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MDS: Classification and Advances in Therapy

MDS: Classification and Advances in Therapy. BTG2013. S. Varma PGIMER, Chandigarh India. MDS. Highly heterogeneous group of disorders Variable natural history Variable mortality rate Variable response to therapy Commonest cause of death Progressive bone marrow failure

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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 • Variable natural history • Variable mortality rate • Variable response to therapy • Commonest cause of death • Progressive bone marrow failure • Conversion to AML

  3. 100 10 1 0.1 0.01 Age-related Incidence of MDS Rate Disease of elderly Males Females 0 10 20 30 40 50 60 70 80 Age, years McNally RJQ et al. Hematological Oncology 1997. 15:173-189

  4. Classification

  5. Historical Perspective • Pseudo-aplasticanemia • Refractory Anemia • Pre-leukemia • Myelodysplastic syndrome Luzzatto AM. anemiapseudoaplasticaRivVen 1907;47:193. Bomford RR, Rhodes CP. Refractoryanemia. Q J Med 1941;10:175-281.

  6. MDS: FAB Classification 1982

  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

  9. WHO 2008

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

  13. 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;89:2079-2088.

  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) MPSS risk group Score Low 0-4 Intermediate 1 5-6 Intermediate 2 7-8 High ≥9 Kantarjian et al Cancer 2008

  20. 2012 Revised IPSS • Fine tune the prognostic impact of • Cytogenetic abnormalities • Depth of cytopenia Schanz J, et al. J Clin Oncol. 2012;30:820-829. Greenberg PL, et al. Blood. 2012;120:2454-2465.

  21. IPSS-R

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

  27. Newer approaches- Immunosuppressants Immunologic suppression of normal BM function, similar to the situation in aplasticanemia, 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). Stadler M, Leukemia 2004;18:460-5 Jonasova A, Br J Haematol. 1998;100:304-309. Molldrem JJ, Br J Haematol. 1997;99:699-705.

  30. Chromosomal Abnormality: del13q 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 modifiersspecial case of Del 5q syndrome Eligibility: • del(5q) • IPSS low or Int-1 • platelets > 50K/mm3 • neutrophils > 500/mm3 • transfusion dependent

  32. YES Continue Register Response Eligible Patients 10 mg po x 21 Dose Reduction 5 mg qd 5 mg qod NO Off study Week: 0 4 8 12 16 20 24 Study Design

  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 CpGdinucleotides in gene promoters and reactivation of previously silent genes • Cytotoxic activity similar to cytarabine

  37. AZA001: Euro study despite CALGB 9221 Primary endpoint: survival 5 Azacytidine Fennaux et al. Lancet Oncol 2009

  38. Decitabine 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 (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. HematolOncolclin 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 High Risk (Int 2, High risk, blasts>10%) Low risk (low or Int 1, BM 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. 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, SeminHematol ,2012; 49:350-60

  44. Kulasekararaj AG, SeminHematol ,2012; 49:350-60

  45. Kulasekararaj AG, SeminHematol ,2012; 49:350-60

  46. 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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