10 Myelodysplastic syndromes: update on classification

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Invited Lectures

10 Myelodysplastic syndromes: update on classification J.M. Bennett ° . Professor of Medicine, Pathology and Laboratory Medicine, Emeritus, University of Rochester Medical Center and the James P. Wilmot Cancer Center, Rochester, NY, USA Overview: The last decade has witnessed the emergence of several therapeutic options for patients with myelodysplastic syndromes. Objective criteria for diagnosis, proper classification, and risk stratification are more important than ever before. Therapeutic strategies are tailored based on the classification and prognostic risk groups. New therapies, on the other hand, are contributing to our basic understanding of the disease pathogenesis and the evolution of the classification systems. In this presentation I will review the 2008 World Health Organization (WHO) classification of MDS highlighting the major changes compared to French American British (FAB) classification. Myelodysplastic syndromes (MDS) represent a spectrum of neoplastic clonal stem cell disorders characterized by bone marrow failure with variable cytopenias and a percentage of leukemic blasts that range from less than 5% to 19%. The evolution into acute myeloid leukemia (AML) is highly dependent on the initial blast %. The presence of “dysplastic” abnormal morphologic features in one or more cell lines is required to make the diagnosis. In lower grade MDS apoptosis is the hall mark of the disease explaining the discrepancy between hypercellular bone marrow findings and the noted peripheral cytopenias. MDS is a disease of the elderly, the incidence of MDS in the recently published Surveillance, Epidemiology, and End Results (SEER) data increases from less than 5 per 100,000 for patients less than 60 year to 36.2 per 100,000 in patients more than 80 year old. The median age of diagnosis was 76 years. Men and white race have a higher incidence of the disease. WHO classification: The World Health Organization (WHO) revised and updated the MDS classification in 1997. The changes from the FAB classification can be summarized as follows: 1. Recognition of the importance of multi-lineage dysplasia in low risk disease (<5% blasts) with two new categories; refractory cytopenia with multi-lineage dysplasia (RCMD) and refractory anemia with multilineage dysplasia with ring sideroblasts (RCMD-RS). The old RA and RARS categories were restricted to erythroid dysplasia with less than 10% dysplasia in myeloid or megakaryocytic line. This was based on previous observations that presence of multi-lineage dysplasia carries a worse prognosis even in presence of ring sideroblasts. 2. Further refine the RAEB group into RAEB 1 (5−9%) myeloblasts and RAEB 2 (10−19%) blasts. However this

split of the RAEB group creates more homogeneous categories. The higher the percentage of myeloblasts the higher the risk of the disease progression to AML. The presence of Auer rods in patients with <20% blasts did not have any additional significance. 3. Lower the threshold for diagnosing AML to = 20% myeloblasts rather than = 30%. The RAEB-t category was therefore omitted. This is probably the most important clinical change. This was based on observations that RAEB-t patients had similar outcome to older patients with AML. The classification does not dictate the treatment for this group since younger patients that meet this cutoff are treated as AML. Clinical judgment and further studies are needed to decide on how to treat an elderly patient in this category (MDS type of therapy or intensive AML induction). It is also important to note that WHO recognizes presence of certain cytogenetic abnormalities t (8;21), t (15;17), and inversion 16 as being acute leukemia defining even if the blast percentage is less than 20%. 4. Recognize the importance of cytogenetics by adding del. 5q syndrome as a good prognostic separate group. The 5 q syndrome is a subset of patients with isolated 5 q deletion, less than 5% blasts, a distinct clinical picture with refractory macrocytic anemia and normal to elevated platelet counts. The disease occurs in middle age to older women. Patients have a very good prognosis with a low risk of transformation to AML. 5. CMML was incorporated in a new category: myelodysplastic/myeloproliferative disorders (MDS/MPD). It was clear that CMML group in the FAB classification was heterogeneous. The prognosis of CMML depends on the percentage of bone marrow blasts and as recognition of this the WHO classified CMML into type 1 and 2 based on that rather than on peripheral white blood count (WBC). The clinical behavior of “proliferative” CMML is more of a MPD rather than MDS. Recent studies showing more predilection for JAK-2 mutation in CMML and MPD unclassified provides reassurance that this was a right step in further understanding this disease, as demonstrated by the finding of the mutation in most patients with RARS and thrombocytosis. 6. A new category of MDS unclassified was added to include less common patients with neutrophilic or megakaryocytic uni or bi lineage dysplasia without erythroid dysplasia. 7. Therapy related MDS/AML is recognized as separate category outside the WHO classification for de novo MDS. This category, with exposure to alkylating agents, has known recurrent cytogenetic abnormalities and unfortunately a poor prognosis. The exception is those patients exposed to topoisomerase-II inhibitors, who develop specific translocation AML’s such as t(8;21) and respond well to combination chemotherapy. Diagnosis of MDS: The general recommendations for diagnosis of MDS are the same in the WHO system as in

