Myelodysplastic syndromes

Myelodysplastic syndromes - - treatment. (Who, when, what drugs?) Jaroslav Cermak, Institute of Hematology & Blood Transfusion, Prague, Czech Republic. Myelodysplastic syndromes Heterogeneous group of clonal hematological disorders arising from pluripotent progenitor stem cell. Different prognosis in terms of : - overall survival - leukemic transformation 1

MDS - development Second and subsequent hits: Loss of gene function ( hypermethylation tumor suppressors ) Gain of gene function ( oncogenes ) Noxa /insult: onkoproteins radiation First hit: Gene mutation : cell cycle transcription MDS early stage Increased apoptosis Impaired differentiation MDS late stage Decreased apoptosis Impaired differentiation Increased proliferation AML Normal stem cell Progress Dysplastic haemopoiesis Peripheral cytopenias No expansion of blasts Dysplastic haemopoiesis Peripheral cytopenias Expansion of blasts AML = acute myeloid leukaemia. W.K.Hoffman / with permission / Who should be treated? Prognostic factors : - traditional -new 2

FAB classification MDS subtype Blast percentage Peripheral Bone marrow blasts (%) blasts (%) Additional features AML transformation (%) RA Refractory anaemia 1 < 5 10 20 RARS RA with ringed sideroblasts 1 < 5 > 15% ringed sideroblasts in bone marrow 10 35 RAEB RA with excess blasts < 5 5 20 > 50 RAEB-T RAEB in transformation 5 21 29 Optional Auer rods 60 100 CMML Chronic myelomonocytic leukaemia < 5 20 Peripheral monocytosis (> 10 3 /µl) > 40 Bennett JM, et al. Br J Haematol. 1982;51:189 99. Prognostic factors / traditional FAB - 1992 3

International Prognostic Scoring System (IPSS) Score 0 05 0.5 10 1.0 15 1.5 20 2.0 Medullary blasts (%) < 5 5 10 11 20 21 30 Karyotype Good * Intermediate Poor Cytopenia 0/1 2/3 Low risk 0 points Intermediate 1risk 0.5 1.0 points Intermediate 2risk 1.5 2.0 points High risk 2.5 points * Good: normal, Y, del(5q), del(20q). Intermediate: other abnormalities not seen in good or poor. Poor: complex ( 3 abnormalities) or chromosome 7 anomalies. Greenberg P, et al. Blood. 1997;89:2079 88. Prognostic factors / traditional IPSS - 1997 4

Prognostic factors / traditional WHO - 2001 5

WHO Classification-Based Prognostic Scoring System (WPSS) Score Prognostic Variable 1 2 3 WHO RA, RARS, 5q RCMD, RCMD-RS RAEB-1 RAEB-2 category Karyotype Good Intermediate Poor Transfusion requirement No Regular Verylow risk ik 0 points Low risk 1 points Intermediate 2 points High risk 3 4 points Very high risk 5 6 points Good: normal, Y, del(5q), del(20q). Poor: complex ( 3 abnormalities) or chromosome 7 anomalies Intermediate: other abnormalities Malcovati L et al, JCO, 25(23), 2007:3503 351 Prognostic factors / traditional WPSS - 2007 6

New prognostic factors Revised cytogenetics, molecular cytogenetics Revised IPSS MDS Flow cytometry Molecular biology New prognostic cytogenetic scoring system Very good n = 81 (2.9%) Good n = 1,809 (65.7%) Intermediate n = 529 (19.2%) Poor n = 148 (5.4%) Very poor n = 187 (6.8%) Single del(11q) Y Overall survival (months) Normal Single del(5q) del(12p) del(20q) Double incl. del(5q) Single del(7q) +8 i(17q) +19 any others indep. clones Double any other Single der(3q) 7 Double incl. 7/7q Complex 3 abnormalities Complex 60,8 48,5 25,0 15,0 5,7 > 3 abnormalities Schanz J, et al. J Clin Oncol. 2011;29:1963 70. 7

Molecular cytogenetics No significant difference in overall survival and progression free survival in patients with karyotype abnormalities diagnosed either by : chromosomal banding or molecular cytogenetics Tiu R V et al. Blood 2011;117:4552-4560 SNP microarray based karyotyping in MDS 8

