Myelodysplastic Syndromes. Post-ASH meeting 2014 Marie-Christiane Vekemans

Transcription

1 Myelodysplastic Syndromes Post-ASH meeting 2014 Marie-Christiane Vekemans

2 Agenda New biological developments Risk assessment and prognostic factors New therapeutic options

3 Agenda New biological developments Risk assessment and prognostic factors New therapeutic options

4 Molecular genetics NGS identifies recurrent mutations 51% of MDS patients have at least one identified mutation 52% of cases with normal karyotype have at least one mutation Bejar, NEJM 2011

5 Molecular genetics Pathogenesis of MDS involves dysfunction of many cellular pathways RNA splicing SF3B1, SRSF2, U2AF1, ZRSR2 Transcription regulation RUNX1, ETV6 DNA repair TP53 DNA methylation TET2, DNMT3a, IDH1/2 Chromatin modification ASXL1, EZH2 Signal transduction CBL, NRAS, KRAS, JAK2 Cohesin complex STAG2, RAD21, SMC3

6 Molecular genetics Mutations are powerfully associated with clinical features 5 mutated genes are independent predictors of survival TP53, EZH2, RUNX1, ASXL1, ETV6 Individual lesions are associated with a specific clinical phenotype del(5q) (5q- syndrome) TP53 (complex karyotype) SF3B1 (RARS) SRSF2 (CMML) Bejar, NEJM 2011

7 Landscape of genetic lesions 111 genes 738 MDS patients including CMML 78% of MDS patients have one or more oncogenic mutations Over 40 genes mutated in MDS, but the vast majority are rare (<5%) Papaemmanuil, Blood 2013

8 Landscape of genetic lesions 111 genes 738 MDS patients including CMML Mutations in splicing factors are the most common, occur early, play a major role in determining the clinical features of the disease, and probably influence the subsequent genomic evolution of the disease Mutations can coexist or can be mutually exclusive Papaemmanuil, Blood 2013

9 Landscape of genetic lesions 104 genes 944 MDS patients 89% MDS harbored at least one mutation (median, 3 per pt; range 0-12) 47 genes are significantly mutated TET2, SF3B1, ASXL1, SRSF2, DNMT3A and RUNX1 mutated in > 10% of cases Nagata, ASH 2013, # 521; Haferlach, Leukemia 2013

10 Landscape of genetic lesions 104 genes 944 MDS patients Mutations in splicing factors are the most common Higher number of gene mutations in advanced WHO MDS subtypes Nagata, ASH 2013, # 521; Haferlach, Leukemia 2013

11 Agenda New biological developments Risk assessment and prognostic factors New therapeutic options

12 IPSS-R Pronostic variable Cytogenetics Very good - Good - Intermediate Poor Very poor BM blasts (%) >10 - Hb (g/dl) < Pt (10 3 /μl) < ANC (10 3 /μl) 0.8 < Cytogenetic category Cytogenetic abnormalities Very good del(11q), -Y Good Intermediate Poor Very poor normal, del(20q), del(5q), single and double, del(12p) +8, del(7q), i(17q), +19, +21, any other single or double abnormality, independant clones -7, inv(3)/t(3q)/del(3q), 2 abnormalities including -7/del(7q), complex: 3 abnormalities complex : > 3 abnormalities Risk category Risk score Median survival (y) Very low Low Intermediate High Very high >6 0.8 Greenberg, Blood 2012

13 IPSS-R Higher predictive power for LFS and OS Voso, JCO 2013 Higher predictive power over time Pfeilstöcker, ASH 2013, #1544 Useful to identify patients with low response to ESA Santini, ASH 2013, #2761; Santini, Blood 2013 New pronostic score based on EPO > 200 (1), SF > 350 (1), IPSS-R (0-3) Powerful tool to evaluate response to AZA Lamarque, Blood 2012 Powerful tool to evaluate outcome after allosct Della Porta, ASH 2013, #2765 When reassessed to IPSS-R, 65% patients changed categories, 59% to a less favorable prognostic group

14 Molecular markers and prognosis Strong relationship between the number of gene mutations and outcome Papaemmanuil, Blood 2013

15 Molecular markers and prognosis 27/45 genes affect survival A set of 14 prognostic genes can be used to build a clinically relevant prognostic score Nagata, ASH 2013, # 521; Haferlach, Leukemia 2013

16 Treatment and prognosis Impact of cytogenetics on response to AZA 878 MDS patients AZA (75 mg/m 2 x7), median of 6 cycles 66% abnormal karyotype IPSS-R groups : 1%, 4%, 17%, 35%, 25% Baseline cytogenetic pattern is not predictive of response to AZA except for +8, del(5q) (higher CR) and 3q26 (lower RR) Cytogenetics is a strong predictor of survival, especially del(17p), -7/del(7q), del(5q)* (shorter OS) Achieving cytogenetic response has no influence on survival Sebert, ASH 2013, # 389

