Disclosures. How Are Patients With MDS Treated In November 2014? What Are The Greatest Needs In The MDS Field? 11/3/2014. A general approach to MDS

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1 Aplastic Anemia & MDS International Foundation Patient & Family Forum Miami Area November 2014 Disclosures Therapies For MDS: Where Are We Going? David Steensma, MD FACP Associate Professor of Medicine, Harvard Medical School Adult Leukemia Program, Dana-Farber Cancer Institute Hematological Oncology Service, Brigham & Women s Hospital Data monitoring committee: Amgen Scientific advisory board: Genoptix, Celgene, Boehringer Ingelheim, Off-label / experimental use: only azacitidine, decitabine and lenalidomide are FDA approved for MDS Medications currently commonly used for patients with MDS How Are Patients With MDS Treated In November 2014? FDA Approved for MDS-Related Indications Hypomethylating agents / DNA methyltransferase inhibitors / epigenetic drugs Azacitidine (Vidaza ) Approved May 2004 Decitabine (Dacogen ) Approved May 2006 Immunomodulatory drug (imid) Lenalidomide (Revlimid ) Approved December 2005 Iron chelators Deferasirox (Exjade ) Approved November 2005 Deferoxamine (Desferal ) Approved 1968 FDA Approved for Other Indications Blood cell (hematopoietic) growth factors Red cell growth factors Epoetin alfa (Procrit ) Darbepoetin alfa (Aranesp ) White cell / myeloid growth factors Filgrastim, G-CSF (Neupogen ) Pegfilgrastim (Neulasta ) Platelet growth factors Romiplostim (NPlate ) Eltrombopag (Promacta ) Immunosuppressive drugs (ATG, CsA) Thalidomide, androgens, other biologics Chemotherapy or stem cell transplant A general approach to MDS Supportive care for all (transfusions and antimicrobials PRN,?iron chelation) Lower-risk MDS (assessed using IPSS-R, etc.) Cytopenia(s) Disease feature First-line therapy Anemia only Del (5q) Lenalidomide Neutropenia or thrombocytopenia or both Allogeneic SCT candidate? Yes No No del(5q), sepo <500 No del(5q), sepo >500 Higher-risk MDS Therapeutic approach ESA ± G-CSF?Immunotherapy None established; observation, growth factors, aza/decit reasonable Proceed to transplant ASAP; a hypomethylating agent (HMA) or cytotoxic chemotherapy may be useful as a bridge Azacitidine; decitabine as alternate What Are The Greatest Needs In The MDS Field? Partly based on 2014 NCCN guidelines; see 1

2 MDS clinical research priorities More accurate diagnostic methods Current techniques are to some extent subjective Molecular testing is helping in ambiguous cases Better prognostication There are limits to this, but helps decide on therapy Better systems of health care delivery In the US we use our health care dollars poorly / inefficiently Improved therapy Largest specific unmet therapeutic needs Increase proportion of aza/decitabine responders Current complete response rate 10-20% Current overall response rate 40-50% Average duration of response 8-11 months Need to increase also depth of response and duration Treatments for patients after aza/decitabine stop working Treatments for higher lower risk patients Defined by molecular genetics or other features Who else does lenalidomide work for besides people with del(5q)? Other curative therapies besides transplant Outcomes after azacitidine or decitabine failure of patients with MDS Reasons for failure in azacitidine failure study 9% didn t tolerate AZA (69% were not responding, 3 had an initial response) 55% primary failure (progression in 60%, stable disease without response in 40%) 36% secondary failure after initial response (best response: CR 20%, PR 7%, HI 73%) Outcomes after failure Median overall survival for whole cohort post-aza: 5.6 months 2 year survival: 15% Favorable factors: female, younger (<60), better risk karyotype, <10% blasts, some response to azacitidine Comparison to decitabine MDACC: median survival 4.3 months, n=87 Prébet T et al, J Clin Oncol 2011; Aug 20;29(24): Epub 2011 Jul 25. Jabbour E et al, Cancer 2010; 116: Need for additional therapeutic options in MDS : Outcomes after azacitidine / decitabine failure are poor Data available on 435 pts from AZA001, J9950, J0443, French compassionate program Overall median survival after azacitidine failure: 5.6 months Subsequent therapy Number of patients (%) Median survival Allogeneic transplant 37 (9%) 19.5 months Investigational therapy (e.g. IMiD, HDACi, other) Intensive cytotoxic therapy (e.g., 3&7) Low-dose chemotherapy (e.g. LDAC, 6-MP) 44 (10%) 13.2 months 35 (8%) 8.9 months 32 (7%) 7.3 months Palliative / supportive care 122 (28%) 4.1 months Subsequent therapy unknown 165 (38%) 3.6 months Prébet T et al J Clin Oncol 2011; 29: Jabbour E et al Cancer 2010;116(16): Options when azacitidine or decitabine fail to produce a response, or after an initial response is lost Switch to the other hypomethylating agent (0 responses one European series, but 19-40% in H. Lee Moffitt series) Continue the current therapy anyway, with or without adding a second agent (e.g. deacetylase inhibitor) may delay progression Supportive care only feels like giving up Why Has Therapy of MDS Been So Challenging? Clinical trial enrollment lots of trips to major center Off-label therapy (e.g., low-dose cytarabine, clofarabine) doesn t work very well overall Allogeneic stem cell transplant only a few pts eligible 2

