir SJ, Kasper J, Schimmer AD, Al-awar R, Wrana JL Attisano L. Wnt Inhibitor screen reveals iron dependence of beta-catenin signaling in cancers. Cancer Research 71:77628-39, 2011.

Lubieniecka JM, Graham J, Heffner D, Mottus R, Reid R, Hogge D, Grigliatti TA, Riggs WK. A discovery study of daunorubicin induced cardiotoxicity in a sample of acute myeloid leukemia patients prioritizes P450 oxidoreductase polymorphisms as a potential risk factor. Front Genet. 2013 Nov 11;4:231.

Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 121:4854-60, 2013.

Rosen DB, Harrington KH, Cordeiro JA, Leung LY, Putta S, Lacayo N, Laszlo GS, Gudgeon CJ, Hogge DE, Hawtin RE, Cesano A, Walter RB. AKT signaling as a novel factor associated with in vitro resistance of human AML to gemtuzumab ozogamicin. PLoS One. 8:e53518, 2013.

Xing Y, Hogge DE. Combined inhibition of the phosphoinosityl-3-kinase (PI3Kinase) P110δ subunit and mitogen-extracellular activated protein kinase (MEKinase) shows synergistic cytotoxicity against human acute myeloid leukemia progenitors. Leuk Res 37:697-704, 2013.

Brandwein JM, Geddes M, Kassis J, Kew AK, Leber B, Nevill T, Sabloff M, Sandhu I, Schuh AC, Storring JM, Ashkenas J. Treatment of older patients with acute myeloid leukemia (AML): a Canadian consensus. Am J Blood Res. 3:141-64, 2013 .

Lancet JE, Cortes JE, Hogge DE, Tallman MS, Kovacsovics TJ, Damon LE et al Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood 123: 3239-3246, 2014.

Minden MD, Hogge DE, Weir SJ, Kasper J et al. Oral diclopirox olamine displays biological activity in a phase I study in patients with advanced hematologic malignancies. Am J Hematol 89:363-368, 2014.

Brandwein JM, Kassis J, Leber B, Hogge D, Howson-Jan K, Minden MD, Galarneau A, Pouliot J-F. Phasae II study of targeted therapy with temozolomide in acute myeloid leukaemia and high-risk myelodysplastic syndrome patients pre-screened for los O6-methylguanine DNA methyltransferase expression. Brit J Haem 167:664-670, 2014.

Cortes JE, Goldgerg SL, Feldman EJ, Rizzeri DA, Hogge DE et al. Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML. Cancer 121:234-42, 2015.

Ravandi F, Ritchie EK, Sayar H, Lancet JE, Craig MD, Vey N, Strickland SA, Schiller GJ, Jabbour E, Erba HP, Pineux A, Horst HA, Recher C, Klimek VM, Cortes J, Roboz GJ, Odenike O, Thomas X, Havelange V, Maertens J, Derigs H-G, Heuser M, Damon L, Powell BL, Gaidano G, Carella A-M, Wei A, Hogge D, Craig AR, Fox JA, Ward R, Smith JA Acton G, Mehta C, Stuart RK, Kantarjian HM. Voxaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukemia (VALOR): a randomized, controlled, double-blind, multinational, phase 3 study. Lancet Oncol 16:1025-36, 2015.

Yuan X, Koehn J and Hogge DE. Identification of prognostic subgroups among acute myeloidleukemia patients with intermediate risk cytogenetics using a flow-cytometry-based assessment of ABC transporter function. Leuk Res. 39:689-695, 2015.

Chen WC, Yuan JS, Xing Y, Mitchell A Mbong N, Popescu AC, McLeod J, Gerhard G, Kennedy JA, Bogdanoski G, Lauriault S, Perdu S, Merkulova Y, Minden MD, Hogge DE, Guidos C, Dick JE, Wang JC. An integrated analysis of heterogeneous drug responses in acute myeloid leukemia that enables the discovery of predictive biomarkers. Cancer Res. 76:1214-1224, 2016.

Michaelis FV, Atenafu EG, Couban S, Frazer J, Shivakumar S, Hogge DE, Toze CL, Rajkhan W, Kim HJ, Daly A, Slaby J, Finke J, Kiss T, Bredeson C, Sabloff M, Sheppard D, Bakkar M, Brune M, Wall DA, Paulson K, Popradi G, Walker I, Messner HA. Duration of first remission and hematopoietic cell transplantation-specific co-morbidity index but not age predict survival of patients with AML transplanted in CR2: a retrospective multicenter study. Bon Marrow Transplant. 51:1019-1021, 2016.

Cressman S, Karsan A, Hogge DE, McPherson E, Bolbocean C, Regier DA, Peacock SJ. Economic impact of genomic diagnostics for intermediate-risk acute myeloid leukemia. Br J Haematol 174:526-535, 2016.

Khamenehfar A, Gandhi MK, Chen Y, Hogge DE, Li PC. Dielectrophoretic microfluidic chip enables single-cell measurements for multidrug resistance in heterogeneous acute myeloid leukemia patient samples. Anal Chem 174:526-535, 2016.

References

Goy J et al. The clinical and diagnostic pathway for adults with acute leukemia in BC. BC Med J 59:22-28, 2017.

Arber DA et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127:2391-2405, 2016.

Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, Wheatley K, Harrison CJ & Burnett AK. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 116(3):354-365, 2010.

Dohner H, Estey E et al. Diagnosis and Management of AML in adults: 2017 ELN recommendation from an international expert panel. Blood 129:424-447, 2017.
Papaemmanuil E et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med 374:2209-2221, 2016

Greenberg PL et al Mitoxantrone, etoposide and cytarabine with or without valspodar in Patients with relapsed or refractory acute myeloid leukemia and high risk myelodysplastic syndrome: A phase III trial (E2995). J Clin Oncol 22:1078-1086, 2004.

Fenaux et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 28:562-569, 2010.

Dombret H et al International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 126:291-299, 2015

Burnett A, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK, Wheatley K. A Comparison of Low-Dose Cytarabine and Hydroxyurea With or Without All-trans Retinoic Acid for Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome in Patients Not Considered Fit for Intensive Treatment. Cancer 109:1114-24, 2007.

Sorror ML et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 106:2912-2919, 2005.

Treatment
Diagnosis

Aplastic anemia (AA) is a rare condition with an annual incidence of 2 new cases per million population. The disease has a biphasic distribution, most frequently affecting teens/young adults and individuals beyond the age of 60 years. It presents with low blood counts (hematologic cytopenias) affecting at least two but often all three cell lines (hemoglobin, white blood cells and platelets) – i.e. “pancytopenia”. The bone marrow examination shows an empty (“aplastic”) marrow and while the remaining erythroid cells may be somewhat abnormal (dysplastic) in appearance, the white cell precursors and megakaryocytes are morphologically normal. Bone marrow karyotype analysis may fail due to inadequate growth of cells in the culture but, if available, is almost always normal. White cell or megakaryocytic dysplasia or the presence of a clonal karyotypic abnormality should raise the possibility of myelodysplastic syndrome.

Classification

AA is classified according to the severity of the low blood counts as the table below follows.

Etiology

The cause of AA is uncertain in more than 90% of patients. The most common established cause is seronegative hepatitis (~5% of patients). Pregnancy and eosinophilic fasciitis are clearly established causes of AA although it rarely develops in pregnancy and the latter condition is exceedingly rare in its own right. Drugs have long been suspected in the development of AA but a clear link has been difficult to establish for any one agent. Epidemiologic studies suggest exposure to certain chemicals (benzene and pesticides) may place individuals at greater risk of developing AA. AA may also be a manifestation of a congenital/constitutional syndrome (e.g. Fanconi anemia or dyskeratosis congenita/telomeropathy). These disorders may present with isolated marrow failure or there may be other associated congenital abnormalities – musculoskeletal, neurologic, cardiac, renal or other.

Pathogenesis

AA is believed to result from autoimmune destruction of hematopoietic cells by oligoclonal cytotoxic T lymphocytes (CTL). These CTLs are part of the immune system’s reponse to an external challenge but in AA patients, they persist abnormally, possibly as a result of a genetic tendency to do so. CTLs produce interferon-γ and TNF-α which, in turn, damage the hematopoietic tissue. One treatment approach (see below) is to use drugs to “dampen” this abnormal immune response – immunosuppression.

 

Reticulocytes
(x 109/L)
Reticulocytes
(x 109/L)
ANC
(x 109/L)
Platelets
(x 109/L)
Severe AA (SAA)
[at least 2/3 of the criteria needed]
<20<0.5<20
Very severe AA (VSAA)<20<0.2<20
Non-severe AA (NSAA)Not meeting above criteriaNot meeting above criteriaNot meeting above criteria
Treatment

Supportive care remains the mainstay for managing AA patients – transfusion of red blood cells and/or platelets and the administration of antimicrobial agents to combat infections. Definitive therapy is generally between allogeneic bone marrow transplantation (BMT) and immunosuppression (see Treatment Algorithm). Young AA patients with a matched sibling donor will have BMT recommended as the long-term event-free survival is now in the order of 80-85% (see Outcomes). These results have improved through the years through refinement of diagnostic techniques, BMT preparative regimens and better supportive care drugs. Older AA patients and those without a sibling donor will generally be given immunosuppression – a combination of intravenous antithymocyte globulin (ATGAM) for four days, oral Cyclosporine for approximately two years and a short course of corticosteroids (Prednisone). Immunosuppression is associated with a 60-70% partial or complete response rate and, historically, a 60% survival at 10 years (see Outcomes). About one in three responders to immunosuppression will relapse (although 90% never require blood product support, only long-term Cyclosporine maintenance), and 15% of responders develop a clonal disease (such as MDS). Therefore, only ~40% of AA patients treated with immunosuppression will be able to stop all medications and maintain satisfactory blood counts for the remainder of their life. For patients lacking a sibling donor and for those with AA that is relapsed or refractory to immunosuppression, BMT from a volunteer unrelated donor is a viable treatment alternative. Results of unrelated donor BMT for AA have improved significantly through the years (for the same reasons listed above for matched sibling donors; see Outcomes) and long-term event free survival are now in the order of 70-75%.

Treatment options for patients refractory to Cyclosporine/ATGAM and who are unable to undergo BMT include, in addition to ongoing standard supportive care:

  1. Thymoglobulin – another ATG product with an ~30% response rate in patients that fail to respond to ATGAM
  2. Eltrombopag – a daily oral agent that produces an ~40% response rate with ~25% of patients having a multilineage response
  3. Alemtuzumab – an intravenous drug given for 10 days that is associated with a ~30% response rate

Algorithms
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Protocols
BCCA Chemotherapy Protocols and PPOs

Outcomes

 

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Diagnosis – Burkitt Lymphoma

Burkitt lymphoma is an uncommon non-Hodgkin’s lymphoma. It is a B-cell lymphoma with an extremely short doubling time and often presents with extranodal sites. Characteristic cytogenetic changes lead to deregulation of the MYC gene. This lymphoma requires rapid assessment and treatment. In British Columbia adult patients with an established or probable diagnosis of Burkitt lymphoma should be referred to the Leukemia/BMT Program at the Vancouver General Hospital. Children should be referred to the BC Children’s Hospital.

Required Tests

  1. Lymph node/tissue biopsy;
  2. CBC and differential
  3. Electrolytes, BUN, creatinine, uric acid, liver function tests, LDH
  4. INR, PTT and fibrinogen
  5. Bone marrow aspirate and biopsy with cytogenetic analysis and flow cytometry for immunophenotyping
  6. Computed tomography (CT) scan of the neck, chest abdomen and pelvis. CT of the head should also be considered, especially if there are CNS symptoms.
  7. Lumbar puncture

Staging
The stage of disease is of major therapeutic and prognostic significance. The staging system used is based on the Ann Arbor system with additional consideration of the bulk or size of individual tumours. The formal stage is assigned using table below.

Symptoms

A = No B symptoms

B = presence of at least one of these:

  1. Unexplained weight loss > 10% baseline during 6 months prior to staging
  2. Unexplained fever > 38oC/font>
  3. Night sweats

Prognosis
Patients diagnosed with Burkitt lymphoma can have a 5-year disease free survival rate of 60-80%. The prognosis is dependant upon the stage of disease and the age of the patient.

StageInvolvement
1Single lymph node region (1) or one extralymphatic site (1E).
2Two or more lymph node regions, same side of the diaphragm (2) or local extralymphatic extension plus one or more lymph node regions same side of the diaphragm (2E)
3Lymph node regions on both sides of diaphragm (3) which may be accompanied by local extralymphatic extension (3E)
4Diffuse involvement of one or more extralymphatic organs or sites
Diagnosis – Double Hit Lymphoma

Double hit lymphomas typically contain a MYC/8q24 breakpoint in combination with a BCL2/18q21 breakpoint. The partner of the BCL2/18q21 breakpoint mostly is the IGH locus at 14q32. The abnormalities are typically associated with the B-cell lymphoma, Unclassifiable, with Features intermediate between Diffuse Large B-cell Lymphoma and Burkitt Lymphoma (BCLU) as well as the Diffuse large B-cell Lymphoma histology. This diagnosis is dependent upon demonstration of the typical cytogenetic changes. Patients who have immunohistochemical evidence of upregulation of the MYC oncogene and the BCL2 oncogene expression but without cytogenetic evidence of the rearrangements are not considered to have true Double Hit Lymphoma.

Required Tests
Same as Burkitt Lymphoma

Staging
Same as Burkitt Lymphoma

Prognosis
Patients diagnosed with Double Hit Lymphoma do significantly worse than patients with Burkitt Lymphoma. Prognosis has been found to be influenced by the histology, stage, CNS involvement and age of the patient.

Treatment

Algorithms

Protocols
BCCA Chemotherapy Protocols and PPOs

 

Publications
  1. Mead GM, Barrans SL, Qian W, Walewski J, Radford JA, Wolf M, Clawson SM, Stenning SP, Yule CL, Jack AS. A prospective clinicopathologic study of dose-modified CODOX-M/IVAC in patients with sporadic Burkitt lymphoma defined using cytogenetic and immunophenotypic criteria (MRC/NCRI LY10 trial). Blood 112:2248-2260, 2008.
  2. Song KW, Barnett MJ, Gascoyne RD, Horsman DE, Forrest DL, Hogge DE, Lavoie JC, Nantel SH, Nevill TJ, Shepherd JD, Smith CA, Sutherland HJ, Voss NJ, Toze CL and Connors JM. Haematopoietic stem cell transplantation as primary therapy of sporadic adult Burkitt lymphoma. Br J Haem 133:634-637, 2006.
  3. Petrich AM, Gandhi M, Jovanovic B, Castillo JJ, Rajguru S, Yang DT, Shah KA, Whyman JD, Lansigan F, Hernandez-Ilizaliturri FJ, Lee LX, Barta SK, Melinamani S, Karmali R, Adeimy C, Smith S, Dalal N, Nabhan C, Peace D, Vose J, Evens AM, Shah N, Fenske TS, Zelenetz AD, Landsburg DJ, Howlett C, Mato A, Jaglal M, Chavez JC, Tsai JP, Reddy N, Li S, Handler C, Flowers CR, Cohen JB, Blum KA, Song K, Sun HL, Press O, Cassaday R, Jaso J, Medeiros LJ, Sohani AR, Abramson JS. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis. Blood 124(15):2354-61, 2014

 

Diagnosis

Updated: February 2011 – currently under review

CLL (Chronic Lymphocytic Leukemia)

  • Least 5 x109/ B lymphocytes/L in peripheral blood
  • Clonality confirmed by flow cytometry

SLL (Small Lymphocytic Leukemia)

  • Lymphocytes in peripheral blood not greater than 5 x 109/L
  • Lymphadenopathy and / or splenomegaly
  • Confirmation of dx by marrow and / or histopathologic exam of node biopsy

MBL (Monoclonal B-cell Lymphocytosis)

  • Absolute B-cell lymphocytye count < 5 x 109/L
  • Absence of lymphadenopaty, organomegaly, cytopenias, or disease related symptoms
  • All lymph nodes < 1.5 cm
  • No cytopenias
  • No symptoms
  • Progression to CLL at a rate of 1 to 2% per year

Diagnosis and Testing

1. Immunophenotyping (can be done at VGH, BCCA or SPH):

  • typical is co-expression of CD5+ and B-cell antigens CD19+, CD20 dim, CD23+, sIg dim+, and cyclin D1-, with kappa or lambda light chain restriction
  • FISH for t(11:14) should be done in all cases with atypical immunophenotype – i.e., CD23 dim or negative, CD20 bright, sIg bright

2. History with attention to:

  • B symptoms
  • Performance status
  • Infections
  • Bleeding
  • Auto-immune disorders
  • Skin and other cancers
  • FHx of CLL and lymphoid malignancy (See also Lymphoid Cancer Families Study)

3. Physical with attention to:

  • Lymph node size and location of enlargement
  • Spleen and liver size
  • Signs of infection

4. Blood work:

  • CBC Diff plats retic count and peripheral blood smear
  • Lytes, BUN, CR, LFTs including LDH, uric acid, calcium
  • Direct antiglobulin test
    ;B2 microglobulin
    SPEP and quantitative Igs
  • Hepatitis serologies to include HIV, HCV, HBsAg, Anti-HBc, Anti-HBs

Staging

Document clinical stage at diagnosis and at progression. In BC, the Rai stage is most commonly used, as the table below.