17 Treatment and prognosis Prognostic impact of somatic mutations on response to HMA TET2 mutations (and to a lesser extent DNMT3a) predict a better response and more prolonged survival with DNMT inhibitors TP53 mutations predict a poorer response to AZA are associated with poorer survival with AZA in HR MDS Maciejewski, Leukemia, 2013 ; Kulasekararaj, BJH 2013; Bally, ASH 2012

18 Agenda New biological developments Risk assessment and prognostic factors New therapeutic options

19 Current issues in treatment of MDS Higher risk MDS (IPSS high or int-2) AZA only moderately improves survival Prognosis after AZA failure very poor Patients with complex karyotype have a very poor outcome, irrespective of treatment (including allo-sct) Lower risk MDS (IPSS low or int-1) Some low risk MDS have a poor prognosis Anemia non del(5q) : only 50% respond to ESA, for a median of 2y Del(5q) : only 65% respond to LEN, for a median of 2.2y Thrombocytopenia TPO receptor agonists in clinical trials

20 Maximizing the use of available treatments Hypomethylating agents Lenalidomide Combination with other available drugs : ESA Chemotherapy (anthracyclines, AraC) Other (iron chelating agents) Allo-SCT New drugs in MDS HDAC inhibitors Chemotherapy Clofarabine Sapacitabine Immunotherapy Gemtuzumab ozogamicin Signal transduction inhibitors TPO agonist receptors

21 Maximizing the use of available treatments HR MDS - AZA single agent AZA Intense schema Reversal of gene hypomethylation is seen at the end of each cycle Increasing the duration of treatment could improve AZA results Ades, ASH 2013, #1513

22 Maximizing the use of available treatments HR MDS - AZA single agent, intensified schedule 21 HR MDS AZA-14 75mg/m 2 x5 4 cycles CR/PR CR/PR AZA-21 75mg/m 2 x5 4 cycles AZA-14 75mg/m 2 x5 4 cycles AZA-28 75mg/m 2 x7 CR/PR/HI Until progression Off-study ORR 55% after 4 cycles, 70% after 8 cycles 1y OS 69% Cycles delayed in a limited proportion of patients, with no extra toxicities Ades, ASH 2013, #1513

23 Maximizing the use of available treatments HR MDS - AZA combinations 36 HR MDS, Ph II AZA 75mg/m 2 x5, LEN 10mg x21 AZA LEN Idarubicin HDACi ORR 72%, CR 44%, HI 28%, median response 17m, 37 m if CR Superior efficacy of AZA-LEN versus AZA 20 HR MDS, Ph I/II AZA 75mg/m 2 x7, IDA 5 or 10mg/m 2 d8 ORR 35%, CR in 2, PR in 2, no relapse in responders Valproate 76 HR MDS, Ph II No survival benefit Entinostat 136 HR MDS, Ph II No survival benefit Vorinostat Gemtuzumab 88 HR MDS, Ph II AZA 75mg/m 2 x5, Gemtuzumab 3mg/m 2 d8 CR 35%, median RFS 7 months, median OS 11 months Sekeres, JCO 2011 & Am J Hematol 2011; Ades, ASH 2012; Issa, ASH 2008; Prebet, ASH 2010; Silvermann, ASH 2013, #386; Nand, Blood 2013

24 Median 6 cycles Maximizing the use of available treatments HR MDS AZA + HDACi, safe and well tolerated 40 HR MDS Ph II HDACi AZA 55mg/m 2 x7 Vorinostat 200mg bid d3-16 AZA 75mg/m 2 x7 Vorinostat 300mg bid d3-9 AZA 55mg/m 2 x7 Vorinostat 300mg bid d3-9 ORR 70%, 42% CR, 27% HI, 84%* RBC-TI Median time to response 2 cycles, median duration of response 16 months (9.5, 23, 27m) Persistance of clone in 45% (modulating rather than cytotoxic effect) Median OS 21 months Silvermann, ASH 2013, #386

25 Maximizing the use of available treatments HR MDS - LEN combinations LEN HR MDS with del(5q) fit for ICT : DNR + AraC + LEN unfit for ICT : AZA + LEN Karyotype generally complex Very poor response to ICT and HMA alone Ades, ASH 2013, # 620; Ades, ASH 2013, # 2750

26 Maximizing the use of available treatments HR MDS - AZA + ICT, very short DFS 82 HR MDS fit for ICT Ph I/II LEN INDUCTION CONSOLIDATION x6 MAINTENANCE DNR 45mg/m 2 x3 ARAC 200mg/m 2 x7 LEN 10mg x21 DNR 60mg/m 2 x3 ARAC 200mg/m 2 x7 LEN 10mg x21 DNR 60mg/m 2 x3 ARAC 200mg/m 2 x7 LEN 25mg x21 DNR 45mg/m 2 x1 ARAC 60mg/m 2 x10 LEN 10mg x14 DNR 60mg/m 2 x1 ARAC 60mg/m 2 x10 LEN 10mg x14 DNR 60mg/m 2 x1 ARAC 60mg/m 2 x10 LEN 25mg x14 LEN 10mg x14 LEN 10mg x14 LEN 25mg x14 66y ORR 61%, CR 46%, CyR 59%, CCyR 44% Early death 19% No addtional myelosuppression Median DFS 5.8 months in responders Complex karyotype with del(5q), CR 44% No difference between cohorts Ades, ASH 2013, # 620