5/15/2012 SNP array analysis impact on outcome High density SNP arrays have facilitated the detection of cryptic chromosomal aberrations(75% of MDS and AML have abnormal cytogenetics by SNP array) and are of prognostic importance but need to be evaluated in large prospective studies Next generation sequencing in MDS Mutated gene No. of samples All samples p 439 ((100)) 1.86 ((1.60 2.14)) TET2 90 (20.5) 1.88 (1.26 2.55) ASXL1 63(14.4) 1.33 (0.96 1.88) 0.003 RUNX1 38 (8.7) 1.16 (0.77 1.53) < 0.001 TP53 33 (7.5) 0.65 (0.44 1.10) < 0.001 EZH2 28 (6.4) 0.79 (0.67 1.40) < 0.001 NRAS 16 (3.6) 1.03 (0.44 1.98) 0.006 JAK2 13 (3.0) 2.14 (1.02 3.12) 0.96 ETV6 12 (2.7) 0.83 (0.62 2.29) 0.04 CBL 10 (2.3) 1.52 (0.14 1.71) 0.02 IDH2 9 (2 (2.1) 1) 1 58 (0 1.58 (0.50 2.14) 50 2 14) 0 03 0.03 NPM1 8 (1.8) 2.18 (0.59 2.74) 0.43 IDH1 6 (1.4) 3.30 (0.35 9.52) 0.52 KRAS 4 (0.9) 0.89 (0.36 7.44) 0.54 GNAS 3 (0.7) PTPN11 3 (0.7) BRAF 2 (0.5) PTEN 1 (0.2) CDKN2A 1 (0.2) Median survival (95% CI) (year) p value 0.48 Hazard Ratios for Death in a Multivariable Model.* Mutational status TP53 mutation present vs. absent 2.48 (1.60 3.84) <0.001 EZH2 mutation present vs. absent 2.13 (1.36 3.33) <0.001 ETV6 mutation present vs. absent 2.04 (1.08 3.86) 0.03 RUNX1 mutation present vs. absent 1.47 (1.01 2.15) 0.047 ASXL1 mutation present vs. absent 1.38 (1.00 1.89) 0.049 Somatic point mutations are common in myelodysplastic syndromes and are associated with specific clinical features. Mutations in TP53, EZH2, ETV6, RUNX1, and ASXL1 are predictors of poor overall survival in patients with myelodysplastic syndromes, independently of established risk factors. Bejar R, et al. N Engl J Med 2011;364:2496 506. 9

5/15/2012 Flow cytometry Aberrant flow cytometry patterns well correlate with morphology, subclassification of MDS and with prognostic systems, but prospective validation of the impact of immunophenotypic patterns is necessarry. Loosdrecht et al., Haematologica 2008 Revised IPSS ( IPSS-R ) 7012 patients with primary MDS from 11 countries Significant parameters for prognostic classification : Hb, WBC, PLT (depth of cytopenias) new prognostic cytogenetic system (5 subgroups) percentage of bone marrow blasts 5 different prognostic subgroups survival leukemic transformation P.Greenberg with permission 10

Conclusions : all traditional prognostic systems : a significant difference in overall survival and risk of leukemic transformation between : very low, low, intermediate 1 and intermediate 2, high, very high subgroups. new prognostic parameters : mayhave a significant prognostic impact (SNP arrays, next generations sequencing of gene mutations, FCM) but their impact needs to be validated. When should we treat? 11

Favourable prognosis : prolonged survival, low risk of leukemic transformation Very low Low Intermediate 1 CONSERVATIVE TREATMENT RISK TREATMENT Intermediate 2 High Very high INTENSIVE TREATMENT Adverse prognosis : short survival, high risk of leukemic transformation INTENSIVE TREATMENT v.s. SUPPORTIVE CARE in MDS IPSS risk group SCT (+/- chemotherapy) nonsct relapse TRM 3yDFS 3yDFS LW 0 20 80 73 IM-1 6 30 64 54 IM-2 29 31 40 21 H 42 29 29 6 Degg et al., 2002, Greenberg et al., 1998 12

How should we treat? NON INTENSIVE TREATMENT INTENSIVE TREATMENT Control and modification of behaviour of the clone Eradication of the clone RBC and PLT transfusions chelation growth factors immune supression hypomethylating agents chemotherapy stem cell transplantation 13