 

Recommended Prior to Treatment

  1. As per diagnosis but also:
    • Hepatitis panel including Hep B/C, HIV, MCV, HSV, VZV
    • FISH for: Del 17p, Dep 11q, Del 13q, +12
    • At VGH or RCH, FISH testing is also done to look for IgH abnormalities
  2. FISH should be repeated prior to each major change in treatment and for change in disease behaviour, i.e., for more aggressive disease behaviour
  3. Chest x-ray
  4. Prior to treatment it may be helpful depending upon clinical circumstances to consider imaging (CT scans) and marrow aspirate and biopsy if appropriate
  5. Marrow aspirate and biopsy should always be done in the situation of unexplained cytopenias, evaluation of possible transformation, and prior to SCT

Prognosis & Risk Stratification

Prognostic factors in CLL include:

  1. Stage – advanced 3 or 4 shorter overall survival
  2. Bulky disease
  3. B-symptoms
  4. Transformation of CLL
  5. B2 microglobulin
  6. FISH (see table below)
  7. IgVH mutation status: Mutated IgVH has better prognosis, however it is not clear how this may impact on therapeutic decisions, and not widely available, not currently available in BC
  8. Flow cytometry: CD 38+ less favourable than CD 38-
Modified Rai StageClassical Rai StageFindings
Low Risk0Lymphocyte count > 5.0 x 109/L. Bone marrow contains > 40% lymphocytes 
Intermediate Risk1Stage 0 + lymphadenopathy
Intermediate Risk2Stage 0 + hepatomegaly and splenomegaly
High Risk3Stage 0 + anemia (Hgb < 110 g/L)
High Risk4Stage 0 + thrombocytopenia (Platelets < 100 x 109/L)
Staging
Unfavourable17p delShort time to progression / time to therapy and overall survival
Refer for consideration of allo SCT once 17p- is found and therapy is required
11q delSuboptimal TTP, TTT, OS
Early consideration for allo SCT – likely around first progression
Neutralnormal
+12
Favourable13q del as sole abnormality
FISH
Treatment

Indications for Therapy

Multiple well conducted multicentre studies have demonstrated no advantage to therapy for CLL for early stage asymptomatic patients.
Therapy is therefore recommended for:

  1. Symptomatic early stage patients
  2. Advanced stage patients
  3. In the setting of active/symptomatic disease including:
    • Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia
    • Massive (≥ 6cm below costal margin) or progressive or symptomatic splenomegaly
    • Massive (≥ 10cm) or progressive or symptomatic lymphadenopathy
    • Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months
    • Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroids
    • Constitutional symptoms including:
    ○ Unintentional weight loss of 10% or more within the prior 6 months
    ○ Significant fatigue (ECOG ≥ 2) – including inability to work or perform usual activities
    ○ Fevers higher than 38°C for 2 or more weeks without evidence of infection
    ○ Night sweats for more than 1 month without evidence of infection

Therapy for Advanced Stage & Symptomatic CLL

Initial Therapy

  • See BCCA website in addition to the information provided below
  • FR
  • With presence of 17p deletion, refer to L/BMT Program for allo SCT to be performed as consolidation of response to primary therapy or most recent therapy

Therapy at Progression

Therapy is dependent upon response depth and duration to last therapy. If good response and long lasting, > 3 years, consider re-use of first therapy. See BCCA website in addition to the information provided below.

Useful therapies may include:

  1. FR or FCR
  2. C(V may be given or omitted)PR or CHOP R
  3. GDP R – may be useful if bulky disease
  4. Alemtuzumab
    • May be useful in cases without bulky disease
    • Special handling/monitoring of infection including prophylaxis of viral infection and monitoring for CMV reactivation

Note:

  • If 17p deletion, refer to L/BMT Program for allo SCT as consolidation of therapy
  • If transformation, refer to L/BMT Program for allo SCT as consolidation of therapy

Referral to the L/BMT Program

Patients should be considered for referral to the L/BMT Program for evaluation of suitability for SCT in the setting of poor risk CLL. This may include:

  1. Presence of 17p deletion requiring therapy: This is an indication for consolidation of best therapy with allografting either as initial therapy when required or when 17p deletion is detected at any time with CLL
  2. Non-response (< PR) or early progression after purine analog containing therapy (< 1 to 2 years)
  3. Progression within approximately 2 years after purine analog containing combination therapy or therapy of similar efficacy

Stem Cell Transplant

Pre-SCT Work-Up

  1. History
  2. Physicial
  3. Blood work:
    As per Diagnosis but include B2 microglobulin, DAT, FISH, viral serologies including Hepatitis, SPEP and quant Igs
    Chimerism testing to be sent on patient and donor if reduced intensity/NMA SCT considered
  4. Marrow to include % lymphs and imaging as appropriate to include CT scan to be done from neck to groin within approximately 1 month prior to SCT

To Document Pre-SCT

  1. Max Rai stage reached pre-SCT and date
  2. Presence of B symptoms ever pre-SCT and date
  3. Response/disease status pre-SCT – i.e., CR, PR, etc. (IWCLL criteria)
  4. Response to:
    • Last therapy pre-SCT:
    ? > PR = sensitive to last treatment
    vs. < PR = refractory to last treatment
    • Fludarabine therapy administered:
    if PR or >, code as fludarabine sensitive
    if < PR, code as fludarabine resistant
  5. Code number of prior therapies
  6. Document presence or absence of transformation to a higher grade, i.e., Richter’s transformation, PLL, or other and date
  7. Presence of current or prior autoimmune cytopenias related to the CLL such as anemia (autoimmune hemolytic anemia), thrombocytopenia (ITP), neutropenia, pure red cell aplasia (PRCA) and date
  8. If alemtuzumab (campath) has been used as part of therapy, note date of start and finish of campath and ideally delay SCT until at least 30 days and ideally 100 days have elapsed following completion of campath

Conditioning Regimens

  1. Non-myeloablative: fludarabine/cyclophosphamide. Suitable primarily for CLL patients who have the following:
    • Matched sibling donor
    • Responsive disease – PR or > to last therapy
    • Lack of deletion 17p in FISH
  2. Reduced-intensity: busulfan/fludarabine. Suitable for CLL patients with the following:
    • Either sibling donor or unrelated donor
    • Responsive or resistant disease (< PR to last therapy)
    • 17p deletion in FISH
    • If donor is unrelated add antibody – thymoglobulin
  3. Reduced-intensity: treosulfan/fludarabine/thymoglobulin
    • Only in case of second or > SCT such as:
    ○ Allo post auto SCT
    ○ Second allo SCT for graft failure if inter-transplant duration is less than 1 year
    • Discussion with L/BMT group and pharmacy etc. as the following is required:
    ○ Health Canada Approval
    ○ CAP Approval
  4. Although there is some evidence for a dose-response in CLL, most available evidence supports advancement of conditioning in cases where the CLL is not sensitive as outlined above, but there is no strong evidence to support the use of myeloablative SCT in CLL

Donors

There is no detectable difference in OS for CLL with use of fully matched related vs. unrelated donors. Our results and those in the literature support somewhat suboptimal outcomes with use of mismatched as opposed to fully matched unrelated donors, so that this type of SCT should only be considered in selected high risk situations where no other reasonable options are present.

Comorbidity Index

Our results and those of others indicate less optimal survivals for patients with CLL proceeding to allo-SCT with higher comorbidity indices. Results are best for patients with comorbidity scores of 0-2. Only in selected circumstances after discussion with the L/BMT group should allo-SCT be considered for CLL with CoI of 3. Allo-SCT for CLL should in general not be performed for patients with CoI of over 3.

Assessment of Response Post SCT
Post SCT Work-Up

As clinically indicated but to include:

  1. Day +75: peripheral blood chimerism lymphoid, myeloid
    Notes on Chimerism:
    Chimerism testing should be done to determine at least once that full donor chimerism has been reached – as defined by > 90% donor cells lymphoid and myeloid in peripheral blood• If gender mismatch donor, do FISH X:Y
    • If not fully chimeric at day +75, should be rechecked until document full donor chimerism at:
    ○ After d/c immunosuppression cyclosporine or FK506 (~ 1-3 months after stopped)
    ○ After onset of immunosuppression – GVHD
    ○ 1 year post SCT
    • If fully chimeric, and no evidence of active CLL/progression/graft failure, no need to recheck unless substantial disease progression or evidence of graft failure occurs
    • Document date full donor chimerism achieved (>90% donor in all fractions tested, or by FISH X/Y if gender mismatch donor)
  2. Day +100
    • Blood work including CBCD platelets, lytes, BUN, CR
    • LFTs including LDH, SPEP and quant Igs
    • FISH peripheral blood if not normal pre-SCT or if change in disease status (i.e., if CLL progression and FISH previously normal)
    FISH X:Y if gender mismatch donor
    • Marrow for % lymphs/assessment of remission status
    • Imaging of previously involved areas for lymph size/remission status
  3. 1 year: same as Day +100. Aim for CR at 1 year.
  4. Thereafter as appropriate to document CR as defined by IWCLL criteria. All of the following must be met as assessed at least 2 months after completion of therapy:
    • Peripheral blood lymphocyte count < 4 x 109/L
    • Absence of significant lymphadenopathy
    • Nodes < 1.5 cm by physical exam
    • Post SCT CT scan neck/chest, abdomen/pelvis desirable if previously abnormal or if symptoms abnormal on exam
    • No hepatomegaly or splenomegaly on exam
    • Post SCT CT abdomen should be performed if previously abnormal
    • Absence of constitutional symptoms
    • Blood counts otherwise in the normal range:
    ○ ANC > 1.5 x 109/L
    ○ Platelets > 100 x 109/L
    ○ Hemoglobin >110 x 109/L

Other Recommendations

  • Date of CR post SCT should be documented
  • Date of clearance of FISH abnormalities post SCT should be documented
  • Achievement of CR and resolution of FISH abnormalities is strongly associated with GVHD
  • Ideally CR would be achieved by 1 year
  • Escape from GvL can occur – watch parameters including blood counts, physical exam, % lymphs in marrow, FISH testing, size of nodes on imaging – want to see all improving and heading towards CR – if not, i.e., if increase in % lymphs, % FISH abnormalities, nodal size or similar then manipulate situation if possible with decrease in immunosuppression, treatment of CLL with agents to include antibody (rituxan) or DLI as appropriate

Progressive Disease (IWCLL criteria)

  • This is defined as appearance of any new lesion such as enlarged nodes, splenomegaly, hepatomegaly or other organ infiltrates or an increase in 50% or more of greatest diameter of any previous site.
  • Document date of occurrence if occurring post SCT
    ○ Lymphadenopathy – appearance of new nodes or increase in size by 50% or > in greatest determined diameter of any previous site
    ○ De Novo hepato or splenomegaly or increase in enlargement by 50% or more
    ○ Increase in number of blood lymphocytes by 50% or more with at least 5 x 109/L lymphs
    ○ Transformation to a more aggressive histology – ideally confirm by biopsy
    ○ Occurrence of a cytopenia attributable to CLL

Algorithms

Protocols
BCCA Chemotherapy Protocols and PPOs

Outcomes

Coming soon.

Publications
  1. Dreger P, Döhner H, Ritgen M, Böttcher, Busch R, Dietrich S, Bunjes D, Cohen S, Schubert J, Hegenbart U, Beelen D, Zeis M, Stadler M, Hasenkamp J, Uharek L, Scheid C, Humpe A, Zenz T, Winkler D, Hallek M, Kneba M, Schmitz N, Stilgenbauer S. Allogeneic stem cell transplantation provides durable disease control in poorrisk chronic lymphocytic leukemia: long-term clinical and MRD results of the GCLLSG CLL3X trial. Blood 116(14):2438-2447, 2010.
  2. Gerrie AS, Gillan TL, Bruyere H, Chan MJ, Dalal C, Toze CL. Impact of Immunoglobulin Heavy Chain (IGH) Translocations in Chronic Lymphocytic Leukemia (CLL): Negative Effect on Patients with Isolated Deletion 13q Abnormality. Blood (ASH Annual Meeting Abstracts), November 2010; 116:2434.
  3. Toze C, Dalal CB, Gillan TL, Nevill TJ, Barnett MJ, Nantel SH, Hogge DE, Forrest DL, Sutherland H, Song K, Broady R, Power M, Narayanan S, Smith CA, Shepherd J. Allogeneic Hematopoietic Stem Cell Transplantation for CLL: Eradication of Specific FISH Abnormalities with Relation to Gvhd and Transplant Outcomes. Blood (ASH Annual Meeting Abstracts), November 2010; 116:3465.
  4. Dreger P. Allotransplantation for chronic lymphocytic leukemia. American Society of Hematology 2009, 602-609.
  5. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the InternationalWorkshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood 111:5446-5456, 2008.
  6. Schetelig J, van Biezen A, Brand R, Caballero D, Martino R, Itala M, Garcia-Marco JA, Volin L, Schmitz N, Schwerdtfeger R, Ganser A, Onida F, Mohr B, Stilgenbauer S, Bornhäuser M, de Witte T, Dreger P. Allogeneic Hematopoietic Stem-Cell Transplantation for Chronic Lymphocytic Leukemia With 17p Deletion: A Retrospective European Group for Blood and Marrow Transplantation Analysis. J Clin Oncol 26:5094-5100, 2008.
Diagnosis

Updated: May 2016

CML is a myeloproliferative disease associated with the Philadelphia (Ph) chromosome and/or the BCR/ABL fusion gene. The disease is characterized by three phases: chronic phase (CML-CP), accelerated phase (CML-AP) and blast phase (CML-BP).

Required tests

  • CBC and differential
  • Serum creatinine, uric acid, liver function tests
  • Bone marrow aspirate and biopsy with cytogenetic analysis
  • Molecular analysis for BCR/ABL [quantitative PCR (QPCR)] from peripheral blood or bone marrow

The diagnosis of CML-CP requires:

  1. The majority of patients present with leukocytosis and/or thrombocytosis
  2. Blasts < 10% of WBCs in peripheral blood and/or nucleated bone marrow cells
  3. Peripheral blood basophils < 20%
  4. Hypercellular bone marrow mainly due to myeloid hyperplasia
  5. Presence of Ph chromosome t(9;22) on bone marrow cytogenetic analysis and/or evidence of BCR/ABL by molecular analysis

The diagnosis of CML-AP requires one or more of the following in addition to the presence of the Ph chromosome and/or BCR/ABL positivity:

  1. Blasts 10-19% of WBCs in peripheral blood and/or of nucleated bone marrow cells
  2. Peripheral blood basophils ≥ 20%
  3. Persistent thrombocytopenia (<100 x 109/L) unrelated to therapy or persistent thrombocytosis (>1000 x 109/L unresponsive to therapy
  4. Increasing spleen size or WBC count unresponsive to therapy
  5. Cytogenetic evidence of clonal evolution

The diagnosis of CML-BP requires one or more of the following in addition to the presence of the Ph chromosome and/or  positivity:

  1. Blasts ≥ 20% of peripheral blood white cells or of nucleated bone marrow cells
  2. Extramedullary blast cell proliferation
  3. Large foci or clusters of blasts in the bone marrow biopsy

Prognosis
A number of prognostic scoring systems have been developed to stratify patients with CML into various risk groups. The mostly widely used is the Sokal score (Blood 1984;63:789-99) or Hasford score (J Nat Cancer Inst 1998;90:850-858). These scoring systems can provide valuable information concerning an individual patient’s prognosis and may help to guide therapy.

Treatment

Treatment decisions for patients with CML are complex due to the variety of therapies now available. They include:

  1. Oral tyrosine kinase inhibitors (imatinib mesylate, dasatinib, nilotinib, bosutinib, ponatinib)
  2. Parenteral therapeutic agents (interferon alpha +/- cytarabine)
  3. Oral chemotherapeutic agents (busulfan and hydroxyurea)
  4. Hematopoietic stem cell transplantation (myeloablative allogeneic and non-myeloablative allogeneic)

In general, first-line therapy for all patients newly diagnosed with CML-CP is the tyrosine kinase inhibitor imatinib. Alternatives to imatinib include second generation tyrosine kinase inhibitors (nilotinib, dasatinib, bosutinib), third generation TKI (ponatinib), interferon alpha, oral chemotherapeutic agents and stem cell transplantation. For patients with advanced phase disease, initial therapy with imatinib is recommended and consideration of allogeneic stem cell transplantation is appropriate for those who are transplant eligible.

Tyrosine Kinase Inhibitors (Imatinib Mesylate)
Imatinib (IM) is a tyrosine kinase inhibitor that can selectively inhibit the aberrant tyrosine kinase resulting from the BCR/ABL gene fusion characteristic of CML. Results comparing IM with IFN for patients with CML-CP (IRIS trial) have shown superior rates of complete hematologic response (97 vs 69%), major cytogenetic response (87 vs 35%), and complete cytogenetic response (76 vs 14%) at 18 months of therapy.. IM is generally well tolerated with few side effects. The recommended starting dose is 400 mg orally once daily. IM can also provide short-term disease control in CML-AP and CML-BP where it is now considered the drug of choice (recommended starting dose is 600-800 mg/day). Responses can be transient however, and allogeneic hematopoietic stem cell transplantation is recommended for responding AP or BP patients (if feasible).

Second Generation Tyrosine Kinase Inhibitors (Dasatinib, Nilotinib, Bosutinib)
Dasatinib, nilotinib and bosutinib are more potent tyrosine kinase inhibitors compared to imatinib. They are effective against a number of bcr-abl mutations and are currently licensed for use for CML patients with either resistance or intolerance to imatinib. Nilotinib and dasatinib also have Health Canada approval for first line use in newly diagnosed patients, however overall survival appears to be unchanged in comparison to IM for CML patients in chronic phase. Therefore consideration should be given to the relative toxicities and efficacy of these drugs for individual patients.

Third Generation Tyrosine Kinase Inhibitors (Ponatinib)
Ponatinib is the latest TKI to be developed and it has recently obtained Health Canada approval for the treatment of CML where other TKI inhibitor therapy is not indicated. The major advantage of ponatinib over the other TKIs is its efficacy against the T315I mutation in BCR-ABL. It has activity against a broad spectrum of mutations and is currently utilized for patients with resistance or intolerance to second generation TKIs or those patients with the T315I mutation.

