Are we always prolonging survival?

Transcription

1 New therapies for myelodysplastic syndromes beyond hypomethylating agents and IMIDs Valeria Santini UF Ematologia, Università di Firenze Lisbon, May 4 th, 2012 Are we always prolonging survival? 1

2 Survival after decitabine failure in MDS/AML patients Median S 4.3 mos Jabbour et al, Cancer 116:3830(2008) Survival after azacitidine failure in MDS/AML patients Median survival 5.6 mos Prebet et al, JC 29:3322 (2011) 2

3 Survival according to salvage therapy Prebet et al, JC 29:3322 (2011) ths) Median Survival (mont Effect of Cytogenetic Abnormalities on verall Survival after azacitidine HR = 0.63 ( ) 35 NR HR = ( ) AZA HR = 0.55 ( ) HR = 0.33 ( ) CCR HR = 0.45 ( ) HR = ( ) HR = 0.42 ( ) Non-complex Complex Non-complex Complex Non-complex Complex Normal -5/5q- -7/7q- Trisomy 8 Deaths: # pts: There was a trend for a survival advantage with AZA vs CCR in pts with normal karyotype Patients with non-complex karyotypes had a substantially longer S than patients with complex karyotypes, regardless of treatment AZA, azacitidine; CCR, conventional care regimen; HR, hazard ratio; NR, not reached; S, overall survival. Mufti GJ, et al. Blood. 2009;114(22):

4 Therapy under investigation for Myelodysplastic Syndrome Are we able to recapture p responses and prolong survival? 4

5 CLFARABINE in HR MDS 5

6 S and EFS in MDS patients treated with clofarabine vs clofarabine plus ARA-C Faderl et al, Blood

7 Clofarabine in MDS 30 pts with higher risk MDS Rx with IV clofarabine 15 vs 30 mg/m2/dx5 (n=15) or P clofarabine mg/m2/dx5 Q4-6 wks Faderl, 2007 Median age 68 yrs; prior AZA or DAC 67%; CG abnormal 80% 27/30 evaluable: CR 7 (26%), HI 2 (7%), R 11/27=41% Responses with IV clofarabine 6/15 = 40% Faderl,

8 Clofarabine In patients with MDS who failed azacitidine or decitabine, response rates range from 20% to 40%,but current dosing schedules are excessively toxic 8

9 Rigosertib Dual PLK/PI3K inhibitor Mechanism of Action Non competitive multi kinase inhibitor Does not affect ATP binding site Inhibits PLK 1 pathway Induces spindle abnormalities and polynumeric centrosomes, resulting in chromosomal catastrophe and apoptosis Inhibits a and b isoforms of PI3 kinase Reduces levels of Cyclin D1 and Akt phosphorylation Correlates with activity of the drug Inhibits activation of anti apoptotic t proteins ti including Mcl 1 Rapid, cycle dependent induction of apoptosis Confidential 18 9

10 NIH Findings in MDS Patients Rigosertib was initially developed in solid tumors NIH found high level of Cyclin D1 expression in high risk MDS patientswithtrisomy 8 Rigosertib inhibited Cyclin D1 in primary Trisomy 8 MDS bone marrow clone in vitro Rigosertib did not induce myelotoxicity in vitro Increase of mature CD15+ myeloid cells Decrease of immature CD33 cells or CD34 blasts Decrease of Trisomy 8 cells Decrease in Cyclin D1 in 3 patients responding to rigosertib, with no change in non responders Confidential 19 Rigosertib Phase I/II study Rigosertib 1800 mg/day continuos infusion 3 days every 15 days 36 MDS patients after hypomethylating agent failure PR in 46% of patients verall survival 49 weeks Raza et al, Blood 2011 (abs ASH) ngoing phase III trial randomizing rigosertib to BSC in HR-MDS patients after azacitidine or decitabine failure 10