Invited Lectures the FAB system. One should perform a 500 cell differential, eliminating lymphocytes and plasma cells. It involves performing a bone marrow biopsy and aspirate utilizing hematoxylin & eosin; reticulin; Romanowsky and iron stains and counting the number of blasts. The percentage of blasts is calculated, and patients are categorized according to this percentage (e.g., <5%, 5−9%, 10−19%, >20 or if they have CMML, which can be any percentage of blasts with a monocytosis of greater than 1,000/uL. If the absolute percentage of erythroid precursors is 50% or greater, the % blasts is based on the non-erythroid precursors (essentially granulocytes and monocytes). For example, a differential count of 8% blasts, 6% promyelocytes, 15% granulocytes, and 70% erythroid precursors would convert the % of blasts to "27% " blasts (8/30) changing the subgroup from RAEB 1 to AML. Iron stains are essential to address the percentage of ring sideroblasts. The bone marrow biopsy could complement the bone marrow aspirate in several ways namely cellularity, dysmegakaryopoiesis, and identifying clusters of immature cells-myeloblasts or promyelocytes − displaced from the paratrabecular area to the intertrabecular areas and referred to as abnormal localization of immature precursors (ALIP). In addition the reticulin stain provides additional information about the degree of reticulin fibrosis which can add prognostic information. Incorporation of immunocytochemistry to identify CD34/117+ blasts can be very helpful in separating hypocellular MDS from Aplastic Anemia and Hypocellular AML. Cytogenetics are critical to obtain since prognostic information is provided and is an important component of several scoring systems. For example the presence of 5q – will also impact on the therapeutic choice. Conventional cytogenetics obtained from bone marrow aspirate could be complemented by interphase FISH tests that could be obtained from bone marrow or peripheral blood samples. In fact a “FISH panel” with probes for 5q-, 7, 8, and 20q – are in common use. Implications of WHO classification: The Dusseldorf MDS registry was the first to validate the prognostic superiority of the WHO classification. In a retrospective reclassification of 1600 cases of MDS, the new classification was able to distinguish differences in outcome between RA/RS and RCMD/RCMD-RS as well as between RAEB 1 and RAEB 2. Later on the same group validated the WHO classification prospectively where 1095 patients were included; the median overall survival for RA and RARS was not reached. The median overall survival for RCMD was 31 months, RCMD-RS 28 months, RAEB-1 27 months, RAEB-2 12 month, and 5q− 40 months. The frequency of AML progression 2 years after diagnosis was: RA 0%, RARS 8%, RCMD 9%, RCMD-RS 12%, RAEB-1 13%, RAEB-2 40%, and 5q− 8%. The MDS Foundation has developed a website based educational program highlighting myelodysplastic features and morphology, hopefully this will be a useful

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tool to improve reporting on MDS (now available at www.mds-foundation.org). The 2008 WHO classification: In the summer of 2008 a revised version of the WHO syllabus was published. For the first time, the WHO 2008 classification proposes diagnosis of “Presumptive MDS” in cases with persistent clinical cytopenias without dysplasia if certain cytogenetic abnormalities are present. On the other hand, the term idiopathic cytopenia of unknown significance (ICUS) is applied if patients had persistent cytopenias without alternative explanation, no dysplasia and without the specific cytogenetic abnormalities. The changes under WHO 2008 classification can be summarized in the following: 1. Refractory cytopenia with unilineage dysplasia (RCUD) includes cases where dysplasia is demonstrated in = 10% of one cell line. The patients have unicytopenia or bicytopenia but not pancytopenia. Under this category is refractory anemia (RA), Refractory Neutropenia (RN) and Refractory thromobocytopenia (RT). Cases of RN and RT were previously classified as MDS unclassified. 2. MDS associated with isolated del 5 q is a category for patients with unilineage erythroid dysplasia, isolated del 5(q), and less than 5% blasts. The term 5q− Syndrome is less emphasized in the new WHO classification given that lenalidomide therapeutic benefit is the same for patients with 5 q syndrome or isolated del 5(q). 3. MDS unclassified includes patients with pancytopenia and unilineage dysplasia. Patients with no overt dysplasia but cytogenetic evidence of MDS. Cases of RCUD and RCMD where bone marrow blasts are less than 5% and peripheral blasts are 1%. 4. Provisional entity of refractory cytopenia of childhood has been proposed as well. 5. RAEB-1 now includes cases with 5−9% bone marrow blasts and 2−4% peripheral blood blasts. No Auer rods are present. 6. RAEB-2 includes cases with 10−19% bone marrow blasts and 5−19% peripheral blood blasts. Auer rods presence regardless of blast percentage qualifies as RAEB-2 or CMML-2 classification. 7. Majority of cases of MDS with myelofibrosis (MDSF) are RAEB cases. Accurate estimate of blasts % is difficult and fibrosis is associated with a worse outcome. 8. For CMML, diagnostic requirements remain the same, a subset of patients with CMML and eosinophilia are associated with genetic abnormalities including PDGFR are better classified as myeloid neoplasms with eosinophilia. Those patients can respond to imatinib mesylate therapy. 9. Atypical CML is renamed as atypical CML, BCR/ABL negative to emphasize importance of obtaining those tests. 10. Provisional entity of RARS-T (refractory anemia with ring sideroblasts with thrombocytosis) is proposed.