Interferon alpha (IFN)
IFN results in hematologic remissions in the majority of patients with CML-CP. However, only approximately 10-30% of patients achieve a major cytogenetic response (<35% Ph negative cells in the bone marrow) resulting in an improved overall survival (median, 7-10 years). The recommended dose is 5 x 10(6) U/m2 SQ per day, however responses may be seen with lower doses (2 x 10(6) U/m2 daily). The addition of low-dose cytarabine (20 mg/m2 SQ per day for 10 days each month) has been shown to increase the number of major cytogenetic responses at 12 months. IFN alone or in combination with cytarabine can result in considerable toxicity particularly in the elderly and its use has now largely been replaced by TKI therapy. Results with IFN in CML-AP or CML-BP are poor and its use is not recommended.

Oral Chemotherapeutic Agents
The most commonly utilized agents are hydroxyurea and busulfan. The majority (~90%) of patients will have a hematologic remission with these agents, however therapy will not be curative, has not been shown to prolong overall survival and rarely results in a cytogenetic response. Therefore, therapy with these agents is considered palliative, although hydroxyurea can provide excellent blood count control with minimal toxicity while more definitive therapies are explored such as tyrosine kinase inhibitors, IFN or stem cell transplantation.

Hematopoietic Stem Cell Transplantation (HSCT)
Results of HSCT for CML are directly related to the phase of disease at the time of transplant; CML-CP transplanted within 1 year from diagnosis results in the best outcome with 65-70% chance at long-term disease-free survival as compared to 35-40% chance of being “cured” if transplanted in AP or CP2. Patients with CML-BP will be considered potential transplant candidates if they first respond to more conservative therapy (ie. IM or second generation tyrosine kinase inhibitors or multiagent chemotherapy). Decisions regarding the timing and type of transplant (allogeneic myeloablative vs non-myeloablative, sibling donor vs unrelated donor) should be made in consultation with a member of the Leukemia/BMT group.

Assessment of Response & Follow-Up
Criteria

  • Complete Hematologic Response (CHR): complete normalization of peripheral blood white count (< 10 x 109), and platelet count (< 450 x 109) sustained for at least 4 weeks.
  • Major Cytogenetic Response (MCR): < 35% Philadelphia positive bone marrow metaphases by conventional cytogenetic analysis. This is equivalent to a 1 log reduction in BCR/ABL transcripts from baseline as measured by QPCR
  • Complete Cytogenetic Response (CCR): No Philadelphia postive bone marrow metaphases by conventional cytogenetic analysis. This is equivalent to a 2 log reduction in BCR/ABL transcripts from baseline as measured by QPCR
  • Major Molecular Response (MMR): Greater than or equal to a 3 log reduction in BCR/ABL fusion transcripts compared to baseline by PCR analysis
  • Complete Molecular Response (CMR): No detectable BCR/ABL transcript

The goal of therapy is to reach a MCR (> 1 log reduction in BCR/ABL transcripts) within 6 months of starting therapy, a complete cytogenetic response (> 2 log reduction in BCR/ABL transcripts) within 12 months of therapy and preferably a major molecular response (> 3 log reduction in BCR/ABL transcripts) within 18 months of starting therapy. See treatment algorithms for detailed milestone objectives.

Tests & Intervals

  • CBC and differential weekly until CHR then monthly until stable then every 3-6 months thereafter
  • Serum creatinine, uric acid, liver function tests – weekly until stable then every 3 months
  • Peripheral blood QPCR every 3 months until MMR achieved and maintained for at least 6 months, then QPCR is measured every 6 months
  • Bone marrow aspirate and biopsy- at diagnosis, then as clinically indicated

Algorithms

Protocols
BCCA Chemotherapy Protocols and PPOs

Diagnosis

Updated: May 2017

Chronic myelomonocytic leukemia (CMML) is a hematologic cancer with overlapping features of both a myelodysplastic syndrome (MDS) and a myeloproliferative neoplasm (MPN). The disease is characterized by a persistent monocytosis (defined as an absolute monocyte count >1×109/L). Clinical presentation of CMML is variable and some patients have signs and symptoms of a MPN with an elevated WBC count and enlargement of the liver and spleen as the predominant features. In contrast, others present with a MDS picture with a normal or decreased WBC count and symptoms related primarily to low blood counts – fatigue, shortness of breath, easy bleeding/brusing, fever/night sweats and/or frequent infections.

Diagnosis of CMML is made according to 2008 World Health Organization (WHO) criteria (table 1), which requires examination of peripheral blood (PB) and bone marrow (BM) samples [1]. Bone marrow monocytosis is frequently observed, but not required for diagnosis. Cases with ≥20% blasts (myeloblasts + monoblasts + promonocytes) should be classified as acute myeloid leukemia (AML). Cases with PB blasts <5% and BM <10% are classified as CMML-1 and cases with PB blasts 5-19% and/or BM blasts 10-19% are classified as CMML-2.

Bone marrow examination is important to do in all suspected cases of CMML as it allows for exclusion of other hematologic neoplasms, which can have overlapping clinical and hematologic characteristics. It is recommended that chronic myeloid leukemia (CML) be excluded during diagnostic work-up and testing for BCR-ABL1 rearrangements using FISH or PCR should be performed for this purpose. In addition, testing for rearrangements of PDGFRA and PDGFRB genes is necessary in cases with associated eosinophilia. In contrast to CMML, patients with lymphoid and myeloid neoplasms associated with PDGFRA/B rearrangement often achieve durable responses with Imatinib treatment.

Conventional karyotyping and, if indicated, molecular mutation testing, should be performed to aid in diagnosis and for estimating prognosis. In cases where overt dysplasia is absent in morphologic evaluation, a diagnosis of CMML can be made if an acquired clonal cytogenetic or molecular genetic abnormality (e.g. a TET2 mutation) is present. If overt dysplasia is not present and no clonal genetic abnormality is identified, monocytosis should be persistent for at least 3 months and other causes of monocytosis (i.e. infection, solid tumours and autoimmune disease) should be systematically excluded before assigning a diagnosis of CMML.

Etiology and Pathogenesis
CMML is most prevalent in older adults (age > 50 years), and the median age at diagnosis is approximately 70 years [2]. In general, the etiology of CMML is unknown in the majority of patients, although it appears to be related to prior chemotherapy or radiotherapy in some individuals[3]. Similarly to MDS, there is some evidence that risk may be increased with exposure to ionizing radiation, organic solvents such as benzene, agricultural chemicals and smoking[4].

Genome sequencing studies indicate that genetic abnormalities are present in the majority of CMML cases, although no genetic anomaly is pathognomonic. Stepwise acquisition of specific genetic mutations within myeloid and monocytic precursors likely contributes to the development of CMML. Although these genetic lesions also occur in other myeloid malignancies, the relatively frequency in CMML appears to be different and the most commonly mutated genes (≥10% of cases) have been reported as: SRSF2, TET2, ASXL1, SETBP1, KRAS, NRAS, CBL and EZH2[6].

Prognosis
CMML patients were included in the cohorts used for the development of risk-stratification systems for MDS (IPSS -15%, IPSS-R – 9%)[7, 8]. These cohorts excluded patients with higher WBC counts (>12 x 109/L), possibly limiting their applicability in patients with “myeloproliferative” CMML. Several other CMML-specific scoring systems have been developed including: the MD Anderson Scoring System, MD Anderson Prognostic Score, Düsseldorf Score (DUSS), Mayo prognostic model and CMML-specific prognostic scoring system (CPSS). These have recently been compared in a prospective cohort, and the results generally confirm the validity of each and reported comparable performance in estimating prognosis[9]. At our centre, we most often use the CPSS as this is a CMML-specific score that was developed and validated in two separate, relatively large cohorts and is simple to calculate(Table 2)[10]. The reported median overall survival in the validation cohort for the four risk categories (Low, Int-1, Int-2, High) was 61, 31 15 and 9 months; the corresponding 2-year risk of transformation to AML was 8%, 25%, 49% and 100%, respectively. Mutations in ASXL1, which occur in approximately 40% of CMML cases, also appear to be independently associated with worse prognosis [6, 11].

 

Treatment

Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) offers the only possibility for cure in CMML. Reported long-term survival following this treatment has been less favourable than that seen in other myeloid malignancies but has generally been reported to be in the 30-40% range [12]. We consider HSCT for eligible patients with a well matched donor in non-low-risk disease (CPSS Int-1/Int-2/high risk). There are no prospective studies in CMML that have evaluated this approach, although a previously published retrospective analysis of MDS patients suggests delaying HSCT in lower risk MDS is associated with a survival benefit[13]. Similarly to MDS, CMML patients with low-risk disease have a superior survival and lower risk of transformation to AML, suggesting that the majority of these patients are unlikely to benefit from HSCT given the increased early mortality associated with this treatment.

Hypomethylating agents: Azacitidine

We recommend considering treatment with Azacitidine in non-low-risk CMML patients. A landmark, phase III trial demonstrating a survival advantage of Azacitidine over conventional care regimens in MDS included some patients with CMML (3%), suggesting a benefit might extend to some of these patients [14]. Several smaller retrospective and prospective studies of Azacitidine in CMML have reported overall response rates of approximately 40%, comparable response rates to that observed in MDS [15, 16]. There are no prospective studies exclusively in CMML patients comparing azacitidine to other treatments, although a retrospective matched-pairs analysis reported a longer median OS for Azacitidine over Hydroxyurea in first-line treatment (p = 0.072, median OS 27.7 vs. 6.2 months)[17]. Treatment with Azacitidine prior to HSCT appears to be safe and may decrease disease burden as well as preventing progression to AML before transplant if significant delay is anticipated [18]. The most frequent toxicities related to Azacitidine include: cytopenias, GI side-effects (nausea, constipation and diarrhea) and reactions at injection sites. Cytopenias often worsen initially (initial 1-3 months) with subsequent improvement in responding patients.

Hydroxyurea

Hydroxyurea is frequently used in CMML and an older clinical trial has demonstrated its superiority over etoposide (VP16) in proliferative CMML[19]. It does not produce significant bone marrow responses or improve cytopenias but can be helpful in alleviating splenomegaly, decreasing leukocytosis and improving symptoms related to myeloproliferation.

Transfusion support

Red cell transfusions can provide relief of fatigue and shortness of breath in anemic CMML patients. Transfusion thresholds vary from patient to patient depending upon age, activity level and other medical problems (especially heart and lung disease). In general, red cells should be considered for a hemoglobin <80 g/L, but a higher threshold can be considered based on the presence of symptoms related to anemia. Patients that have had ≥25 units of red cells and a serum ferritin >1000-1500 can be considered for iron chelation therapy provided they have lower risk CMML and an estimated life-expectancy of greater than 2 years (i.e. Int-1). Platelet transfusions are often given when the platelet count is <10 x 109/L and may be required more than once weekly. However, patients with clinical bleeding issues may have to have a higher transfusion threshold (i.e., <20-30 x 109/L) while those without bleeding may not need (or wish) to have preemptive platelet transfusions.

 

Algorithms

Protocols
CCA Chemotherapy Protocols and PPOs

1. Persistent peripheral blood monocytosis >10 x 109/L
2. No Philadelphia chromosome or BCR-ABL1 fusion gene
3. No rearrangement of PDGFRA or PDGFRB genes (should be excluded in cases with eosinophilia)
4. Less than 20% blasts in peripheral blood and bone marrow -blasts included myeloblasts, monoblasts and promonoblasts
5. Dysplasia in 1 or more myeloid lineages. If dysplasia is minimal or absent then a diagnosis of CMML can be made if other requirements are met and:
-an acquired, clonal cytogenetic or molecular genetic abnormality is present in hematopoietic cells or
-monocytosis has persisted for at least 3 months and
-all other causes of monocytosis have been excluded
Table 1 – Diagnostic criteria for CMML
Adapted from 2008 WHO classification of tumours of hematopoietic and lymphoid tissues
Variable Score
Variable012
WHO subtypeCMML-1 (Blasts + PM < 5% in PB and < 10% BM)CMML-2 (Blasts + PM 5 – 19% in PM and 10 – 19% in BM or Auer rods)
FAB subtypeCMML-MD (WBC < 13 x 109/L)CMML-MP (WBC < 13 x 109/L)
Cytogenetics*LowIntermediateHigh
RBC transfusion dependent**NoYes
Table 2 – CPSS Score
*Cytogenetic classification: Low: Normal, isolated –Y, Intermediate: other abnormalities, High: trisomy 8, complex karyotype (≥3 abnormalities), chromosome 7 abnormalities
**RBC transfusion dependency is defined as having at least 1 RBC transfusion every 8 weeks over a period of 4 months.
Risk groups: low – 0, intermediate-1 – 1, intermediate-2 – 2-3, high 4-5
Table adapted from (Such et al, Blood, 2013)
Publications
  1. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, ed. S. Swerdlow, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW.2008, Lyon: International Agency of Research on Cancer (IARC).
  2. Germing, U., et al., Validation of the WHO proposals for a new classification of primary myelodysplastic syndromes: a retrospective analysis of 1600 patients. Leuk Res, 2000. 24(12): p. 983-92.
  3. Takahashi, K., et al., Clinical characteristics and outcomes of therapy-related chronic myelomonocytic leukemia. Blood, 2013. 122(16): p. 2807-11; quiz 2920.
  4. Strom, S.S., et al., Risk factors of myelodysplastic syndromes: a case-control study. Leukemia, 2005. 19(11): p. 1912-8.
  5. Itzykson, R., et al., Clonal architecture of chronic myelomonocytic leukemias. Blood, 2013. 121(12): p. 2186-98.
  6. Mason, C.C., et al., Age-related mutations and chronic myelomonocytic leukemia. Leukemia, 2015.
  7. Greenberg, P., et al., International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood, 1997. 89(6): p. 2079-88.
  8. Greenberg, P.L., et al., Revised international prognostic scoring system for myelodysplastic syndromes. Blood, 2012. 120(12): p. 2454-65.
  9. Padron, E., et al., An international data set for CMML validates prognostic scoring systems and demonstrates a need for novel prognostication strategies. Blood Cancer J, 2015. 5: p. e333.
  10. Such, E., et al., Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Blood, 2013. 121(15): p. 3005-15.
  11. Itzykson, R., et al., Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol, 2013. 31(19): p. 2428-36.
  12. Kekre, N. and V.T. Ho, Allogeneic hematopoietic stem cell transplantation for myelofibrosis and chronic myelomonocytic leukemia. Am J Hematol, 2016. 91(1): p. 123-30.
  13. Cutler, C.S., et al., A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood, 2004. 104(2): p. 579-85.
  14. Fenaux, P., et al., Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol, 2009. 10(3): p. 223-32.
  15. Ades, L., et al., Predictive factors of response and survival among chronic myelomonocytic leukemia patients treated with azacitidine. Leuk Res, 2013. 37(6): p. 609-13.
  16. Drummond, M.W., et al., A multi-centre phase 2 study of azacitidine in chronic myelomonocytic leukaemia. Leukemia, 2014. 28(7): p. 1570-2.
  17. Pleyer, L., et al., Azacitidine in CMML: matched-pair analyses of daily-life patients reveal modest effects on clinical course and survival. Leuk Res, 2014. 38(4): p. 475-83.
  18. Kongtim, P., et al., Treatment with Hypomethylating Agents before Allogeneic Stem Cell Transplant Improves Progression-Free Survival for Patients with Chronic Myelomonocytic Leukemia. Biol Blood Marrow Transplant, 2016. 22(1): p. 47-53.
  19. Wattel, E., et al., A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Groupe Francais des Myelodysplasies and European CMML Group. Blood, 1996. 88(7): p. 2480-7.
Diagnosis

Acute graft versus host disease (GVHD) is the most frequent complication after allogeneic haematopoietic stem cell transplantation (SCT). The incidence of acute GVHD is related to the degree of mismatch between HLA proteins and ranges from 35-45% in recipients of fully matched sibling donors to 80% in recipients of unrelated donor grafts. Other major risk factors for the development of GVHD are older patient (and possibly older donor) age, greater intensity of the conditioning regimen, and donor/recipient sex mismatch, especially with allosensitised female donors. In non-myeloablative transplants, acute GVHD is more likely to occur if donor T-cell chimerism is established rapidly after transplantation. With conventional conditioning regimens, the time of onset of GVHD is typically 2-3 weeks after SCT. With reduced intensity conditioning regimens, acute GVHD may occur later (see below).

Classification
Historically, acute GVHD was distinguished from chronic GVHD by the time of onset (before or more than 100 days after HSCT). In the era of reduced-intensity conditioning regimens and donor lymphocyte infusions, this distinction is no longer clear-cut. Patients may present with a clinical picture of acute GVHD several months after SCT, while GVHD with characteristics of the ‘chronic’ form may occur within 60 days after transplantation. The NIH Consensus Conference recognises 2 categories of GVHD as follows:

1. Acute GVHD (absence of features of chronic), comprising

  • classic acute GVHD (before day 100)
  • persistent, recurrent, or late acute GVHD (after day 100, often upon withdrawal of immunosuppression).

2. Chronic GVHD, comprising

  • classic chronic GVHD (no signs of acute GVHD), and
  • an overlap syndrome, in which features of acute and chronic are present

Clinical Features
Skin is most commonly affected and is usually the first organ involved, often coinciding with engraftment of donor cells. The characteristic maculopapular rash is pruritic and can spread throughout the body, sparing the scalp. In severe cases the skin maybe painful, blister and ulcerate.

Gastrointestinal tract involvement of acute GVHD usually presents as diarrhoea but may also include vomiting, anorexia and/or abdominal pain. The diarrhoea is secretory and often voluminous. Bleeding occurs as a result of mucosal ulceration and carries a poor prognosis. Involvement may be patchy leading to a normal appearance on endoscopy.

Liver disease may be difficult to distinguish from other causes of liver dysfunction following SCT such as veno-occlusive disease, drug toxicity, viral infection or sepsis. The liver is rarely biopsied because of thrombocytopenia, therefore the diagnosis is made clinically.

