ADVANCES IN THE MANAGEMENT OF MYELODYSPLASTIC SYNDROMES Corey Cutler, MD MPH FRCPC Associate Professor of Medicine, Harvard Medical School Dana-Farber Cancer Institute, Boston, MA HCT Outcomes - MDS 2001-2011 1
The Case for HCT in MDS p=0.031 2 Confirmatory Trials Ongoing: 1. German Prospective Vidaza Trial (N. Kröeger) N= 254, newly diagnosed Age 55-70, Int-2 / High or Int-1 with Adverse Cytogenetics Azacytidine followed by Donor vs. No donor biologic assignment RIC transplantation vs. Aza + BSC p=0.11 2. BMT CTN 1102 (R. Nakamura / C. Cutler) N = Up to 400 Age > 50, Int-2 / High IPSS Donor vs. No donor assignment RIC transplantation vs. BSC QoL and Cost Effectiveness analyses Robin et al, ASH 2013 #301 Topics to Be Discussed How to Transplant for MDS Pre-Transplant Therapy Optimal Timing Conditioning Intensity Donor Type Who to Transplant for MDS (or, who NOT ) Age, Comorbidity Genetic Features 2
Role of Pre-HCT Therapy Della Porta et al, Blood 2014 Role of Pre-HCT Therapy Nakai et al, Leukemia 2005 Field et al, BMT 2010 Gerds et al, BBMT 2012 3
Role of Pre-HCT Therapy SFGM / GFM Registry Analysis Damaj et al, JCO 2013 Role of Pre-HCT Therapy NCT01812252 ; Courtesy A. Gerds 4
Timing of HCT for MDS When? Not too early, but not too late Probably no single formula to fit all patients Figure 1 Markov Models useful since there is NO randomized data MDS RIC Transplantation Non-transplant Therapies Alive Post Transplantation Alive Dead 5
Summary of Decision Models Myeloablative, Sibling Donor Cutler 2004 Low Risk IPSS Int-1 Risk IPSS Int-2 Risk IPSS High Risk IPSS RIC, Sibling or Matched, Unrelated Donor Koreth 2013 RIC or Ablative, Sibling or Matched, Unrelated Donor Allesandrino 2013 p < 0.001 Transplant Non-Transplant IPSS vs. IPSS-R Allesandrino * Allesandrino * * * * Allesandrino * Greenberg et al, Blood 2012 6
IPSS-R Model Continuous-time Markov model, n=1000 (Pavia, GITMO) Results: No transplant for Very Low IPSS-R Delayed transplant for Low IPSS-R (but not more than 5 years) Immediate transplant for Int IPSS-R Results unaffected by adjustment for QoL Della Porta et al, #531 ASH 2014 IPSS-R Model IPSS-based policy* IPSS-R % IPSS-R based policy IPSS Low IPSS Intermediate-1 Delayed Immediate Very low 37 Delayed Low 50 Delayed Intermediate 13 Immediate High - Very low / Low 48 Delayed Intermediate 40 Immediate High 11 Immediate Very high 1 immediate Della Porta et al, #531 ASH 2014 7
Probability of Survival, % 5/21/2015 Transplant Decision Tree MDS Transplant Technique Type of Transplant Donor Type Degree of Match Stem Cell Source Conditioning Intensity Allogeneic Autologous Related Unrelated Matched Mismatched Highly Mismatched Bone Marrow PBSC Umbilical Cord Blood High (Myeloablative) Reduced Intensity Donor Type Matters 100 90 80 70 60 50 40 Relative Risk (95% CI): 8/8 MUD vs. Sib 1.12 (0.89-1.39) 7/8 MUD vs. Sib 1.43 (1.08-1.91) 7/8 MUD vs. 8/8 MUD 1.29 (1.00-1.65) Sib (N=176) 100 90 80 70 60 50 40 30 20 10 8/8 MUD (N=413) 7/8 MUD (N=112) 30 20 10 0 0 0 6 12 18 24 30 36 Months Saber et al, Blood 2013 8
Probability, % 5/21/2015 Donor Type Matters 100 100 80 80 60 60 40 Partially-matched UD (N=289) Cord Blood (N=153) 40 20 0 20 Mismatched UD (N=65) Haploidentical donor (N=95) Log Rank p-value = 0.24 0 0 1 2 3 4 5 6 7 8 9 Years Courtesy W. Saber 2014 Conditioning Intensity Think left and think right and think low and think high. Oh, the thinks you can think up if only you try! - T. S. Geisel The stars, I see, will kiss the valleys first: The odds for high and low s alike - Shakespeare 9
Conditioning Intensity Luger et al, BMT 2012 BMT CTN 0901 Advanced MDS / AML< 5% blasts Randomize RIC regimens Bu/Flu Flu/Mel GVHD Prophylaxis per Institutional practice MA Regimens Bu/Flu Bu/Cy Cy/TBI 18 Month Overall Survival 10
BMT CTN 0901 DSMB Review April 2014 n=272 of 356 planned Memorandum released There appears to be a benefit of the myeloablative conditioning over the reduced intensity conditioning for patients who meet the eligibility criteria of 0901 But: Patients aged 18-65 (median age: 55) Only with low-blast count MDS (<5%) Majority had AML EBMT RICMAC Trial RCT: MDS, CMML or secondary AML with <20% blasts n= 129: MRD (n=34), MUD (n=59), MMURD (n=30) 18-60 years (for URD), 18-65 years (for MRD); median 51.4 ~70% of patients were Int-1 or -2 Two-third of patients had chemotherapy before HSCT Reduced intensity: Bu 8mg/kg po or IV equivalent Flu 180mg/m² Myeloablative: Bu 16mg/kg po or IV equivalent Cy 120 mg/kg 64% received ATG, all others received CsA and MTX Kröger et al, ASH 2014 11