11 SAPACITABINE NUCLESIDE ANALG NH 2 NH 2 CH 3 (CH 2 ) 14 C NH N N N N N N H H N C N C H H H Deoxycytidine CNDAC Sapacitabine (CS-682, CYC-682) Sapacitabine in hypomethylating agent refractory MDS 39 elderly patients refractory to hypomethylating agents mean age 73 yrs R 23% Arm A 23% Arm B 38% 1-year survival Arm C 8% Low toxicity Good safety profile Well tolerated in elderly pts 11

12 Sapacitabine: Patients and Results 39 pts, median age 73 yrs, 79% 70 yrs BM blasts > 10% in 46% Median number of cycles 2, 4 cycles in 33% Responses: RR 23% (Arm A: 23%, B: 38%, C: 8%): 1 CR/8 HI median time to response 1 2 cycles one death 30 days (unrelated) common AEs: fatigue, nausea, diarrhea, constipation, anemia, neutropenia, alopecia Garcia Manero G et al. Blood 2009; 114: 698 (abs) SAPACITABINE in MDS/AML patients after hypomethylating agent failure Kantarjian et al, JC 28:285 (2009) 12

13 Histone deacetylase inhibitors are mantaining biological promises? HDAC inhibitors Short-chain fatty acids (SCFA) Butyrate derivatives, Valproic acid Hydroxamic acids Trichostatin A, vorinostat, Pyroxamide, panabinostat,itf2357 Epoxyketone-containing cyclic Trapoxins tetrapeptides Non-epoxyketone-containing cyclic tetrapeptides Benzamides FK228, Apicidin MGCD-0103, MS-275, CI

14 DNMTi and HDACi cooperate to restore histone H4 acetylation control butyrate -ach4 NT but But+ DAC DAC H4 DAC 1.6 Butyrate +DAC 1.85 MALIZED %.D. NRM NT D1 D1 DAC +DAC Gozzini and Santini, Annals of Hematol, 2005 HDACi single drugs in HR-MDS HDACi Nb RRHI + CR+ MLFSCRi Kuendgen Valproic acid 58 16% 11% 5% Cancer 2005 [14,15](+ ATRA in 27 pts) Garcia-Manero Blood 2008 [40] Vorinostat 41 17% 7% 10% Gojo Blood 2005 [16] Ent inostat (MS 275) 38 0% NE 0% Garcia-Manero MGCD % 13% 0% Blood 2008 [59] Byrd Blood 2005 [60] Romidepsi n (FK228) 10 0% 0% 0% ttman ASH 2008 [61] Panobinostat (LBH589) 65 (26 AMLs) 20% 12% 8% Prebet & Vey,

15 5-AZA + VPA + ATRA in HR-MDS Leukemia: verall survival MDS0205 Valproic Acid 600 mg/die up to max mg/die, until serum concentration of g/ml is reached, within a max of 14 days At serum concentration obtained 5-Azacytidine (AZA) 75mg/m 2 /day sc for 7 days every 28 days (1 cycle of 28 days), plus Best Supportive Care. PR, CR, Hematological Improvement: at least 4 additional cycles of Valproic Acid/ Azacytidine Continue Therapy for 2 years in patients achieving PR or CR Minor response, stable disease, failure: at least 4 additional cycles Valproic Acid/Azacytidine, adding ATRA 30 mg/m 2 /die (day +8 to +28) Enrolled: 62 patients Enrolment Time: 11 months 15

