Gemtuzumab Ozogamicin in NPM1-Mutated Acute Myeloid Leukemia: Early Results From the Prospective Randomized AMLSG 09-09 Phase III Study

Abstract

Purpose: High CD33 expression in acute myeloid leukemia (AML) with mutated NPM1 provides a rationale for the evaluation of gemtuzumab ozogamicin (GO) in this AML entity. We conducted a randomized trial to evaluate GO in combination with intensive induction and consolidation therapy in NPM1-mutated AML.

Patients and methods: Between May 2010 and September 2017, patients ≥ 18 years old and considered eligible for intensive therapy were randomly assigned up front for induction therapy with idarubicin, cytarabine, etoposide, and all-trans-retinoic acid with or without GO. The early (P = .02) primary end point of event-free survival (EFS) was evaluated 6 months after completion of patient recruitment.

Results: Five hundred eighty-eight patients were randomly assigned (standard arm, n = 296; GO arm, n = 292). EFS in the GO arm was not significantly different compared with that in the standard arm (hazard ratio, 0.83; 95% CI, 0.65 to 1.04; P = .10). The early death rate during induction therapy was 10.3% in the GO arm and 5.7% in the standard arm (P = .05). Causes of death in both arms were mainly infections. The cumulative incidence of relapse (CIR) in patients achieving a complete remission (CR) or CR with incomplete hematologic recovery (CRi) was significantly reduced in the GO arm compared with the standard arm (P = .005), with no difference in the cumulative incidence of death (P = .80). Subgroup analysis revealed a significant beneficial effect of GO in female, younger (≤ 70 years), and FLT3 internal tandem duplication-negative patients with respect to EFS and CIR.

Conclusion: The trial did not meet its early primary end point of EFS, mainly as a result of a higher early death rate in the GO arm. However, in patients achieving CR/CRi after induction therapy, significantly fewer relapses occurred in the GO compared with the standard arm.

FIG 1.

CONSORT diagram. ATRA, all-trans-retinoic acid; GO, gemtuzumab ozogamicin; HCT, hematopoietic cell transplantation.

FIG 2.

Kaplan-Meier plot illustrating event-free survival defined according to European LeukemiaNet 2017 recommendations in the gemtuzumab ozogamicin (GO) arm and standard arm as randomized (age-stratified hazard ratio [HR], 0.83; 95% CI, 0.65 to 1.04; P = .10). Overall, 289 events were observed (standard arm, n = 157; GO arm, n = 132).

FIG 3.

Cumulative incidence plot illustrating cumulative incidence of relapse (CIR) in the gemtuzumab ozogamicin (GO) arm and standard arm as randomized (age-stratified hazard ratio [HR], 0.66; 95% CI, 0.49 to 0.88; P = .005). CR, complete remission; CRi, complete remission with incomplete hematologic recovery.

FIG 4.

Forest plot of cause-specific proportional hazards models for event-free survival. DNMT3A, DNA methyltransferase 3A; FLT3, FMS-like tyrosine kinase 3 gene; GO, gemtuzumab ozogamicin; HR, hazard ratio; ITD, internal tandem duplication; LQ, lower quartile; s-AML, secondary acute myeloid leukemia after previous myelodysplastic syndrome or myeloproliferative neoplasm; t-AML, therapy-related acute myeloid leukemia; TKD, tyrosine kinase domain; UQ, upper quartile.

FIG A1.

Forest plot of cause-specific proportional hazards models for cumulative incidence of relapse. DNMT3A, DNA methyltransferase 3A; FLT3, FMS-like tyrosine kinase 3 gene; GO, gemtuzumab ozogamicin; HR, hazard ratio; ITD, internal tandem duplication; LQ, lower quartile; s-AML, secondary acute myeloid leukemia after previous myelodysplastic syndrome or myeloproliferative neoplasm; t-AML, therapy-related acute myeloid leukemia; TKD, tyrosine kinase domain; UQ, upper quartile.

FIG A2.

Kaplan-Meier plots illustrating (A and B) event-free survival (EFS) defined according to European LeukemiaNet 2017 recommendations and (C and D) cumulative incidence plots according to sex in the GO arm and standard arm as randomized. CR, complete remission; CRi, complete remission with incomplete hematologic recovery.

FIG A3.

Kaplan-Meier plots illustrating (A and B) event-free survival (EFS) defined according to European LeukemiaNet 2017 recommendations and (C and D) cumulative incidence plots according to FLT3 internal tandem duplication (ITD) status in the GO arm and standard arm as randomized. CR, complete remission; CRi, complete remission with incomplete hematologic recovery.

FIG A4.

Kaplan-Meier plots illustrating event-free survival (EFS) defined (A) according to 2017 European LeukemiaNet (ELN) recommendations and (B) according to protocol in younger patients (≤ 70 years old) in the GO arm and standard arm as randomized.