Fractionated vs single-dose gemtuzumab ozogamicin with determinants of benefit in older patients with AML: the UK NCRI AML18 trial

Abstract

Addition of gemtuzumab ozogamicin (GO) to induction chemotherapy improves outcomes in older patients with acute myeloid leukemia (AML), but it is uncertain whether a fractionated schedule provides additional benefit to a single dose. We randomized 852 older adults (median age, 68-years) with AML/high-risk myelodysplasia to GO on day 1 (GO1) or on days 1 and 4 (GO2) of course 1 induction. The median follow-up period was 50.2 months. Although complete remission (CR) rates after course 1 did not significantly differ between arms (GO2, 63%; GO1, 57%; odds ratio [OR], 0.78; P = .08), there were significantly more patients who achieved CR with a measurable residual disease (MRD)<0.1% (50% vs 41%; OR, 0.72; P = .027). This differential MRD reduction with GO2 varied across molecular subtypes, being greatest for IDH mutations. The 5-year overall survival (OS) was 29% for patients in the GO2 arm and 24% for those in the GO1 arm (hazard ratio [HR], 0.89; P = .14). In a sensitivity analysis excluding patients found to have adverse cytogenetics or TP53 mutations, the 5-year OS was 33% for GO2 and 26% for GO1 (HR, 0.83; P = .045). In total, 228 (27%) patients received an allogeneic transplantation in first remission. Posttransplant OS was superior in the GO2 arm (HR, 0.67; P = .033); furthermore, the survival advantage from GO2 in the sensitivity analysis was lost when data of patients were censored at transplantation. In conclusion, GO2 was associated with a greater reduction in MRD and improved survival in older adults with nonadverse risk genetics. This benefit from GO2 was dependent on allogeneic transplantation to translate the better leukemia clearance into improved survival. This trial was registered at www.isrctn.com as #ISRCTN 31682779.

Graphical abstract

Figure 1.

Consolidated Standards of Reporting Trials diagram.

Figure 2.

MRD response and survival outcomes. (A) Flow cytometric MRD levels in bone marrow after course 1 according to treatment arm. Median levels, presented as a percentage, were significantly lower in the GO2 arm (median, 25%-75% quartiles with 1-99 percentiles are shown). Comparisons were performed using the Mann-Whitney U test for continuous variables. Patients with MRD <0.1% were 72% (218 of 302) in the GO2 arm and 62% (191 of 307) in the GO1 arm. Patients with undetectable MRD were 57% (173 of 302) in the GO2 arm and 49.5% (152 of 307) in the GO1 arm. Results represent all patients with MRD data (including those not in CR/CRi after course 1). (B) OS. (C) OS of patients without adverse cytogenetics or mutated TP53.

Figure 3.

Forest plot for OS according to the treatment arm stratified based on residual disease response after course 1. MRD <0.1%, MRD negative or detectable but <0.1%.

Figure 4.

Residual disease response rates by molecular subtypes per treatment arm. MRD negative, MRD not detectable; MRD low positive, MRD detected but <0.1%; MRD positive, MRD ≥0.1% (ELN flow cytometry MRD threshold).

Figure 5.

Transplant-related survival outcomes. (A) OS according to the treatment arm of patients who received an allogeneic stem cell transplantation in CR1, landmarked from the date of transplantation. The OS at 4 years from CR1 ASCT was 54% after GO2 induction vs 39% after GO1 (P = .021). (B) OS according to the treatment arm of patients without adverse cytogenetics or mutated TP53 censored at ASCT.

Figure 6.

Effect of transplant vs no transplant on survival. (A) OS based on whether patients received ASCT by Mantel-Byar analysis. In the Mantel-Byar analysis, all patients started in the no transplant group and were transferred to the transplant group at the time of transplantation. (B) Mantel-Byar analysis for survival according to ASCT in CR1 by treatment arm. KM, Kaplan-Meier.