Low Risk MDS Scoring System. Prognosis in Low Risk MDS. LR-PSS Validation 9/19/2012

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1 Advances in MDS What s on the Horizon Tapan M. Kadia, MD Department of Leukemia MD Anderson Cancer Center Outline Newer Prognostic Systems Hypomethylating agent failures Newer Treatment approaches Role of Stem Cell Transplant Advances in Biology of MDS Newer Prognostic Systems Why are they needed? New Systems LR-PSS IPSS-R Prognostic System for t-mds 1

2 Low Risk MDS Scoring System Patients with MDS and lower risk disease by IPSS have a heterogeneous outcome. Need to better define risk categories in patients with low or Int-1MDS Prognostication Risk-adapted strategies 500 pts with low or Int-1 MDS (by IPSS) analyzed. Prognosis in Low Risk MDS Score Median Survival (months) Adverse Factor Adverse cytogenetics 1 Age 60 2 Hgb < 10 1 Platelets < 50 2 Platelets BM Blasts 4% 1 Garcia-Manero G, et al. Leukemia 22:538-43, 2008 Points LR-PSS Validation Bejar R, et. al. Blood, 2011;118: Abstract 969 2

3 New Cytogenetic Categories Normal Female Karyotype 46 XX Complex Karyotype, incl. monosomy 7 New Cytogenetic Categories Karyotype is a strong independent prognostic indicator in MDS. New cytogenetic techniques, more data, longer followup since the original IPSS has led to increase in knowledge about cytogenetic abnormalities. Schanz et. al. analyzed data from 2,902 international patients to create a new comprehensive cytogenetic hierarchy and scoring system. New Cytogenetic Categories Garcia-Manero G. AJH, 2012 adapted from Schanz J, et.al. JCO 30:820-9,

4 Revised International Prognostic Scoring System (IPSS-R) Original IPSS was published in 1997 and has been an important tool Newer data, newer scoring systems, shortcomings of original IPSS prompted development of a more precise model International effort deriving patient data from 7012 patients in 11 countries Patients with primary, untreated, MDS per FAB definition were included. Multivariate analysis allowed development of a score Greenberg P, et al. Blood 2012: Jun 27 [Epub ahead of print] IPSS R Refinements of the Original Refined cytogenetic categories Data from Schanz et. al. formed basis for cytogenetic categories 16 specific chromosome abnormalities vs. 6 5 specific cytogenetic risk groups vs. 3 Depth of cytopenias given weight New marrow blast cutoffs ( 2%, 3-4%, 5-10%, >10%) Specific patient differentiating factors Age, PS, serum ferritin, LDH, β2-microglobulin Greenberg P, et al. Blood 2012: Jun 27 [Epub ahead of print] IPSS-R Cytogenetics Cytogenetics in 5 subgroups Carry most weight in scoring system Karyotype Category Very Good Good Intermediate Poor Very Poor Chromosomes -Y, del (11q) Diploid, del(5q), del (12p), del (20q), double including 5q del(7q), +8, +19, I(17q), and other single or double clones -7, inv(3)/t(3q) /del(3q), double including - 7/del(7q), complex with 3 abnl Complex with >3 abnl Median OS (y) Greenberg P, et al. Blood Jun 27. [Epub ahead of print] 4

5 IPSS-R for MDS Score Variable BM blasts (%) 2 >2 to < >10 Cytogenetics Hemoglobin (mg/dl) Very Good 10 8 to <10 <8 Platelets to <100 < 50 ANC 0.8 < 0.8 Risk Group Scores Very Low 1.5 Low > Intermediate > High > Good Interm. Poor Very Poor Very High > 6 Greenberg P, et al. Blood Jun 27. [Epub ahead of print] Survival of MDS Patients by IPSS-R Very Low Low Intermed High Very High Pts (%) Median OS (yrs) Age NR > > Greenberg P, et al. Blood Jun 27. [Epub ahead of print] Risk of 25% Evolving to AML Very Low Low Intermed High Very High Pts (%) Median Time to AML (y) NR Greenberg P, et al. Blood 2012: Jun 27 [Epub ahead of print] 5