16 TREATMENT RESPNSE After 4 cycles n=41 After 8 cycles n=26 Hematological improvement 12 (29.3%) 4(15.4%) Stable disease 20 (48.9%) 10 (38.5%) Failure 4 (9.7%) 4 (15.4%) CR 1 (2.4%) 3 (11.5%) PR 4(97%) (9.7%) 5(19.2%) Median time to CR/PR: 5.4 months (range: ) ATRA was added in 11 pazients on cycle 5, without significant benefit. Voso et al, 2009 Genotype Patients n (%) CDA c/c 41 (98) c/a 1 (2) a/a 0 (0) CDA a/a 16 (37) a/g 21 (49) g/g 6 (14) GSTP Ile/Ile 19 (46) Ile/Val 18 (44) Val/Val 4 (10) PHARMACGENMICS Genotype Patients n (%) CYP2C19*2 42 wt/wt 26 (62) wt/mt 14 (33) mt/mt 2 (5) CYP2C19*3 38 wt/wt 38 (100) wt/mt 0 (0) mt/mt 0 (0) CYP3A4 Promoter 43 a/a 40 (93) a/g 3 (7) g/g 0 (0) The CYP2C19*2 polymorfism impacts the valproic acid dose necessary to reach the target concentrationonday1ofaza.carriersofthissnp require higher VPA doses that WT subjects (median 609 vs 600 mg, range , vs , p=0.0021). Voso et al,

17 Combination of azacitidine and vorinostat in high risk MDS patients Azacitidine Azacitidine - cohorts 1-8 Vorinostat t cohorts 1-4 Vorinostat cohorts 5 7 Vorinostat cohort Day This represents 1 cycle. Cycle will be repeated every 28 days for a minimum of 4 cycles. Schedule overlap Silverman LR, et al. Blood. 2008;112:[Abstract 3656]. Azacitidine plus vorinostat: responses Enrolled 23 Evaluable for response 18 verall Response* 15 (83.3%) CR 9 (50%) CRi 2 (11%) CR+CRi 11 (61%) PR 0 HI 4 (22%) Stable 2 (11%) NR 1 ( 6%) Too Early 2 IE for response 3 Withdrew prior to Rx 1 Transfusion Independence (n = 9 (83%) 11) Silverman LR, et al. Blood. 2008;112:[Abstract 3656]. 17

18 Clinical Response to aza plus vorinostat Higher Risk MDS/ AML (n = 10) 5 CR; 1 CRi; 2 HI; 1 NR; 1 SD; (3 IE; 2 TE) 8 ( 80%) Poor Risk Cytogenetics (n = 4) 3 CR; 1 HI; (2 IE; 1 TE) 4 (100%) Med No. cycles to response 2 Med No. cycles administered 5 ( 1-15 ) Silverman LR, et al. Blood. 2008;112:[Abstract 3656]. Prolonged Administration of Azacitidine with or without Entinostat Increases Rate of Hematologic Normalization for Myelodysplastic Syndrome and Acute Myeloid Leukemia with Myelodysplasia Related Changes: Results of the US Leukemia Intergroup Trial E1905 Thomas Prebet, M.D., Ph.D., Zhuoxin Sun, PhD, Steven D. Gore, M.D., Peter L. Greenberg, MD, Mark Juckett, MD, Lisa Malick, Mitchell R Smith, MD, PhD, Elisabeth Paietta, PhD, Magdalena Czader, Janice Gabrilove, M.D., Harry P ErbaDM, PhD and Martin S. Tallman, MD 18

19 Entinostat (MS275) Class II HDACi rally available Evaluation in phase I/II trials single agents Toxicity manageable Limited clinical activity Gojo Blood 2007 E1905 study Phase II randomized study in MDS and saml Arm A= Azacitidine alone 50mg/m 2 /d 10 days Arm B= AZA 10 days + Entinostat day 3 and day 10 Primary objective To determine the rate of Hematologic trilineage response (TR= CR+PR+ tri lineage HI) Aim= doubling of TR rate/calgb9221 (15% 30%) 19

20 Patients characteristics (n=136) Whole population Median age 72 years MDS / AML/ CMML 64%/32%/4% Cytogenetic risk group Favorable=26% intermediate=15% Unfavorable= 31% Missing or NE= 27% IPSS (<1.5/ 1.5+)* 28%/ 72% RBC dependent 63% Platelet dependent 25% *= MDS patients only Response evaluation (IWG 2000) Arm A AZA alone Arm B AZA+ Entinostat Complete Remission 12% 7% Partial Remission 9% 7% Trilineage HI 10% 10% HI not trilineage 12% 19% No response 57% 56% 20