3 Clone size 11/3/2014 Unlike leukemia, there are no widely useful MDS cell lines. Several animal models now exist, but may not be representative. This makes screening targeted agents more challenging. Challenge #1 to narrowly targeted therapies Genetically modified mouse for disease modeling Genomic architecture of MDS. Frequency of driver mutations identified in the sequencing screen or by cytogenetics in the cohort of 738 patients, broken down by MDS subtype. Long tail of lesions present at <2% level Challenge #2 to developing narrowly targeted therapies Images from medieval BestiarumVocabulum Papaemmanuil E et al. Blood 2013;122: MDS mutation landscape: Obvious targets are few Clonal architecture of MDS progression to AML: 6 patient examples BRAF(<) GNAS(<) Proliferation JAK2 3% KRAS CBL 2% NRAS 4% CDKN2A (<) PTPN11(<) PTEN(<) Impaired Differentiation RUNX1 9% ETV6 3% IPSS independent good prognosis No clear independent effect IPSS independent poor prognosis SETBP1 7% Time Challenge #4 to narrowly targeted therapies EZH2 6% TET2 2 Epigenetic regulation DNMT3A (8%) UTX IDH1/2 2% ASXL1 14% ATRX < NPM1(2%) SF1 SF3B1 22% Other U2AF1 8% ZRSR2 5% TP53 8% Pre-mRNA splicing PRPF40B SRSF2 1 SF3A1 U2AF65 < Targetable mutation Walter MJ et al N Engl J Med 2012; 366: Painful. Despite that, there are many new agents in development Challenge #5 (to any new therapies) Bejar and Steensma, Blood

4 Really, a lot! (But not all agents are created equal) What Is Coming Next? Bejar and Steensma, Blood 2014 Predicting the future accurately is notoriously difficult. Where are our robot housekeepers, rocket trains, and flying cars?! Some themes Combination therapies lots of aza plus studies ongoing or getting going Increased use of targeted therapies (even if targets not entirely understood) Using old drugs in new ways (e.g., oral formulations of azacitidine and decitabine, altered schedules) Greater use of allogeneic stem cell transplant expanded donor pool and stem cell source options, bioengineered cellular products, older patients New nucleoside analogues SGI-110: second-generation hypomethylating agent dinucleotide of decitabine and deoxyguanosine delivered as a subcutaneous injection allows a longer half-life and more extended decitabine exposure 15 pts with Int-2/High risk MDS Median age 74; all had previous aza/decitabine 5 responders (33%), duration days Most common AE: injection site pain, diarrhea Rigosertib after Azacitidine N BM CR (+HI) HI ORR All patients 32 6 (1) 4 10/32 (3) 3-day infusions 17 4 (1) 3 7/17 (4) 3-day pivotal (1800 mg/d) 13 4 (1) 2 6/13 (46%) Survival probability (%) Weeks Median: 68 wks OS by Marrow Blast Response BM Blast Response Not Assessed Progressive Disease Stable BM Blast Count 50%+ BM Blast Decrease O Connell C et al, EHA 2013, abstract P189 Slide borrowed from Dr. Rami Komrokji Raza et al. Blood 2011;

