Long-Term Outcome of Patients with Myelodysplastic Syndromes (MDS) Treated with Hypomethylating Agents (HMA): A Report on Behalf of the MDS Clinical Research Consortium
Authors: Jabbour Elias , Sasaki Koji , Sekeres Mikkael A. , Komrokji Rami S , Steensma David P. , DeZern Amy E. , Gail Roboz J , Daver Naval G. , Pemmaraju Naveen , Kadia Tapan , DiNardo Courtney D. , Wang Xuemei , Nogueras-Gonzalez Graciela , Borthakur Gautam , Estrov Zeev , Kantarjian Hagop M. , Garcia-Manero Guillermo 
Published: October 2019

Abstract
Background:
Therapy with HMA is now the standard of care for pts with MDS and chronic myelomonocytic leukemia (CMML) with complete response (CR) rates of 7% to 35%, median response durations of 9 to 10 months, and median survival of 20 to 24 months. While allogeneic stem cell transplantation (ASCT) is curative in pts with MDS, the long-term outcome of pts treated with HMA remains unknown.
Aims:
The aims of the study are to assess the long-term outcome of pts with MDS treated with HMA and to identify prognostic factors of long-term outcome. This may help selecting patients for this long-term treatment in whom ASCT may not be indicated.
Methods:
We reviewed the records of 511 pts with diagnosed MDS (n=409) and CMML (n=102) treated from 4/2000 to 4/2014 and who were treated with HMA. Pts who received ASCT (n=65) were excluded. Thus, a total of 446 pts were evaluable for the study. The probabilities of leukemia-free survival (LFS) and overall survival (OS) were estimated using the method of Kaplan and Meier. Univariate and multivariate analyses were performed to identify potential factors associated with the achievement of response with logistic regression models and survival with Cox proportional hazard regression models.
Results:
The median follow-up for the entire cohort was 13.6 months. Pt characteristics are outcomes described in Table 1. Best responses to HMA were CR in 124 (28%) pts, CRp in 27 (6%), PR in 9 (2%), HI in 31 (7%). Median duration of response was 7 months (1-68). 130 (29%) transformed into AML after a median of 11 months (11-60). At the last follow-up 133 (30%) remained alive. The median LFS and OS were 16.1 and 16.2 months respectively. The 2- and 5-year LFS and OS rates were 29% and 11% and 34% and 12%, respectively. By multivariate analysis, baseline characteristics associated with OS included WBC (>4 vs. ≤4), ferritin (>500 vs. ≤500), hemoglobin (>10 vs. ≤10), platelets (>500 vs. ≤500) and cytogenetics (high vs. intermediate vs. low risk) (p<0.05). Since the relative impact of each of these 5 factors on survival was similar, we assigned an arbitrary value of 1 to each of them, except for cytogenetics (0=low risk; 1=intermediate risk; and 2=high risk). Patients with 0-2 (n=265) or 3-5 (n=180) adverse factors had a median survival of 18 and 14 months, respectively (p= 0.001). To assess the benefit of achieving a response, we repeated the multivariate survival analysis using an 8-week landmark that excluded 38 patients who died within 8 weeks. The median survival was 15 months overall (8 and 20 months for patients with and without CR/CRp, PR/HI, respectively; p<0.001). The multivariate analysis included 315 patients and selected the achievement of response (CR/CRp/PR/HI vs. others), WBC (>4 vs. ≤4), ferritin (>500 vs. ≤500), platelets (>500 vs. ≤500) and cytogenetics (0=low risk; 1=intermediate risk; and 2=high risk) as independently associated with survival improvement Patients with 0-2 (n=244) or 3-5 (n=162) adverse factors had a median survival of 19 and 13 months, respectively (p<0.001).
Conclusion:
Our current analyses identified a small subset of pts with MDS in whom outcome of therapy with HMA is excellent and can be differentially predicted.
Table 1. Patient Characteristics and Outcomes Parameter (N=446) Number (%); Median [range] Age (years) 70 (13-92) White Blood Cell Count (x 109/L) 3.5 (0.5-212) Ferritin 465.0 (0-10971) Hemoglobin (g/dL) 9.7 (6-16) Platelets (x 109/L) 68.0 (4-987) Bone marrow blasts (%) 6.0 (0-19) Prior malignancy 198 (44) Prior chemotherapy 133 (30) Prior radiotherapy 85 (19) Prior Transfusion 134 (30) Cytogenetics (by IPSS) Low 213 (48) Intermediate 78 (17.5) High 144 (8) Missing 11 (2.5) WHO RA 47 (10.5) RARS 16 (4) RCMD 75 (17) RAEB 204 (46) MDS-U 8 (2) CMML 95 (21) Missing 1 (0.2) IPSS Low 46 (10) Intermediate-1 193 (43) Intermediate-2 156 (35) High 36 (8) Missing 15 (3) MDA Score Low 59 (13) Intermediate-1 113 (25) Intermediate-2 124 (28) High 113 (25) Missing 37 (8) Type of HMA Azacitidine/ AZA+ 189 (42) Decitabine/DAC 257 (58) Response to HMA CR 124 ( 28) CRp 27 (6) PR 9 (2) HI 31 (7) NR 121 (27) Died on therapy 23 (5) NE 6 (1.4) Missing 105 (23.5) Median duration of response (mos) 7.2 (1-68) Transformed into AML 130 (29) Dead 313 (70)

Disclosures
No relevant conflicts of interest to declare.