RATIFY Trial: Promising Combination Therapy for Acute Myeloid Leukemia

Patients (pts) with FLT3-mutant (mut) acute myeloid leukemia (AML) have a poor prognosis, limited treatment options, and a significant chance of relapse. Patients in first complete remission (CR) after intensive chemotherapy (IC) induction consolidation showed a trend towards increased survival with oral azacitidine (Oral-AZA) compared to placebo (PBO) as maintenance treatment (MT) in the phase 3 QUAZAR AML-001 research (QUAZAR; NCT01757535). Although midostaurin (MIDO) plus chemotherapy was approved by the Food and Drug Administration (FDA) for the treatment of patients with FLT3-mutant acute myeloid leukemia (AML), the lack of randomization before MT makes inferences about the efficacy of MIDO as MT difficult. No head-to-head clinical trials have compared the efficacy of MT with Oral-AZA to that of MIDO.

Through an indirect tx comparison (ITC) of QUAZAR and RATIFY data, we compared the survival outcomes of MT with Oral-AZA versus MIDO in patients with FLT3-mut AML who achieved first CR after IC ( ±consolidation tx). The efficacy outcomes from the RATIFY MT phase were compared with the results of an ITC of OS and RFS comparing Oral-AZA vs MIDO, using data from QUAZAR patients with FLT3-mut AML who had achieved a CR with full blood count recovery (meeting RATIFY eligibility criteria) (Larson RA et al. Leukemia 2021). The anchored Bucher technique was used for the primary analysis because it assumes the relative tx impact is consistent across studies with similar effect modifiers. The possibility of violating the proportional hazards (PH) assumption was further investigated using time-varying approaches (parametric and spline models).

The primary analysis population for QUAZAR consisted of all 205 RATIFY MT-phase patients and 56 patients with FLT3-mut AML who achieved a CR (Oral-AZA, 24; PBO, 32). (MIDO, 120; PBO, 85). Patients in the QUAZAR and RATIFY cohorts, respectively, had a mean age of 66.4 and 42.7 years, a female preponderance of 55% and a male predominance of 50%, a point mutation in the FLT3 tyrosine kinase domain in 36% and 29%, no favorable cytogenetic risk in 0% and 57%, and no stem cell transplantation in the first CR in either cohort. Both OS and RFS Bucher ITCs favored Oral-AZA over MIDO. However, this difference was not statistically significant (Table). Exploratory analysis with QUAZAR patients (n = 9; age-matched to RATIFY pts) showed that OS and RFS results with Oral-AZA vs PBO were similar to those of all QUAZAR pts, despite the age difference between the two groups (QUAZAR pts were 55 y; RATIFY pts, 18-59 y). Some of these analyses appear to have violated the PH assumption, so researchers looked into parametric models with the best possible fit. Oral-AZA was found to have higher OS and RFS rates (generalized gamma model) compared to MIDO (Table). When a spline model was used, the same outcomes were realized.

Source:https://library.ehaweb.org/eha/2022/eha2022-congress/357434/esther.natalie.oliva.oral.azacitidine.vs.midostaurin.as.maintenance.treatment.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D2233%2Aot_id%3D26840%2Amarker%3D1769%2Afeatured%3D17676

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT00651261

Esther Natalie Oliva, Clara Chen, Seyavash Najle Rahim, Beatrice Seuro, Alberto Vasconcelos, Lona Gaugler, Barry Skikne, Thomas Prebet, Heather Cameron, C.L. Beach, Gwilym Thompson (Abstract release date: 05/12/22) EHA Library. Natalie Oliva E. 06/10/2022; 357434; P571

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