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MDS Classification by Subhash Varma

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MDS Classification by Subhash Varma

  1. 1. MDS: Classification and Advances in Therapy BTG2013 S. Varma PGIMER, Chandigarh India
  2. 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. 3. Age-related Incidence of MDS McNally RJQ et al. Hematological Oncology 1997. 15:173-189 Males Females 0 10 20 30 40 50 60 70 80 0.01 0.1 1 10 100 Rate Disease of elderly Age, years
  4. 4. 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;10:175-281.
  5. 5. MDS: FAB Classification 1982 FAB subtype Blast % RS% Monocyte s >1x109/l Survival (months) PB BM RA <1 <5 <15 - 50 RARS <1 <5 >15 - 75 RAEB <5 5-20 variable - 11 CMML <5 <20 variable + 11 RAEB-T >5; Auer rods 20-30; Auer rods variable +/- 5
  6. 6. 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
  7. 7. Comparison of MDS Classifications FAB classification WHO Classsification 2001 WHO Classification 2008 RA RA Refractory cytopenia with unilineage dyplasia • Refractory anemia • Refractory neutropenia • Refractory thrombocytopenia RARS RARS Refractory anemia with ring sideroblasts (RARS) RCMD RCMD RCMD-RS RCMD-RS RAEB RAEB I and 2 RAEB I and 2 RAEB-T RAEB II/ AML RAEB II/ AML CMML MDS-UC MDS-UC MDS associated with isolated del(5q) MDS associated with isolated del(5q) Childhood myelodysplastic syndrome • Refractory cytopenia of childhood
  8. 8. 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
  9. 9. Cazzola M. Hemaologica 2011 Outcomes in MDS in Different WHO Subtypes
  10. 10. 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
  11. 11. Prognostic scores Most widely used There are benefits and limitations of all these scores
  12. 12. IPSS: Prognostic Variables 0 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 - - - 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 group Overall score Median survival (years) Low 0 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 Greenberg P et al. Blood 1997;89:2079-2088.
  13. 13. Prediction of survival by IPSS
  14. 14. 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
  15. 15. WHO Prognostic Scoring System *BM fibrosis grade 2-3 shifts risk group by one step
  16. 16. 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
  17. 17. Comparison of IPSS and WPSS (258 MDS Patients)
  18. 18. 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 0-4 Intermediate 1 5-6 Intermediate 2 7-8 High ≥9 Kantarjian et al Cancer 2008
  19. 19. 2012 Revised IPSS Schanz J, et al. J Clin Oncol. 2012;30:820-829. Greenberg PL, et al. Blood. 2012;120:2454-2465. 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 NR 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 Fine tune the prognostic impact of •Cytogenetic abnormalities •Depth of cytopenia
  20. 20. IPSS-R Risk Category Risk Score Very low ≤ 1.5 Low >1.5 - 3 Intermediate >3 – 4.5 High >4.5 - 6 Very High >6 Variable 0 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 - - - - -
  21. 21. 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
  22. 22. 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
  23. 23. 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
  24. 24. Role of Growth Factors 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 Most widely prescribed class of medications for MDS (55%)
  25. 25. 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
  26. 26. 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%
  27. 27. 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;100:304-309. Molldrem JJ, Br J Haematol. 1997;99:699-705. Stadler M, Leukemia 2004;18:460-5
  28. 28. Chromosomal Abnormality: del13q Only del (13 q ) Del (13q) plus other abnormalities number 16 6 GPI def clone 16 3 Response to IST 100% (14/14) 40% (2/5) 10 yr OSR 83% 63% Progression to AML None 2 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
  29. 29. 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
  30. 30. Study Design Dose Reduction 5 mg qd 5 mg qod Week: 0 4 8 12 16 20 24 Eligible Patients R e g i s t e r R e s p o n s e 10 mg po x 21 NO Off study YES Continue
  31. 31. Results Frequency of Cytogenetic Response According to Karyotype Complexity
  32. 32. 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”
  33. 33. 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
  34. 34. 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
  35. 35. Decitabine 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
  36. 36. 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 (5- 2-2 or 50mg/m2 5-2-5 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
  37. 37. 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
  38. 38. 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 <60 Age≥60 Intensive chemo DMTI Clinical trial DMTI Clinical trial Intensive Chemo Failure Attallah: Cancer Therap 2008;26:208-16 Failure
  39. 39. 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
  40. 40. 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
  41. 41. 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-04449913 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
  42. 42. 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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