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Up to 60% of the patients harbor the JAK2 V617F mutation. The platelet threshold is 450,000/mm3 and often higher. 11. The term Myeloproliferative Disorders was replaced by the term: Myeloproliferaitve Neoplasms. Future: There is a clear need for standardized way to diagnose MDS and classify it, a need for minimal required diagnostic criteria and more objective criteria. Answers for such needs may come from incorporation of flow cytometry findings, cytogenetic findings and identifying molecular signatures by gene arrays or proteomics or applying different technologies. A committee is examining how to combine the most salient features of these prognostic scoring systems into one universally acceptable program. It is more important than ever to appropriately diagnose and classify MDS patients given our new treatment options. Acknowledgements: I am indebted to Dr. Rami Komrokji for his most valuable contributions in helping to frame the rapidly evolving pathology in MDS. References [1] Ma X., Does M., Raza A., et al. T. Myelodysplastic syndromes: incidence and survival in the United States. Cancer 2007;109(8):1536−42. [2] Rollison D. E., Howlader N., Smith M. T., et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001–2004, using data from the NAACCR and SEER programs. Blood 2008;112(1):45−52. [3] Steensma D. P., Bennett J. M. The myelodysplastic syndromes: diagnosis and treatment. Mayo Clinic proceedings 2006;81(1):104−30. [4] Valent P., Horny H. P., Bennett J. M., et al. Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: Consensus statements and report from a working conference. Leukemia research 2007;31(6):727−36. [5] Komrokji R. S., Bennett J. M. Evolving classifications of the myelodysplastic syndromes. Current opinion in hematology 2007;14(2):98–105. [6] Bennett J. M., Catovsky D., Daniel M. T., et al. Proposals for the classification of the myelodysplastic syndromes. British journal of haematology 1982;51(2):189−99. [7] Bennett J. M. World Health Organization classification of the acute leukemias and myelodysplastic syndrome. Int J Hematol 2000;72(2):131−3. [8] Vardiman J. W., Harris N. L., Brunning R. D. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100(7):2292–302. [9] Strupp C., Gattermann N., Giagounidis A., et al. Refractory anemia with excess of blasts in transformation: analysis of reclassification according to the WHO proposals. Leuk Res 2003;27(5):397–404. [10] Levine R. L., Loriaux M., Huntly B. J., et al. The JAK2V617F activating mutation occurs

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[12]

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in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood 2005;106(10):3377−9. Szpurka H., Tiu R., Murugesan G., et al. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation. Blood 2006;108(7):2173−81. Germing U., Strupp C., Kuendgen A., et al. Prospective validation of the WHO proposals for the classification of myelodysplastic syndromes. Haematologica 2006;91(12):1596–604. Baumann I Niemeyer CM, Bennett JM. Childhood myelodysplastic syndrome. In: Swerdlow S.H. Campo E., Harris N.L., Jaffe E.S, ed. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Fourth Edition. Lyon: IARC; 2008:104−7. Buesche G., Teoman H., Wilczak W., et al. Marrow fibrosis predicts early fatal marrow failure in patients with myelodysplastic syndromes. Leukemia 2008;22(2):313–322.

11 Real-time prognostic evaluation in MDS L. Malcovati ° . Department of Hematology and Oncology, University of Pavia Medical School and; Fondazione IRCCS Policlinico San Matteo, Pavia, Italy *E-mail: [email protected] Myelodysplastic syndromes (MDS) are hematological disorders characterized by peripheral cytopenia and an increased risk of developing acute myeloid leukemia (AML). The impressive heterogeneity of the natural history of MDS complicates clinical decision-making regarding therapeutic modalities and timing of intervention. Since 1997 the International Prognostic Scoring System (IPSS) has become the gold standard for clinical trials and decision-making [1]. This model combines marrow blast percentage, cytogenetics and peripheral cytopenias, and results in four risk group with different survival and risk of leukemic evolution. In 2001, the WHO formulated a new classification of MDS, based on uni- or multilineage dysplasia, bone marrow blast count and distinctive cytogenetic features [2]. This proposal was shown to provide a relevant prognostic information in both retrospective and prospective studies [3,4], and was largely confirmed in the updated classification 2008. Among MDS patients without excess blasts, the isolated involvement of the erythroid lineage as compared with multi-lineage dysplasia is definitely associated with a significantly better prognosis. Within WHO subgroups the onset of a regular transfusion requirement was found to affect the outcome [4], and can be considered an independent indicator of disease severity. Analyzing pre-transfusion hemoglobin levels in independent