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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 ▫ Conversion to AML Age-related Incidence of MDS 100 Disease of elderly Rate 10 1 0.1 0.01 0 10 Males Females 20 30 40 50 60 70 80 Age, years McNally RJQ et al. Hematological Oncology 1997. 15:173-189 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. MDS: FAB Classification 1982 FAB subtype RA Blast % PB BM <1 RS% Monocyte Survival s >1x109/l (months) <5 <15 - 50 RARS <1 <5 >15 - 75 RAEB <5 5-20 variable - 11 CMML <5 <20 variable + 11 +/- 5 RAEB-T >5; 20-30; variable Auer rods Auer rods 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 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 WHO 2008 Subtype Blood Bone Marrow RCUD Single cell line Mostly erythroid Dysplasia: ≥10% cells RARS Anemia Erythroid dysplasia >15% ringed sideroblasts RCMD Bi/pancytopenia >10%Dysplasia: ≥2 cell lineage <5%blasts RAEB-1 Cytopenia <5% blast Uni-multi lineage dysplasia 5-9% blasts, No Auer rods RAEB-2 Cytopenia, 5-19% blasts or Uni-multi lineage dysplasia Auer rods 10-19% blasts or Auer rods MDS-U Cytopenia Uni / multilineage/ no dysplasia Characteristic MDS CG + MDS with 5q Anemia, normal or ↑Platelets Unilineage erythroid dysplasia, isolated del 5q, <5%blast Outcomes in MDS in Different WHO Subtypes Cazzola M. Hemaologica 2011 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 Prognostic scores Most widely used There are benefits and limitations of all these scores IPSS: Prognostic Variables 0 0.5 1.0 1.5 2.0 <5 5-10 — 11-20 21-30 Karyotype Good Intermediate Poor Cytopenias 0/1 2/3 - - - Marrow blasts % Overall score Median survival (years) 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 Risk group Low 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. Prediction of survival by IPSS 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 • 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 WHO Prognostic Scoring System *BM fibrosis grade 2-3 shifts risk group by one step 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 • Not applicable for secondary MDS Comparison of IPSS and WPSS (258 MDS Patients) MDACC Prognostic Scoring System (MPSS) Variable Score 1 Performance Status Score 2 ≥2 Age in years 60-64 ≥ 65 Platelets x 109/L 50-199 30-49 Hemoglobin gm% <30 <12 Bone marrow blasts 5-10 WBC x 109/L 11-29 >20 Karyotyping Prior transfusion Score 3 Chromosome 7 abnormality Complex karyotype (>2 abn) Yes MPSS risk group Low Intermediate 1 Intermediate 2 High Score 0-4 5-6 7-8 ≥9 Kantarjian et al Cancer 2008 2012 Revised IPSS Fine tune the prognostic impact of •Cytogenetic abnormalities •Depth of cytopenia Cytogenetic Abnormality Median OS, Mos Median Time to AML, Mos 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 inv(3)/t(3q)/del(eq), -7, double including del(7q), complex (3) 15.8 21.0 complex (≥ 3) 5.9 8.2 Prognostic Subgroup Very good Poor Very poor Schanz J, et al. J Clin Oncol. 2012;30:820-829. Greenberg PL, et al. Blood. 2012;120:2454-2465. IPSS-R 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 - - - - - Risk Category Risk Score Very low ≤ 1.5 Low >1.5 - 3 Intermediate >3 – 4.5 High >4.5 - 6 Very High >6 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 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 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 Role of Growth Factors 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 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 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% 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. 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 16 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 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 Study Design YES Eligible Patients R e g i s t e r Week: 0 R e s p o n s e 10 mg po x 21 4 8 12 16 20 24 Continue Dose Reduction 5 mg qd 5 mg qod NO Off study Results Frequency of Cytogenetic Response According to Karyotype Complexity 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 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 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 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 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 (52-2 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 Predictive Factors for Achieving Response to Hypomethylating Agents Positive • Negative • Mol/ Cyto: ▫ Mutated TET2 ▫ Mutated EZH2 ▫ Phosphoinositase – Phospholipase C beta 1 hypomethylation • Clinical Variable ▫ Doubling of Platelets • Mutated P 53 • Abnormal/ complex karyotype • • • • BM Blasts >15% Previous therapy Transfusion dependency BM fibrosis grade 3 Santini V, ASH 2012 MDS Low risk (low or Int 1, BM blasts <10%) High Risk (Int 2, High risk, blasts>10%) Any age Iron Chelation Growth factors DMT Inhibitors Lenolidamide Immunomodulation Clinical trial Age <60 Intensive chemo DMTI Clinical trial Failure Age≥60 DMTI Clinical trial Intensive Chemo Failure Progression/ failure HSCT Attallah: Cancer Therap 2008;26:208-16 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 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 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 Take Home Message • Myelo-dysplastic syndromes are heterogeneous disorders • Prognostic scores are evolving with use of cytogenetics 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