Patients with acute myeloid leukemia (AML) who are older and unfit for intensive chemotherapy have a poor prognosis, which is further encumbered by the scarcity of well-tolerated standard therapies. The National Cancer Comprehensive Network Guidelines include combinations of glasdegib with low-dose cytarabine (GLAS + LDAC) and venetoclax with LDAC (VEN + LDAC) as nonintensive chemotherapy (NIC) options. As these regimens have not been compared in a head-to-head trial, indirect treatment comparisons (ITCs) to assess their comparative effectiveness are of clinical interest. Hazard ratios (HRs) for overall survival (OS) estimate relative survival valued equally throughout follow-up, whereas landmark measures of OS may overvalue or undervalue survival at a single time point. Thus, a simulated treatment comparison (STC) study was designed to compare HRs for OS between GLAS + LDAC and VEN + LDAC among older AML patients who are unfit for intensive chemotherapy.
Two data sets were used in this analysis. In the first data set, individual patient data (IPD) were extracted for the active arm (GLAS + LDAC) population (n = 116) from the BRIGHT AML 1003 study, which compared low-dose cytarabine with or without GLAS. In the second data set, published summary data were extracted from the VIALE-C phase 3 VEN + LDAC trial (n = 211). STC was utilized based on Decision Support Unit guidelines from the United Kingdom National Institute for Health and Care Excellence. Parametric time-to-event regression models for OS were generated using the GLAS + LDAC IPD, and optimal exponential models are presented based on fit statistics. OS HRs were estimated after adjusting for baseline patient characteristics of the GLAS + LDAC trial to match the VEN + LDAC trial. Accounting for all mutually available patient covariates (age, sex, de novo vs secondary AML, bone marrow blast >50%, Eastern Cooperative Oncology Group performance status, and cytogenetic risk), full and backwards stepwise models (retention P value <.2) were constructed. OS HRs with 95% confidence intervals (CIs) were compared indirectly by ITC (unadjusted for covariates) and STC (adjusted). Both ITC and STC utilized post-hoc analysis results for VEN + LDAC. A sensitivity analysis of prespecified analysis results for VEN + LDAC was performed.
The survival probability appeared similar throughout follow-up as suggested by overlapping Kaplan-Meier curves for GLAS + LDAC and VEN + LDAC. However, comparisons of crude survival rates do not account for differences in patient characteristics. Patients in the GLAS + LDAC trial were more likely to be male, have secondary AML, and have worse cytogenetic risk profiles when compared with patients in the VEN + LDAC trial.
Unadjusted ITC estimates numerically, but not statistically, favored GLAS + LDAC over VEN + LDAC, with a reduction in mortality HR of 0.66 (95% CI, 0.38-1.15). Following STC with full covariate adjustment, the estimated comparative advantage of GLAS + LDAC over VEN + LDAC increased (HR, 0.56; 95% CI, 0.24-1.31). Sensitivity analysis results were consistent with these findings.
In conclusion, both unadjusted ITC and adjusted STC showed that the OS HR numerically, but not statistically, favored GLAS + LDAC over VEN + LDAC in older patients with AML who were unfit for intensive chemotherapy. These findings suggest decisions between these 2 recommended NIC regimens should take into account safety profile, burden of administration, and patient preference, as opposed to basing these decisions solely on differences in survival outcomes.
Reference
Abstract 624. ASH 2020. December 7, 2020. Comparative Effectiveness of Glasdegib or Venetoclax in Combination with Low-Dose Cytarabine Using Simulated Treatment Comparisons.