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Hypomethylating agents improve outcomes for older patients with CMML
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SAN DIEGO — Despite a lack of randomized trial data supporting their use, hypomethylating agents are commonly used in the management of chronic myelomonocytic leukemia in the United States, according to results of a retrospective cohort study presented at the ASH Annual Meeting and Exposition.
Further, hypomethylating agent (HMA) therapy was associated with a 28% reduction in risk for death in patients treated with HMAs after 2006 compared to matched patients who were diagnosed in 2001 to 2003, before HMAs were approved.
“The issue with hypomethylating agents is that their approval in the U.S. was based on randomized studies of azacitidine and decitabine that mostly included myelodysplastic syndrome patients,” Amer M. Zeidan, MBBS, MHS, assistant professor of medicine in hematology at Yale University School of Medicine, said during his presentation. “Only a small minority of patients had chronic myelomonocytic leukemia [CMML], but the approval extended to patients with CMML. For that reason, coupled with lack of active CMML–specific therapies, HMAs have been used in the United States. Nonetheless we have very little data on how often they are used in the U.S. and regarding the effectiveness of HMAs in the real-life setting of CMML.”
Zeidan and colleagues used the market entry of HMAs azacitidine in 2004 and decitabine in 2006 as a natural experiment to estimate the influence of HMA therapy on survival of patients for whom those were available compared to those who did not
Researchers used the SEER–Medicare database to identify 1,378 patients (median age at diagnosis, 79 years; 61% men) with CMML aged 66 years or older.
“As 85% of CMML patients in the United States are aged 65 years or older and therefore eligible for the Medicare program, and since the SEER program covers 30% of the U.S. population, the combined SEER-Medicare was an excellent study setup,” Zeidan told HemOnc Today.
Patients were diagnosed from 2001 to 2011 and had follow-up through 2013. The dataset of this observational study was mature, as 90% of patients died during follow-up.
Researchers used procedure codes from Medicare claims to determine who received HMA therapy after CMML diagnosis.
Median OS from diagnosis was 13 months (95% CI, 12-14).
During follow-up, 259 patients (13.9%) received HMA therapy, which included azacitidine only (8.6%), decitabine only (6.8%) or both (3.3%). Median duration from diagnosis to initiation of hypomethylating agent therapy was 2 months.
From 2001 to 2003, only 3.6% of patients received HMA therapy. However, from 2007 to 2011, the proportion of patients who received this therapy ranged from 23.5% to 31% of patients diagnosed with CMML each year.
Only 14 patients (1%) underwent allogeneic hematopoietic stem cell transplantation during follow-up.
Unadjusted median OS was 10 months (95% CI, 8-12) among patients diagnosed from 2001 to 2003 compared with 14 months (95% CI, 12-16) among those diagnosed in 2007 to 2011(P = .013).
Researchers then conducted propensity score matching to evaluate outcomes of 225 patients diagnosed during 2007 to 2011 who received HMA therapy with 395 patients diagnosed from 2001 to 2003, prior to HMA therapy availability. They did not compare HMA users and nonusers in the post-2006 era to reduce the impact of unobserved variables that might affect the decision to use this therapy.
Results of this analysis also showed an OS benefit with HMA therapy (17 months vs. 11 months; HR = 0.72; 95% CI, 0.58-0.91; P = .005).
Another propensity score–matched analysis of patients who did not receive HMA therapy — 484 of whom were diagnosed from 2001 to 2003 and 395 of whom were diagnosed from 2007 to 2011 — showed no survival difference (HR = 1.09; 95% CI, 0.91-1.32).
“To my knowledge, this is the largest reported cohort of patients with CMML treated with hypomethylating agents,” Zeidan said. “Hypomethylating are commonly used in the United States despite the lack of randomized clinical trial evidence for their use. Our data support the use of HMAs in CMML. The survival benefit seems to be limited to the first 24 months after initiating therapy with HMAs which is consistent with the what was observed in patients with MDS who receive HMAs who typically experience failure of these agents by that time point.” – by Alexandra Todak
Reference:
Zeidan AM, et al. Abstract 394. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
Disclosure: This project was supported by a Young Investigator Award from Yale University. Zeidan reports consultant roles with and honoraria from Ariad, Celgene, Gilead, Incyte and Pfizer, all which are unrelated to the study. Please see the abstract for a list of all other researchers’ relevant financial disclosures.