The comparative effectiveness of glasdegib in combination with low-dose cytarabine versus azacitidine by bone marrow blasts counts among patients with newly-diagnosed acute myeloid leukemia who are ineligible for intensive chemotherapy.

Abstract

e19512 Background: Acute myeloid leukemia (AML) is an orphan disease with one of the lowest five-year survival rates among myeloid malignancies. Recently, a randomized, open label study among previously untreated, chemotherapy-ineligible AML patients demonstrated improved overall survival (OS) among patients treated with glasdegib (GLAS) + LDAC compared with LDAC alone. Two trials of AZA vs. conventional care regimens report data by bone marrow blast (BMB) counts: one with 20-30% and the other with >30%. In the absence of head-to-head comparisons, this study aims to perform the indirect treatment comparison between GLAS+LDAC and AZA by BMB counts. Methods: As there were potential imbalances between the GLAS and AZA trials and within the AZA trial arms in the baseline characteristics (e.g. poor cytogenetics% and de novo%), simulated treatment comparisons (STCs) for GLAS+LDAC vs. LDAC were performed to derive robust estimation by adjusting for the imbalances in the baseline effect modifiers. Afterwards, the classical network meta-analysis (NMA) was conducted. To derive the hazard ratio (HR) of GLAS+LDAC vs. AZA, three NMAs were conducted in each BMB group. Each NMA used a different HR of GLAS+LDAC vs. LDAC: 1) an unadjusted HR (classical NMA), 2) an STC adjusted HR adjusting for potential imbalances between the trials, and 3) an STC adjusted HR additionally accounting for potential imbalances between arms within the AZA trial. Results: In the 20-30% BMB group (N = 30), the OS HRs of GLAS+LDAC vs. AZA resulting from the three respective NMAs were as follows: 1) 0.46 [95% confidence interval: 0.10-2.14], 2) 0.31 [0.06-1.69], and 3) 0.36 [0.06-2.15]. In the > 30% BMB group (N = 80), the HRs were 1) 0.69 [0.39-1.20], 2) 0.48 [0.23-0.97], and 3) 0.48 [0.24-1.00]. All the HRs suggest that patients with GLAS+LDAC have a survival advantage over patients with AZA. Conclusions: Both the classical NMAs and the NMAs based on the STC adjusted HRs correcting for the potential imbalances at baseline suggest that GLAS+LDAC may be preferred over AZA as a treatment option for previously untreated chemotherapy-ineligible AML patients regardless of BMB counts. [Table: see text]

Update on glasdegib in acute myeloid leukemia – broadening horizons of Hedgehog pathway inhibitors

“…Based on this methodology, glasdegib associated with LDAC tended to demonstrate consistently favored OS hazard ratios (HR) over either AZA or decitabine (HR = 0.424; 95 % CI = 0.228-0.789 and HR = 0.505; 95 % CI = 0.269-0.949, respectively). A second study performed an indirect treatment comparison between glasdegib + LDAC and AZA depending on bone marrow blasts count (77). Both unadjusted HRs and HRs corrected for the potential imbalances at baseline between the trials suggested that glasdegib + LDAC association may be preferred over AZA, regardless of bone marrow blasts count, in previously untreated, chemotherapy-ineligible AML patients.…”

The cost-effectiveness of glasdegib in combination with low-dose cytarabine, for the treatment of newly diagnosed acute myeloid leukemia in adult patients who are not eligible to receive intensive induction chemotherapy in Canada

“…There are no direct, head-to-head comparisons available comparing glasdegib þ LDAC and azacitidine. Therefore, this study relied on the indirect treatment comparisons (ITCs) conducted in a recent publication 12 , where OS was statistically compared between glasdegib þ LDAC and azacitidine via the common comparator LDAC alone by BMB (Table 1). These HRs were further applied to the OS curve of glasdegib þ LDAC in each BMB subgroup to derive the OS curve of azacitidine ( Figure 2).…”

“…OS HRs of glasdegib þ LDAC versus azacitidine obtained from a previous publication12 . GLAS þ LDAC vs. LDAC AZA vs. LDAC GLAS þ LDAC vs. AZA 20-30% BMB 0.17 [0.06-0.48] 0.37 [0.12-1.13] 0.46 [0.10, 2.14] >30% BMB 0.62 [0.38, 1.02] 0.90 [0.70, 1.16] 0.69 [0.39, 1.20] Remarks HR in favor of GLAS þ LDAC HR in favor of AZA HR in favor of GLAS þ LDAC Abbreviations: AZA, azacitidine; BMB, bone marrow blasts; GLAS, glasdegib; HR, hazard ratio; LDAC, low-dose cytarabine; NMA, network meta-analysis; OS, overall survival.…”

Profile of Glasdegib for the Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML): Evidence to Date

“…[36][37][38][39][40] After the FDA approval of glasdegib, certain comparative analyses found a possible survival advantage with glasdegib/LDAC vs HMA monotherapy. 41,42 The treatment landscape changed in 2018 when the oral BCL2 inhibitor venetoclax was approved in combination with an HMA or LDAC in the treatment of newly diagnosed in AML in patients aged 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy. The Phase 1b trial leading to approval and the confirmatory Phase 3 VIALE-A trial, which compared azacitidine/venetoclax to azacitidine/placebo, showed previously unprecedented CR/Cri rates of 66-74% and median OS 16.9 months with nonintensive therapy.…”