EBMT RICMAC Trial Myeloablative (n=62) RIC (n=65) P-value NRM 1 year 26% (15-37%) 17% (8-26%) NRM 2 years 28% (17-40%) 20% (9-30%) 0.17 Relapse 2 years 15% (5-25%) 18% (8-27%) 0.51 RFS 2 years 57% (44-70%) 62% (50-75%) 0.49 OS 2 years 62% (49-75%) 76% (65-87%) 0.06 Cox model: OS difference for RIC vs MAC (HR=0.42, p=0.03) No difference in RFS, CIR or NRM Main improvement was in patients with Lower risk cytogenetics Patient Selection Who Else Should NOT Undergo Transplant? Patient Characteristics Age Comorbidity Disease Characteristics Molecular Features 12
Age and Comorbidity McClune et al, J Clin Onc 2009 Sorror et al, J Clin Onc 2014 Molecular Prognosis Adjusted for blast %, conditioning regimen, HLA match and complex karyotype Gene Adjusted HR (95% CI) p-value TP53 (n=18) 2.30 (1.10, 4.81) 0.027 TET2 (n=11) 2.40 (1.07, 5.38) 0.033 DNMT3A (n=16) 2.08 (1.00, 3.26) 0.049 Bejar et al, J Clin Onc 2014 13
Molecular Prognosis Molecular Prognosis N=339 patients with MDS (50%) or AML (50%) who underwent Allogeneic HCT U2AF1-4.1% SRSF2-9.4% SF3B1-6.2% Multivariate Model: U2AF1 mutations predicted: Shorter OS (HR 2.6; P=.011) Higher Relapse (HR 3.02, P=.007). Courtesy F. Thol 14
Preventing / Treating Relapse Chimerism based-monitoring Total CD34 + Platzbecker et al, Leukemia 2012 Real-time MRD monitoring by genomics Early intervention MAY/MAY NOT impact outcome Maintenance 5-Azacytidine Ph I dose and schedule finding study 5-Aza: 8, 16, 24, 32, 40 mg/m 2 Monthly x 4; Starting 30 days from transplant Toxicities modest; 32-40 mg/m 2 optimal doses No demonstration of change in methylation Trend towards less chronic GVHD with more cycles NB: AML >CR1 / high-risk CR1 (n=37) MDS Int-2/High IPSS (n=8) de Lima et al, Cancer 2010 15
Ongoing Studies Aza / 5 Aza Post-Transplant NCT01995578 (MSKCC T cell depleted) NCT01168219 (NCI) NCT01747499 (Wash U) NCT01835587 (Oral Aza) NCT02204020 (Pittsburgh) NCT02124174 (Chicago, Aza + Valproate) NCT01700673 (5-Aza + GM-CSF) NCT00887068 (RCT MDACC open since 2009) GVAX : GM-CSF Secreting Tumor Cell Vaccine Autologous tumor cell GM-CSF transduction (E1, E3 deleted Adenovirus serotype 5 vector) Irradiation (10,000 rads) No proliferation potential GM-CSF secretion maintained 7 days in vitro Biologic activity observed in melanoma, lung cancer, MDS/AML human trials 16
GVAX Mechanism of Action Dermis Immature DCs GM-CSF gene Irradiated Autologous Myeloblast GM-CSF Secretion Recruitment of DCs Eradication of residual disease Dying Myeloblast Processing Leukemia Antigens Leukemia Specific Donor Immune Cells Activation of Donor Immune Cells Mature DC GVAX Clinical Trial No. Transplanted 24 Median age at HCT (range) Donor Related Unrelated Disease AML MDS-RAEB CML-myeloid BC Median marrow blast % (range) 62 (41-71) 11 13 16 6 2 20% (6-91) HCT n = 24 Started GVAX n = 15 Completed 6 vaccines n = 10 8 ineligible to start GVAX: Disease (3), agvhd (4), sepsis/mof (1), IPS (1) Did not complete 6 vaccines n = 5 1 died in CR (13 mos) 4 died of disease 9 CR (median F/U = 26 months) Ho et al, PNAS 2009 17
MDS-Specific Conditioning Targeting High Risk molecular features Navitoclax (ABT-263) Bcl-2 inhibitor for p53 and related mutants Targeting Myeloid precursors Iomab-B (BC8-I 131 ) CAR-T cells against myeloid antigens (Not long lasting) Differentiating agents: Eltrombopag Other Strategies Adoptive Cellular Therapy trials NK cells BiTEs, BiKEs against tumor antigens PD-1/PD-L1 pathway interruption Many others 18
Transplant for MDS - Conclusions Encourage EARLY referral when appropriate Patient selection important Some patients DO NOT benefit from transplant and should not be offered transplant Advanced age/comorbidity Very adverse molecular features Absence of suitable donor Do not delay for pre-transplant therapy in the absence of data Maximize conditioning intensity wherever possible. Maybe. Stay tuned. Careful attention to relapse risk and adoption of posttransplant relapse mitigation strategies 19