Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531

Abstract

Purpose: To improve survival rates in children with acute myeloid leukemia (AML), we evaluated gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation. Our primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. Our secondary objectives examined outcomes by risk group and method of intensification.

Patients and methods: Children, adolescents, and young adults ages 0 to 29 years with newly diagnosed AML were enrolled onto Children’s Oncology Group trial AAML0531 and then were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of GO (3 mg/m2/dose) administered once in induction course 1 and once in intensification course 2 (two of three).

Results: There were 1,022 evaluable patients enrolled. GO significantly improved EFS (3 years: 53.1% v. 46.9%; hazard ratio [HzR], 0.83; 95% CI, 0.70 to 0.99; P.04) but not OS (3 years: 69.4% v. 65.4%; HzR, 0.91; 95% CI, 0.74 to 1.13; P = .39). Although remission was not improved (88% v. 85%; P = .15), posthoc analyses found relapse risk (RR) was significantly reduced among GO recipients overall (3 years: 32.8% v. 41.3%; HzR, 0.73; 95% CI, 0.58 to 0.91; P = .006). Despite an increased postremission toxic mortality (3 years: 6.6% v. 4.1%; HzR, 1.69; 95% CI, 0.93 to 3.08; P = .09), disease-free survival was better among GO recipients (3 years: 60.6% v. 54.7%; HzR, 0.82; 95% CI, 0.67 to 1.02; P = .07).

Conclusion: GO added to chemotherapy improved EFS through a reduction in RR for children and adolescents with AML.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

CONSORT diagram. (*) Elective reasons included terminating therapy because of physician's choice or patient's refusal of further protocol therapy. (†) Donor availability defined for intermediate- and high-risk patients only. Alt, alternative donor; DS, Down syndrome; Int, intensification course; MFD, matched family donor; SCT, stem-cell transplantation.

Fig 2.

Overall survival (OS) and event-free (EFS) survival rates from study entry by study arm. (A) All patients; (B) low-risk (LR) patients; (C) intermediate-risk (IR) patients; (D) high-risk (HR) patients. GO, gemtuzumab-ozogamicin arm; No-GO, did not receive gemtuzumab-ozogamicin (control arm). Median survival rates for each group is listed in Appendix Table A7, where applicable.

Fig 3.

Outcomes among patients from end of induction 2 (IND2) by risk group and study arm among patients in remission after the end of IND2. (A) Disease-free survival from end of IND2. (B) Overall survival from end of IND2. (C) Relapse risk from end of IND2. (D) Treatment-related mortality from end of IND2. GO, gemtuzumab-ozogamicin arm; No-GO, did not receive gemtuzumab-ozogamicin (control arm).

Fig A1.

Outcome by study arm in patients who underwent stem-cell transplantation (SCT). (A) Disease-free survival (DFS) and relapse risk (RR) from end of intensification (INT) 1 in intermediate-risk patients by intent-to-treat with matched family donor (MFD) SCT versus chemotherapy and by study arm. (B) DFS from end of induction (IND) 2 by high-risk (HR) factor (FLT-3 internal tandem duplication high allelic ratio [ITD HAR] or other, such as poor-risk cytogenetics or persistent disease at end of IND1) by study arm. (C) RR from end of IND2 by HR factor (ITD HAR or other, such as poor-risk cytogenetics or persistent disease at end of IND1) by study arm. GO, gemtuzumab-ozogamicin arm; No-GO, did not receive gemtuzumab-ozogamicin (control arm).

Fig A2.

Comparison of Children's Oncology Group Acute Myeloid Lymphoma trials. (A) Event-free and (B) overall survival by AAML0531 treatment arm compared with AAML03P1 (gemtuzumab pilot similar to the gemtuzumab-ozogamicin arm [GO] arm, ie, arm B of AAML0531) and CCG-2961 (used Ida-DCTER [idarubicin, decadron, cytarabine, thioguanine, etoposide, daunorubicin] intensive timing chemotherapy) pre- and postsuspension to add supportive care measures that included mandatory hospitalization until count recovery, avoidance of corticosteroids, prophylactic fluconazole, and intravenous immunoglobulin.