StageSkinLiver*Intestinal Tract*
Maculopapular rash <25% of body surfaceBilirubin 35-50 μmol/lDiarrhoea 500-1000 ml/day or nausea (± vomiting)**
Maculopapular rash 25% -50% of body surfaceBilirubin 51-100 μmol/lDiarrhoea 1000-1500 ml/day
 Generalised erythrodermaBilirubin 101-255 μmol/lDiarrhoea >1500 ml/day or cramps or blood or ileus
Generalised erythroderma with bullous formation and desquamationBilirubin >255 μmol/lSimultaneous presence of any two of the four criteria for stage 3 severity
* If patient has documented GVHD of the liver or gut, and documented alternative cause of hyperbilirubinaemia/diarrhoea (i.e. veno-occlusive disease or mucositis, CMV enteritis or C difficile infection) then downstage GVHD by 1 stage.
** With histological evidence
GradeSkinLiverGut
0 (none)000
I (mild) +1 to +200
II (moderate)0 to +3#, or +1, and/or+1
III (severe)*+2 to +3 and/or+2 to +4
IV (life-threatening)**+4+4
Functional Grading of Acute GVHD (Glucksberg)
# Stage 3 alone is considered overall grade II
* 25% long-term survival; ** 5% survival
** 5% long-term survival
Treatment

The response to primary therapy is of central importance as responses correlate with survival.

Glucocorticoids are the mainstay of acute GVHD therapy. Complete responses are seen in 25% to 40% of patients, and clinically relevant improvement, defined as regression of skin rash or decrease in the volume of diarrhoea and the extent of liver function abnormalities in 40%-50% of patients with grades II or IV acute GVHD.

Treatment
At the onset of acute GVHD

  • Start methylprednisone (MP) 2mg/kg/d IV x 3-5 days (1mg/kg q12 hourly)
  • Continue cyclosporine at therapeutic levels

A biopsy is not mandatory prior to commencing treatment.

Monitoring of Response
If no progression (increase in the stage in any system) after the 6th dose, then continue same therapy. If complete remission, or less than Grade II after the 10th dose of MP start a steroid taper:

Suggested Steroid Taper:
Days 6-10: 1.5mg/kg/day
Days 11-15: 1 mg/kg/day
Days 16-20: 0.5 mg/kg/day
Days 21-28: 0.25mg/kg/day
Days 29+: taper as tolerated; suggest 10% per week

Management of Steroid Refractory Acute GVHD
If manifestations of GVHD in any organ worsen over 3 days of treatment of if the skin does not improve by 5 days, it is unlikely that a response will be achieved in a timely fashion, and secondary therapy should be considered.

See table below.

Other Considerations
Infections are the major non-relapse cause of death in patients receiving therapy for GVHD and all patients should receive infection prophylaxis. This should include PCP prophylaxis with Septra and prevention of herpes virus with acyclovir. While on GVHD therapy, patients need to be monitored for viral reactivation, in particular CMV (and EBV in patients receiving ATG). If there is evidence of reactivation treatment with ganciclovir (and rituximab for EBV), should be given. All patients should receive azole prophylaxis against fungal infections. Invasive molds, especially aspergillus are common in patients with prolonged steroid use.

Chronic immunosuppressive therapy has multiple toxicities. Prolonged therapy with steroids results in muscle weakness and wasting. It is important to make every effort to keep patients mobile and to involve a physiotherapist to develop an individual exercise program. Diabetes, hypertension, osteoporosis, avascular necrosis and other Cushingoid features are common with chronic steroid use and should be monitored for Calcineurin inhibitors frequently cause renal impairment and levels need to be monitored.

Algorithms

Protocols
BCCA Chemotherapy Protocols and PPOs

Organs with Predominant GVHD Manifestation Potential Secondary/Tertiary Therapies
SkinAnti-CD25 monoclonal antibody (basiliximab); ATG**;
LiverATG**; Anti-CD25
GI Tract“Non-absorbable” steroids (beclomethasone, budesonide); ATG*; TNF-α blockade (entanercept);
Management of Steroid Refractory Acute GVHD
In patients with prominent intestinal manifestation, the addition of beclomethasone or budesonide may allow a reduction in the dose of sytemically administered steroids.
** Substitute Anti-CD52 in patients whose conditioning regimen included ATG
Publications
  1. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers MDE. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 11:945-955, 2005.
  2. Vogelsang GB. How I treat chronic graft-versus-host disease. Blood 95:1196-201, 2001.
  3. Przepiorka D, Kernan NA, Ippoliti C, Papadopoulos EB, Giralt S, Khouri I, Lu J-G, Gajewski J, Durett A, Cleary K, Champlin R, Andersson BS, and Light S. Daclizumab, a humanized anti-interleukin-2 receptor alpha chain antibody, for treatment of acute graft-versus-host disease. Blood 95:83-89, 2000.
  4. Sullivan KM, Witherspoon RP, Storb R, Deeg HJ, Dahlberg S, Sanders JE, Appelbaum, FR, Doney KC, Weiden  P, Anasetti C, Loughran TP, Hill R, Shields A, Yee G, Shulman H, Nims J, Strom S, and Thomas ED. Alternating-Day Cyclosporine and Prednisone for Treatment of High-Risk Chronic Graft-v-Host Disease. Blood 72:555-561, 1998.
  5. Abraham R, Szer J, Bardy P and Grigg A. Early cyclosporine taper in high-risk sibling allogeneic bone marrow transplants. Bone Marrow Transplantation 20:773-777, 1997.
  6. Przepiorka D, Weisdorf D, Martin P, Lingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplantation 15(6):825-8, 1995.
Diagnosis

Updated: May 2016

The diagnosis and management of Hodgkin Lymphoma at initial presentation is covered in some detail on the BC Cancer Agency website. The scope of this management guideline will focus on the role of stem cell transplantation in the management of relapsed and refractory Hodgkin lymphoma.

Diagnosis
Definitions
Relapsed Hodgkin lymphoma is defined as relapse of previously treated Hodgkin lymphoma more than three months following completion of all planned chemotherapy and/or radiation therapy.

Primary refractory Hodgkin lymphoma is defined as disease which has failed to respond to initial standard therapy OR disease which has been shown to progress within three months of completion of a standard course of treatment.

Background
High dose chemotherapy and autologous stem cell transplant improves progression free survival in patients with relapsed and primary refractory Hodgkin Lymphoma as demonstrated in two randomized controlled trials (Schmitz N et al, Lancet 2002; Linch DC et al Lancet 1993). Multiple subsequent trials have demonstrated long term disease free survival in the order of 50% for patients with HL in first relapse/progression treated with HDC/ASCT (Yuen et al Blood 1997; Lavoie et al Blood 2005). For patients treated in first relapse, progression free survival is in the order of 62%. For primary progressive disease, progression free survival of 31%-39% has been reported, even in patients who did not respond to salvage chemotherapy pre HDT/ASCT (31% PFS at 5 years – Josting et al Blood 2000, 39% PFS at 15 years Lavoie et al Blood 2005). These results are clearly superior to survival historically reported with chemotherapy salvage alone 17% at 20 years for relapsed Hodgkin Lymphoma (Longo et al JCO 1992; Yuen AR et al Blood 1997 89; 814-22 Stanford non randomized experience).

Updated results of 256 autologous transplants in BC for Hodgkin Lymphoma were reported in 2014. For all patients transplanted the 10 year overall survival was 62% and failure free survival was 57%. All patients are taken to transplant in BC irrespective of their response to salvage chemotherapy, as even patients with disease which is refractory to salvage chemotherapy were shown to have a 10 year failure free survival of 31% and overall survival of 29%. (Gerrie AS et al Ann Oncol, 2014: 25(11); 2218-23).

Diagnosis of Relapse or Progression
Disease relapse is, when possible, confirmed by biopsy. Biopsy confirmation of relapse is especially important for late cases of relapse (greater than 5 years), where secondary malignancy is in the differential diagnosis. Restaging CT scans of neck, thorax, abdomen and pelvis should also be part of the relapse/ progression workup.

Referral of the patient to the Leukemia and BMT Program of BC for assessment is made at the diagnosis of relapse.

PET scanning has been shown to be predictive of outcome post HDT/SCT when performed after salvage chemotherapy and before autologous transplant. Timing of the PET scan is important – these should not be performed less than 3 weeks from the most recent cycle of chemotherapy (Juweid ME et al, JCO 2007 Consensus statement). GCSF used for stem cell collection can alter the bone marrow signal on PET scan and similarly, PET scans should be interpreted with caution if performed within <3 weeks of high dose GCSF. (Kazama et al Eur J Med Mol Imaging 2005).

Treatment

Salvage Chemotherapy
Salvage chemotherapy is generally recommended to achieve some disease control and to prevent progression while arrangements for stem cell collection and pre-transplant organ function workup are underway. This process takes about 6 weeks in total, for non-urgent cases. Standard salvage chemotherapy – usually GDP (gemcitabine, cisplatin and dexamethasone) is given at the local BC Cancer Agency unit. (See protocol)

For the purposes of follow up post HDT/SCT, either a CT scan or CT PET should be performed post salvage chemotherapy and pre transplant. Ideally CT scans should be performed in the referring centre where comparative scans are easily available for interpretation of response criteria. PET scanning has been shown to be predictive of outcome post HDT/SCT when performed after salvage chemotherapy and before autologous transplant. Timing of the PET scan is important – these should not be performed less than 3 weeks from the most recent cycle of chemotherapy (Juweid ME et al JCO 2007 Consensus statement). GCSF used for stem cell collection can alter the bone marrow signal on PET scan and similarly, PET scans should be interpreted with caution if performed within <3 weeks of high dose GCSF. (Kazama et al Eur J Nucl Med Mol Imaging 2005).

Where possible, PET CT scan will be arranged in Vancouver prior to transplantation.

The assessing Bone Marrow Transplant physician will arrange workup investigations prior to high dose chemotherapy and autologous stem cell transplant. These investigations are performed to ensure that HDT can be administered without excessive toxicity. These investigations include: creatinine clearance, pulmonary function tests, ECG and echocardiogram or MUGA scan and routine viral serology. The bone marrow transplant physician assessing the patient may require further investigations based upon clinical history and examination.

Presentation of cases at BCCA Lymphoma Conference is recommended particularly to guide local oncologists with respect to post transplant assessment and the early consideration of post-transplant radiation therapy assessment in certain cases. The modality of repeated imaging can also be discussed.

Stem Cell Collection
Stem cell collection is performed in the Centennial Pavillion at Vancouver General Hospital. The patient is provided with a prescription for high dose GCSF (10mcg/kg) for a total of 5 days. This medication is administered by subcutaneous injection and the first dose is given by Hematology/ BMT nursing staff. Subsequent doses may be self-administered by the patient or by a local practitioner. Side effects of GCSF include low back/pelvic pain which can at times be quite severe.

Stem cell collection is carried out on day 4 and 5 of GCSF therapy. This procedure takes place in the Apheresis Unit at VGH. Apheresis nurses assess every patient prior to this procedure to assess the suitability of the patients peripheral veins for the apheresis procedure. In certain cases, insertion of a central line (vascath) is required for this procedure.

The Bone marrow transplant physician will review all organ function workup criteria and ensure that an adequate number of stem cells (CD34+ cells target >2 x 106/kg body weight) is collected. Arrangements are made for the patient to have a Hickman line inserted prior to hospital admission for the delivery of this therapy.

The patient is then admitted to the VGH Leukemia and BMT Unit to undergo the procedure of HDT/ASCT.

High Dose Chemotherapy with BEAM or High dose Etoposide and Melphalan (EM)
High dose chemotherapy with BEAM or EM (see protocols) is given as an inpatient at Vancouver General Hospital. 24 hours following the last dose of chemotherapy, the patients’ autologous stem cells are reinfused. Side effects of high dose chemotherapy include GI upset, mucositis, a period of pancytopenia lasting about 2 weeks with associated need for blood transfusion support and risk of serious or life threatening infection.

Mortality associated with this procedure is less than 5%. Following recovery from the initial toxicity of the transplant course, the patient is discharged for follow up at the Bone Marrow Transplant Day Ward. When the patient has had satisfactory recovery of hematological parameters and is free of fever, the patient is discharged home. All patients are given a follow up appointment with their primary BMT physician at this point. The patients’ BMT physician will arrange a follow up PET scan at 6 weeks post-transplant. At the post-transplant follow up clinic appointment, the BMT physician will arrange for subsequent lymphoma follow up to be transferred back to the referring oncologist. The Leukemia BMT physician will ensure that the patient receives the post-transplant vaccination recommendations as per the BC CDC, which should commence at 6 months post-transplant.

Carmustine/ BCNU given as part of BEAM and CBV protocols can cause pneumonitis, which may occur following initial recovery from stem cell transplant. Any patient who presents with respiratory symptoms at this point should undergo CT of chest and pulmonary function testing and should be treated empirically with high dose prednisolone.

Long term side effects of high dose chemotherapy include infertility, an increased risk of cardiac and thyroid disease and an increased risk of secondary malignancy (Lavoie et al Blood 2005; Forrest D et al JCO 2002).

Maintenance Therapy
Maintenance therapy post transplant: Based on the results of the AETHERA trial, post transplant therapy with brentuximab vedotin has been shown to significantly improve progression free survival for high risk Hodgkin lymphoma patients, which may translate into a higher cure rate with longer follow-up. (Moskowitz CH et al, Lancet 2015, 385; 1853-1862) All patients with relapsed/refractory Hodgkin lymphoma who undergo autologous stem cell transplantation should be considered for brentuximab maintenance therapy. This therapy is not yet funded through BCCA however a compassionate access request can be submitted for these patients.

Role of Allogeneic Transplant
In the event of relapse post autologous transplant, patients may be referred back to the BMT program for assessment with respect to suitability for reduced intensity allogeneic transplantation. Factors which predict for responsiveness to allogeneic transplantation include chemosensitivity and duration of initial response to autologous transplant. (Alvarez et al,Biol Blood Marrow Trans, 2006, 12(2); 172-83). Registry data show progression free survival rates of around 30% at three years following reduced intensity allogeneic transplant. (Robinson SP et al, Hematologica 2008, 94(2), Marcais A et al, Hematologica 2013, 98(9), Kako S et al, American Journal of Hematology, 2014, 90(2)). In the era of novel agents targeting CD30 positive cells such as brentuximab and agents targeting PD1 such as pembrolizimab and nivolumab, the role and timing of allogeneic transplant is less clear.

Long-term Follow Up
All patients who receive HDT/ASCT should undergo repeated vaccination programs six months following the date of transplantation. The guidelines for the vaccines required are available on the BC Centres for Disease Control website.

Algorithms

Protocols
BCCA Chemotherapy Protocols and PPOs

Publications
  1. Alvarez I, Sureda A, Caballero MD, Urbano-Ispizua A, Ribera JM, Canales M, García-Conde J, Sanz G, Arranz R, Bernal MT, de la Serna J, Díez JL, Moraleda JM, Rubió-Félix D, Xicoy B, Martínez C, Mateos MV, Sierra J. Nonmyeloablative stem cell transplantation is an effective therapy for refractory or relapsed hodgkin lymphoma: results of a spanish prospective cooperative protocol. Biol Blood Marrow Transplant, 2006 Feb;12(2):172-83.
  2. Forrest, D.L., Hogge, D.E., Nevill, T.J., Nantel, S.H., Barnett, M.J., Shepherd, J.D., Sutherland, H.J., Toze, C.L., Smith, C.A., Lavoie, J.C., Song, K.W., Voss, N.J., Gascoyne, R.D. & Connors, J.M. (2005) High-dose therapy and autologous hematopoietic stem-cell transplantation does not increase the risk of second neoplasms for patients with Hodgkin’s lymphoma: a comparison of conventional therapy alone versus conventional therapy followed by autologous hematopoietic stem-cell transplantation. J Clin Oncol, 23, 7994-8002.
  3. Gerrie, A.S., Power, M.M., Shepherd, J.D., Savage, K.J., Sehn, L.H., & Connors, J.M.  Chemoresistance can be overcome with high-dose chemotherapy and autologous stem-cell transplantation for relapsed and refractory Hodgkin lymphoma.  Ann Oncol, 2014: 25(11); 2281-23.
  4. Josting, A., Rueffer, U., Franklin, J., Sieber, M., Diehl, V. & Engert, A. (2000) Prognostic factors and treatment outcome in primary progressive Hodgkin lymphoma: a report from the German Hodgkin Lymphoma Study Group. Blood, 96, 1280-1286.
  5. Juweid, M.E., Stroobants, S., Hoekstra, O.S., Mottaghy, F.M., Dietlein, M., Guermazi, A., Wiseman, G.A., Kostakoglu, L., Scheidhauer, K., Buck, A., Naumann, R., Spaepen, K., Hicks, R.J., Weber, W.A., Reske, S.N., Schwaiger, M., Schwartz, L.H., Zijlstra, J.M., Siegel, B.A. & Cheson, B.D. (2007) Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol, 25, 571-578.
  6. Kazama, T., Swanston, N., Podoloff, D.A. & Macapinlac, H.A. (2005) Effect of colony-stimulating factor and conventional- or high-dose chemotherapy on FDG uptake in bone marrow. Eur J Nucl Med Mol Imaging, 32, 1406-1411.
  7. Kako S, Izutsu K, Kato K, Kim SW, Mori T, Fukuda T, Kobayashi N, Taji H, Hashimoto H, Kondo T, Sakamaki H, Morishima Y, Kato K, Suzuki R, Suzumiya J; Adult Lymphoma Working Group of the Japanese Society for Hematopoietic Cell Transplantation. The role of hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma. Am J Hematol, 2015 Feb;90(2):132-8.
  8. Lavoie, J.C., Connors, J.M., Phillips, G.L., Reece, D.E., Barnett, M.J., Forrest, D.L., Gascoyne, R.D., Hogge, D.E., Nantel, S.H., Shepherd, J.D., Smith, C.A., Song, K.W., Sutherland, H.J., Toze, C.L., Voss, N.J. & Nevill, T.J. (2005) High-dose chemotherapy and autologous stem cell transplantation for primary refractory or relapsed Hodgkin lymphoma: long-term outcome in the first 100 patients treated in Vancouver. Blood, 106, 1473-1478.
  9. Linch, D.C., Winfield, D., Goldstone, A.H., Moir, D., Hancock, B., McMillan, A., Chopra, R., Milligan, D. & Hudson, G.V. (1993) Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI randomised trial. Lancet, 341, 1051-1054.
  10. Longo, D.L., Duffey, P.L., Young, R.C., Hubbard, S.M., Ihde, D.C., Glatstein, E., Phares, J.C., Jaffe, E.S., Urba, W.J. & DeVita, V.T., Jr. (1992) Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin’s disease after combination chemotherapy: the low probability for cure. J Clin Oncol, 10, 210-218.
  11. Marcais A., Porcher R., Robin M., Mohty M., Michalet M., Blaise D., Tabrizi R., Clement L., Ceballos P., Daguindau E., Bilger K., Dhedin N., Lapusan S., Bay J.O., Pautas C., Garban F., Ifrah N., Guillerm G., Contentin N., Bourhis J.H., Yakoub Agha I., Bernard M., Cornillon J., & Milpied N. Impact of disease status and stem cell source on the results of reduced intensity conditioning transplant for Hodgkin’s lymphoma: a retrospective study from the French Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC). Haematologica, 2013 Sep;98(9):1467-75.
  12. Moskowitz C.H., Nademanee A., Masszi T., Agura E., Holowiecki J., Abidi M.H., Chen A.I., Stiff P., Gianni A.M., Carella A., Osmanov D., Bachanova V., Sweetenham J., Sureda A., Huebner D., Sievers E.L., Chi A., Larsen E.K., Hunder N.N., Walewski J., & AETHERA Study Group. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial.  Lancet, 2015 May 9;385(9980):1853-62.
  13. Robinson, S.P., Sureda, A., Canals, C., Russell, N., Caballero, D., Bacigalupo, A., Iriondo, A., Cook, G., Pettitt, A., Socie, G., Bonifazi, F., Bosi, A., Michallet, M., Liakopoulou, E., Maertens, J., Passweg, J., Clarke, F., Martino, R., & Schmitz, N. Reduced intensity conditioning allogeneic stem cell transplantation for Hodgkin’s lymphoma: identification of prognostic factors predicting outcome. Haematologica, Feb 2009, 94 (2) 230-238
  14. Schmitz, N., Pfistner, B., Sextro, M., Sieber, M., Carella, A.M., Haenel, M., Boissevain, F., Zschaber, R., Muller, P., Kirchner, H., Lohri, A., Decker, S., Koch, B., Hasenclever, D., Goldstone, A.H. & Diehl, V. (2002) Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomised trial. Lancet, 359, 2065-2071.
  15. Yuen, A.R., Rosenberg, S.A., Hoppe, R.T., Halpern, J.D. & Horning, S.J. (1997) Comparison between conventional salvage therapy and high-dose therapy with autografting for recurrent or refractory Hodgkin’s disease. Blood, 89, 814-822.
Diagnosis

