Gemtuzumab Ozogamicin Plus Standard Induction Chemotherapy Improves Outcomes in Intermediate Risk Cytogenetic Acute Myeloid Leukemia

Background: Gemtuzumab ozogamicin (GO) is a CD33-directed antibody-drug conjugate approved for the treatment of newly diagnosed (ND) and refractory/relapsed CD33-positive acute myeloid leukemia (AML). Meta-analysis of individual patient (pt) data from 5 randomized controlled trials (n=3325) confirmed a significant survival benefit of GO added to intensive induction chemotherapy for pts with AML without adverse cytogenetics. While favorable-risk ND-AML pts, specifically core-binding factor AML (CBF-AML), particularly benefited with a 5-year overall survival (OS) improvement of 20.7% (log rank p= 0.0006), pts with intermediate-risk AML also showed a significant 5-yr survival improvement of 5.7% (p=0.005) (Hills RK et al Lancet Oncol 2014: 15, 986). However, the smaller difference in these latter pts coupled with apprehension for risk of sinusoidal obstruction syndrome (SOS) following hematopoietic stem cell transplantation (HSCT) has led many clinicians to not use 7+3 plus GO in the intermediate-risk AML population.

Aim/Objective: To perform a retrospective analysis of outcomes of 7+3 plus GO vs 7+3 in ND intermediate-risk cytogenetic AML pts treated at a single comprehensive cancer center.

Methods: We studied the demographic, clinical and genetic data of intermediate risk ND-AML pts treated at Roswell Park Comprehensive Cancer Center (n=113) between 2015-2022. Conventional cytogenetics and fluorescence in situ hybridization (FISH) were performed. Genomic profiling was performed using next-generation sequencing methods (FoundationOne®CDx). Risk stratification was defined per the European LeukemiaNet (ELN)-2017 classification. 7+3 plus GO pts received at least one dose of GO 3 mg/m² (up to one 4.5 mg vial) plus cytarabine 100 mg/m² continuous IV infusion on days 1-7, and daunorubicin 60 mg/m² IV on days 1-3 (7+3). Control pts received 7+3 alone. Prophylactic heparin was administered to prevent hepatic SOS based on institutional standards if not thrombocytopenic. Outcomes included response rate to induction, successful bridging to HSCT, relapse rate, and overall survival.

Results: 113 intermediate-risk ND-AML pts were studied: 33 received 7+3 plus GO and 80 received 7+3. Median age was 57 vs. 59 years, respectively (range: 19-76 years). Moreover, there was no significant difference in the percentage of pts > 60 yrs (45% vs 48%). Gender was equally distributed. Pts treated with 7+3 plus GO had a significantly higher rate (p=0.019) of complete remission (CR) and complete remission with incomplete count recovery (CRi) (27/33, 82%) than 7+3 (44/80, 55%; Figure 1A). Among pts with available minimal residual disease (MRD) status detected by multiparameter flow cytometry, 100% achieved MRD-negative status after 7+3 plus GO (18/18) compared to 86% with 7+3 (12/14). Non-responders to 7+3 plus GO were enriched for ASXL1, DNMT3A, TET2, and TP53 mutations as compared to responders who harbored more FLT3, IDH1/2, KRAS/NRAS and RUNX1 mutations. Among pts achieving CR/CRi, 48% after 7+3 plus GO vs 30% after 7+3 (p=0.13) were successfully bridged to HSCT. Cumulative incidence of relapse after CR/CRi was significantly lower after 7+3 plus GO (11%) than 7+3 (43%; p=0.007). Finally, 7+3 plus GO pts demonstrated a superior, yet not statistically significant, median overall survival (OS) benefit (median OS not reached) compared to 7+3 alone (median OS = 35 months; Figure 1B). No pts receiving 7+3 plus GO developed SOS.

Conclusions: Intermediate risk ND-AML pts treated with 7+3 plus GO at our academic center had significantly higher rates of MRD-negative CR and CRi, lower rates of relapse, and higher percentage of pts receiving HSCT as compared with 7+3 alone. Non-responders in the 7+3 plus GO group harbored adverse risk genetic mutations that likely dictated the failure to response. Although addition of GO was associated with a non-significant trend towards improved overall survival, longer follow-up is warranted to decipher an absolute survival advantage of this regimen.

Przespolewski:ALX Oncology: Other: Site Principal Investigator; Merck: Other: Site Principal Investigator; Jazz Pharmaceuticals: Research Funding. Thompson:Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Griffiths:Astex Pharmaceuticals: Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Research Funding; Celldex Therapeutics: Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medicom Worldwide: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Physician Educational Resource: Honoraria; Picnic Health: Honoraria; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AAMDSIF: Honoraria. Wang:Genentech: Consultancy; Macrogenics: Consultancy; Takeda: Consultancy, Honoraria, Other: Advisory Board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory Board; Rafael Pharmaceuticals: Other: Data Safety Monitoring Committee; Dava Oncology: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory Board; Gilead: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria, Other: Advisory Board; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: member of data monitoring committee ; Kura Oncology: Consultancy, Honoraria, Other: Advisory Board, Steering Committee, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Astellas: Consultancy, Honoraria; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board.