Management of Patients with Myelodysplastic Syndromes: Introductory Concepts

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1 Management of Patients with Myelodysplastic Syndromes: Introductory Concepts David T. Bowen Contents 8.1 Introduction Disease Heterogeneity Evaluating Clinical Trial Data: Response Criteria Guidelines for the Diagnosis and Management of MDS References Introduction The management discussion presents sizable challenges for physician and myelodysplastic syndrome (MDS) patient alike. Firstly, a confident diagnosis is not always possible, particularly in patients with refractory anemia plus other confounding medical conditions (e.g., autoimmune disease, rheumatoid arthritis) where honesty requires discussion with the patients about the balance of probabilities. Secondly, assuming a confident diagnosis, a prognosis should be established to inform discussion about treatment options. The International Prognostic Scoring System (IPSS) score (Greenberg et al. 1997) and theworld Health Organization (WHO) classification (Bennett 2000) provide valuable prognostic guidance, but only in broad terms. Thirdly, co-morbidity is common in this predominantly older patient population, restricting the use of more aggressive interventions such as chemotherapy and stem cell transplantation. Finally, the physician and patient must evaluate the efficacy of all interventions from the medical literature, with inevitable interpretive difficulties on both sides. 8.2 Disease Heterogeneity The heterogeneity of the group of diseases collectively known as the myelodysplastic syndromes is obvious, but is often overlooked or over-simplified when considering the management recommendations for an individual patient. It is easy to comprehend the differences between diseases with discrepant morphological features such as refractory anemia with ringed sideroblasts (RARS) versus refractory anemia with excess blasts. What is less accessible is the considerable heterogeneity within individual disease categories, which is only starting to be disentangled with the progression from French-American-British (FAB) to WHO classification (witness the WHO distinction between RARS and refractory cytopenia with multilineage dysplasia RCMD ± RS). The WHO classification clearly has improved prognostic power in comparison with FAB (Germing et al. 2000) and is now a better complementary prognostic tool together with the IPSS score. While the IPSS score allows discussion of median survival times with patients, the ranges (confidence intervals) are not provided and clinical experience indicates that these are wide.

2 90 Chapter 8 Management of Patients with Myelodysplastic Syndromes: Introductory Concepts 8.3 Evaluating Clinical Trial Data: Response Criteria The acceptance of new interventions into routine management is dependent upon a solid evidence base for its efficacy and safety. The demonstration of efficacy of an interventional agent will be judged by its ability to produce clinical or hematological improvement or both to an extent that is considered clinically meaningful by both physician and patient. The debate surrounding the clinical use of recombinant erythropoietin in the management of MDS is a good example. An International Working Group (IWG) has attempted to address this issue producing standardized response criteria for MDS patients treated with interventional therapy (Cheson et al. 2000). These criteria include responses that alter the natural history of MDS, cytogenetic response, quality of life, and hematologic improvement (HI) (Table 8.1). Also included are recommended study endpoints. These standardized response criteria are perhaps most useful for Hematologic Improvement, given that those criteria describing the alteration of natural history of the disease are similar to those in routine use for the therapy of acute leukemia, with a few notable exceptions including criteria for disease progression. Hematologic Improvement is now subdivided by lineage and defined in terms of quality (major/minor). Importantly, a minimum qualifying duration of response (at least 2 months) is also included. While considered by some to be somewhat cumbersome (Raza 2001), at least this approach attempts to dissect the nature of response, allowing the reader to distinguish responses that they would consider clinically meaningful (e.g., major erythroid response with transfusion independence) from those that may be less so (e.g., a minor platelet