6 Prognostic Score for t-mds Prognostic Score for t-mds Prognostic Score for t-mds 6

7 Hypomethylating Agent Failure Overall Response to hypomethylating agents ranges from 28-48% Median duration of response 8-10 months Improved OS Decreased transfusion requirements Patients who do not respond to hypomethylating agents or progress after initial response have poor prognosis. Outcomes after Decitabine Failure Retrospective review: 87pts with MDS / CMML who received decitabine ORR = 57% (CR = 24%; PR 2%, mcr 7%, HI 24%) Median f/u 21 months (range 6 89) Patterns of failure: Transformation to AML (25%) Cytopenias, persistent MDS (75%) Jabbour E, et al. Cancer Outcomes after Decitabine Failure 13 of 89 patients (15%) were alive. Median survival post decitabine failure : 4.3 months Estimated 12-month survival rate : 28% Jabbour et al. Cancer

8 Therapies & Outcomes after Decitabine Failure 33% 30% 100% 50% 20% 20% Jabbour E, et al. Cancer Newer Treatment Approaches Combination therapies AZA + Lenalidomide AZA + vorinostat Rigosertib Oral Azacytidine Very Low Dose Decitabine ARRY-614 ATG, Cyclosporine, Steroids Chemotherapy? Hypomethylating combinations Lenalidomide + Azacytidine Simultaneously Phase I study showed safety and efficacy (ORR=67%) Phase II study: AZA 75 mg/m 2 x 5 days + LEN 10mg PO Daily x 21 days. Higher risk MDS (IPSS 1.5 or 5% blasts) Sekeres MA, et al. Blood 2011; 118: Abstract 607 8

9 Hypomethylating combinations Sekeres MA, et al. Blood 2011; 118: Abstract 607 Hypomethylating combinations Sekeres MA, et al. Blood 2011; 118: Abstract 607 ORR: 26/36 (72%) CR: 15 (42%) HI: 10 (28%) mcr: 1 (3%) Lenalidomide + AZA Median Time to Response: 3 months Median CR duration: 16 months (range 3-36+) Median OS in CR pts: 27 months (7-55+) Sekeres MA, et al. Blood 2011; 118: Abstract 607 9

10 Hypomethylating combinations Azacytidine + Lenalidomide Sequentially Phase I/II Study in patients with R/R AML and high risk MDS (blasts >10%) Phase I study: AZA 75 mg/m 2 on days 1-5 followed by Escalating doses of LEN Daily for 5 or 10 days starting on day 6. LEN dose escalation: 10, 15, 20, 25, 50, 75 mg x 5 days 75 mg x 10 days Garcia-Manero G, et al. Blood 2011; 118: Abstract 2613 AZA LEN N=28 patients enrolled; Median age 65 (31-79) AML: 19 patients MDS or CMML: 9 patients Common Non-Hematologic toxicities: Fatigue, loss of appetite, constipation, rash, fever, weight loss No DLTs; MTD not reached 1 unexpected death in 75 mg x 10 day arm Responses 3/5 (60%) previously untreated patients achieved CR In previous treated patients, no responses, but 47% had stable disease. Garcia-Manero G, et al. Blood 2011; 118: Abstract 2613 Azacytidine + Vorinostat AZA + SAHA Phase II Study in patients with untreated MDS/AML not eligible for other therapies Advanced PS, co-morbidities, history of malignancy Bilirubin >2 or creatinine >2 allowed Median OS in this population is poor (<60 days) Combination epigenetic therapy is safe & effective; low induction death Dose and schedule: AZA 75 mg/m 2 IV Daily x 5 days (d 1 5) Vorinostat (SAHA) 200 mg PO TID x 5 (d 1 5) Cycles repeated every 28 days Garcia-Manero G, et al. Blood 2011; 118: Abstract