Updated: April 2011 – currently under review

The protocols and policies for staging, management and therapy for the indolent lymphoma, including follicular lymphoma, lymphoplasmacytic and marginal zone are outlined on the BC Cancer Agency website. The scope of this management guideline will focus on the role of stem cell transplantation in the management of relapsed and refractory indolent lymphoma.

Indolent Lymphoma
Patients who have had suboptimal response to conventional therapy (<PR) or short period of disease control (less than 1-2 years) may be considered for referral to the Leukemia/BMT Program of BC.

Patients with a good HSCT specific comorbidity score (less than 3) indicating good organ function are most likely to benefit from allo SCT.

Although much study has been done for autografting in indolent lymphoma, there has yet to be a clear survival advantage demonstrated for these patients following autografting in the modern chemoimmunotherapy regimens. Autografting is not curative for indolent lymphoma.

Therefore at the L/BMT Program of BC allografting is considered for suitable patients with these diagnoses.

The data on dose intensity in allografting for indolent lymphoma is somewhat conflicting. Selected patients may be considered for the reduced dose or non-myeloablative regimens in particular if they retain some evidence of responsiveness to standard therapies.

For lymphoplasmacytic lymphoma in particular the data would support use of the reduced intensity regimens over the myeloablative protocols.

Ideally allografting would be performed for high risk patients prior to disease transformation, as results of allo SCT post transformation are suboptimal when compared to pre-transformation.

Transformed Lymphoma
Patients with indolent lymphoma who have transformed to higher grade disease can be referred to the Leukemia/BMT Program of BC for consideration of autografting. Prior studies by our group and others have shown that allografting has suboptimal results due to both high TRM and high relapse rates. Autografting in this group yields improved overall survival compared to allografting. There are no good studies comparing use of standard therapy to autografting in the transformed setting, however it is known that results are poor with conventional therapy, and observational studies suggest better results with high dose therapy and autografting.

For Richter’s or other transformation of CLL please see the L/BMT Program’s CLL algorithm. It should be noted that allografting for transformed CLL appears to have reasonable outcomes and will be considered for suitable patientss with good risk comorbidity scores.

For lymphoma transformation involving ‘double-hit’ with both bcl-2 and c-myc translocations, i.e., Burkitt type, see the Burkitt lymphoma algorithms. These lymphomas require specialized therapy including Burkitt-type management. They are a medical emergency and should be referred to the L/BMT Program as soon as possible.

Treatment
Publications
  1. Garnier A, Robin M, Larosa F, Golmard J-L, Gouill SL, Coiteux V, Tabrizi R, Bulabois C-E, Cacheux V, Kuentz M, Dreyfus B, Dreger P, Rio B, Moles-Moreau M-P, Bilger K, Bay J-O, Leblond V, Blaise D, Tournilhac O, Dhédin. Allogeneic hematopoietic stem cell transplantation allows long-term complete remission and curability in high-risk Waldenström’s macroglobulinemia. Results of a retrospective analysis of the Société Française de Greffe de Moelle et de Thérapie Cellulaire. Haematologica 95:950-955, 2010.
  2. Piñana JL, Martino R, Gayoso J, Sureda A, de la Serna J, Diez-Martin JL, Vazquez L, Arranz R, Tomas JF, Sampol A, Solano C, Delgado J, Sierra J, Caballero D for the GELTAMO Group. Reduced intensity conditioning HLA identical sibling donor allogeneic stem cell transplantation for patients with follicular lymphoma: long-term follow-up from two prospective multicenter trials. Haematologica 95:1176-1182, 2010.
  3. Al-Tourah A, Gill KK, Chhanabhai M, Hoskins PJ, Klasa RJ, Savage KJ, Sehn LH, Shenkier TN, Gascoyne RD, and Connors JM. Population-Based Analysis of Incidence and Outcome of Transformed Non-Hodgkin’s Lymphoma. J Clin Oncol 26:5165-5169, 2008.
  4. Armand P, Kim HT, Ho VT, ;Cutler CS, Koreth J, Antin JH, LaCasce AS, Jacobsen ED, Fisher DC, Brown JR. Canellos GP, Freedman AS, Soiffer RJ, Alyea EP. Allogeneic Transplantation with Reduced-Intensity Conditioning for Hodgkin and non-Hodgkin Lymphoma: Importance of Histology for Outcome. Biology of Blood and Marrow Transplantation 14:418-425, 2008.
  5. Ramadan KM, Connors JM, ;Al-Tourah AJ, Song KW, ;Gascoyne RD, Barnett MJ, Nevill TJ, Shepherd JD, Nantel SH, Sutherland HJ, Forrest DL, ;Hogge DE, Lavoie JC, Abou-Mourad YR, Chhanabhai M, Voss NJ, Brinkman RB, Smith CA and Toze CL. Allogeneic SCT for relapsed composite and transformed lymphoma using related and unrelated donors: long-term results. Bone Marrow Transplantation 42:601-608, 2008.
  6. Rezvani AR, Storer B, Maris M, Sorror ML, Agura E, Maziarz RT, Wade JC, Chauncey T, Forman SJ, Lange T, Shizuru J, Langston A, Pulsipher MA, Sandmaier BM, Storb R, and Maloney DG. Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation in Relapsed, Refractory, and Transformed Indolent Non-Hodgkin’s Lymphoma. J Clin Oncol 26:211-217, 2008.
  7. Ramadan KM, Connors JM, Al-Tourah A, Gascoyne RD, Song KW, Barnett MJ, Nantel SH, Nevill TJ, Shepherd JD, Sutherland HJ, Lavoie J, Forrest DL, Hogge DE, Voss NJ, Brinkman R, Abou Mourad YR, Power MM, Narayanan S, Smith CA and Toze CL. Salvage Therapy with Allogeneic Stem Cell Transplantation Results in Better Outcome for Patients with Relapsed/Refractory Follicular Lymphoma Compared to Those with Transformed Non-Hodgkin Lymphoma: A Population-Based Comparative Study. Poster Session. Blood (ASH Annual Meeting Abstracts) 112: Abstract 975, 2008.
  8. Ramadan KM, Song KW, Connors JM, Al-Tourah A, Gascoyne RD,  Barnett MJ, Nantel SH, Nevill TJ, Shepherd JD, Sutherland HJ, Lavoie J, Forrest DL, Hogge DE, Voss NJ, Brinkman R, Abou Mourad YR, Power MM, Narayanan S, Smith CA and Toze CL. Comparison of Outcome Between Refractory/Relapsed De Novo Diffuse Large B-Cell and Transformed Lymphoma Using Related and Unrelated Allogeneic Hematopoietic SCT. Poster Session. Blood (ASH Annual Meeting Abstracts) 112: Abstract 2173, 2008.
  9. Montoto S, Davies AJ, Matthews J, Calaminici M, Norton AJ, Amess J, Vinnicombe S, Waters R, Rohatiner AZS, and Lister TA. Risk and Clinical Implications of Transformation of Follicular Lymphoma to Diffuse Large B-Cell Lymphoma. J Clin Oncol 25:2426-2433, 2007.
  10. Toze CL, Barnett MJ, Connors JM, Gascoyne RD, Voss NJ, Nantel SH, Nevill TJ, Shepherd JD, Sutherland HJ, Lavoie JC, Forrest DL, Song KW and Hogge DE. Long-term disease-free survival of patients with advanced follicular lymphoma after allogeneic bone marrow transplantation. British Journal of Haematology 127: 311-321, 2004.
  11. Hosing C, Saliba RM, McLaughlin P, Andersson B, Rodriguez MA, Fayad L, Cabanillas F, Champlin ;RE & Khouri IF. Long-term results favor allogeneic over autologous hematopoietic stem cell transplantation in patients with refractory or recurrent indolent non-Hodgkin’s lymphoma. Annals of Oncology 14: 737-744, 2003.
Guidelines

Updated: October 2010 – currently under review

Long-Term Follow-Up Post-Allo SCT Guidelines Table (PDF)

Immunodeficiency
Antigen-specific T and B cell responses are profoundly deficient early after HSCT and gradual reconstitution occurs over 1-2 years. However recovery can take significantly longer due to ongoing immunosuppressive therapy, CGVHD, in HLA-mismatched transplants and with T-cell depleted grafts. Some physicians follow CD4 counts and CD4/8 ratios as a way to asses need for prophylactic antimicrobial therapy. Concurrent hypogamaglobulinaemia also increases the risk of infections in this group of patients.

Infections by capsulated bacteria (S. pneumoniae, H. influenza, and N. meningitides) remain a significant problem along with recurrent sino-pulmonary infections related to hypogamaglobulinaemia. The most common fungal infections are caused by Aspergillus species (lung/sinuses). However infections by Candida and Mucor species can also be seen. In terms of viral infections herpes viruses including VZV (particularly in the first year) and CMV (late reactivations and disease can occur in the presence of significant immunocompromise if early reactivations/disease have been an issue) infections can be problematic. Pneumocystis jirovicii (PCP) and Toxoplasma gondii infections are seen even several months post transplant and prophylaxis ideally with Co-trimoxazole should be continued until the patient is off all immunosuppression.

Recommendations

  • Penicillin V 300mg bid should be commenced in all non-allergic patients on therapy for CGVHD.
  • Fungal prophylaxis with an azole should be considered whilst patients are on systemic corticosteroid therapy
  • Pneumocystis prophylaxis (with Septra DS one tablet bid twice weekly in non-allergic patients) should be continued for as long as patients are on immunosuppressive therapy
  • Valaciclovir prophylaxis should be continued for at least one year post-transplant and continued on in patients on ongoing immunosuppressive therapy for CGVHD.
    Immunoglobulin assays should be done at yearly intervals in patients on corticosteroids or in the presence of recurrent infections and replacement therapy (IVIg 0.4g/kg monthly) commenced in patients with IgG < 4g/L.
  • Please follow AHA guidelines for dental procedures (Dajani et al.)
  • Post transplant vaccination with inactivated vaccines should be commenced at 1 year post-transplant or when a patient is considered to be able to respond to the same i.e., off most immunosuppressive therapy (vaccination schedule in L/BMT Manual). Live attenuated vaccines should be avoided for the first 2 years and in those with CGVHD.

Oral & Ocular
Oral
CGVHD and prior radiotherapy both contribute to the sicca syndrome seen commonly post HSCT. This sicca syndrome increases the risk of caries development in these patients. Ongoing symptomatic CGVHD can be a significant issue. Surveillance for oral malignancy should be done as ongoing GVHD increases the risk in this patient population.

Recommendations

  • Hygiene measures, fluoride treatment and artificial saliva (if appropriate) should be recommended.
  • Dental evaluation should be done at 3 months and then subsequently at least annually. Earlier or more frequent assessments may be required based on symptoms.

Ocular

Kerato conjunctivitis sicca occurs as part of a generalized sicca syndrome including xerostomia, vaginitis, and dry skin and occurs with greater frequency in patients with CGVHD (40% vs. 20%). The decreased tear flow also increases the risk of sterile conjunctivitis, corneal epithelial defects and epithelial ulceration. Topical management includes the use of lubricating eye drops, lachrymal duct occlusion, autologous serum drops and possibly sclera lens. In the context of CGVHD topical cyclosporine and topical retinoic acid have been found to be useful. Topical steroids may be associated with sight threatening bacterial and viral keratitis and therefore should be used with caution.

Posterior sub-capsular cataracts occur in the majority (80% at 6-10 yrs) of patients who have received TBI as part of conditioning for transplant. The other risk factors include older age at transplant and corticosteroid therapy longer than 3 months. Cataract surgery offers a simple and excellent solution to this complication.

Posterior chamber complications include ischaemic microvascular retinopathy, hemorrhage, bilateral optic disc edema and infectious retinitis. Risk factors for ischemic micro vascular retinopathy (incidence: 10% post allo-HSCT) include TBI based conditioning, use of cyclosporine for immunosupression and is manifested as disc edema and cotton wool spots. Withdrawal of cyclosporin is often associated with improvement in vision. Infectious retinitis can be due to fungi, herpes viruses (including CMV) and T.gondii.

Recommendations

  • Routine ophthalmological evaluation (including Schrimer’s test) at 3 months and subsequently yearly should be performed particularly in patients with CGVHD. Earlier more frequent assessments will be required in patients with ongoing symptoms.
  • New onset of visual symptoms/deterioration in vision should be prompt urgent ophthalmology review. (Please note the patient diagnosis, conditioning therapy and current medications in the consult request).

Pulmonary Complications
Significant numbers of patients (15-40%) develop late respiratory complications post allogeneic HSCT. These include infectious complications of the immunocompromised host (not discussed here) and noninfectious complications of the lung. The most common obstructive noninfectious complications include bronchiolitis obliterans (BO), bronchiolitis obliterans organizing pneumonia (BOOP) and idiopathic pneumonia syndrome (IPS). The risk factors for developing respiratory compromise include abnormal pulmonary function pre-transplant, chemotherapy received during the course of the disease, chemo/radiotherapy used in pre-transplant conditioning, immune mediated lung injury (CGVHD), infections and smoking.

The most common sub-type of chronic obstructive pulmonary disease (with reduction of FEV1/FVC) seen in this patient group is Bronchiolitis obliterans (BO) which occurs in up to 14% of this population and is associated with significant morbidity and mortality (up to 50%). BO is characterized by a nonspecific inflammatory injury affecting mainly the small airways. In the early stages it is an obstructive respiratory disease but in the advanced stages has both restrictive and obstructive functional changes. Risk factors include CGVHD, recurrent infections, reduced serum immunoglobulin levels, older age of donor/recipient, busulphan in pre-transplant conditioning and GVHD prophylaxis with Methotrexate. The median onset of symptoms is 1 year post-HSCT. Symptoms include a non-productive cough, wheeze, dysnoea and recurrent respiratory tract infections. Patients may be asymptomatic with abnormal PFTs in 20% of cases. The progress is associated with a gradual decline in respiratory function. CXR is often normal in the early stages and in the later stages reveals changes of hyperinflation. High resolution CT (HRCT) scan in the expiratory phase reveals air-trapping (characteristic mosaic image). Small airways thickening and bronchiectasis may also be seen. The diagnosis of BO can be made when the following diagnostic criteria are met: (1) FEV1/FVC ratio <0.7 and FEV1<75% of predicted value; (2) evidence of air trapping or small airway thickening or bronchiectasis on HRCT; (3) absence of infection in the respiratory tract. Management is based on treatment of CGVHD with immunosuppressive therapy including with corticosteroids (1-1.5 mg/day for 2- 6 weeks) followed by a slow taper over 6-12 months and CSA/FK. The addition of a third immunosuppressive agent such as azathioprine, MMF, thalidomide, infliximab, ATG or the use of Azithromycin (250 mg three times/week has been associated with improvement of pulmonary function in some cases. Prompt treatment of infections and replacement of immunoglobulins (with IVIg when IgG levels <4g/L) may help delay progress of the respiratory compromise. Bronchodilators and inhaled corticosteroids can be used. ECP has been found to be useful in small studies.

