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MDS: Classification and Advances in Therapy

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1 MDS: Classification and Advances in Therapy
BTG2013 S. Varma PGIMER, Chandigarh India

2 MDS Highly heterogeneous group of disorders Commonest cause of death
Variable natural history Variable mortality rate Variable response to therapy Commonest cause of death Progressive bone marrow failure Conversion to AML Myelodysplastic syndromes are a group of heterogeneous disorders characterized by persistent cytopenias, hypercellular marrow and presence of dysplasia that results from increased proliferation as well as increased apoptosis

3 Age-related Incidence of MDS
0.01 0.1 1 10 100 Rate Disease of elderly Males Females This graph shows that it is a disease of the elderly. The outcomes are related not only to severity of the cytopenias and progression of the disease but also to the co-morbidities in the elderly Age, years McNally RJQ et al. Hematological Oncology :

4 Classification

5 Historical Perspective
Pseudo-aplastic anemia Refractory Anemia Pre-leukemia Myelodysplastic syndrome Luzzatto AM. anemia pseudoaplastica Riv Ven 1907;47:193. Bomford RR, Rhodes CP. Refractory anemia. Q J Med 1941;10:

6 MDS: FAB Classification 1982
FAB subtype Blast % RS% Monocytes >1x109/l Survival (months) PB BM RA <1 <5 <15 - 50 RARS >15 75 RAEB 5-20 variable 11 CMML <20 + RAEB-T >5; Auer rods 20-30; +/- 5

7 MDS: Limitations of FAB Classification
Multilineage cytopenia with <5% BM blasts Rough prediction of prognosis Cytogenetics not given importance Ill defined entities: childhood MDS, T-MDS & other secondary MDS Immunophenotyping and genetic techniques not included

8 Comparison of MDS Classifications
FAB classification WHO Classsification 2001 WHO Classification 2008 RA Refractory cytopenia with unilineage dyplasia Refractory anemia Refractory neutropenia Refractory thrombocytopenia RARS Refractory anemia with ring sideroblasts (RARS) RCMD RCMD-RS RAEB RAEB I and 2 RAEB-T RAEB II/ AML CMML MDS-UC MDS associated with isolated del(5q) Childhood myelodysplastic syndrome Refractory cytopenia of childhood

9 WHO 2008 Bone Marrow Blood Subtype Dysplasia: ≥10% cells
Single cell line Mostly erythroid RCUD Erythroid dysplasia >15% ringed sideroblasts Anemia RARS >10%Dysplasia: ≥2 cell lineage <5%blasts Bi/pancytopenia RCMD Uni-multi lineage dysplasia 5-9% blasts, No Auer rods Cytopenia <5% blast RAEB-1 10-19% blasts or Auer rods Cytopenia, 5-19% blasts or Auer rods RAEB-2 Uni / multilineage/ no dysplasia Characteristic MDS CG + MDS-U Unilineage erythroid dysplasia, isolated del 5q, <5%blast Anemia, normal or ↑Platelets MDS with 5q Shows the peripheral blood and bone marrow criteria for diagnosis of various subtypes of MDS that are dependent upon cytopenia, number of blasts, presence of dysplasia and cytogenetic abnormalities.

10 Outcomes in MDS in Different WHO Subtypes
Cazzola M. Hemaologica 2011

11 Advances in Management
Improved prognostic scores Disease related variables Host factors Appropriate clinical decision Disease eradication/ control Prolonging overall survival Managing complications of disease and therapy Improving quality of life

12 There are benefits and limitations of all these scores
Prognostic scores Most widely used There are benefits and limitations of all these scores

