Impact of hematopoietic cell transplantation and quizartinib in newly diagnosed patients with acute myeloid leukemia and FMS-like tyrosine kinase 3-internal tandem duplications in the QuANTUM-First trial

Abstract

QuANTUM-First (ClinicalTrials.gov identifier: NCT02668653) was a randomized phase III trial in patients with newly diagnosed FLT3-internal tandem duplication (ITD)-positive acute myeloid leukemia (AML) treated with quizartinib or placebo plus standard induction and consolidation chemotherapy and/or allogeneic hematopoietic cell transplantation (allo-HCT), followed by single-agent maintenance therapy. We evaluated the impact of allo-HCT performed in first complete remission (CR1) or composite CR1 (CRc1) on overall survival (OS), considering treatment randomization. Post-hoc extended Cox regression multivariable analyses were conducted in patients who achieved complete remission/composite complete remission by the end of induction, including allo-HCT in CR1/CRc1 as a time-dependent variable to identify prognostic and predictive factors for OS. There were 297 patients with complete remission by the end of induction (quizartinib, N=147; placebo, N=150); of these, 157 (52.9%) underwent allo-HCT in CR1 (quizartinib, N=84; placebo, N=73). There were 368 patients with composite complete remission by the end of induction (quizartinib, N=192; placebo, N=176); of these, 196 (53.3%) underwent allo-HCT in CRc1 (quizartinib, N=110; placebo, N=86). Multivariable analyses revealed quizartinib treatment and allo-HCT in either CR1 (hazard ratio [HR]=0.553, 95% confidence interval [95% CI]: 0.383-0.798, P=0.0015 and HR=0.527, 95% CI: 0.349-0.796, P=0.0023, respectively) or CRc1 (HR=0.645, 95% CI: 0.470‒0.886, P=0.0068 and HR=0.557, 95% CI: 0.391-0.793, P=0.0012, respectively) as significant predictive factors for a longer OS. No new safety signals were identified. Patients who underwent protocol-specified allo-HCT in CR1/CRc1 experienced post-transplant-related complications, mostly grade ≥2 graft-versus-host disease, as expected. This post-hoc analysis further supports the use of quizartinib and allo-HCT in CR1/CRc1 as an efficacious and well-tolerated treatment strategy for newly diagnosed FLT3-ITD-positive AML patients fit for intensive chemotherapy.

Figure 1.

Diagram of the patients flow in the study. ^aIncludes protocol-specified allogeneic hematopoietic cell transplantation (allo-HCT). ^bIncludes protocol-specified allo-HCT and non-protocol-specified allo-HCT. FLT3-ITD: FMS-like tyrosine kinase 3-internal tandem duplication; ITT: intent-to-treat; HiDAC: high-dose cytarabine; CR1: first complete remission; CRc1: first composite complete remission.

Figure 2.

Extended Cox regression analysis of overall survival, stratified by region, age, and white blood cell count. (A, B) Multivariable extended Cox regression post-hoc analysis was conducted in patients who achieved complete remission by the end of induction (A) and in patients who achieved composite complete remission by the end of induction (B), including allogeneic hematopoietic cell transplantation in first complete remission (A) and in first composite complete remission (B) as time-dependent variables and adjusted for FLT3-ITD variant allele frequency and sex. OS: overall survival; CR: complete remission; allo-HCT: allogeneic hematopoietic cell transplantation; CR1: first complete remission; HR: hazard ratio; CI: confidence interval; FLT3-ITD: FMS-like tyrosine kinase 3‒internal tandem duplication; VAF: variant allele frequency; ECOG: Eastern Cooperative Oncology Group; CRc: composite complete remission; CRc1: first composite complete remission.

Figure 3.

Kaplan-Meier plot of overall survival by treatment arm in patients who achieved complete remission (CR)/composite CR by the end of induction per independent review committee, by allogeneic hematopoietic cell transplantation in first CR/first composite CR. Post-hoc analysis. (A) The group of patients who underwent allogeneic hematopoietic cell transplantation (allo-HCT)^a in first complete remission (CR1). (B) The group who did not undergo allo-HCT^a in CR1.^b (C) The group who underwent allo-HCT in first composite complete remission (CRc1). (D) The group who did not undergo allo-HCT in CRc1.^{b a}Includes protocol-specified and non-protocol-specified allo-HCT. Some patients had both protocol-specified and non-protocol-specified allo-HCT. ^bOverall survival was censored at the starting date of the conditioning regimen for allo-HCT. OS: overall survival; HR: hazard ratio; 95% CI: 95% confidence interval; NR: not reached; NE: not evaluable; CRc1: first composite complete remission.

Figure 4.

Time-dependent Simon and Makuch plot of overall survival from initial randomization by allogeneic hematopoietic cell transplantation in first complete remission (CR)/first composite CR in patients who achieved CR/composite CR by the end of induction per independent review committee. Post-hoc analysis. (A) The group who achieved CR by the end of induction. (B) The group who achieved composite CR by the end of induction. ^a“W/o allo-HCT in CR1” refers to patients who achieved CR without allogeneic hematopoietic cell transplantation (allo-HCT) in the study or patients who achieved CR with allo-HCT outside first CR. ^b“W/o allo-HCT in CRc1” refers to patients who achieved composite CR without allo-HCT in the study or patients who achieved composite CR with allo-HCT outside of first composite CR. OS: overall survival; CR1: first complete remission; CRc1: first composite complete remission; CRc: composite complete remission.