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

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Presentation on theme: "MDS: Classification and Advances in Therapy BTG2013 S. Varma PGIMER, Chandigarh India."— Presentation transcript:

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

2 MDS Highly heterogeneous group of disorders ▫ Variable natural history ▫ Variable mortality rate ▫ Variable response to therapy Commonest cause of death ▫ Progressive bone marrow failure ▫ Conversion to AML

3 Age-related Incidence of MDS McNally RJQ et al. Hematological Oncology : Males Females Rate Disease of elderly Age, years

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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%Monocyte s >1x10 9 /l Survival (months) PBBM RA <1<5<15-50 RARS<1<5>15-75 RAEB<55-20variable-11 CMML<5<20variable+11 RAEB-T>5; Auer rods 20-30; Auer rods variable+/-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 RAEBRAEB I and 2 RAEB-TRAEB II/ AML CMMLMDS-UC MDS associated with isolated del(5q) Childhood myelodysplastic syndrome Refractory cytopenia of childhood

9 WHO 2008 Bone MarrowBloodSubtype Dysplasia: ≥10% cellsSingle cell line Mostly erythroid RCUD Erythroid dysplasia >15% ringed sideroblasts AnemiaRARS >10%Dysplasia: ≥2 cell lineage <5%blasts Bi/pancytopeniaRCMD Uni-multi lineage dysplasia 5-9% blasts, No Auer rods Cytopenia <5% blast RAEB-1 Uni-multi lineage dysplasia 10-19% blasts or Auer rods Cytopenia, 5-19% blasts or Auer rods RAEB-2 Uni / multilineage/ no dysplasia Characteristic MDS CG + CytopeniaMDS-U Unilineage erythroid dysplasia, isolated del 5q, <5%blast Anemia, normal or ↑Platelets MDS with 5q

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

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

13 IPSS: Prognostic Variables Marrow blasts %<55-10 — KaryotypeGoodIntermediatePoor Cytopenias0/1 2/3--- 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. Risk groupOverall scoreMedian survival (years) Low05.7 Intermediate or Intermediate or Poor >/= Greenberg P et al. Blood 1997;89:

14 Prediction of survival by IPSS

15 IPSS Pros 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 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) VariableScore 1Score 2Score 3 Performance Status≥ 2 Age in years60-64≥ 65 Platelets x 10 9 /L <30 Hemoglobin gm%<12 Bone marrow blasts WBC x 10 9 /L>20 KaryotypingChromosome 7 abnormality Complex karyotype (>2 abn) Prior transfusionYes MPSS risk groupScore Low0-4 Intermediate 15-6 Intermediate 27-8 High≥9 Kantarjian et al Cancer 2008

20 2012 Revised IPSS Schanz J, et al. J Clin Oncol. 2012;30: Greenberg PL, et al. Blood. 2012;120: Prognostic Subgroup Cytogenetic Abnormality Median OS, Mos Median Time to AML, Mos Very gooddel(11q), -Y 60.8NR GoodNormal, del(20q), del(5q) alone or double, del(12p) 48.6NR Intermediate +8, del(7q), i(17q), +19, any other single or double, independent clones Poor inv(3)/t(3q)/del(eq), -7, double including del(7q), complex (3) Very poorcomplex (≥ 3) Fine tune the prognostic impact of Cytogenetic abnormalities Depth of cytopenia

21 IPSS-R Risk CategoryRisk Score Very low≤ 1.5 Low> Intermediate>3 – 4.5 High> Very High>6 Variable CytogeneticsV. good-Good-IntPoorV. poor BM blast%≤2->2 - <5-5-10>10- Hgb≥10-8-<10<8--- Platelets≥ < ANC≥0.8<

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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 GCSFSupport 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 Most widely prescribed class of medications for MDS (55%)

27 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 31.5 months). Jonasova A, Br J Haematol. 1998;100: Molldrem JJ, Br J Haematol. 1997;99: Stadler M, Leukemia 2004;18:460-5

30 Chromosomal Abnormality: del13q Only del (13 q )Del (13q) plus other abnormalities number166 GPI def clone163 Response to IST100% (14/14)40% (2/5) 10 yr OSR83%63% Progression to AMLNone2 22 patients with bone marrow failure MDS U 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/mm 3 neutrophils > 500/mm 3 transfusion dependent

32 Study Design Dose Reduction 5 mg qd 5 mg qod Week: Eligible Patients RegisterRegister ResponseResponse 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 Raza et al. Blood 2008 “Revlimid restores erythropoietic activity to the MDS clone”

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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 AZAControls Median survival24.5 months15 months Progression to AML27 months13 months Transfusion independence45%11% Fennaux et al. Lancet Oncol 2009

38 Decitabine DACControls Overall survival10 months8.5 months Progression to AML at 1 yr22%33% CR/ PR/ HI13/6/5%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/m 2 /d) highest CR – Aza vs Decitabine head to head trial results awaited Optimal dose, schedule, route – Azacitidine: – 7 day 75mg/m 2 /d sc q 28 days ( or 50mg/m schedule) – Decitabine: – 3 day 15mg/m 2 /dose IV 8 hrly (total dose 135mg/m 2 ) inpatient – 5 day 20mg/m 2 /d over 1 hr (total dose 100mg/m 2 ) 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 Low risk (low or Int 1, BM blasts <10%) Any age Iron Chelation Growth factors DMT Inhibitors Lenolidamide Immunomodulation Clinical trial Progression/ failure HSCT High Risk (Int 2, High risk, blasts>10%) Age <60Age≥60 Intensive chemo DMTI Clinical trial DMTI Clinical trial Intensive Chemo Failure Attallah: Cancer Therap 2008;26: Failure

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43 Arsenic Trioxide* - Response by IWG Criteria 4 (16%)8 (38%) Total patients with response 44Major All lineages 04Minor 00 11Major 31 Neutrophil (<1.5 x 10 9 /L) 00Minor HR Pts (n = 25) LR Pts (n = 21) Major 36 Platelet (<100x 10 9 /L) Minor Major 40 Erythroid (Hgb <11 g/dL) Response Type Pts Deficient in Lineage at Baseline Lineage Response List AF, et al. Blood (11):1539a. List AF, et al. Blood (11): 1539a. *Dose & Schedule: 0.25 mg/kg/d M-F x 2 q 4 weeks.

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 AgentActionCurrent status ErlotinibOral TKI tageting EGFRPhase 2, hypomethylating agent failed MDS cases ORR 15% Stable disease 32% TosedostatAminopeptidase inhibitor Phase 1/ 2, ORR 28% in AML/MDS patients >60 years EzatiostatGlutathione analoguePhase 2, 40 % efficacy in lenalidomide treated MDS patients SiltuximabChimaric monoclonal Ab neutralising IL6 Phase 2 for Anemia related to MDS Kulasekararaj AG, Semin Hematol,2012; 49:350-60

46 AgentActionCurrent status BMN673PARP inhibiotrsPhase 1, open label trial for AML, MDS, MCL, CLL MLN4924Small molecule inhibitor of Neddylation activating enzyme Phase 1, AML and MDS PF Hedgehog pathway inhibitor Phase 1/ 2, for myelofibrosis, AML, MDS SCIO496MAP kinase inhibitorsPhase 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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