27 RESPONSE 2-4 cycles 35 HR MDS Maximizing the use of available treatments HR MDS - AZA + LEN, early discontinuation unfit for ICT LEN AZA-28 75mg/m 2 x5 LEN 5mg x14 LEN 5mg x21 69y Ph I/II LEN 10mg x21 ORR 20%, 30% in cohort 3, CR 17%, most of them with complex karyotypes, CyR in 2/3 Early discontinuation in 43% (< 2d cycle)(death, progression, toxicity) 1-year OS 39% Ades, ASH 2013, #2750

28 Maximizing the use of available treatments LR MDS LEN single agent, CyR and RBC-TI 286 LR MDS with del(5q) LEN MDS-003 MDS-004 Achievement of CyR associated with a prolonged RBC-TI and a reduced risk of AML progression Sekeres, ASH 2013, #390

29 Maximizing the use of available treatments Hypomethylating agents Lenalidomide Combination with other available drugs : ESA Chemotherapy (anthracyclines, AraC) Other (iron chelating agents) Allo-SCT New drugs in MDS HDAC inhibitors Chemotherapy Clofarabine Sapacitabine Immunotherapy Gemtuzumab ozogamicin Signal transduction inhibitors TPO agonist receptors

30 Signal transducers New drugs

31 New drugs Rigosertib Raza, ASH 2013, #2745 Signal transduction inhibitors Volasertib Polo-like inhibitor Maertens, ASH 2012 # 615 Ezatiostat Galili, J Hematol Oncol 2012 p38amapk inhibitor ARRY-614 dual p38 MAPK/Tie2 inhibitor Sokol, Leukemia 2013 Garcia-Manero, ASH 2013, #387 Erlotinib Thepot, Berlin 2013

32 until RBC-TI New drugs LR MDS signal transduction inhibitors, urinary toxicity 48 LR MDS RBC-TD PI3-k inhibitor 71y Ph II Rigosertib 560mg bid 2 weeks/3 Rigosertib 560mg bid continuously ESA Continuous dosing stopped after 9 patients due to high urinary toxicity (reversible) Dosing modification 560mg/280mg RBC-TI 35% Efficacy in 11 out of 12 patients refractory to prior ESA No myelotoxicity Raza, ASH 2013, #2745

33 BM biopsy at week 30 BM biopsy at week 56 New drugs LR MDS TPO receptor agonists Raises platelets counts, Decreases platelets transfusion needs Thrombocytopenia Romiplostim Double blind Romiplostim 750μg weekly Placebo weekly Romiplostim 750μg weekly Placebo weekly? Giagounidis, submitted

34 AlloSCT Sole potential curative option Outcome dependent on disease- and patient-related factors No prospective trials comparing SCT with non transplant approaches 2 retrospective studies AZA vs ICT and SCT : no statistical differences (OS, relapse, NRM). AZA before SCT could reduce tumor burden without impacting physical condition AZA as salvage therapy after SCT relapse Damaj, JCO 2012; Gerds, BBMT 2012

35 DLI DLI DLI DLI AZA mg/m 2 /d x5 AZA mg/m 2 /d x5 AZA mg/m 2 /d x5 AZA mg/m 2 /d x5 AZA mg/m 2 /d x5 AZA mg/m 2 /d x5 AZA mg/m 2 /d x5 AZA mg/m 2 /d x5 AlloSCT 30 HR MDS AML in relapse after allosct Median 3 cycles ORR 30%, including 7 CR (23%) and 2 PR (7%); 5 patients remained in CR for 777 days Salvage therapy with AZA increases reg T-cells in peripheral blood of patients with AML or MDS and early relapse after allosct Schroeder, Leukemia 2013

36 DLI DLI DLI AZA mg/m 2 /d x5 AZA-28 35mg/m 2 /d x5 AZA-28 35mg/m 2 /d x5 AZA-28 35mg/m 2 /d x5 AZA-28 35mg/m 2 /d x5 AZA-28 35mg/m 2 /d x5 AZA-28 35mg/m 2 /d x5 AZA-28 35mg/m 2 /d x5 AZA-28 35mg/m 2 /d x5 AZA-28 35mg/m 2 /d x5 BHS TC 10 HR MDS AML < 30% blasts in relapse after allosct Minimum 6 cycles

37 Conclusion Mutations associated with clinical features and outcome Future risk-based classification systems Evaluate further prognostic features in larger patients cohorts Molecular : single, combination, evolutionary Cytogenetics : SNP, FISH Flow cytometry Microenvironment Maximizing the use of available treatement Cost, reimbursement New drugs, clinical trials In HR front-line in combination with HMA In LR alone or as add on therapy after failure to HMA alone or combined to ESA or LEN after ESA failure -non del(5q)- or LEN failure -del(5q)-

38 THANK YOU