BOOP occurs earlier in the course of HSCT, between 1-12 months post transplant with an incidence of <2%. Patients present acutely with fever cough, dysnoea. The CXR reveals patchy peripheral consolidation, ground glass attenuation and nodular opacities PFTs reveal a restrictive pattern with reduced TLC and DLCO. Bronchoscopy and biopsy helps to rule out infection and confirm diagnosis. Despite the lack of evidence systemic or inhaled corticosteroids are considered first line therapy and can result in improvement of the condition.

An idiopathic pneumonia syndrome can be seen within 3 months post transplant. The etiologies include infections (bacterial and viral), radiotherapy, chemotherapy (e.g. Busulfan, bleomycin, BCNU) and CGVHD.

Restrictive defects (with reduction of TLC and possibly DLCO) occur in the early (3-6/12 post-transplant) and are often stable and can improve in the subsequent years post-transplant.

Recurrent sino-pulmonary infections can occur. Replacement of immunoglobulins and smoking cessation can help in the management of these infections.

Recommendations

  • Regular clinical evaluations at least 6 monthly or more frequently in the presence of CGVHD should be performed.
  • Smoking cessation should be advocated.
  • Pulmonary function testing at 3 months and subsequently yearly post transplant in the presence of CGVHD or symptoms.
  • Radiology (CXR, HRCT) to be done based on symptoms or abnormal PFT.
  • Referral to respirology is recommended in the presence of abnormal PFT and/or symptoms for management and consideration of BAL and biopsy.

Cardiac
Compared to the general population the risk of late death due to cardiac complications is 2-3 fold higher after allo-HSCT and 4 fold higher in females even after auto-HSCT. There are few studies looking at cardiac late effects in adults. In children the use of TBI and anthracyclines pre-transplant is associated with a 5 year cumulative incidence of cardiac impairment of 26% ( majority asymptomatic). It is highly likely therefore that similar changes would be observed in adults and the true magnitude of these defects will become apparent with longer term studies.

A retrospective EBMT study found a cumulative incidence of arterial event (cerebrovascular/cardiovascular/peripheral arterial) of 6% at 15 years. The CI of an arterial event for patients with a high cardiovascular score (defined as presence of ≥50% of the risk factors including arterial hypertension, diabetes, dyslipidaemia, increased body-mass index, physical inactivity and smoking) was 17%, as compared with 4% in those with a low risk score. The increased incidence has been postulated to be secondary due to endothelial damage provoked by CGVHD and possibly decrease in microvessels. Also, there is an increase in the incidence of cardiovascular risk factors in this patient population.

Recommendations

  • History of cardiac and cardiovascular risk factors since previous visit should be assessed and clinical examinations conducted.
  • Life style modification (smoking, weight loss etc) should be recommended.
  • Cardiovascular risk factors (HT, DM, Lipids) should be assessed yearly and therapy optimized
  • Consider ECHO/ECG at 1year for patients who have received TBI/anthracyclines and base subsequent follow-up on results/symptoms

Liver & Renal
Liver
A number of factors can cause derangement of liver function including but not limited to medication, CGVHD, viral hepatitis and iron overload. The management of CGVHD is available in the relevant guideline.

Recommendations

  • Monitor liver function tests at least yearly
  • Ferritin assessment should be done at 1year post-transplant. Monitoring should continue in patients with ongoing RBC transfusions, Hepatitis C infection or elevated LFTs. Spontaneous reductions in ferritin do occur over several years post transplant. Iron overload should be confirmed with Trasferrin saturation. Iron overload can be managed with venesections. The role of chelation is unclear at present. No formal guidelines are available on level at which venesection should be commenced.
  • HBsAg, HBcAg, anti-HBsAb, Hepatitis C PCR should be done at 100 days and 1 year post-transplant. In patients with known Hepatitis B or C monitoring should continue with viral load assays and therapy as recommended by hepatologist should be instituted. Patients with a history of Hepatitis B infection should commence Lamivudine 100mg/day at commencement of chemotherapy and continue for 6 months post or until they are off all immunosuppression.
  • Liver biopsy at 8-10 years post SCT should be considered in Hepatitis C positive patients due to the increased risk of cirrhosis.

Renal
Chronic renal dysfunction post transplant is seen quite frequently (27% at 10 years, 3% with severe renal disease i.e., GFR< 30 mls/min/1.73 m2) several years post transplant and can be related to the disease process, nephrotoxins (prior chemotherapy/medication e.g. platinum compounds, carmustine, ifosfamide, anti-infectious agents, immunosuppressive drugs), sepsis, age at transplant, female gender, reduced GFR pre-transplant and hypertension. Management includes discontinuation of the offending nephrotoxic agent, hydration, treatment of sepsis, management of HT and referral to a nephrologist. Nephrotic syndrome can be seen as a manifestation of CGVHD usually responding within 12 weeks to treatment with corticosteroids and cyclosporine (the exception being that seen after NMAs which are quite refractory to therapy). Radiation induced nephritis can be seen up to 6 months post transplant. Substantial hemorrhagic cystitis can subsequently lead to bladder wall scarring and contraction.

Recommendations

  • Regular assessments of renal function should be performed (6-12 monthly BUN, creatinine).
  • Yearly 24 hour urine protein estimations should be considered in patients with CGVHD. Yearly GFR estimated in patients with abnormal renal function.
  • Renal dysfunction should be appropriately investigated (medications, ultrasound, biopsy) and nephrology consult considered.

Endocrine
Thyroid
Subclinical compensated hypothyroidism with elevated TSH and normal serum free T4 occurs in 7-15% of patients in the 1st year following allo-HSCT. Replacement therapy at this point is not mandated but a close follow-up (3 monthly TFT) is warranted. Median time to development of overt hypothyroidism is 4 years in up to 11-15% of patients, particularly in those who have received TBI or head and neck radiation. These patients should be commenced on therapy. Radiation induced and auto-immune thyroiditis can occur.

Radiation to the head and neck results in a dose related increase in malignancy risk. The relative risk of thyroid cancer is increased 3 fold compared to an age and sex matched population. The other factors increasing malignancy risk include female sex, age at HSCT and CGVHD.

Recommendations

  • Yearly TSH, free T4 assessments and management based on results. Referral to endocrinology for abnormal results is advisable.
  • High index of suspicion to be maintained to diagnose thyroid malignancy

Gonadal Hormones
Gonadal dysfunction is very common post transplant. The risk of hypogonadism is related to age at transplant (older age associated with greater risk), gender (females >males) and pre-transplant conditioning therapy (TBI, busulfan>single agent melphalan, cyclophosphamide). Men appear to mostly retain normal testosterone levels although infertility is almost universal (recovery seen in 10-15% over several years). In women the risk of hypergonadotrophic hypogonadism is very high and almost universal with TBI or Busulfan conditioning with recovery of ovarian tissue occurring in 5-10% of women years later. The chances of recovery are greater (50%) in patients receiving BEAM chemotherapy. Prepubertal girls have a significantly higher chance of recovery. However if puberty is not achieved by 12-13 years then referral to a specialist is warranted.

Recommendations

Men:

  • Testosterone assessments should be done in men with symptoms of erectile dysfunction or loss of libido. Alternatively it could be routinely assessed at 3 months, 1 year.
  • In terms of fertility pre-chemotherapy sperm banking with subsequent assisted fertility techniques should be considered.

Women:

  • Women should undergo yearly clinical and endocrinological assessments (FSH, LH, estrogen assays). Patients should be referred to endocrinology for HRT to help maintain libido, sexual function, retain bone density and reduce the risk of cardiovascular and lipid disorders.
  • Yearly gynaecological assessments should be done in women with ongoing GVHD as vaginitis, strictures and synechiae formation can be ongoing issues.
    In terms of fertility embryo cryopreservation prior to receipt of chemotherapy is the only technique proven to be beneficial. However, as this requires a delay in treatment of several weeks and a willing partner, it may not be suitable in a number of patients.

Adrenal Gland
Recommendations

  • Chronic steroid use can lead to reversible suppression of pituitary/adrenal axis. Slow terminal tapering of corticosteroids is recommended with formal assessment of adrenal function if patients develop symptoms of adrenal insufficiency on steroid withdrawal. Stress dose steroids should be given in times of acute illness.
  • Secondary hyperglycaemia is often seen due to steroid therapy of GVHD and patients should be investigated and managed appropriately, ideally with referral to endocrinology.

Skeletal system
Osteopenia/Osteoporosis
Osteopenia is a systemic condition characterized by reduced bone mass and increased susceptibility to bone fracture. Osteoporosis is associated with a more significant reduction in bone mass and a greater tendency to bone fracture. The risk of developing either can be related to dose and duration of steroid, cyclosporine/FK 506 use, TBI, inactivity and in women who are hypoestrogenic. As per WHO criteria nearly 50% of all patients have reduced bone density with 10% having osteoporosis 12-18 months post transplant. Nontraumatic stress fractures occur in 10% of patients.

Recommendations

  • Yearly dual photon densimetry in the presence of abnormalities or if the patient is on steroid therapy is recommended.
  • Therapy with Calcium, Vitamin D, HRT in women, exercise, and judicious use of corticosteroids can be useful.
  • Bisphosphonate therapy (Fosamax 70mg weekly) in osteoporosis can lead to improvement in bone density in the lumbar spine but the benefit to the femoral neck and hence fracture reduction is less clear. Please also assess thyroid hormone function in patients with reduced bone density.

Avascular Necrosis of Bone
The risk of developing avascular necrosis is between 4-10% at median time of 18 months post-transplant. The risk factors include corticosteroid therapy, fractionated TBI>12GY. Patients receiving transplants for ALL and SAA appear to be at a greater risk than those with other disease sub-types. Pain is often the presenting feature with 80% of AVNs occurring at the hip joint and 10% at the knees. AVN of the wrist and ankle bones can also occur. X-ray changes usually occur late. MRI of the relevant joint is the investigation of choice. Joint replacement is warranted in the majority (80%) of patients. Long term follow up of the prostheses is needed in younger patients.

Muscles and Fascia
Corticosteroid induced muscle weakness is often seen in patients on therapy for GVHD. This preferentially affects the proximal muscles resulting in myalgia and weakness which is often slow to resolve on cessation of steroid therapy. Alternate day dosing can result in reduction in the incidence of myopathy.

CGVHD can also be associated with polymyositis with severe proximal muscle weakness, myalgia, arthralgia and results in elevated CK, aldolase. The diagnosis can be confirmed with a muscle biopsy and treated with steroid therapy. CGVHD can also cause fasciitis and disabling sclerodermatous changes.

Recommendations

  • Regular clinical evaluation at clinic visits.
  • Physiotherapy offered for patients on long term corticosteroid therapy, fasciitis, sclerodermatous changes.

Secondary Malignancy
The incidence of secondary malignancy is increased 2-3 fold post transplant compared to gender, age and region matched population. The cumulative risk is 2.5% at 10 years and 8.8% at 20 years. The transplant related risk factors include radiotherapy, length and severity of immunosuppression and CGVHD. The risk increases with time after transplant especially for radiation induced malignancies.

The incidence of PTLDs is 1% at 10 years with the majority being EBV related and occurring within 6 months post transplant. The risk is increased with greater recipient-donor HLA disparity, T-depletion and GVHD.

The risk factors for Squamous cell carcinoma (SCC) include male sex, CGVHD and immunosupression. There is a 5 fold increase in SCC in patients with CGVHD at 1-4 years post-transplant with the risk remaining high for several years. The risk of cutaneous malignancy risk is increased by exposure to radiotherapy and photosensitive effects of medication.

Non-SCC (breast, thyroid, brain, bone, CNS, connective tissue, melanoma) risk is linked to radiotherapy, age at which radiotherapy was received and risk increases with increasing time from transplant. Patients who have been irradiated have a 10 fold higher risk compared to non-irradiated patients for up to 30 years post transplant. There is a 6 fold increase in breast malignancy in patients receiving local radiotherapy/TBI prior to transplant. The risk particularly increased after 10 years post-transplant. The risk is significantly increased when the radiotherapy was received prior to 18 years of age. The relative risk of developing thyroid malignancy is 6 times for patients post transplant. The risk increase with younger age, radiation exposure, female sex and CGVHD. The risk factors for developing CNS malignancy (RR almost 6) is younger age at transplant, radiotherapy and receipt of anthracyclines and alkylators. Risk for developing Melanomas (RR3.5) is radiation exposure, T-cell depletion and short (<1 year) latency period. High index of suspicion needs to be maintained for the diagnosis of all of the above as routine screening is not available for most.

Recommendations

  • Patients should be reminded to perform regular self breast and skin examinations.
  • Patients should be advised to stop smoking.
  • Patients should be advised to avoid excessive UV exposure and use sun-screen regularly.
  • Mammography should commence at 40 years (for patients without a family history or who have not received mantle radiotherapy). In patients with Hodgkins Lymphoma or who have received local radiotherapy it should commence at 10 years post therapy or at 40 years whichever is earlier.
  • Pap smears should be done every 1-2 years as per protocol.
  • Yearly dental exam for oral malignancy should be done.
  • Yearly gynaecological exam is recommended.
  • Colorectal cancer screening in the form of yearly stool FOB should begin at 50 years as per BCCA protocol.
  • Digital rectal examination (DRE) either routinely or in men with urinary symptoms should be considered in patients between 50-70 years. If DRE is abnormal perform PSA and refer to urologist if PSA >4.
Publications
  1. Michelle L. Griffith et al. Dyslipidaemia after allogeneic hematopoietic stem cell transplantation: evaluation and management. Blood 2010; 116:1197-1204.
  2. J. Douglas Rizzo et al. Solid cancers after allogeneic hematopoietic cell transplantation. Blood 2009; 113; 1175-1183.
  3. Andre Tichelli et al. Late Pulmonary, Cardiovascular, and Renal Complications after Hematopoietic Stem Cell Transplantation and Recommended Screening Practices. Hematology (ASH education book) 2008: 125-133.
  4. Andre Tichelli et al. Late cardiovascular events after allogeneic hematopoietic stem cell transplantation: a retrospective multicenter study of the Late Effects working Party of the European Group for Blood and Marrow Transplantation. Haematologica 2008; 93(8): 1203-1210.
  5. JD Rizzo et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, Center for International Blood and Marrow transplant research, and the American society for Blood and Marrow Transplantation (EBMT/CIBMTR/ASBMT). Bone Marrow Transplantation 2006; 37:249-261.
  6. Gerard Socie et al. Nonmalignant late effects after stem cell transplantation. Blood 2003; 101: 3373-85.
Treatment

The overall incidence of Leukemia from SEER data is 12.3/100,000 men and women. This further subdivided into 3.6/100,000 for AML, 1.6/100,000 ALL, 1.5/100,000 CML, and 4/100,000 CLL. The median age of diagnosis is 67 years and the median age of death is 74 years. The major focus of post-therapy follow-up remains the detection of relapse. The specifics regarding this should be found in the disease specific guidelines and will not be discussed here. The surveillance for some of the complications of therapy and suggestions for follow-up are discussed in this section.

Cardiac function compromise can be seen secondary to anthracycline use and is often manifested during therapy. Routine testing is done prior to cycles of chemotherapy. The role of routine testing post therapy completion is less clear. The potential for toxicity should however be kept in mind and monitored for in terms of history and physical examination during follow up visits. Focused testing (e.g. Echocardiogram) can then be done based on clinical concern. For young adults treated on the ALL 13-01 protocol, periodic cardiac evaluation by echocardiography is recommended.

Renal or liver function derangement is most commonly seen secondary to nephrotoxic agents used in supportive therapy (e.g. aminoglycosides, anti-fungals). This should be followed up as warranted by the degree of dysfunction and appropriate specialist referral made as deemed appropriate. Iron overload and viral hepatitis should be kept in mind as causes of liver function derangement.

Secondary MDS/AML can occur following the chemotherapy for Leukemia. Topoisomerase 2 inhibitors are associated with a shorter latency period (~2 years) to development of secondary MDS/AML. Recurrent cytogenetic abnormalities (e.g. 11q23 abnormalities) are often detected on analysis. The average time to development of secondary MDS/AML with the other chemotherapy agents is often longer at 4-7 years and complex/adverse markers (e.g. -7) are often noted on cytogenetic analysis. Regardless, this type of leukemia is often extremely refractory to therapy and the prognosis is poor.

Sub-fertility is often an issue post therapy. In men pre-chemotherapy sperm banking with subsequent assisted fertility techniques should be recommended. In women embryo cryopreservation prior to receipt of chemotherapy is the only technique proven to be beneficial. However, as this requires a treatment delay of several weeks and a willing partner, it may not be suitable in a number of patients. In women there is also a risk of development of hypergonadotrophic hypogonadism and this should be kept in mind during follow-up and HRT instituted as deemed appropriate.

Cranial radiotherapy can be associated with some exposure of the thyroid gland and therefore yearly TSH, T4 should be considered. Thyroid malignancy can also occur high index of suspicion should be maintained. Young patients (<20 years) can develop secondary benign and malignant brain tumors post cranial radiotherapy with a latency period of 15-20 years. Again a high index of suspicion needs to be maintained.

Ophthalmology assessment should be completed every 2-3 years for young adults treated on the ALL 13-01 protocol.

Drug Toxicity Surveillance
Not including acute toxicity during therapy.

The following table summarizes some of the common drug related toxicity seen in the follow-up of patients treated for Leukemia.

Click table to open as a PDF.

Drug Toxicity Table

Diagnosis

Updated: May 2016

Lymphoblastic lymphoma is an uncommon non-Hodgkin’s lymphoma. It is the nodal variant of acute lymphoblastic leukemia (ALL). Typically lymphoblastic lymphoma is of T-cell immunophenotype with a minority being of B-cell immunophenotype. Classically this lymphoma is diagnosed in young men although it can occur in both genders and without age limitations. T-cell lymphoblastic lymphoma commonly present in the anterior mediastinum. This lymphoma requires rapid assessment and treatment. In British Columbia adult patients with an established or probable diagnosis of lymphoblastic lymphoma should be referred to the Leukemia/BMT Program at the Vancouver General Hospital. Children should be referred to the BC Children’s Hospital.