11 AZA + SAHA - Patient Characteristics Garcia-Manero G, et al. Blood 2011; 118: Abstract 608 AZA + SAHA - Outcomes Garcia-Manero G, et al. Blood 2011; 118: Abstract 608 ON Na (Rigosertib) Multikinase inhibitor that selectively induces mitotic arrest and apoptosis in cancer cells, sparing normal cells IV and oral formulations being studied in MDS/AML 11

12 Preliminary Data - Rigosertib Phase I/II trial of IV formulation in MDS 60 pts (51 RAEB, 9 RCMD) IV rigosertib given over 2-6 days weekly or every other week. 8 pts with HI; OS was related to marrow blast response (incl. hypomethylating failures) & IPSS Among 15 pts with hypomethylating failure treated with 1800 mg/d x 3d every other week, med OS was 49 wks. Well tolerated Phase II and III trials in MDS pts with hypomethylating failure are ongoing. Raza A, et al. Blood 2011; 118: Abstract 3822 Preliminary Data - Rigosertib Phase I trial of oral formulation in MDS Objective to test oral bioavailability, dose-finding MDS pts with 1 cytopenia and 1 prior therapy 33 pts; Dose escalation from 70 to 700 mg orally twice daily for 2 wks out of 3 wk cycle. 560 mg twice daily was rec phase II dose; drug is bioavailable to active concentrations Responses: 2 marrow CR (140mg and 560 mg dose levels) 4 HI (erythroid) in lower risk, transfusion-dependent pts. Komrokji R, et al. Blood 2011; 118: Abstract 3797 Oral Azacytidine New formulation of 5-azacytidine may have several advantages: More convenient for patients Easier access Prolonged/extended dosing more feasible Low dose chronic exposure of hypomethylating agent may be more effective Bioavailability, safety, & efficacy being confirmed 12

13 Oral Azacytidine Phase I Study in MDS, CMML & AML Dose escalation ( mg) with once daily dosing x 7d every 28d Exposure increased with higher doses. Bioavailability: 6.3% - 20% Well tolerated: diarrhea, nausea, vomiting, neutropenic fever, fatigue 43pts; HI in MDS/CMML only; ORR= 35% in prev treated and 73% in untreated Garcia-Manero G, et al. JCO Oral Azacytidine Phase I Study in AML Mutiple schedules including multiple daily doses: mg orally daily x 7d every 28d 300 mg daily for 14 or 21 days 200 mg twice daily for 14 or 21 days Pharmacokinetics similar to previous study. Increased exposure with twice daily dosing; no drug accumulation Well tolerated; again: diarrhea, nausea, vomiting, neutropenic fever, fatigue; also pneumonia, syncope, headache, mental status changes 23pts; ORR= 26% (6/23): 5 HI (22%) and 1 CRi (4%) Gore S, et al. Blood 2011; 118: Abstract 1546 Low Dose Decitabine in LR MDS Garcia-Manero G, et al. Blood 2011; 118: Abstract

14 Low-dose Decitabine in Lower Risk MDS 67 pts with low-int 1 risk MDS randomized (Bayesian) to decitabine 20 mg/m2 daily x 3 or weekly x 3 Q4-6 wks Parameter Daily Weekly Rx Median cycles OR 10/43 (23%) 7 CR, 3 HI % Tx Ind RBC PLTS /22 (23%) 1 MCR, 1 PR, 3 HI % 2 yr OS Garcia-Manero G, et al. Blood 2011; 118: Abstract 3812 ARRY-614 in MDS ARRY-614 in MDS P 38 MAP kinase and TIE 2 inhibitor 45 pts with low (n=11) or int-1 (n=34) risk MDS; median age 72 yrs (47-84); median prior Rx 3; prior hypomethylator 82%; prior EPO 49% ARRY mg/d, mg BID DLTs: rash, fatigue 8/43 (19%) had HI: 4 HI E, 5 HI N, 4 HI P ; bilineage response in 5 Future plans: combos with hypomethylators and EPO Komrokji, et al. Blood 2011; 118: Abstract

