Long-Term Outcome of Chronic Myelomonocytic Leukemia (CMML) Patients Treated with Hypomethylating Agents (HMA): A Single-Institution Experience
Authors: Diaz Duque Adolfo , Cabrero Monica , Ravandi Farhad , Pemmaraju Naveen , Borthakur Gautam , Kantarjian Hagop M. , Cortes Jorge E. , Kadia Tapan M. , Daver Naval G. , Jabbour Elias , Garcia Manero Guillermo , Sasaki Koji 
Published: October 2019

Abstract
CMML is a myelodysplastic/myeloproliferative disease considered a separate entity by WHO, but from a therapeutic perspective, most clinicians consider CMML a subtype of myelodysplastic syndromes (MDS), for which hypomethylating agents (HMA) are the standard of therapy. Herein, we report on the long-term outcome of patients with CMML treated with HMA as well as prognostic associated factors.
Methods:
We reviewed the records of 102 consecutive patients with CMML treated between March 2004 and June 2014. Patients who underwent ASCT were excluded (n=5), and thus a total of 97 patients were analyzed. Responses were assessed according to IWG 2006. Differences among variables were evaluated by the Chi-square test and Mann–Whitney U test for categorical and continuous variables, respectively. Progression-free survival (PFS) was defined as the time from start of therapy to leukemia transformation or death. Overall survival (OS) was defined as the time from start of therapy to death. Patients who were alive were censored at the last follow-up date. PFS and OS were estimated using Kaplan-Meier analysis, and multivariate analysis was performed by Cox regression.
Results:
Median age at diagnosis was 71 years (50-87). Treatment was azacitidine (AZA) in 30 patients (31%) and decitabine (DEC) in 67 (69%), and they received a median of 6 courses of therapy (1-70). IPSS risk score was low in 18 patients (18.6%), int-1 in 47 (48.5%), int-2 in 23 (23.7%), and high in 4 (4.1%). Fourteen patients (14.4%) had poor-risk cytogenetics. Among patients with available mutation data, we found RAS mutations in 18 out of 79 analyzed cases (22.7%), FLT3-ITD mutations in 3 out of 86 (3.5%), NPM1 mutations in 2 out of 40 (5%), and Jak2 mutations in 1 out of 36 (2.8%).
Overall response rate (ORR) was 51%, and best responses to HMA were complete remission (CR) in 51 (52%) patients, partial response (PR) in 3 (3.1%), and hematological improvement (HI) in 7 (7.2%). Median duration of response was 11.5 months (range, 1.1 to 67.5). There was no difference in response rate between DAC and AZA therapies. With a median follow-up of 11 months (1-73), 27 cases (28%) transformed into AML after a median of 19 months (5-59). At the last follow-up, 32 patients (33%) remained alive. The median PFS and OS were 18 and 23 months, respectively. The 1- and 2-year OS rates were 94.7% and 85.6%, respectively, and the 1- and 2-year PFS rates were 92.7% and 81.3%, respectively. By multivariate analysis, patients with higher hemoglobin levels (HR=0.83, 95%CI [0.72-0.97]; p=0.024) and those who achieved CR (HR=0.46 [0.26-0.81]; p=0.007) had better OS, whereas high-risk cytogenetics was associated with poorer OS (HR: 2.89 [1.34-6.21]; p=0.007). Only achievement of CR was an independent factor with impact on PFS (HR: 0.32 [0.18 – 0.55]; p<0.001). We did not identify any independent factor with significant impact on response rate.
Conclusions
HMA is a suitable therapy for patients with CMML, and the achievement of CR is the most important goal to improve patient outcomes.

Disclosures
Cortes: Celgene: Research Support Other.