Required Tests

  • Lymph node / tissue biopsy
  • CBC and differential
  • Electrolytes, BUN, creatinine, uric acid, liver function tests, LDH
  • INR, PTT and fibrinogen
  • Bone marrow aspirate and biopsy with cytogenetics analysis and flow cytometry for immunophenotyping
  • Computed tomography (CT) scan of the neck, chest, abdomen and pelvis. CT of the head should also be considered, especially if there are CNS symptoms.
  • Lumbar puncture

Staging
The stage of disease is of major therapeutic and prognostic significance. The staging system used is based on the Ann Arbor system with additional consideration of the bulk or size of individual tumours. The formal stage is assigned using the following system.

(See table below)

Symptoms

See table below.

Prognosis
Patients diagnosed with lymphoblastic lymphoma can have a 5-year disease free survival rate of 60-80%. The prognosis is dependent upon the stage of disease and the age of the patient. Patient with bone marrow involvement are considered to have acute lymphoblastic lymphoma and should be treated accordingly.

StageInvolvement
1Single lymph node region (1) or one extralymphatic site (1E)
2Two or more lymph node regions, same side of the diaphragm (s) or local extralymphatic extension plus one or more lymph node regions, same side of the diaphragm (2E)
3Lymph node regions on both sides of diaphragm (3) which may be accompanied by local extralymphatic extension (3E)
4Diffused involvement of one or more extralymphatic organs or sites
Staging
A=No B symptoms
B=Presence of at least one of these:
1. Unexplained weight loss > 10% baseline during 6 months prior to staging
2. Unexplained fever > 38°C
3. Night sweats
Symptoms
Treatment

Algorithms

Protocols

BCCA Chemotherapy Protocols and PPOs

Outcomes

Publications
  1. Song KW, Barnett MJ, Gascoyne RD, Chhanabhai M, Forrest DL, Hogge DE, Lavoie JC, Nantel SH, Nevill TJ, Shepherd JD, Smith CA, Sutherland HJ, Toze CL, Voss NJ, and Connors JM. Primary therapy for adults with T-cell lymphoblastic lymphoma with hematopoietic stem-cell transplantation results in favorable outcomes. Ann Oncol 18:535-540, 2007.
Diagnosis

Updated: March 2011 – currently under review

Mantle cell lymphoma comprises approximately 5% of all non-Hodgkin’s lymphoma. It is a B-cell lymphoma which has a characteristic translocation between chromosome 11 and 14. This translocation results in deregulated overexpression cyclin D1. Patients who are diagnosed with this lymphoma should be referred to a local oncologist/hematologist to initiate treatment. The local oncologist/hematologist should then consider referring the patient to the Leukemia/BMT Program at the Vancouver General Hospital for possible high-dose chemotherapy followed by stem cell rescue as consolidation of their initial chemotherapy (autotransplant). The referral to the BMT Program should be made early in order to have adequate time to arrange for the autotransplant.

Required Tests

  • Lymph node / tissue biopsy
  • CBC and differential
  • Electrolytes, BUN, creatinine, uric acid, liver function tests, LDH
  • INR, PTT and fibrinogen
  • Bone marrow aspirate and biopsy with cytogenetics analysis and flow cytometry for immunophenotyping
  • Computed tomography (CT) scan of the neck, chest, abdomen and pelvis. CT of the head should also be considered, especially if there are CNS symptoms.

Staging
The stage of disease is of major therapeutic and prognostic significance. The staging system used is based on the Ann Arbor system with additional consideration of the bulk or size of individual tumours. The formal stage is assigned using the following system.

(See table below)

Symptoms

See table below.

Prognosis
Mantle Cell lymphoma remains an incurable lymphoma. For patients who are eligible for autotransplant, median survival is greater than 5 years.

StageInvolvement
1Single lymph node region (1) or one extralymphatic site (1E)
2Two or more lymph node regions, same side of the diaphragm (s) or local extralymphatic extension plus one or more lymph node regions, same side of the diaphragm (2E)
3Lymph node regions on both sides of diaphragm (3) which may be accompanied by local extralymphatic extension (3E)
4Diffused involvement of one or more extralymphatic organs or sites
Staging
A=No B symptoms
B=Presence of at least one of these:
1. Unexplained weight loss > 10% baseline during 6 months prior to staging
2. Unexplained fever > 38°C
3. Night sweats
Symptoms
Treatment
Publications
  1. Mangel J, Leitch HA, Connors JM, Buckstein R, Imrie K, Spaner D, Crump D, Crump M, Pennell N, Boudreau A & Berinstein NL. Intensive chemotherapy and autologous stem-cell transplantation plus rituximab is superior to conventional chemotherapy for newly diagnosed advanced stage mantle-cell lymphoma: a matched pair analysisAnn Oncol 15:283-290, 2004.
Diagnosis

Updated: May 2016

Required Tests

  • Serum and urine protein studies
    – Serum protein electrophoresis
    – Serum protein immunofixation and quantitative immunoglobulin
    – Urine protein 24 hour quantitation and electrophoresis
    – Serum free light chain levels: should be considered particularly where there is a high suspicion of myeloma but the serum protein electrophoresis is negative.
  • Serum calcium, uric acid, creatinine, albumin, LDH
  • Beta-2-microglobulin for staging at diagnosis only (not used for monitoring)
  • CBC
  • Skeletal radiographic survey (skull, spine, humeri, pelvis, femora, ribs)
  • MRI should be considered for patients with high clinical suspicion for cord compression or to exclude soft tissue lesions in a painful area. CT may be considered but intravenous contrast studies are relatively contra-indicated because they may cause renal injury.
  • PET scan for patients with a solitary plasmacytoma.
  • Bone marrow aspiration and biopsy, with:
    – FISH probe translocation t(4;14)
    – FISH probe for Del(17p)
    – FISH probe for translocation t(14;16)
  • Hepatitis Bsurface Ag, hepatitis Bcore Ab, hepatitis C Ab

Note: Bone scanning is seldom useful in myeloma.

The diagnostic criteria of myeloma have recently been modified (Lancet Oncol 2014 Nov;15(12):e538-548). To be diagnosed with myeloma, there must be clonal bone marrow plasma cells =10% or biopsy proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events:

  • Myelomadefining events:
    ○ Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
    – Hypercalcemia: serum calcium >0.25mmol/L higher than the upper limit of normal or >2.75mmol/L
    – Renal insufficiency: creatinine clearance <40ml/min or serum creatinine >177µmol/L.
    – Anemia: Hemoglobin value of >20g/L below the lower limit of normal, or a hemoglobin value <100g/L.
    – Bone Lesions: one or more osteolytic lesions on skeletal radiography, CT or PET-CT.
  • Any one or more of the following biomarkers of malignancy:
    ○ Clonal bone marrow plasma cell percentage ≥60%
    ○ Involved:uninvolved serum free light chain ratio ≥100 minimum involved FLC level of at least 100mg/L required)
    >1 focal lesion on MRI studies

A diagnosis of smouldering myeloma is made when both of the below critera are met:

  • Serum monoclonal protein (IgG or IgA) ≥30g/L or unrinary monoclonal protein ≥500mg per 24h and/or clonal bone marrow plasma cells 10-60%.
  • Absence of myeloma defining events or amyloidosis

Staging
Durie and Salmon Staging System (see table below)

International Staging System (ISS)
The International Staging System (ISS) for myeloma is currently the more widely used. It depends only on the serum albumin and beta-2-microglobulin (B2M) and is actually more of a prognostic score than a staging system.

See table below.

Revised International Staging System (ISS)

Recently, the International Myeloma Working Group have incorporated cytogenetic abnormalities and the LDH as a part of the staging system.

See table below.

 

StageFindings
1Hgb > 100 g/L Calcium < 2.88 mmol/L Bones = no more than 1 lytic lesion
1M-protein: IgG < 50 g/L IgA < 30 g/L
1Total urinary light chain < 4 g/24 h
2Between 1 and 3
3Any one of these:
3Hgb < 85 g/L Calcium > 2.88 mmol/L Bones = multiple lytic lesions
3M-protein: IgG > 70 g/L IgA > 50 g/L
3Total urinary light chain > 12 g/24 h
3A = creatinine≤ 180 mmol/L
3B = creatinine > 180 mmol/L
Staging: Durie and Salmon Staging System
(Durie, Cancer, 1975;36:842-54)
StageFindings
Serum B2M < 3.5 mg/L and serum albumin ≥ 35 g/L
Neither stage I or III
Serum B2M ≥ 5.5 mg/L
International Staging System (ISS)
(Greipp, J Clin Oncol, 2005;23:3412)
StageFindings
IISS stage I and standard-risk CA by FISH and normal LDH
IINeither R-ISS stage I or III
IIIISS stage III and either high-risk CA by FISH or high LDH
Revised International Staging System (ISS)
(Palumbo, J Clin Oncol, 2015;33:2863)
Del(17p), translocation t(4;14), translocation t(14;16) detected by FISH are considered high-risk CA
LDH is classified as normal or high according to local laboratory definition of normal range. High is a value greater than normal.
Treatment

Treatment Options
1. Immunizations

All patients should receive the immunizations recommended in the BCCA guidelines. (see BCCA website)

2. Standard chemotherapy

Chemotherapy is the treatment of choice. Even though a cure is not possible, chemotherapy often offers satisfactory palliation. The standard regimen for younger patients (approximately below 65 to 70 years of age) is high dose chemotherapy and autologous hematopoietic stem cell transplant. For older patients combination therapy with melphalan, prednisone and bortezomib is considered standard therapy (see BCCA website). Patients who are candidates for high dose chemotherapy and stem cell transplantation (see section 3 below) should NOT be treated with melphalan because this may make it impossible to gather adequate stem cells to support transplantation. Such patients should be discussed with a member of the Leukemia/BMT group before treatment is initiated.

3. Hematopoietic stem cell transplantation

Selected patients younger than approximately 65-70 years of age are considered eligible for high-dose chemotherapy followed by hematopoietic stem cell transplantation. These patients should receive induction chemotherapy which is not toxic to the stem cells. Currently such patients will receive induction chemotherapy that includes dexamethasone and bortezomib. It is recommended that cyclophosphamide also be added in combination to deepen the remission prior to transplant. Physicians with potentially eligible patients should discuss referral with a member of the Leukemia/BMT group. Patients who are candidates for high dose chemotherapy and hematopoietic stem cell transplantation should NOT be treated with melphalan or other alkylating agents because this may make it impossible to gather adequate stem cells to support transplantation.

4. Bisphosphonates

Third generation bisphosphonates are effective in preventing some of the skeletal destruction caused by myeloma and improve survival (Berenson, NEJM, 1996;334:488). Intravenous pamidronate, 30 mg in 500 mL saline over 1 h, once every 4 to 6 weeks, should be given to all patients receiving chemotherapy for myeloma. Prior to initiation of pamidronate the patients should be seen by the dentist to address their dental health and have necessary invasive dental procedure done to reduce the risk of osteonecrosis of the jaw. In order minimize the risk of osteonecrosis or renal toxicity, the duration of pamidronate treatment should be kept to the time shown in the randomized trial to have been beneficial. For patients who undergo high dose chemotherapy and stem cell transplantation Pamidronate should be continued at approximately monthly intervals until assessment of response. Most patients reach a complete or very good partial response in which case pamidronate should be stopped after 12 doses; otherwise, continued for 24 months then stopped. For patients who do not undergo a stem cell transplant pamidronate should be continued for 24 months then stopped. After the pamidronate is stopped it should only be resumed, for another 24 month course, if the myeloma again requires systemic treatment. All patients treated with bisphosphonates should be provided with guidelines for dental care (see BCCA website)

5. Secondary chemotherapy

Secondary treatments for recurrent myeloma include the following:

The choice of the timing and order of these drugs must be individualized. Active research is being conducted into alternative salvage treatments. The Leukemia/BMT group should be contacted about the status of such investigations.

6. No initial therapy

Rarely, multiple myeloma is an indolent disease either progressing slowly or remaining static (Smouldering multiple myeloma; please see diagnosis section). Hence, therapy may be initially withheld in patients who fulfill all of the following criteria. Such patients do not need to be treated with bisphosphonates.

  • No symptoms
  • Satisfactory peripheral blood counts
  • Normal serum calcium
  • Stable paraprotein in the serum or urine
  • No renal or neurological disease due to myeloma
  • No more than one lytic bone lesion

7. Radiation

Local radiation should be considered for patients with any of the following:

  • A symptomatic lytic bone lesion or soft tissue plasmacytoma which is not responding to systemic treatment
  • Threatening or actual pathological fracture
  • Spinal cord compression (recall that spinal cord compression is an emergency; a radiation oncologist should be contacted immediately to discuss treatment plans)

8. Renal Impairment in Multiple Myeloma

Renal impairment occurs in up to 25% of patients upon presentation. Damage to the renal tubules is caused by free light chains. Other causes which contribute to renal impairment include dehydration, hypercalcemia, nephrotoxic drugs (such as NSAIDS) and infections. Patients presenting with renal failure have higher early death rate and worse overall prognosis. Renal impairment may be the initial manifestation of multiple myeloma for which reason, patients should be worked up for myeloma should they present with renal impairment. A renal biopsy should also be considered. Early diagnosis and treatment can influence the degree and the ability to reverse renal impairment and the ability to administer anti-myeloma medication.
Initial measures to control and reverse renal impairment include:

  • Vigorous rehydration
  • Discontinuation of nephrotoxic drugs
  • Treatment of precipitating factors (eg. Hypercalcemia, hyperuricemia and infections)

Once myeloma is suspected or diagnosed treatment should be initiated as soon as possible. The following are recommended:

  • Dexamethasone. Appropriate doses are 20-40mg po daily for 4 days. This can be started immediately.
  • Bortezomib: Dose adjusting is not necessary in renal impairment. Approval through the Compassionate Access Program (CAP) is required. For patients who will not be eligible for transplant due to age and fitness an application for bortezomib should be made through the UMYMPBOR protocol. For patients who may be eligible for transplant application for bortezomib should be made through the UMYBORPRE protocol.
  • Consultation with the nephrology service to guide renal management

Assessment of Response
The response criteria have been evolving based upon the availability of newer more sensitive testing and more effective treatments. The most commonly used criteria are:

  • The EBMT/IBMTR criteria (BJH, 1998;102, 1115-1123)
  • IMWG critieria (Durie, Leukemia, 2006;20;1467-1473)

Simplified criteria that can be used for clinical management is the following:

Criteria of Adequate Response:

  • Reduction of serum paraprotein to less than 50% of the pretreatment level and urine paraprotein to less than 10% of pretreatment level
  • Improvement or stabilization of bone marrow function
  • Improvement or stabilization of kidney function
  • Normalization of serum calcium
  • No new osseous or extra-osseous lesions
  • Resolution of all symptoms

Criteria of Relapse or Progression:

  • Progressive rise in level of paraproteinemia and/or paraprotenuria by more than 25%
  • Development of hypercalcemia
  • Appearance of new osseous or extra-osseous lesions
  • Progressive bone marrow failure

Development of anemia, thrombocytopenia or neutropenia singly or in combination usually reflects one of two problems, drug toxicity or progressive disease. Concurrent assessment of bone marrow (aspiration + biopsy) and paraproteins (serum + urine) will usually resolve the question. If progressive disease, bone marrow examination typically shows heavy infiltration with abnormal plasma cells and rising paraprotein levels. If drug toxicity, bone marrow examination shows hypocellular marrow, usually with residual myeloma and the paraprotein levels are either falling or remaining stable. Pancytopenia developing unexpectedly in patients on long-term therapy with alkylating agents may be due to secondary leukemia or myelodysplasia.

The development of a falling or stable paraprotein level and separate signs of progressive disease (such as new bone lesions) suggest that the myeloma is becoming non-secreting or light chain escape is occurring and the intact paraprotein may not be as useful to follow disease. Consider testing serum free light chain levels if light chain escape is suspected.

Follow-up Evaluation

On Treatment

(see table below)

Off Treatment

The same tests should be performed as when the patient is on treatment, but the interval can be 3 months between lab tests and yearly for the skeletal surveys.

Algorithms

Protocols
BCCA Chemotherapy Protocols and PPOs

Publications
  1. Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritis E, Richardson P, Landgren O, Paiva B, Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Lonial S, Rosinol L, Zamagni E, Jagannath S, Sezer O, Kristinsson SY, Caers J, Usmani SZ, Lahuerta JJ, Johnsen HE, Beksac M, Cavo M, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie BG, Miguel JF. International Myeloma Working Group updated criteria for the diagnosis of myeloma. Lancet Oncol. 2014 Nov; 15(12):e538-48.
  2. Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV; International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia. 2006 Sep;20(9):1467-73.
  3. Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM. Long-term follow-up on overall survival from the MM-009 and the MM010 phase III trials of lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009 Nov 23(11);2147-52.
  4. Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, Miguel JS, Bladé J, Boccadoro M, Cavenagh J, Alsina M, Rajkumar SV, Lacy M, Jakubowiak A, Dalton W, Boral A, Esseltine DL, Schenkein D, Anderson KC. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 2007; Nov 15; 110(10): 3557-60.
  5.  San Miguel JS, Weisel K, Moreau P, Lacy M, Song K, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A, Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C, Zaki M, Dimopoulos M. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1055-66.
Diagnosis

Updated: May 2017

Myelodysplastic syndrome (MDS) is a clonal stem cell disorder characterized by low blood counts despite a bone marrow that is usually quite cellular. However, the cells within the bone marrow have an abnormal (“dysplastic”) appearance and frequently are dysfunctional. MDS has a tendency to develop into cancer of the bone marrow (acute leukemia or “AML”) although the speed with which this occurs in MDS is highly variable. Furthermore, patients with MDS may have separate medical problems that have a more significant impact on their quality and duration of life.