21 Response evaluation (IWG 2000) Arm A AZA alone Arm B AZA+ Entinostat Complete 12% 7% Remission Trilineage Trilineage Response: Response: Partial Remission 9% 7% 31% 24% Trilineage HI 10% 10% HI not trilineage 12% 19% No response 57% 56% Analysis of overall survival S Comparison 0.1 Log Rank Test p= Month Treatment TTAL FAIL CNSR MEDIAN Azacitidine Azacitidine+Entinostat

22 Do we have other targets? Gemtuzumab zogamicin (G) IgG4 anti-cd33 CH3 H NH DNA minor groove binding CH3 I S CH3 CH3 CH3 H Linker Me Me NHN S Me S CH3 CH3 H HN H CH3 CH2 N CH3 CH3 H H CH3 NH Calicheamicin derivative Binds to CD33 and gets internalized Linker cleaved intracellularly Calicheamicin binds to DNA Double strand break apoptosis 22

23 5 AZA DNMT HDACi 5 AZA HDACi CR HDAC 1-2 CR DNMT HDAC 1-2 MBP MBP CpGCpG CpG TF CA HAT H 3 H 4 H 2 A H MBP CpG CpG HMT calicheamicin 3 2 B H H 4 H H 2 A 2 B SHP-1 Double strand break Gene derepression SHP-1 SHP-1 SHP-1 Apoptosis Syk Syk Syk Syk CD 33 -CD33 Gemtuzumab zogamicin (G) G plus arsenic trioxide id 30 HR-MDS or AML with prior azacitidine RR 7/30 Sekeres et al. Cancer (2011) 23

24 Are we able to improve cytopenias other than anemia in LR MDS?? LR-MDS: S depends on platelet number Gonzales-Porras et la. Cancer 2011; on line pub 24

25 Therapy with romiplostim and azacitidine in LR- MDS 2010 by American Society of Hematology Kantarjian H M et al. Blood 2010;116: Therapy with romiplostim in LR- MDS Sekeres et al.,cancer, 2011 ;117:

26 LR-MDS: is eltrombopag different? Will B, Blood 2009 Pre-clinical research: eltrombopag in MDS/AML Reduced proliferation of non-megakaryocytic acute myelogenous leukemia and other leukemia and lymphoma cell lines in response to eltrombopag, Erickson-Miller et al. (Leukemia Research, 2010) Effect of the Non-peptide Thrombopoietin Receptor Agonist Eltrombopag on Bone Marrow Cells from Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome Will et al. (Blood, 2009) Study of the In Vitro Effect of the Nonpeptide Thrombopoietin -Receptor Agonist SB (Eltrombopag) on Megakaryopoiesis of Patients with Low/Intermediate-1 Risk Myelodysplastic Syndrome Mavroudi et al. (Leuk Res, 2010) A prototype nonpeptidyl, hydrazone class, thrombopoietin receptor agonist, SB , is toxic to primary human myeloid leukemia cells. Kalota et al. (Blood, 2010) 26

27 Eltrombopag MDS/AML Clinical Program Phase I/II (MDS/AML) PMA Phase II (MDS/AML) TRC Two global, randomized, placebo-controlled studies, both: enroll patients with int2/high risk MDS or AML treat patients not receiving active treatment at baseline assess clinically relevant efficacy endpoints allow assessment of safety for 6 months supported by entire eltrombopag program (>3100 pts) Immune mediated LR-MDS : predictors of response The best candidates to ATG plus CSA age lower than 60 years (Molldren 2002, Sauntararajah 2002, 2003) a normal karyotype a hypoplastic bone marrow (Lim 2007, Molldrem 2002, Sauntararajah 2002) HLA-DRB1-15 antigen (yessloand 2008, Sauntararajah 2002) ( no Stadler 2008) 27

28 Immune mediated LR-MDS : is immunosuppressive therapy prolonging survival? Atg + Csa BSC crossover Survival Time (years) Passweg et al, JC 2011; 29: