Impact of Cytogenetic Abnormalities and Cytogenetic Response to Hypomethylating Agents (HMAs) in Patients (pts) with Lower Risk Myelodysplastic Syndromes (MDS)
Authors: Montalban-Bravo Guillermo , Garcia-Manero Guillermo , Short Nicholas J. , Sasaki Koji , Sekeres Mikkael A. , Komrokji Rami S. , Steensma David P. , DeZern Amy E. , Roboz Gail J. , Kadia Tapan , Borthakur Gautam , DiNardo Courtney , Miller Darla , Estrov Zeev , Pemmaraju Naveen , Daver Naval , Konopleva Marina , Cortes Jorge E. , Kantarjian Hagop M. , Jabbour Elias 
Published: October 2019

Abstract
Introduction: Although pts with lower risk MDS have longer OS and transformation free survival than pts with higher risk disease, a subset of pts with lower risk MDS have higher risk cytogenetics. There is scarce data on the impact of cytogenetic abnormalities on response to HMAs in this patient population, the ability of these agents to induce cytogenetic responses along with the prognostic relevance of clonal evolution in this subset of pts.
Methods: Pts with lower risk MDS treated with HMAs between 2012 and 2015 were evaluated. Information regarding baseline cytopenias, prior malignancy or chemotherapy, initial and on therapy bone marrow cytogenetic findings and response to therapy by IWG criteria were collected. Pts were stratified according to IPSS/IPSS-R cytogenetic groups and MDACC Lower risk model. Data regarding time to cytogenetic response, clonal evolution and clinical evolution was also reviewed. Statistical analysis included Chi-squared for categorical variables, T-student for continuous variables and Kaplan-Meier for OS and EFS.
Results: A total of 83 pts were evaluated. Pt characteristics are in Table 1. Overall response rate was 61% with 39% CR, 10% CRn, 2% CRp, 1% CRi and 10% pts showing hematological improvement only. No significant difference in response rates (68% vs 61%, p=0.51) to HMAs was observed between pts with or without cytogenetic abnormalities. In pts with abnormal karyotype, 10 (26%) had complete cytogenetic response (CCyR) and 12 (31%) had partial cytogenetic response (PCyR) after a median of 7 months of therapy (range 2-18). Clonal evolution during therapy was observed in 12 (14%) pts after a median time of 8 months, and was associated with loss of response in 6 (50%) pts. There was no correlation between the achievement of a CR and cytogenetic response (p=0.36).The median follow-up was 13 months (2-30 months). Stratification of pts by IPSS or IPSS-R cytogenetic scores did not significantly predict differences for EFS (p=0.31 and p=0.47) nor OS (p=0,52 and p=0.18). By applying the MDACC low-risk scoring system, the 13-month survival rate was 100%, 83%, and 73%, for pts with categories 1, 2, and 3 respectively (p=0.35). No differences in EFS were observed between these groups. The 1-year EFS and OS rates were 79% vs 24% (p<0.001), and 83% vs 67% (p=0.3) for pts with and without any response (Figure 1). Pts achieving CR had 1-year EFS and OS rates of 83% and 92%, respectively. The 1-year EFS and OS rates were 89% vs 50% (p=0.26) and 77% vs 74% (p=0.84), for pts with or without a cytogenetic response. Among pts with morphologic CR, achieving a cytogenetic response did not confer a significant benefit in EFS (100% vs 75%; p=0.69) or OS (88% vs 75%, p=0.91). Acquisition of clonal evolution did not significantly impact EFS (56% vs 31%; p=0.37) nor OS (59% vs 57%, p=0,5). Presence of complex cytogenetics was associated with a trend for a shorter OS (67% vs 80%, p=0,072) and EFS (42% vs 66%, p=0.36).
Conclusions: Achieving response to HMA therapy in pts with low-risk MDS is associated with improvement of outcome. Current IPSS or IPSS-R cytogenetic scores do not predict for outcome with HMA therapy. MDACC Lower risk model showed a tendency to better stratify OS of pts with low risk MDS treated with HMA. Cytogenetic evolution does not appear to impact outcome in patient with low-risk MDS treated with HMAs.
Table 1. Studied factor Normal Karyotype Abnormal Karyotype Age 68 (44-85) 72 (55-84) SexMaleFemale 33 (70%)14 (30%) 21 (58%)15 (42%) IPSS CategoryLowIntermediate-1 10 (21%)37 (79%) 3 (8%)33 (92%) MDACC Lower risk modelLow (category 1)Intermediate (category 2)High (category 3) 6 (13%)25 (53%)16 (34%) 1 (3%)13 (36%)22 (61%) Mean blood counts at baselineHemoglobinPlateletsWBCANC 10.2g/dL (7.3-14.4)103 x109/L (4-404)6.8 x109/L (0.7-35.2)4.5 x109/L (0.2-23-2) 10.5 g/dL (7.8-15.5)96.x109/L (7-325)5.6 x109/L (1.2-32.2)2.7 x109/L (0.2-16.9) Number of clones at baseline 1 2 (1-4) Baseline % of blasts 5 (0-10) 2 (0-8) Baseline Cytogenetic abnormalities-Ydel(20q)del(11q)del(5q)del(7q) or -7+8OtherComplex Cytogenetics - 2 (6%)2 (6%)2 (6%)5 (14%)5 (14%)6 (17%)14 (39%)6 (17%) Cytogenetics at baseline by IPSSGoodIntermediatePoor 47 (100%) 8 (22%)20 (56%)8 (22%) Cytogenetics at baseline by IPSS-RVery goodGoodIntermediatePoorVery poor 47 (100%) 3 (8%)7 (19%)18 (50%)3 (8%)5 (14%) Prior malignancy 19 (40%) 13 (36%) Therapy related 7 (15%) 9 (25%) Number of Cycles of HMA 9 (2-25) 11 (2-29)
Figure 1. Figure 1.

Disclosures
Sekeres: 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; TetraLogic: Membership on an entity's Board of Directors or advisory committees. Komrokji:Incyte: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Research Funding, Speakers Bureau; Pharmacylics: Speakers Bureau. Steensma:Celgene: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Onconova: Consultancy. DiNardo:Novartis: Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Daver:ImmunoGen: Other: clinical trial, Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Cortes:Teva: Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.