13 IPSS: Prognostic Variables
0.5 1.0 1.5 2.0 Marrow blasts % <5 5-10 11-20 21-30 Karyotype Good Intermediate Poor Cytopenias 0/1 2/3 - Risk group Overall score Median survival (years) Low 5.7 Intermediate 1 0.5 or 1.0 3.5 Intermediate 2 1.5 or 2.0 1.2 Poor >/= 2.5 0.4 Overall score is the sum of the scores for following parameters: BM blasts %: score 0 =< 5%; 0.5=5-10%; 1.5=11-19%; 2.0=20-30%. Cytopenias: score 0 = no/ one cytopenia; 0.5 = 2 or 3 cytopenias. Cytogenetics: score 0 (good)= Normal karyotype, -Y, 5q- or 20q-; score 1.0 (poor)= 7q- or -7, complex translocations; score 0.5 (intermediate)= all others. Greenberg P et al. Blood 1997;89:

14 Prediction of survival by IPSS

15 IPSS Pros Cons Simplicity:
Use of only 3 variables Applicable at centers with limited lab support Widely used in clinical practice and research Bulk of scientific data on MDS is based of IPSS Cons Includes patients with 20-30% blasts CMML Does not consider severity of cytopenias Strong predictor of outcome Can not be applied in pre-treated patients

16 WHO Prognostic Scoring System
*BM fibrosis grade 2-3 shifts risk group by one step

17 WPSS Pros Cons Simplicity: use of only 3 variables
Accurate prediction of survival and risk of leukemic evolution at any time during the course of their disease Useful in predicting post transplant outcome Cons Not applicable for secondary MDS

18 Comparison of IPSS and WPSS (258 MDS Patients)

19 MDACC Prognostic Scoring System (MPSS)
Variable Score 1 Score 2 Score 3 Performance Status ≥ 2 Age in years 60-64 ≥ 65 Platelets x 109/L 50-199 30-49 <30 Hemoglobin gm% <12 Bone marrow blasts 5-10 11-29 WBC x 109/L >20 Karyotyping Chromosome 7 abnormality Complex karyotype (>2 abn) Prior transfusion Yes MPSS risk group Score Low Intermediate Intermediate High ≥9 Kantarjian et al Cancer 2008

20 2012 Revised IPSS Fine tune the prognostic impact of
Cytogenetic abnormalities Depth of cytopenia Prognostic Subgroup Cytogenetic Abnormality Median OS, Mos Median Time to AML, Mos Very good del(11q), -Y 60.8 NR Good Normal, del(20q), del(5q) alone or double, del(12p) 48.6 Intermediate +8, del(7q), i(17q), +19, any other single or double, independent clones 26.0 78.0 Poor inv(3)/t(3q)/del(eq), -7, double including del(7q), complex (3) 15.8 21.0 Very poor complex (≥ 3) 5.9 8.2 AML, acute myeloid leukemia; IPSS, International Prognostic Scoring System; IPSS-R, revised IPSS; MDS, myelodysplastic syndromes; NR, not reached; OS, overall survival. Schanz J, et al. J Clin Oncol. 2012;30: Greenberg PL, et al. Blood. 2012;120:

21 IPSS-R Variable 0.5 1 1.5 2 3 4 Cytogenetics V. good - Good Int Poor
0.5 1 1.5 2 3 4 Cytogenetics V. good - Good Int Poor V. poor BM blast% ≤2 >2 - <5 5-10 >10 Hgb ≥10 8-<10 <8 Platelets ≥100 50-100 <50 ANC ≥0.8 <0.8 Risk Category Risk Score Very low ≤ 1.5 Low > Intermediate >3 – 4.5 High > Very High >6

22 Advances in therapy of MDS

23 Treatment considerations
Myelodysplasia are incurable without HSCT Highly variable natural history Treatment considerations must take into account many factors, including the Pathologic diagnosis The prognosis based on the IPSS or WPSS Cell line /s affected Feasibility of performing a clinical trial

24 Tools to treat MDS Observation Supportive therapy (Transfusions)
Hematopoietic growth factors Iron chelation Lenalidomide (Revlimid 2005) Hypomethylating agents Azacitidine (Vidaza 2004) Decitabine (Dacogen 2006) Immunosuppression Allogeneic stem cell transplantation Newer agents

25 To Trick or Treat Treatment should be reserved and potentially diagnosis to be transmitted to the patient and family, only if there are symptoms resulting from anemia or other cytopenias or perhaps pre-symptomatic anemia or severe thrombocytopenia. Old and frail patients or those who have equivocal diagnostic features, benefit from a period of observation. Neutropenia without infection is a poor justification for initiation of therapy. Stone RM. Blood 2009