Non-intensive treatment : correction of cytopenia RBC and PLT transfusions 0 >3 0-1 2-3 12 1-2 44 % of MDS patients 2 TU of RBC only 14% of patients 0 TU of RBC Iron overload the most serious consequence of repeated RBC transfusions Chelation treatment Removalofexistingiron surplusfromthebody Prevention of iron overload in MDS patients Who should be treated with chelators? - no definitive consensus - patients with serum ferritin > 1000-1500 μg/l - patients who received > 20-25 TU of RBC - measurement of NMR of heart using T2* - probably the best estimation of organ iron stores Who should receive chelators as a prophylaxis? - patients with isolated erythroid dysplasia receiving > 2 TU of RBC/month - presence of comorbidities (coronary disease, rheumatic disease) significantly increases risk of iron overload 14

Deferasirox - first line treatment of iron overloaded MDS patients -effectively decreases toxic iron (LPI level) - less effective than deferiprone in removal of iron from myocardium - chelation may lead to improvement in blood cell counts,? improvement in survival Deferiprone - not routinely used in MDS patients (risk of granulocytopenia) - alternative treatment for patients not indicated for deferasirox (adverse effects, renal insufficiency) Non-intensive treatment : Erythropoietin (EPO) MDS Score: 0 Probability of erythroid response 74% High ih Serum EPO (U/L) Transfusion requirement Score < 500 U/L 0 500 U/L 1 < 2 prbc per month 2 prbc per month 0 1 Score: 1 23% Intermediate Score: 2 7% Low EPO may be combined with G CSF for treating anemia and granulocytopenia Administration of EPO may be connected with prolonged overall survival. Hellström Lindberg E, et al. Br J Haematol. 1997;99:344 51. Jädersten M,et al. Blood 2005;106 :803 811. 15

Non-intensive treatment : Immune suppression Total of 88 patients with MDS Randomized dti trial 45 patients with ATG+CSA 43 patients with BSC (RBC; Epo) Response rates ATG+CSA: 13/45 (29%) BSC: 4/43 (9%) Overall survival at 2 years ATG+CSA: 49% BSC: 63% p = 0.828 BSC = best standard of care; OS = overall survival. Proportion remaining alive 1.0 ATG+CSA BSC ecrossover 0.8 0.6 0.4 0.2 0.0 0 1 2 3 4 5 6 7 Time from randomization (years) Indication for immunosuppressive treatment : requested criteria LW or IM 1 IPSS score, patients who are indicated for treatment but not eligible for SCT. recommended criteria hypoplastic MDS, HLA Dr 15, PNH like MDS Passweg JR, et al. J Clin Oncol. 2011;29:303 9. Non-intensive treatment : Lenalidomide PATHOGENESIS OF 5q syndrome Jädersten et al.,haematologica 2010; 85, 328 581. Lenalidomide in del 5q : reversion of SPARC gene function, expression of mirna 145, mirna 156a. stimulation of Cdc25c, PPAcα (regulation of cell cycle) 16

Non-intensive treatment : Lenalidomide (MDS 003,004) RBC TI (%) Transfusion independence (MDS 004) * 70 60 50 40 30 20 10 0 6 * 41 56 52 weeks of treatment Transfusion independence : MDS 003 : 69 % isolated del 5q 67% del 5q + complex abberations 52% del 5q + 1 abberation MDS 004 : 56% LW + IM1 patients + lenalidomide 10 mg/day x 28 41% LW + IM1 patients + lenalidomide 5 mg/day x 28 6% placebo List A, et al. N Engl J Med 2006; 355: 1456 65, Fenaux P, et al. Blood. 2011;118:3765 76. Risk analysis of outcome in del(5q) MDS treated or not with lenalidomide ce on Cumulative inciden of AML progressio 1.0 0.8 0.6 0.4 0.2 Untreated LEN-treated 0 0 1 2 3 4 5 6 Number of patients at risk, n Time (years) 125 79 58 39 24 18 9 53 97 119 128 120 98 LEN-treated Untreated 2-year cumulative incidence 7% 12% 5-year cumulative incidence 23% 20% Median time to AML progression not reached not reached Kuendgen A, et al. Blood. 2011;118:[abstract 119]. 17

DNA hypermethylation and MDS N NH 2 DNA NH 2 methyltransferase N CH 3 O N Cytosine O N Cytosine + methyl group DNA methylation is regulated by DNA methyltransferases (DNMTs) Methylation occurs at CpG dinucleotides in DNA Esteller M. N Engl J Med 2008;358:1148 59 MDS DNMTs hypermethylate cytosine bases of DNA in gene promoters Repressed transcription of tumour suppressor genes Dysregulated proliferation/differentiation of haematological precursor cells HYPOMETHYLATING AGENTS Methyl transferase inhibitiors : azacytidine, deoxyazacytidine Histon deacytelase inhibitors : vorinostat, valproic acid 18

