Epigenetic therapy (Epi) with the hypomethylating agents, azacitidine (Aza) and decitabine (Dec), is increasingly being utilized for induction treatment of older AML patients (pts) based on studies demonstrating both tolerability and prolonged survival. By contrast, standard “7+3” intensive chemotherapy (IC) effectively induces remission in many individuals but is associated with significant toxicity and higher mortality. We compared our institute's experience with Epi vs. IC for the upfront treatment of newly diagnosed AML pts ≥60 years old.
We performed a retrospective chart review of 164 pts ≥ 60 yrs old with newly diagnosed AML who underwent initial therapy at our center between 3/2008-2/2013. Half (n=84; 51%) received IC with regimens containing cytarabine 100 mg/m2 IV for 7 days and daunorubicin 60 mg/m2 IV for 3 days. Half were treated with Epi (n=82; 49%) regimens containing either Dec (20 mg/m2 IV daily for 5 or 10 days) or Aza (75 mg/m2 sq daily for 7 days). Kaplan Meier method, log rank test, and univariate cox proportional hazard models were used to assess overall survival (OS) and correlation with covariates of interest.
Baseline pt characteristics demonstrated a difference in the median age of pts in each group (IC 67 vs. Epi 75 yrs; p <0.01). All other factors were comparable: ECOG status 0-2 (96% vs. 96%, p=1.0), WBC (12.0 x 109/dL vs. 4.5 x 109/dL; p=0.08), hemoglobin (9.2g/dL vs. 9.4g/dL; p=0.39), platelets (69 x 109/dL vs. 54 x109/dL; p=0.99), marrow blasts (53% vs. 45%; p=0.10), peripheral blasts (21% vs. 9%; p=0.14), poor-risk cytogenetics (56% vs. 66%; p=0.21).
At our center, older AML pts receiving IC had superior complete response at any time point (CRatp)(43% vs. 21%; p< 0.01) and higher overall response rates (ORR=CR+CRp) (50% vs. 28%; p<0.01) versus Epi-treated pts. IC also resulted in a longer median OS as compared to Epi (10.6 vs. 7.9 mos; p=0.01). Thirty-day mortality and leukemia-free survival (LFS) were similar across the two groups (IC 10% vs. Epi 11%; p=0.8; 11.2 vs. 9.3 mos; p=0.47 respectively). Interestingly, in pts with AML characterized by poor-risk cytogenetics (n=77; 46%), the choice of induction (IC vs. Epi) did not impact outcome and yielded similar CRatp (39% vs. 27%; p= 0.4) and OS (10.3 vs. 7.8 months; p=0.4). Choice of Epi drug (Aza vs. Dec) did not impact results. Thirty-three percent of pts (n=55; IC 38% vs. Epi 28%) had refractory or relapsed disease (RR-AML) after induction, requiring ≥1 salvage treatment. We found that selection of either IC or Epi as prior treatment had no effect on CR or ORR in RR-AML pts receiving salvage. In multivariate Cox regression analysis, older age, higher ECOG score, increased peripheral blasts, and poor-risk cytogenetics were independently associated with inferior survival. By comparison, marrow blast percentage, hemoglobin, and choice of induction therapy did not impact OS (IC vs. Epi: HR 0.79; CI 0.508-1.237, p= 0.31).
Our results suggest that IC and Epi represent clinically equivalent approaches for the upfront treatment of older AML pts. In spite of significantly higher CR and ORR in the IC group, our finding of improved OS following IC vs. Epi was not substantiated in multivariate analysis, suggesting that this difference may be explained by the comparatively younger age of pts in the IC group. Leukemia-free survival and 30-day mortality were the same for IC vs. Epi-treated pts, as were all response and survival outcomes in the poor-risk cytogenetics subgroup. These data highlight the growing need for prospective clinical trials to conclusively determine the respective roles of IC vs. Epi therapy in older AML pts.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.