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Clinical Trial
. 2023 Dec 7;142(23):1960-1971.
doi: 10.1182/blood.2023020301.

Sorafenib plus intensive chemotherapy in newly diagnosed FLT3-ITD AML: a randomized, placebo-controlled study by the ALLG

Sun Loo  1   2   3 , Andrew W Roberts  1   2   3 , Natasha S Anstee  2   3 , Glen A Kennedy  4 , Simon He  5 , Anthony P Schwarer  6 , Anoop K Enjeti  7   8 , James D'Rozario  9 , Paula Marlton  10 , Ian A Bilmon  11 , John Taper  12 , Gavin Cull  13 , Campbell Tiley  14 , Emma Verner  15 , Uwe Hahn  16 , Devendra K Hiwase  17 , Harry J Iland  18   19 , Nick Murphy  20 , Sundra Ramanathan  21 , John Reynolds  22 , Doen Ming Ong  22 , Ing Soo Tiong  1   22 , Meaghan Wall  23 , Michael Murray  24 , Tristan Rawling  25 , Joanna Leadbetter  26 , Leesa Rowley  27 , Maya Latimer  9 , Sam Yuen  7 , Stephen B Ting  6 , Chun Yew Fong  5 , Kirk Morris  4 , Ashish Bajel  1 , John F Seymour  1 , Mark J Levis  28 , Andrew H Wei  1   2   3   22
Affiliations
Clinical Trial

Sorafenib plus intensive chemotherapy in newly diagnosed FLT3-ITD AML: a randomized, placebo-controlled study by the ALLG

Sun Loo et al. Blood. .

Abstract

Sorafenib maintenance improves outcomes after hematopoietic cell transplant (HCT) for patients with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML). Although promising outcomes have been reported for sorafenib plus intensive chemotherapy, randomized data are limited. This placebo-controlled, phase 2 study (ACTRN12611001112954) randomized 102 patients (aged 18-65 years) 2:1 to sorafenib vs placebo (days 4-10) combined with intensive induction: idarubicin 12 mg/m2 on days 1 to 3 plus either cytarabine 1.5 g/m2 twice daily on days 1, 3, 5, and 7 (18-55 years) or 100 mg/m2 on days 1 to 7 (56-65 years), followed by consolidation and maintenance therapy for 12 months (post-HCT excluded) in newly diagnosed patients with FLT3-ITD AML. Four patients were excluded in a modified intention-to-treat final analysis (3 not commencing therapy and 1 was FLT3-ITD negative). Rates of complete remission (CR)/CR with incomplete hematologic recovery were high in both arms (sorafenib, 78%/9%; placebo, 70%/24%). With 49.1-months median follow-up, the primary end point of event-free survival (EFS) was not improved by sorafenib (2-year EFS 47.9% vs 45.4%; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.51-1.51; P = .61). Two-year overall survival (OS) was 67% in the sorafenib arm and 58% in the placebo arm (HR, 0.76; 95% CI, 0.42-1.39). For patients who received HCT in first remission, the 2-year OS rates were 84% and 67% in the sorafenib and placebo arms, respectively (HR, 0.45; 95% CI, 0.18-1.12; P = .08). In exploratory analyses, FLT3-ITD measurable residual disease (MRD) negative status (<0.001%) after induction was associated with improved 2-year OS (83% vs 60%; HR, 0.4; 95% CI, 0.17-0.93; P = .028). In conclusion, routine use of pretransplant sorafenib plus chemotherapy in unselected patients with FLT3-ITD AML is not supported by this study.

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Conflict of interest statement

Conflict-of-interest disclosure: A.H.W. has served on advisory boards for Novartis, AstraZeneca, Astellas, Janssen, Amgen, Roche, Pfizer, AbbVie, Servier, Gilead, Bristol Myers Squibb, Shoreline, Macrogenics, and Agios; receives research funding to the Institution from Novartis, AbbVie, Servier, Janssen, BMS, Syndax, Astex, AstraZeneca, and Amgen; and serves on speaker’s bureaus for AbbVie, Novartis, BMS, Servier, and Astellas. A.H.W., A.W.R., and N.S.A. are employees of the Walter and Eliza Hall Institute (WEHI); WEHI receives milestone and royalty payments related to the development of venetoclax. Current and past employees of WEHI may be eligible for financial benefits related to these payments, and A.H.W., A.W.R., and N.S.A. receive such financial benefits. A.W.R. is listed as an inventor on a patent related to venetoclax assigned to AbbVie and Genentech. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Study schema. APL, acute promyelocytic leukemia; BD, twice daily; IDA, idarubicin; IDAC, intermediate-dose cytarabine.
Figure 2.
Figure 2.
Kaplan-Meier estimates of survival outcomes according to the treatment arm. (A) Kaplan-Meier estimate of EFS in the sorafenib and placebo arms. (B) Kaplan-Meier estimate of RFS in the sorafenib and placebo arms. (C) Kaplan-Meier estimate of OS in the sorafenib and placebo arms. (D) Kaplan-Meier estimate of OS based on a landmark analysis at 120 days after randomization to SOR or PBO and HCT in hematologic remission. CR1, first remission; PBO, placebo; SOR, sorafenib.
Figure 3.
Figure 3.
Correlative analysis of FLT3L levels, P-FLT3 levels, and survival outcome according to FLT3-ITD allelic burden. (A-B) Peripheral blood plasma FLT3L levels assessed on days 4, 10, 15, and 28 after induction in sorafenib (A) and placebo arms (B). (C) P-FLT3 levels at day 10 relative to day 4 with a representative example immunoblot of P-FLT3 changes in a PIA responder and nonresponder. Patients with a PIA response but without a clinical response are noted with an asterisk (∗). (D-E) Kaplan-Meier estimate of OS in the sorafenib or placebo arms among patients with FLT3-ITD allelic ratio ≥0.7 (D) or <0.7. D, day (E).
Figure 4.
Figure 4.
FLT3-ITD analysis using high-sensitivity PCR-NGS. (A-B) Kaplan-Meier estimate of RFS (A) and OS (B) according to postinduction FLT3-ITD MRD status assessed by PCR-NGS. (C) Kaplan-Meier estimate of RFS according to postinduction FLT3-ITD MRD status and treatment arm. (D) Scatter plot distribution of FLT3-ITD MRD after induction as indicated by variant allele frequency according to treatment arm and remission status. (E) FLT3-ITD status at relapse assessed by CE among patients in the sorafenib and placebo arms. Seven patients without available CE results at relapse were not included. (F) Presence of FLT3-ITD microclones with variant allele frequency (VAF) ≤ 1% in sorafenib-treated patients at relapse assessed by PCR-NGS. LLD, lower limit detection < 0.001%.
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