5 Rigosertib (ON01910.Na) randomized trial for post-hma failure Eligible patients: MDS (FAB) with 5-30% blasts and at least one cytopenia; WBC < 25x10 9 /L No response or progression after 6 cycles azacitidine or 4 cycles decitabine Not an allogeneic stem cell transplant candidate, or refused transplant No low-dose cytarabine within last 2 years Bilirubin <1.5 and creatinine <2 mg/dl n=180 Randomize 2:1 n=90 8 months median survival ON Na 1800 mg/24 hr as a 72-hr continuous infusion on Days 1, 2, and 3 of a 2-week cycle Primary Endpoint: Overall survival Secondary Endpoints: IWG 2006 response, AEs, etc 6 months median survival Best Supportive Care (BSC) or Low-Dose Cytarabine (LDAC) Oral rigosertib for lower-risk patients 34 evaluable patients Transfusion dependent, IPSS Low/Int-1 MDS 8 got continuous dosing, 26 intermittent Of intermittent dosing, 50% became transfusion independent For 2 pts, this lasted >9 months Urinary adverse events most common Urgency/frequency 38% Dysuria 15% Hematuria 15% More common with continuous dosing Raza A ASCO 2013 Abstract 7031 Eltrombopag vs Placebo in IPSS Low- or Intermediate-1 Risk MDS and low platelet count receiving supportive care Phase II, national, multicentre, prospective, randomized, single blind study for patients with plt ct <30 Randomization 2:1 Patients (N = 69) Wk 24 Eltrombopag + Standard care (n = 46) Placebo + Standard care (n = 23) CR and R Eltrombopag + Standard care Standard Care Dose start: 50 mg with increases every 2 weeks up to 300 mg daily. Response Platelet responses at 16 weeks: Eltrombopag N= 9 Placebo N=5 Response, n 3 0 Complete Rresponse, n 5 0 NR 1 5 Total, n (%) 8 (89) 0 (0) WHO bleeding grade 2, events 0 8* Time to Response: In 4 cases, early responses after 1 week; In 2 cases by 8 weeks and in 2 cases by 12 weeks. Median daily eltrombopag dose eltrombopag at response was 75 mg (IQR mg). Combination Therapy Approach: Improve upon existing therapies Example: At least 2 clinic trials in development combine: Azacitidine + Deferasirox (Exjade) Advantage: drugs are already FDA approved for MDS Lenalidomide + Azacitidine Trial Multicenter, single-arm open-label phase II continuation study (N = 36) Patient eligibility Higher-risk MDS: CMML-2, RAEB-1 or -2, IPSS intermediate 2 or high (score 1.5), or revised IPSS score 4 or 5 No previous treatment with lenalidomide or azacitidine Maximum of seven 28-day treatment cycles administered Lenalidomide 10 mg on Days 1-21 Azacitidine 75 mg/m 2 on Days 1-5 After 7 cycles, patients could continue azacitidine monotherapy off study Median patient follow-up: 12 mos (range: 3-55) Positive results can quickly change practice! Slide borrowed from Dr. Rami Komrokji Sekeres MA, et al. Blood. 2012;120:

6 Response Rate (%) I I 11/3/2014 Lenalidomide + Azacitidine Azacitidine + Vorinostat combination trial in sicker patients Lenalidomide/ Azacitidine (N = 36) CR Hematologic improvement Median CR duration: 17+ mos (range: 3-39+) Median OS among CR: 37+ mos (range: 7-55+) 8 patients evolved to AML at median of 18 mos after CR Treatment well tolerated; FN was most common grade 3/4 AE (22%) Eligibility Age 18 years Untreated MDS ( Int-1) or AML And any of the following: Total bilirubin 2 mg/dl Creatinine 2 mg/dl ECOG performance status > 2 Excluded from all other clinical trials: Presence of other active malignancy Dose and schedule AZA 75 mg/m 2 IV QD days 1 to 5 Vorinostat 200 mg PO TID days 1 to 5 Cycles repeated every 28 days Patients (N=30) CR (%) CRp (%) ORR (%) ALL 8 (26) 1 (3) 30 Diploid (7) 3 (42) /-7 (16) 3 (10) 1 (3) (3) 2 (66) 0 66 Slide borrowed from Dr. Rami Komrokji Sekeres MA, et al. Blood. 2012;120: Slide borrowed from Dr. Rami Komrokji Garcia-Manero et al. Blood 2011 S1117 (US/Canada Intergroup) study Eligible: Higher-risk MDS or CMML (5-19% blasts or IPSS Int-2/High) n=80 n=80 Azacitidine monotherapy (7 days x 75 mg/m2/day) Azacitidine + lenalidomide (10 mg/d for 21/28 days) Power: 8 probability of detecting a 20% difference in ORR (with alpha 0.05) Altering the cytokine milieu n=80 Azacitidine + vorinostat (600 mg/day) Primary endpoint: overall response rate [ORR] (IWG 2006) Secondary endpoints: overall and progression-free survival, safety Principal investigator: Mikkael Sekeres, Cleveland Clinic Previous attempts S. Z. Fields et al. Constitutive Activation of TGF-β Signaling Suppresses Hematopoiesis in MDS TNF alpha antagonists such as those approved for autoimmune conditions (etanercept, infliximab) Pentoxifylline/ciprofloxacin/dexamethasone Thalidomide Amifostine [thiophosphate free radical scavenger] (0 responses in Mayo trial) Siltuximab [anti-il6 antibody] ( patient randomized trial, 0 responses) Activins Exogenous Inhibitors GDFs / BMPs* Sotatercept Follistatin Inhibin FLRG ACE-0536 Neutralizing Betaglycan antibody Modified ALK4 propeptide ALK7 Other* II II II II ActRIIA ActRIIB P Smad2 Smad3 LY Smad6 Smad7 Smad4 Gene expression Figure 2. Activin receptor signaling pathw ay and exogenous inhibitors. Activins and some GDFs bind type II receptor (e.g., ActRIIA) Fields with highet affinity al: and trigger Expert formationopin. of a ternary Investig. complex with type I Drugs receptor (e.g., (2013) ALK4). Activated22(1) type I eceptor then phosphorylates Smad2/3 (regulatory Smads), which form a heteromeric complex with Smad4 (co-smad) that ranslocates to the nucleus and regulates gene expression. Smad6/7 (inhibitory Smads) mediate feedback Zhou onl, kinase et activity al. BLOOD of 2008; 112:3434. ype I receptors, and small molecule inhibitors (e.g., LY ) also target this activity in ALK4, ALK7, and ALK5. Sotatercept Phospho-Smad2 IHC Zhou L et al. Cancer Res 2011;71:

7 Dose Escalation 11/3/2014 TGF-Family Regulation of Erythropoiesis by Activin-A Erythroid Differentiation Factor Extracellular Activin Domain Receptor Type IIA (ActRIIA) ACE-011 ACE-011 (Sotatercept) high affinity ActRIIA receptor fusion protein which act as a ligand trap sustained inhibition of Activin-A & TGF-β superfamily ligand Eligibility - Low/Int-1 - WHO MDS - MDS/MPN - Hgb<9g/dl Ongoing Randomized Phase II Study of Sotatercept (ACE-011) in Lower Risk MDS Dose Finding Phase Sotatercept n= mg/kg SC q 21 d 1 mg/kg SC q 21 d n=20 Human IgG 1 Fc Domain ACCELERON Pharma TGF-β Superfamily Ligands ActRIIA Dose 1 2 n=20 2 mg/kg SC q 21 d Endpoints: 1 O - HI-E (IWG 2006) 2 O - HI-E duration - Progression What About Stem Cell Transplant And Immunotherapy? 800 to 1000 transplants in the US annually for MDS indication Genetic Predictors of Response Analysis of MDS patients treated with stem cell transplantation or hypomethylating agents Kristen E. Stevenson MS Petar Stojanov J. Eric Zaneveld Michal Bar-Natan MD Bennett Caughey Hui Wang PhD Guillermo Garcia-Manero MD Hagop M. Kantarjian, MD Rafael Bejar MD, PhD ASH Oral Presentation December 10 th, 2012 Corey Cutler MD, MPH Jerome Ritz MD Kristian Cibulskis Gad Getz PhD David P. Steensma MD Richard M. Stone MD Rui Chen PhD Donna S. Neuberg ScD Benjamin L. Ebert MD, PhD MDS Cohorts and Sequencing Methods Targeted the coding regions of 74 genes including 42 known to be mutated in MDS Stem Cell Transplant Cohort HaloPlex PCR Bennett Caughey & Mick Correll Illumina HiSeq 2000 ASXL1 DNMT3A GNAS LUC7L2 NOTCH2 PTPN11 TET2 ATRX EED IDH1 MAML1 NPM1 RUNX1 TP53 BCOR ETV6 IDH2 MPL NRAS SF3A1 U2AF1 BRAF EZH2 JAK2 MYBL2 PHF6 SF3B1 U2AF2 CBL FLT3 KIT NF1 PRPF40B SRSF2 WT1 CBLB GATA2 KRAS NOTCH1 PRPF8 SUZ12 ZRSR2 Hypomethylating Agent Cohort 48-plex sheared DNA libraries Realignment and Analysis using GATK pipeline at the Broad Institute Petar Stojanov Agilent SureSelect Eric Zaneveld - Hui Yang - Rui Chen 7

8 SCT Cohort Treatment Outcomes HR for Overall Survival Adjusted Gene HR p-value (95% CI) 3.90 TP53 (n = 14) <0.001 (1.85, 8.22) 3.54 DNMT3A (n = 14) (1.45, 8.64) Overall Survival After Transplant TP53 and DNMT3A Mut Absent (n=46) TP53 or DNMT3A Mut Present (n=26) p < Immune Reconstitution after Stem Cell Transplantation Primary areas for translational research Develop new ways to enhance reconstitution of donor stem cells to reduce the risk of infection Develop new approaches to manipulate the immune system to prevent and treat GVHD Develop new methods to enhance graft-versus-leukemia (GVL) and reduce the risk of relapse after transplant Kristen Stevenson and Donna Neuberg Immune Reconstitution after Stem Cell Transplantation Adaptive Immnotherapy Develop methods to isolate virus-specific T cells from stem cell transplant donors e.g Anti-CMV, anti-ebv Monitor immune reconstitution in transplant patients to identify mechanisms of immune tolerance Develop bio-engineered leukemia vaccines to enhance GVL Prodigy WDVax CyTOF MDS Cell Cytotoxic T lymphocyte Tumor Cell Chimeric Antigen Receptor Modified T-cell GVAX: GM-CSF Secreting Tumor Cell Vaccine If I can help Collect MDS cells prior to transplant In the laboratory, treat the sick MDS cells to make them a target for the donor s immune system (GM-CSF transduction) Generate vaccine Give vaccine after transplant to reduce risk of relapse Trials ongoing david_steensma@dfci.harvard.edu or dsteensma@partners.org (617)

9 Thank you! Dana-Farber Cancer Institute DFCI Adult Leukemia Clinical Program: Richard Stone MD Daniel Deangelo MD PhD Martha Wadleigh MD Gregory (Goyo) Abel MD MPH (pop sci) R. Coleman Lindsley MD PhD (translational) Harvard Medical School quadrangle Sarah Cahill PA-C Katherine Edmonds NP Adriana Penicaud PA-C Susan Buchanan PA-C Ilene Galinsky NP & Clinical Research Coordinators Regulatory Team 9