26 Role of Growth Factors GCSF
Most widely prescribed class of medications for MDS (55%) GCSF Support improves ANC (75% patients) Has no impact on overall survival. Not recommended for routine infection prophylaxis Thrombopoietic agents Most have no significant impact on transfusion needs: Main utility Fewer dose modifications of disease modifying agents Romiplostim: 500/750mcg weekly Eltrombopag: under study Erythropoiesis stimulating agents (ESA) First line therapy for IPSS low or Int-1 risk MDS with EPO <500U/L (NCCN guidelines) Response rates; 20-30%, ?OS/PFS/ QOL, durability:2 years Epoeitin alpha: 60,000-80,000 U once per week Darbopoietin alpha: 500mcg once 3 weekly

27 Newer approaches- Immunosuppressants
Immunologic suppression of normal BM function, similar to the situation in aplastic anemia, has been postulated to account for cytopenias in some MDS patients Specific candidates- Refractory anemia with relatively hypoplastic marrow

28 Predictor of Response to Immunosuppressant
HLA-DR-15-positivity RA (<5% blasts) IPSS Low/Int-1 Age <60 years Brief transfusion history Trisomy 8 abnormality Normal cytogenetics Marrow cellularity <30%

29 ATG Phase II study (N=35) on MDS-RA
Both equine and rabbit ATG were found to be active Response to Equine ATG: 29% (34/115) Rabbit ATG: RR 42%. 75% responders durable response (median months). Stadler M, Leukemia 2004;18:460-5 Jonasova A, Br J Haematol. 1998;100: Molldrem JJ, Br J Haematol. 1997;99:

30 Chromosomal Abnormality: del13q
22 patients with bone marrow failure MDS U Only del (13 q ) Del (13q) plus other abnormalities number 16 6 GPI def clone 3 Response to IST 100% (14/14) 40% (2/5) 10 yr OSR 83% 63% Progression to AML None 2 MDS-U with del (13q) is a benign disorder with good response to IST Del (13q) should not be considered intermediate risk abnormality Hosokawa et al, Haematologica 2012;97:1845

31 Biological response modifiers special case of Del 5q syndrome
Eligibility: del(5q) IPSS low or Int-1 platelets > 50K/mm3 neutrophils > 500/mm3 transfusion dependent

32 Study Design Dose Reduction 5 mg qd 5 mg qod Eligible Patients
Week: Eligible Patients Register Response 10 mg po x 21 NO Off study YES Continue

33 Results Frequency of Cytogenetic Response According to Karyotype Complexity

34 Len in non del(5q) MDS Can be considered for low risk, adequate ANC and platelet counts Expected response rates are similar to other treatment alternatives Use in high risk MDS remains investigational “Revlimid restores erythropoietic activity to the MDS clone” Raza et al. Blood 2008

35 Hypomethylating agents

36 Hypomethylating agents
Azacytidine and decitabine are potent DNMT inhibitors This leads to hypomethylation of CpG dinucleotides in gene promoters and reactivation of previously silent genes Cytotoxic activity similar to cytarabine

37 5 Azacytidine AZA001: Euro study despite CALGB 9221
Primary endpoint: survival AZA Controls Median survival 24.5 months 15 months Progression to AML 27 months 13 months Transfusion independence 45% 11% Fennaux et al. Lancet Oncol 2009

38 Decitabine DAC Controls Overall survival 10 months 8.5 months
EORTC/GMDSSG 3 day schedule, inter cycle interval 6 weeks, cap of max 8 cycles EORTC/GMDSSG 3 day schedule, inter cycle interval 6 weeks, cap of max 8 cycles DAC Controls Overall survival 10 months 8.5 months Progression to AML at 1 yr 22% 33% CR/ PR/ HI 13/6/5% 0/0/2% Lubbert et al . JCO 2011