AZA 001 overall Survival: Azacitidine vs CCR Proportion Surviving 1.0 0.9 08 0.8 0.7 0.6 0.5 0.4 0.3 15 months 26.2% Log Rank p=0.0001 HR = 0.58 [95% CI: 0.43, 0.77] Deaths: AZA = 82, CCR = 113 Difference: 9.4 months 50.8% 24.4 months 0.2 CCR 0.1 0.0 0 5 10 15 20 25 30 35 40 Time (months) from Randomization AZA Fenaux et al., Lancet Oncol. 2009;10,223 232. Experience from treatment with azacytidine AZA signifcantly prolongs survival in comparison with conventional treatment regimens. Median number cycles to the first response is 2, to the best response is 3-4, 90% of responding patients respond within 6 cycles of treatment. Patients with poor-risk cytogenetics including abnormalities of chromosome 7 showed good response to AZA (not confirmed in more recent studies) AZA is well tolerated even in patients of age 75 and older. A significant effect on survival may be present even in patients who did not achieve CR or PR. 19

Survival (%) 100 80 60 40 Intensive treatment : Combination chemotherapy (anthracycline + cytosin arabinoside) Combination chemotherapy not followed by SCT : limited impact on prolonged survival 3 years overall survival < 15% 20 0 0 20 40 60 80 100 120 140 Wattel E. et al., Br J Haematol, 1997;98:983-991. less efficient than hypomethylating agents (AZA 001 study : OS 25,1 monhts for AZA v.s. 15,7 months for combination chemotherapy). Stem cell transplantation in MDS Which patients should be transplanted immediately, when can be SCT delayed? Should the patients with advanced MDS receive chemotherapy prior to SCT? What is the role of reduced conditioning regimens in MDS? 20

Stem cell transplantation : timing of SCT in relation to IPSS 1.5 10 1.0 0.5 Cutler CS, et al. Blood. 2004;104:579 85. Low Int 1 s of discounted ctancy Gain/loss life expec 0 0.5 1.0 1.5 2.0 2.5 1 2 3 4 5 6 7 8 9 10 High Int 2 Years of delay LW and INT 1 risk patients may benefit from delaying transplantation Patients with early MDS with profound pancytopenia and poor risk karyotype are indicated for immediate SCT (IM 2 risk score) Stem cell transplantation : effect of pretreatment with chemotherapy <10% blasts > 10% blasts Reduction of bone marrow blasts prior SCT may prolong survival of MDS patients with advanced disease. Randomized trials comparing upfront SCT and SCT after combination chemotherapy are needed. Cermak et al., Blood 2010; 116: 1638 De Witte et al. Blood 2001; 98:2326 2331. 21

Stem cell transplantation : effect of reduced conditioning standard conditioning reduced conditioning 3 years OS (%) 48 41 3 years DFS (%) 38 33 Martino et al.,blood 2006;108,836 846 Reduced conditioning regimens : low transplantation related mortality, higher incidence of relapses But : > 40% of patients survive > 3 years in recent studies relapse incidence (%) incidence 27 45 nonrelapse mortality (%) 32 22 FAB subtype (type of SCT + conditioning) DFS 3 years (%) TRM (%) Relapse (%) RA allosct 60-70 25-40 0-5 RAEB allo/stand RAEB-T allo/stand RAEB + RAEB-T allo/reduced d RAEB + RAEB-T auto 35-45 30-40 30-40 30-40 30-50 40-50 30-40 5-20 50-60 15-30 10-20 70-75 Degg et. al. (2005), Sierra et al. (2002), Martino et al. (2005), Mufti et al. (2005). 22

Conclusions Percentage of bone marrow blasts and karyotype abnormities are still the most important prognostic factors in MDS patients and play the most important role in the treatmentt tdecision i (intensive i v.s. conservative approach) Stem cell transplantation still represents the only curative treatment in MDS New factors e.g. molecular genetics changes may affect prognosis and choice of the appropriate treatment New drugs targeting the molecular basis of the disease (e.g. hypomethylating agents) representpromising therapeutic modalities in MDS. 23