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1705 Impact of Hypomethylating Agent Therapy in Myelodysplastic Syndromes with Chromosome 3 Abnormalities

Myelodysplastic Syndromes – Clinical Studies
Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes – Clinical Studies: Poster I
Saturday, December 5, 2015, 5:30 PM-7:30 PM
Hall A, Level 2 (Orange County Convention Center)

David Sallman, M.D.1, Guillermo Garcia-Manero, MD2, Elias Jabbour3, Mikkael A. Sekeres, MD, MS4, Amy E. DeZern, MD, MHS5, David P. Steensma, MD6, Gail J. Roboz, MD7, John Barnard, PhD4*, Najla H. Al Ali, BDS, MSc8*, Cassie Zimmerman, MPH4*, Sherry Pierce, BSN, BA9*, Denise Batista, PhD10*, Jeffrey E Lancet, MD8, Eric Padron, M.D.11, Jaroslaw P. Maciejewski, MD, Ph.D.12, Alan F. List, MD13, Hagop M. Kantarjian, MD9 and Rami S. Komrokji, MD8

1Dept. of Malignant Hematology, Moffitt Cancer Center, Tampa, FL
2Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
3The University of Texas MD Anderson Cancer Center, Houston, TX
4Leukemia Program, Cleveland Clinic, Cleveland, OH
5Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD
6Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
7Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY
8Malignant Hematology Department, H Lee Moffitt Cancer Center & Research Institute, Tampa, FL
9Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
10Johns Hopkins School of Medicine, Baltimore, MD
11Division of Hematologic Malignancies, Moffitt Cancer Center and Research Institute, Tampa, FL
12Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
13Department of Hematologic Malignancies, Moffitt Cancer Center and Research Institute, Tampa, FL

Background In myelodysplastic syndromes (MDS), abnormalities of chromosome 3 (i.e. inversion 3 (inv(3)), translocation 3q (t(3q)), or deletion 3q (del(3q)) represent a poor-risk karyotype  in the Revised International Prognostic Scoring System (IPSS-R). In acute myeloid leukemia (AML) patients with 3q abnormalities, patients with inv(3)/t3;3 represented the most unfavorable group with a median overall survival (OS) of 10.3 months (Lugthart et al., 2010). We previously presented a single institution experience regarding outcomes of MDS patients with chromosome 3 abnormalities.  Here, we sought to further define outcomes of chromosome 3 abnormalities in MDS and address the impact of hypomethylating agents (HMA) on outcome in multiple institutions.

Patients and Methods Patients were identified through the MDS Clinical Research Consortium and were included if they had a WHO diagnosis of MDS, MDS/myeloproliferative neoplasm (MPN), therapy related MDS (t-MDS), or AML (20-30% myeloblasts) and had any karyotypic abnormality involving chromosome 3. Data analyzed included baseline demographics, disease characteristics, IPSS/IPSS-R scores, treatment and outcome. Responses to HMA therapy were evaluated using International Working Group (IWG) 2006 criteria. Kaplan-Meier estimates were used for overall survival.

Results A total of 413 patients were identified with a median age at diagnosis of 67 years. WHO classification was as follows: 9% RA/RARS, 12% RCMD, 26% RAEB-1, 31% RAEB-2, 2% MDS/MPN, 7% MDS Unclassified, 13% AML; 34% had t-MDS. Overall, 97% of patients were higher risk by IPSS-R (i.e., intermediate to very high risk) with a median blast % in bone marrow of 8%.  Distribution of cytogenetic abnormalities were inv(3) (10%), del(3q) (12%), t(3q) (18%), monosomy 3 (22%), 3p abnormalities (22%), and other chromosome 3 changes (17%). Median OS for the cohort was 12.0 months (95% C.I. 10.8 to 13.9 months) and 31% of patients without AML transformed to AML. IPSS-R was predictive of median OS across subgroups (P < 0.00001). The specific cytogenetic abnormality was predictive for survival (P < 0.00001) with median OS for t(3q) 19 months, inv(3) 13 months, del(3q) 13 months, 3p 10 months, monosomy 3 9 months, and other 3 abnormalities 11 months. There was no survival difference between patients with translocations of 3q21 versus 3q26 (median OS 18 months versus 18.6 months, P = 0.96). Patients with an isolated chromosome 3 abnormality had significantly improved OS (25.1 months versus 10.9 months (P < 0.00001). Complex karyotype (>/= 3 abnormalities) was observed in 74% of patients and was associated with decreased OS (11 months versus 21 months, P < 0.00001).  Of patients who received HMA therapy (48%), the overall response rate was 46% (17% hematological improvement (HI), 7% PR, 20% CR, 2% marrow CR (CRm) with stable disease in 23%). Median OS with and without HMA was 15.5 months versus 8.4 months (p=0.038). In int-2/high risk patients by IPSS, HMA treated patient had a median OS of 14.0 months versus 7.6 months for patients not treated with HMAs (P = 0.005) with no benefit for HMAs in lower-risk patients (median OS 24.5 months with HMA versus 38.7 months without; P =0.41). Cox regression modeling with HMA therapy, IPSS and clinical site confirmed the HMA OS benefit in higher-risk patients (HR 0.69; 95% CI 0.53-0.89; P = 0.005), but showed decreased OS in lower-risk patients (HR 2.0; 95% CI 1.03-3.92; P = 0.04). Allogeneic transplantation was performed in 18% (n=75) of patients, with median OS of 18 months versus 10 months in non-transplanted patients (P < 0.00001).

Conclusion In this large cohort of patients with MDS and oligoblastic AML associated with chromosome 3 abnormalities, survival was heterogeneous but overall poor, with isolated chromosome 3 abnormality and t(3q) patients having a more favorable OS than patients with other chromosome 3 anomalies. MDS patients with 3p changes have poor outcomes. Although some patients with chromosome 3 respond to HMA therapy, the overall survival remains poor and novel approaches are needed.

Disclosures: Sekeres: TetraLogic: Membership on an entity’s Board of Directors or advisory committees ; Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees ; Amgen: Membership on an entity’s Board of Directors or advisory committees . Steensma: Amgen: Consultancy ; Celgene: Consultancy ; Incyte: Consultancy ; Onconova: Consultancy . Lancet: Boehringer-Ingelheim: Consultancy ; Kalo-Bios: Consultancy ; Pfizer: Consultancy ; Seattle Genetics: Consultancy ; Celgene: Consultancy , Research Funding ; Amgen: Consultancy . List: Celgene Corporation: Honoraria , Research Funding . Komrokji: Incyte: Consultancy ; Pharmacylics: Speakers Bureau ; Celgene: Consultancy , Research Funding ; Novartis: Research Funding , Speakers Bureau .

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