39 Hypomethylating agents
When to start Int/ high risk MDS (IPSS) Transfusion dependent/ EPO failure Not yet known if early treatment is better than late treatment in MDS Which drug NCCN recommends Azacitidine preference over Decitabine EORTC study failed to show survival benefit. MDACC regimen (5 day 20mg/m2/d) highest CR Aza vs Decitabine head to head trial results awaited Optimal dose, schedule, route Azacitidine: 7 day 75mg/m2/d sc q 28 days ( or 50mg/m schedule) Decitabine: 3 day 15mg/m2/dose IV 8 hrly (total dose 135mg/m2) inpatient 5 day 20mg/m2 /d over 1 hr (total dose 100mg/m2) outpatient Duration Optimal duration- not known To treat responding pts till disease progression, as long as tolerated At least 4 cycles recommended for adequate response Steensma et al. Hematol Oncol clin N Am 2010

40 Predictive Factors for Achieving Response to Hypomethylating Agents
Positive Mol/ Cyto: Mutated TET2 Mutated EZH2 Phosphoinositase – Phospholipase C beta 1 hypomethylation Clinical Variable Doubling of Platelets Negative Mutated P 53 Abnormal/ complex karyotype BM Blasts >15% Previous therapy Transfusion dependency BM fibrosis grade 3 Santini V, ASH 2012

41 MDS HSCT Low risk (low or Int 1, BM blasts <10%) High Risk
(Int 2, High risk, blasts>10%) Any age Age <60 Age≥60 Iron Chelation Growth factors DMT Inhibitors Lenolidamide Immunomodulation Clinical trial Intensive chemo DMTI Clinical trial DMTI Clinical trial Intensive Chemo Failure Failure Progression/ failure HSCT Attallah: Cancer Therap 2008;26:208-16

42 Unconventional and upcoming agents

43 Arsenic Trioxide* - Response by IWG Criteria
4 (16%) 8 (38%) Total patients with response 4 Major All lineages Minor 1 31 Neutrophil (<1.5 x 109/L) 2 HR Pts (n = 25) 3 LR Pts (n = 21) 36 Platelet (<100x 109/L) 40 Erythroid (Hgb <11 g/dL) Response Type Pts Deficient in Lineage at Baseline Lineage Response *Dose & Schedule: 0.25 mg/kg/d M-F x 2 q 4 weeks. List AF, et al. Blood (11): 1539a.

44 What’s on the Horizon? In the quest of effective therapy, currently there are approximately 200 clinical trials are ongoing and numerous agents are at various stages of drug development The need for a novel agent is particularly noted in patients failing hypomethylating agents who are ineligible for stem cell transplant Kulasekararaj AG, Semin Hematol ,2012; 49:350-60

45 Agent Action Current status Erlotinib Oral TKI tageting EGFR
Phase 2, hypomethylating agent failed MDS cases ORR 15% Stable disease 32% Tosedostat Aminopeptidase inhibitor Phase 1/ 2, ORR 28% in AML/MDS patients >60 years Ezatiostat Glutathione analogue Phase 2 , 40 % efficacy in lenalidomide treated MDS patients Siltuximab Chimaric monoclonal Ab neutralising IL6 Phase 2 for Anemia related to MDS Kulasekararaj AG, Semin Hematol ,2012; 49:350-60

46 Agent Action Current status BMN673 PARP inhibiotrs
Phase 1 , open label trial for AML, MDS, MCL, CLL MLN4924 Small molecule inhibitor of Neddylation activating enzyme Phase 1, AML and MDS PF Hedgehog pathway inhibitor Phase 1/ 2, for myelofibrosis, AML, MDS SCIO496 MAP kinase inhibitors Phase 1/ 2 for low and intermediate risk MDS Kulasekararaj AG, Semin Hematol ,2012; 49:350-60

47 Take Home Message Myelo-dysplastic syndromes are heterogeneous disorders Prognostic scores are evolving with use of cyto- genetics and molecular markers Treatment depends upon the prognostic and host factors MTI and IMIDs are being increasingly used HSCT is the only curative treatment Treatment paradigms are evolving

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