Investigations
Patients with low blood counts should have the following performed:

  • Creatinine, electrolytes and liver function testing (including LDH)
  • Serum ferritin
  • B12 levels
  • Reticulocyte count
  • Serum TSH

If no explanation is found for low counts, referral to a hematologist is recommended for:

  • Bone marrow aspirate and biopsy – SENDING A MARROW SAMPLE FOR CYTOGENETIC ANALYSIS IS CRITICAL IN MDS
  • Peripheral blood flow cytometry for paroxysmal nocturnal hemoglobinuria (“PNH”) testing

Patients with either unexplained hematologic cytopenias or documented MDS can be referred to the Marrow Failure Syndromes Clinic at Vancouver General Hospital by sending information by fax to 604-875-4763.

Classification
MDS is currently classified according to the World Health Organization Classification of Hematopoietic and Lymphoid Tumours (2008) in the following manner:

Myelodysplastic syndromes

  • Refractory cytopenia with unilineage dysplasia (RCUD)
  • Refractory anemia with ring sideroblasts (RARS)
  • Refractory cytopenia with multilineage dysplasia (RCMD)
  • Refractory anemia with excess blasts (RAEB-1/2)
  • MDS with isolated deletion of 5q
  • MDS, unclassifiable
  • Refractory cytopenia of childhood

Myelodysplastic/Myeloproliferative neoplasms

  • Chronic myelomonocytic leukemia (CMML-1/2)
  • Atypical chronic myeloid leukemia
  • Juvenile myelomonocytic leukemia (JMML)
  • MDS/MPD neoplasm, unclassifiable.

Prognosis

Prognosis in MDS is dependent upon the International Prognostic Scoring System (IPSS; Greenberg, 1997) that was most recently revised in 2012 (IPSS-R).

Score
Variable00.51.01.52.03.04.0
Cytogenetic
Group
Very
Good
GoodIntermediatePoorVery Poor
Marrow
Blast %
≤ 2> 2,
< 5
 5-10> 10
Hemoglobin
g/L
≥ 100≥ 80,
< 100
 < 80
ANC
x 109/L
 ≥ 0.8 < 0.8
Platelets
x 109/L
≥ 100≥ 50,
< 100 
< 50
Revised International Prognostic Scoring System
Risk CategoryScoreMedian Survival (yrs)
Very Low ≤ 1.58.8
Low > 1.5, ≤ 3.05.3
Intermediate> 3.0, ≤ 4.53.0
High> 4.5, ≤ 6.0 1.6
Very High> 6.00.8
IPSS-R Cytogenetic Risk Groups

Very Good: -y, del(11q)
Good: Normal, del(5q) ±1 other, del(12p), del(20q)
Intermediate: del(7q) alone, +8, +19, i(17q), any other single or double abnormality
Poor: -7, del(7q) with one other abnormality, 3 independent abnormalities
Very Poor: ≥ 4 independent abnormalities

Score for each of the factors are added together to arrive at an overall IPSS-R score (see table below), associated with a distinct prognosis. Age, ECOG performance status, serum ferritin or serum Beta-2 microglobulin may also be included to calculate an IPSS-RA*.
Treatment

Treatment recommendations for MDS are largely based upon general health and IPSS-R risk category although all patients require supportive care. Supportive care consists of blood product transfusions and antibiotic/antiviral/antifungal therapy as required. In general, all patients with “high” or “very high” risk MDS according to the IPSS-R scoring system will be evaluated for stem cell transplantation or Azacitidine therapy. Patients with “low” or “very low” risk MDS will only be considered for non-transplantation treatments such as bone marrow “growth factors”, immunosuppressive therapy or immunomodulatory agents (IMiDs). Depending upon the IPSS-RA* and other unique features of a patient’s MDS, an intermediate-risk patient may be considered for Azacitidine or stem cell transplantation as well. At certain times, an MDS patient may be eligible for participation in a clinical trial, usually designed to evaluate a potential (but unproven) drug or combination of drugs for treating MDS. This general approach is outlined in the Treatment Algorithm.

Transfusion support
Red cell transfusions can provide symptomatic relief (of fatigue and dyspnea) for MDS patients but the transfusion threshold varies from patient to patient, depending upon age, activity level and other medical problems (especially heart and lung disease). In general, red cells should be considered for a hemoglobin <80 g/L but in the presence of heart disease, transfusions may be needed if the hemoglobin is <100 g/L. Patients that have had ≥25 units of red cells and a serum ferritin >1000-1500 will be considered for iron chelation therapy provided they have very low, low or intermediate risk MDS. Platelet transfusions are often given when the platelet count is <10 x 109/L and may be required more than once weekly. However, patients with clinical bleeding issues may have to have a higher transfusion threshold (i.e., <20-30 x 109/L) while those without bleeding may not need (or wish) to have preemptive platelet transfusions.

Allogeneic stem cell transplantation
Stem cell transplantation (SCT) is the only proven curative treatment for MDS but is generally reserved for high or very high risk patients because of the significant risk involved. Furthermore, patients must have a suitable related or unrelated or cord blood donor and be free of other medical illnesses to safely undergo this procedure. Unfortunately about 1/3 of MDS patients die of complications of SCT during the first year and another 1/3 of patients experience a relapse of their MDS. Bearing all of this in mind, 30-35% of patients that have undergone allogeneic SCT have been long-term survivors.

Azacitidine
Azacitidine is a low-dose chemotherapy agent that is given primarily in high and very high risk MDS by subcutaneous injection for 7 days every 4 weeks (See Protocols/PPOs). It is a well-tolerated drug that has been shown in a randomized study, to improve quality of life and prolong survival by an average of 9-10 months when compared to supportive care alone. It is not considered to be a curative drug. Azacitidine may cause nausea, constipation or diarrhea, inflammation at the injection site and, initially, worsening of blood counts. It is helpful in about 50% of patients with MDS but it may take 4-6 months before a benefit is seen.

Growth factors
In MDS patients with a relatively isolated anemia, a red cell stimulant, either Erythropoietin (Eprex) or Darbepoietin (Aranesp), given by injection once weekly, will alleviate the anemia for a period of time, in 25-50% of cases. In patients with a relatively isolated low platelet count, a similar transient response rate can be seen with weekly Romiplostim (Nplate) injections. In MDS patients with serious infections associated with a low white cell count, Granulocyte-colony stimulating factor (G-CSF; Neupogen; Filgrastim) can be given to increase white cell (neutrophil) production although its effects are short-lived. All growth factor therapy is expensive, access to these agents may be limited and none have been convincingly shown to prolong survival in MDS patients.

Immunosuppression
Some MDS patients have a more “underactive” (hypocellular) bone marrow that resembles a bone marrow failure disorder called “aplastic anemia”. These patients appear to have bone marrow damage as a result of an inappropriately overactive immune system. Treatment with drugs to suppress the immune system (immunosuppression), such as Cyclosporine and Antithymocyte globulin (ATG; ATGAM), can improve blood counts in about 30% of patients although response is typically slow. Immunosuppressive treatment is started in hospital and includes a combination of Cyclosporine and intravenous anti-thymocyte globulin (ATGAM) (See Protocols/PPOs). Because allergic reactions can occur with ATG and can occasionally be severe, MDS patients treated with this agent are kept in hospital for about one week.

Immunomodulatory drugs (IMiDs)
Thalidomide is an oral drug that, in the past, has been associated with major birth defects when given to pregnant women. However, it has been used in a number of other conditions and has been shown to improve hemoglobin levels in about 30% of lower risk MDS patients. Thalidomide can cause sedation, constipation and nerve damage (neuropathy) and these side effects led to the development of Lenalidomide (Revlimid), a related drug associated with less sedation and neuropathy. Revlimid is more effective than Thalidomide, especially in MDS patients with deletion of chromosome 5q [del(5q)], and it has been licensed for use in del(5q) patients since 2008 (See Protocols/PPOs). Revlimid is rarely used outside of this unique patient subgroup and drug access, outside of a clinical trial, can be problematic for non-del(5q) MDS patients.

Algorithms

Protocols
BCCA Chemotherapy Protocols and PPOs

Publications
  1. WHO Classification of tumours of haematopoietic and lymphoid tissues 4th edition. Eds. Swerdlow SH et al. International agency for research on cancer. Lyon, France, 2008.
  1. Peter Greenberg, Christopher Cox, Michelle M. LeBeau, Pierre Fenaux, Pierre Morel, Guillermo Sanz, Miguel Sanz, Teresa Vallespi, Terry Hamblin, David Oscier, Kazuma Ohyashiki, Keisuke Toyama, Carlo Aul, Ghulam Mufti, and John Bennett. International Scoring System for Evaluating Prognosis in Myelodysplastic Syndromes. Blood 89:2079-2088, 1997.
  2. Thomas J. Nevill, John D. Shepherd, Heather J. Sutherland, Yasser R. Abou Mourad, Julye C. Lavoie, Michael J. Barnett, Stephen H. Nantel, Cynthia L. Toze, Donna E. Hogge, Donna L. Forrest, Kevin W. Song, Maryse M. Power, Janet Y. Nitta, Yunfeng Dai, Clayton A. Smith. IPSS Poor-Risk Karyotype as a Predictor of Outcome for Patients with Myelodysplastic Syndrome following Myeloablative Stem Cell Transplantation. Biol Blood Marrow Transplant 15:205-213, 2009.
  3. Lewis R. Silverman, Erin P. Demakos, Bercedis L. Peterson, Alice B. Kornblith, Jimmie C. Holland, Rosalie Odchimar-Reissig, Richard M. Stone, Douglas Nelson, Bayard L. Powell, Carlos M. DeCastro, John Ellerton, Richard A. Larson, Charles A. Schiffer, and James F. Holland. Randomi zed Controlled Trial of Azacitidine in Patients With the Myelodysplastic Syndrome: A Study of the Cancer and Leukemia Group B. J Clin Oncol 20:2429-2440, 2002.
  4. Pierre Fenaux, Ghulam J Mufti, Eva Hellstrom-Lindberg, Valeria Santini, Carlo Finelli, Aristoteles Giagounidis, Robert Schoch, Norbert Gattermann, Guillermo Sanz, Alan List, Steven D Gore, John F Seymour, John M Bennett, John Byrd, Jay Backstrom, Linda Zimmerman, David McKenzie, C L Beach, Lewis R Silverman, for the International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 10:223-232, 2009.
  5. Eva Hellström-Lindberg, Nina Gulbrandsen, Greger Lindberg, Tomas Ahlgren, Inger Marie S. Dahl, Ingunn Dybedal, Gunnar Grimfors, Eva Hesse-Sundin, Martin Hjorth, Lena Kanter-Lewensohn, Olle Linder,9 Michaela Luthman, Eva Löfvenberg, Gunnar Öberg, Anja Porwit-MacDonald, Anders Rådlund, Jan Samuelsson, Jon Magnus Tangen, Ingemar Winquist and Finn Wisloff for the Scandinavian MDS Group. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life. Br J Haematol 120:1037-1046, 2003.
  6. Hagop Kantarjian, Pierre Fenaux, Mikkael A. Sekeres, Pamela S. Becker, Adam Boruchov, David Bowen, Eva Hellstrom-Lindberg, Richard A. Larson, Roger M. Lyons, Petra Muus, Jamile Shammo, Robert Siegel, Kuolung Hu, Janet Franklin, and Dietmar P. Berger. Safety and Efficacy of Romiplostim in Patients With Lower-Risk Myelodysplastic Syndrome and Thrombocytopenia. J Clin Oncol 28:437-444, 2010.
  7. Yogen Saunthararajah, Ryotaro Nakamura, Robert Wesley, Qiong J. Wang, and A. John Barrett. A simple method to predict response to immunosuppressive therapy in patients with myelodysplastic syndrome. Blood 102:3025-3027, 2003.
  8. Azra Raza, Peter Meyer, Diya Dutt, Francesca Zorat, Laurie Lisak, Fabiana Nascimben, Morne du Randt, Christopher Kaspar, Cathryn Goldberg, Jerome Loew, Saleem Dar, Sefer Gezer, Parameswaran Venugopal, and Jerome Zeldis. Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood 98:958-965, 2001.
  9. Alan List, Sandy Kurtin, Denise J. Roe, Andrew Buresh, Daruka Mahadevan, Deborah Fuchs, Lisa Rimsza, Ruth Heaton, Robert Knight, and Jerome B. Zeldis. Efficacy of Lenalidomide in Myelodysplastic Syndromes. N Engl J Med 352: 549-57, 2005.
  10. Alan List, Gordon Dewald, John Bennett, Aristotle Giagounidis, Azra Raza, Eric Feldman, Bayard Powell, Peter Greenberg, Deborah Thomas, Richard Stone, Craig Reeder, Kenton Wride, John Patin, Michele Schmidt, Jerome Zeldis, and Robert Knight, for the Myelodysplastic Syndrome-003 Study Investigators. Lenalidomide in the Myelodysplastic Syndrome with Chromosome 5q Deletion. N Engl J Med 355: 1456-1465, 2006.
  11. Peter Greenberg, Heinz Tuechler, Julie Schanz, Guillermo Sanz, Guillermo Garcia-Manero, Francesco Solé, John Bennett, David Bowen, Pierre Fenaux, François Dreyfus, Hagop Kantarjian, Andrea Kuendgen, Alessandro Levis, Luca Malcovati, Mario Cazzola, Jaroslav Cermak, Christa Fonatsch, Michelle Le Beau, Marilyn Slovak, Otto Krieger, Michael Luebbert, Jaroslav Maciejewski, Silvia Magalhaes, Yasushi Miyazaki, Michael Pfeilstöcker, Mikael Sekeres, Wolfgang Sperr, Reinhard Stauder, Sudhir Tauro, Peter Valent, Teresa Vallespi, Arjan van de Loosdrecht, Ulrich Germing, Detlef Haase. Revised International Prognostic Scoring System for Myelodysplastic Syndromes. Blood 120: 2454-2465, 2012.
Diagnosis

Updated: May 2017

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm. It can either appear de nova (primary MF) or secondary following previous essential thrombocytosis (ET) or polycythemia Vera (PV). MF is characterized by the clonal proliferation of a pluripotent hematopoietic stem cell. These abnormal cells release various cytokines and growth factors resulting in marrow fibrosis and other stromal changes. Extramedullary hematopoiesis is common leading to hepatosplenomegaly. Approximately 60% of cases of primary MF or post-ET MF will harbor the V617F mutation in the JAK2 gene; 95% of post-PV MF will have the presence of the JAK2 mutation. Mutations in the thrombopoietin receptor gene (MPL) are found in 3-8% of primary MF and post-ET MF and up to 50% of cases of primary MF and post-ET MF without JAK2 or MPL mutations will harbor a mutation in the calreticulin gene (CALR).

Treatment

The only known curative therapy for MF is allogeneic stem cell transplantation (HSCT). Unfortunately the number of patients eligible for such a procedure is limited by patient co morbidities, advancing age and donor availability. Therefore, the goals of therapy are largely centered on controlling disease symptoms and improving quality of life. Recently, the introduction of the JAK2 inhibitors has lead to improvements in the therapeutic approach of MF. JAK2 inhibitors are effective in both JAK2 negative and positive MF providing improvements in symptomatic splenomegaly and constitutional symptoms. However, there is no clear evidence of disease modifying effect.

The median survival of primary MF is approximately 7 years, but can be variable. A number of prognostic models have been developed in an attempt to predict the clinical course and overall survival of individual patients diagnosed with MF. The IPSS utilizes five variables at diagnosis (age, constitutional symptoms, hemoglobin, leukocyte count and peripheral blood blasts) to categorize patients as low risk, intermediate-1 risk, intermediate-2 risk and high risk, with median survivals of 11, 8, 4 and 2 years respectively. The DIPSS model is derived from the IPSS, but is designed to be utilized during the course of the disease and gives more prognostic weight to the development of anemia. Further refinement of the DIPSS model has lead to the DIPPS-plus model that includes thrombocytopenia, transfusion need and karyotype. Patients within the DIPPS low or intermediate-1 risk category are candidates for close observation or therapy with JAK2 inhibitors for symptomatic splenomegaly or constitutional symptoms. A trial of erythropoietin (if serum EPO<500) or danazol, thalidomide or prednisone may be considered for symptomatic anemia. Patients with DIPPS intermediate-2 or high risk disease should be considered for allogeneic HSCT as deemed appropriate. The potential morbidity and mortality of such a procedure will need careful consideration for each patient in this high risk category. Therapy with a JAK2 inhibitor prior to allogeneic HSCT may be helpful to reduce disease burden, decrease splenomegaly and improve symptom control. Please refer to the treatment algorithm below for further details.

In the future, further refinement of the prognostic models is likely with the incorporation of molecular markers including mutations in ASXL1, EZH2, IDH1/2 and SFSF2 which are associated with a poor prognosis. However, in the absence of other clinical poor prognostic features (DIPPS model), the presence of these mutations is not currently felt to justify an allogeneic HSCT at this time.

Algorithms

Protocols
BCCA Chemotherapy Protocols and PPOs

Publications
  1. Cervantes F.  How I treat myelofibrosis.  Blood 2014; 124(17):2635-2642.
  2. Cervantes F, Dupriez B, Pereira A, et al.  New prognostic scoring system for primary myelofibrosis based on a study for the International Working Group for Myelofibrosis Research and Treatment.  Blood 2009; 113(13):2895-2901.
  3. Gangat N, Caramazza D, Vaidya R et al. DIPPS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count and transfusion status. J Clin Oncol 2011; 29(4):392-397.
  4. Passamonti F, Cervantes F, Vannucchi AM et al.  A dynamic prognostic model to predict survival in myelofibrosis; a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms research and Treatment). Blood 2010; 115(9):1703-1708
  5. Scott BL, Gooley TA, Sorror M, et al.  The Dynamic International Prognostic Scoring System for myelofibrosis predicts outcomes after hematopoietic cell transplantation.  Blood 2012; 119(11):2657-2664
  6. Kroger N, Giorgino T, Scott B et al.  Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis.  Blood 2015; 125(21):3347-3350