15 Nucleoside Analogue: Clofarabine Approved for ALL; also active in AML/MDS Faderl, et. al. Cancer 2012 IV clofarabine 15 vs. 30 mg/m 2 /d x 5 in high risk MDS 58 pts, median age 68, (60% hypomethylating failure) ORR=36% (CR=26%); 8-wk mortality 19%; 30 mg dose had more liver/renal AEs & lower ORR Lim, et. al. Leuk & Lymph 2010 IV clofarabine 5 vs 10 mg/m2/d x 5 in pts with MDS and hypomethylating failure 10 pts, median age 73; 9 eval for response ORR=44% (4/9): 1 CR, 1 PR, 2 HI; med resp duration: 12m Prolonged myelosuppression, bleeding Low Dose Clofarabine in MDS / AML Post Azacitidine Failure Clofarabine IV Days 1-5 and Days 1,3,5,8,10 3 dose levels 5,7.5, 10 mg/m2; total mg/m2/course 19 pts Rx at 5 (n=9), 7.5 (n=10) Dose D 1-5 D 1-10 Total 5 mg/m2 0/6 2/3 2/9 7.5 mg/ m2 2/7 2/3 4/10 All doses 2/13 4/6 6/19 (32%) 6 responses: 1 CR,1 PR, 4 marrow CR DLT myelosuppression in 2/19 Extended dose schedule better? Braun, et al. Blood 2011; 118: Abstract 609 Transplants in Older Pts with MDS? Koreth J, et al. Blood 2011; 118: Abstract

16 Analysis of 4 different cohorts Koreth J, et al. Blood 2011; 118: Abstract 115 OS Analysis in Low/Int-1 IPSS OS Analysis in Low/Int-1 IPSS Koreth J, et al. Blood 2011; 118: Abstract 115 OS Analysis in Low/Int-1 IPSS Koreth J, et al. Blood 2011; 118: Abstract

17 Transplant vs. AZA in Older patients Overall Survival Event Free Survival Platzbecke et al Biol Blood & Marrow Trans (18); 9: Post Transplant Azacytidine Toxicities grade I / II III Thrombocytopenia 7 2 Nausea 9 Fatigue 6 Transaminase elevation 2 1 (AZA + posaconazole) Conjunctival erythema (n=1), Pruritus (n=1), gd I confusion (n=2), retina hemorrhage (possibly preexisting), gd II creatinine elevation (n=1), oral ulcers (n=1), papilledema (n=1), and pulmonary hemorrhage (n=1; second HSCT, fungal pneumonia/hepatic VOD during the 1st AZA cycle, evolving with thrombocytopenia/bleeding). - MTD : 32 mg/m 2 given for 5 days every 28 days de Lima et al Cancer 2010; Molecular Abnormalities in MDS Newer DNA sequencing techniques allowing investigators to uncover genetic mutations in MDS Important role in Diagnosis of MDS Prognostication of MDS Future treatment strategies in MDS Can help define biology if this disease; work ongoing at a rapid pace 17

18 Point Mutations in MDS Bone marrow from 439 pts with MDS analyzed for mutations. Mutations in 18 genes were identified (2 new: ETV6 GNAS) 51% of pts had at least 1 mutation Bejar R, et al NEJM 2011; 364; TET2 mutatons assoc. with normal cytogenetics TP53 assoc. with complex karyotype Mutations in RUNX1, TP53, and NRAS were each assoc. with Severe thrombocytopenia Elevated BM blasts Mutations in MDS Bejar R, et al NEJM 2011; 364; Mutations in MDS and Survival Bejar R, et al NEJM 2011; 364;

19 Mutations in MDS and Survival Bejar R, et al. Blood 2011; 118: Abstract 969 SF3B1 Mutations in MDS New mutation found in 20% (72/354) of MDS cases. Found in 65% of cases of RARS Gene involved in RNA splicing machinery Mutations associated with down regulation of mitochondrial signaling pathways Papaemmanuil E, et al NEJM 2011; 365: On the Horizon Many challenges exist Many new advances are being developed Risk stratification, better diagnosis Newer treatments Stem Cell Transplant and post transplant therapy Understanding the biology on the way to curing this disease 19