response in a patient with no clinical bleeding, incrementing from 25,000/mm 3 to 50,000/mm 3 ). The IWG group accept that these criteria are a useful template to inspire further work in this area (Cheson et al. 2001). Some important discussion points have emerged, including a lack of standardization in the reporting ofbaseline parameters, the time points at which response should be evaluated (Raza 2001), and the relevance of small increments in neutrophil counts (Steensma et al. 2001). The quality of response may need to be more stringent, given that at least in the context of therapy with hematopoietic growth factors, ªcomplete erythroid responsesº using a more stringent definition than the IWG criteria for HI-E major, are considerably more durable and clinically desirable than ªpartial responsesº which would still be considered as HI-E major (Hellstrom-Lindberg et al. 2003). Finally the IWG criteria do not address the issue of potential detrimental effects of interventional therapy, an example of which is progressive thrombocytopenia in some patients treated with recombinant erythropoietin plus granulocyte-colony stimulating factor (Hellstrom-Lindberg et al. 1997), nor potential beneficial effects in patients with rare variants of MDS such as a patient with thrombocytosis whose platelet count is controlled on novel therapy such as thalidomide (personal observation). 8.4 Guidelines for the Diagnosis and Management of MDS Expert working groups from three countries have published guidelines to aid practicing physicians in the dayto-day management of MDS patients (Alessandrino et al. 2002; Bowen et al. 2003; Greenberg et al. 2004). Each guideline was developed using different methodology, from consensus statement (National Cancer Center Network [NCCN]) (Greenberg et al. 2004), through consensus plus comprehensive literature review (UK) (Bowen et al. 2003), to systematic review plus scenarios (Italian) (Alessandrino et al. 2002) (Table 8.2). It is reassuring that all guidelines have broadly drawn the same conclusions, which is largely a consequence of the limited high-quality evidence base for most interventions considered. Two guidelines (UK and NCCN) are driven by the IPSS category and presented as flow charts. In the absence of karyotypic information, the UK guideline recommends the Sanz score for prognostic determination (Sanz et al. 1989), based on the methodological rigor of the derivation of this score. The use of a prognostic model to inform discussion of appropriate management of MDS is, thus, endorsed by the guidelines and works effectively in practice. The UK guideline produced only four grade-a recommendations, defined as requiring at least one randomized controlled trial or meta-analysis. Two of these were positive: Hydroxyurea as the recommended treatment for proliferative chronic myelomonocytic leukemia (CMML), and EPO to be consideredfor selectedpatients with RA/RARS, while two were negative; low-dose cytosine arabinoside and 13-cis retinoic acid were not

3 a 8.4 Guidelines for the Diagnosis and Management of MDS 91 Measurement of response/treatment effect in MDS Altering disease natural history 1. Complete remission (CR) Bone marrow evaluation: Repeat bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, with no evidence for dysplasia a. When erythroid precursors constitute less than 50% of bone marrow nucleated cells, the percentage of blasts is based on all nucleated cells; when there are 50% or more erythroid cells, the percentage blasts should be based on the nonerythroid cells. Peripheral blood evaluation (absolute values must last at least 2 months) b : ± Hemoglobin greater than 11 g/dl (untransfused, patient not on erythropoietin) ± Neutrophils 1,500/mm 3 or more (not on a myeloid growth factor) ± Platelets 100,000/mm 3 or more (not on a thrombopoietic agent) ± Blasts % ± No dysplasia a 2. Partial remission (PR) (absolute value must last at least 2 months) All the complete remission (CR) criteria (if abnormal before treatment), except: bone marrow evaluation. Blasts decreased by 50% or more over pre-treatment, or a less-advanced MDS FAB classification than pre-treatment. Cellularity and morphology are not relevant. 3. Stable disease Failure to achieve at least a PR, but with no evidence of progression for at least 2 months. 4. Failure Death during treatment or disease progression characterized by worsening of cytopenias, increase in the percentage bone marrow blasts, or progression to an MDS FAB subtype more advanced than pre-treatment. 5. Relapse after CR or PR, one or more of the following: (a) Return to pre-treatment bone marrow blast percentage (b) Decrement of 50% or greater from maximum remission/response levels in granulocytes or platelets (c) Reduction in hemoglobin concentration by at least 2 g/dl or transfusion dependence c 6. Disease progression (a) For patients with less than 5% blasts, a 50% or more increase in blasts to more than 5% blasts (b) For patients with 5±10% blasts, a 50% or more increase to more than 10% blasts (c) For patients with 10±20% blasts, a 50% or more increase to more than 20% blasts (d) For patients with 20±30% blasts, a 50% or more increase to more than 30% blasts (e) One or more of the following: 50% or greater decrement from maximum remission/response levels in granulocytes or platelets, reduction in hemoglobin concentration by at least 2 g/dl or transfusion dependence c 7. Disease transformation Transformation to AML (30% or more blasts) 8. Survival and progression-free survival Cytogenetic response (Requires 20 analyzable metaphases using conventional cytogenetic techniques) Major: no detectable cytogenetic abnormality, if pre-existing abnormality was present Minor: 50% or more reduction in abnormal metaphases

4 92 Chapter 8 Management of Patients with Myelodysplastic Syndromes: Introductory Concepts (continued) Fluorescent in situ hybridization may be used as a supplement to follow a specifically defined cytogenetic abnormality Quality of life Measured by an instrument such as the FACT Questionnaire Clinically useful improvement in specific domains: Physical Functional Emotional Social Spiritual Hematologic improvement (HI) Improvements must last at least 2 months in the absence of ongoing cytotoxic therapy b Hematologic improvement should be described by the number of individual, positively affected cell lines (e.g., HI-E, HI-E + HI-N, HI-E + HI-P + HI-N) 1. Erythroid response (HI-E) Major response: for patients with pre-treatment hemoglobin less than 11 g/dl, greater than 2 g/dl, increase in hemoglobin; for RBC transfusion-dependent patients, transfusion independence Minor response: for patients with pre-treatment hemoglobin less than 11 g/dl, 1±2 g/dl increase in hemoglobin; for RBC transfusion-dependent patients, 50% decrease in transfusion requirements 2. Platelet response (HI-P) Major response: for patients with a pre-treatment platelet count less than 10,000/mm 3, an absolute increase of 30,000/mm 3 or more; for platelet transfusion-dependent patients, stabilization of platelet counts and platelet transfusion independence Minor response: for patients with a pre-treatment platelet count less than 10,000/mm 3, a 50% or more increase in platelet count with a net increase greater than 10,000/mm 3 but less than 30,000/mm 3 3. Neutrophil response (HI-N) Major response: for absolute neutrophil count (ANC) less than 1,500/mm 3 before therapy, at least a 100% increase, or an absolute increase of more than 500/mm 3, whichever is the greater Minor response: for ANC less than 1,500/mm 3 before therapy, ANC increase of at least 100%, but absolute increase less than 500/mm 3 4. Progression/relapse after HI (one or more of the following): (a) 50% or greater decrement from maximum response levels in granulocytes or platelets (b) A reduction in hemoglobin concentration by at least 2 g/dl (c) Transfusion dependence c For a designated response (CR, PR, HI), all relevant response criteria must be noted on at least two successive determinations at least 1 week apart after an appropriate period following therapy (e.g., 1 month or longer) a The presence of mild megaloblastoid changes may be permitted if they are thought to be consistent with treatment effect. However, persistence of pre-treatment abnormalities (e.g., pseudo-pelger-huÿt cells, ringed sideroblasts, dysplastic megakaryocytes) is not consistent with CR b In some circumstances, protocol therapy may require the initiation of further treatment (e.g., consolidation, maintenance) before the 2- month period. Such patients can be included in the response category into which they fit at the time the therapy is started c In the absence of another explanation such as acute infection, gastrointestinal bleeding, hemolysis, and so on From: Bruce D. Cheson. Report of an International Working Group to standardize response criteria. Blood 2000; 96: 3671±3674. Copyright American Society of Hematology, used with permission.

5 a References 93 Table 8.2. (Methods used by three separate groups (US NCCN, UK BCSH, and Italian Society of Hematology) to derive guidelines for the management of MDS Consensus ªSystematicº literature review Systematic literature review including abstracts, proceedings, etc. Scenario-based US, NCCN ± ± ± UK, BCSH ± ± Italy, Italian Society of Hematology =Method employed Table 8.3. Discrepant recommendations for the management of MDS between the three guideline groups Azacytidine/decitabine US Consider in: Low/INT-1: various INT-2/High: alternative to intensive therapy Antilymphocyte globulin/cyclosporin A Consider for hypoplastic MDS and for PNH+/ HLA DR2 Autologous SCT Not specifically recommended UK Not considered Consider for hypoplastic MDS (and PNH clone) In clinical research protocol: as per Italian study Italy Highly recommended for IPSS high not suitable for intensive therapy (esp. if abnormal karyotype) Highly recommended for hypoplastic MDS or HLA DR2 Recommended for patients in CR after intensive chemotherapy but lacking an allogeneic donor recommended. The Italian guideline produced three grade-a recommendations, including that for EPO use in RA/RARS, but also immunosuppressive therapy for hypoplastic MDS (especially HLA DR2+), and AMLtype chemotherapy for patients who are not candidates for stem cell transplantation, who are < 55 years old with INT-2/High risk by IPSS, and ECOG performance score 0/1. These latter two recommendations would not have satisfied criteria for a grade A recommendation in the UK guideline. Noteworthy minor differences between the three guidelines included recommendations for autologous transplantation, demethylating therapy (5- azacytidine/decitabine) and immunosuppressive therapy (Table 8.3). No published randomized controlled trials are available to evaluate these interventions, although randomized international studies of both demethylating agents and autologous transplantation are ongoing. References Alessandrino EP, Amadori S, Barosi G, Cazzola M, Grossi A, Liberato LN, Locatelli F, Marchetti M, Morra E, Rebulla P, Visani G, Tura S (2002) Evidence- and consensus-based practice guidelines for the therapy of primary myelodysplastic syndromes: a statement from the Italian Society of Hematology. Haematologica 87:1286±1306 Bennett JM (2000) World Health Organization classification of the acute leukemias and myelodysplastic syndrome. Int J Hematol 72:131±133 Bowen D, Culligan D, Jowitt S, Kelsey S, Mufti G, Oscier D, Parker J, UK MDS (2003) Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes. Br J Haematol 120:187±200 Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, Læwenberg B, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Wijermans PW, Gore S, Greenberg PL (2000) Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 96:3671±3674 Cheson BD, Bennett JM, Kantarjian H, Schiffer CA, Nimer SD, Lowenberg B, Stone RM, Mittelman M, Sanz GF, Wijermans PW, Greenberg PL (2001) Myelodysplastic syndromes standardized response criteria: further definition. Blood 98:19±85

6 94 Chapter 8 Management of Patients with Myelodysplastic Syndromes: Introductory Concepts Germing U, Gattermann N, Strupp C, Aivado M, Aul C (2000) Validation of the WHO proposals for a new classification of primary myelodysplastic syndromes: a retrospective analysis of 1600 patients. Leuk Res 24:983±1092 Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes (published erratum appears in Blood 1998; 91:1100). Blood 89:2079±2088 Greenberg PL, Baer M, Bennett JM, Bloomfield CD, DeCastro CM, Deeg HJ, Devetten M, Emanuel PD, Erba HP, Estey E, Foran J, Gore SD, Millenson M, Navarro W, Nimer SD, O'Donnell MR, Saba HI, Spiers K, Stone R, Tallman MS (2004) Myelodysplastic syndromes. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology v : < Hellstrom-Lindberg E, Negrin R, Stein R, Krantz S, Lindberg G, Vardiman J, Ost A, Greenberg P (1997) Erythroid response to treatment with G-CSF plus erythropoietin for the anaemia of patients with myelodysplastic syndromes: proposal for a predictive model. Br J Haematol 99:344±351 Hellstrom-Lindberg E, Gulbrandsen N, Lindberg G, Ahlgren T, Dahl IM, Dybedal I, Grimfors G, Hesse-Sundin E, Hjorth M, Kanter-Lewensohn L, Linder O, Luthman M, Lofvenberg E, Oberg G, Porwit-Mac- Donald A, Radlund A, Samuelsson J, Tangen JM, Winquist I, Wisloff F, Scandinavian MDS (2003) 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 Raza A (2001) Improve or abandon the standardized response criteria for myelodysplastic syndromes recommended by the International Working Group. Blood 98:251±252 Sanz GF, Sanz MA, VallespÓ T, Caµizo MC, Torrabadella M, GarcÓa S, Irriguible D, San Miguel JF (1989) Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patients. Blood 74:395±408 Steensma DP, Letendre L, Tefferi A (2001) Clarifications to the standard neutrophil response criteria for clinical trials in myelodysplastic syndromes are needed. Blood 97:3321±3322