Less May be More: The Impact of Post-Remission Intensive (IC) Consolidation Cycles on Outcomes in Newly Diagnosed Acute Myeloid Leukemia Receiving IC + Venetoclax

Background: Intensive induction and consolidation chemotherapy (IC) is the standard of care for fit patients (pts) with newly diagnosed acute myeloid leukemia (AML). The addition of venetoclax (VEN) to IC regimens such as cladribine, idarubicin, and cytarabine (CLIA) and fludarabine, cytarabine, idarubicin, and filgrastim (FLAG-IDA) has shown excellent outcomes in clinical trials. However, these IC regimens and subsequent consolidation cycles can be associated with additional risks, including myelosuppression and febrile neutropenia. The optimal number of IC cycles to maximize long-term outcomes while minimizing toxicity is unknown. In this retrospective study, we sought to determine if pts who received fewer cycles of IC + VEN without proceeding to immediate consolidative stem cell transplantation (SCT) experienced worse outcomes.

Methods/Results: From January 2019 to February 2023, 157 pts were treated with frontline IC + VEN at our institution. Of these, 138 pts (86.6%) achieved a complete remission (CR) or CR with incomplete count recovery (CRi). To isolate the impact of IC consolidation number, pts who proceeded immediately to SCT after IC + VEN (n=83) were excluded. The median age of the remaining 49 pts was 48 years (range: 19 - 64). The frontline IC regimen was CLIA + VEN for 28 pts (57.1%) and FLAG-IDA + VEN for 21 (42.9%). By ELN 2022 pts were classified as favorable: 18 (33%), intermediate: 12 (22%), or adverse risk: 25 (45%). Twelve pts (24%) did not stop IC for SCT but underwent a later SCT at a median of 5.1 months from stopping IC (range: 3.8 - 26.9 months). Nineteen pts (38.8%) received ≤1 cycle of intensive consolidation (4 pts with 0 cycles) compared to 30 (61.2%) who received ≥2 cycles of intensive consolidation (median 3, range: 2 - 6). There was no difference in age (p=0.4), treatment regimen (p=0.3), measurable residual disease negativity (p=0.8), or reason for stopping treatment (p=0.13) between pts who received ≤1 cycle compared to ≥2 cycles, although more pts who received ≥2 cycles stopped because they completed the regimen (p=0.023). Maintenance regimens were used in 12/19 [63%] vs 14/30 [47%] of pts who received ≤1 vs ≥2 cycles of IC consolidation, respectively (p=0.269). Significantly more pts who received ≤1 cycle of intensive consolidation underwent future SCT than those who received ≥2 cycles (8/19 [42%] vs 4/30 [13%], p=0.039).

Landmark analysis was performed for overall survival (OS) starting at the end of cycle 1 of consolidation and censored if a patient received SCT (to mitigate the effect of delayed SCT on survival). At a median follow up of 33.5 months, there was no difference in OS between pts who received ≤1 or ≥2 cycles of intensive consolidation (p=0.93). The median 2-year OS for pts who received ≤1 cycle of intensive consolidation was 69% (95% CI: 47 - 100%) compared to 67% (51 - 89%) for those who received ≥2 cycles. Relapse free survival (RFS) was not different between groups (p=0.95) with an estimated 2-year RFS of 63% (95% CI: 41- 99%) versus 58% (41 - 81%), respectively.

Multivariate (MVA) regressions including age, ELN, the use of maintenance therapy, and number of consolidation cycles were constructed for both OS and RFS. Maintenance therapy and the number of consolidation cycles were included as time-dependent variables. While ELN risk was associated with a higher HR for death in MVA (HR 3.6 [95% CI: 1.54 - 8.39] and HR 4.7 [95% CI: 2.18 - 9.92] for intermediate and adverse-risk respectively), maintenance therapy was associated with improved survival (HR 0.2 [95% CI: 0.08 - 0.42]). The number of consolidation cycles in MVA was not significantly associated with an increased hazard of death (HR 0.9 [95% CI: 0.82 - 1.10]). Similarly, when controlling for age and ELN risk, the number of consolidation cycles was not associated with increased hazard of relapse/death (HR 0.9 [95% CI: 0.72 - 1.09]). The use of maintenance therapy decreased risk of relapse/death (HR 0.12 [95% CI: 0.04 - 0.38]).

Conclusions: Among pts treated with IC + VEN, those who received ≤1 intensive consolidation cycle did not have worse OS or RFS than those who received ≥2 cycles. MVA identified the use of maintenance therapy, but not number of IC consolidation cycles, as a predictor of improved OS and RFS. Prospective trials are needed to confirm whether fewer cycles IC + VEN coupled with lower intensity maintenance can yield comparable outcomes to multiple consolidations while mitigating toxicity for pts not receiving SCT.

DiNardo:Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; Genetech: Honoraria; Rigel: Research Funding; Notable Labs: Honoraria; Schrodinger: Consultancy, Honoraria; Astex: Research Funding; Foghorn: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Cleave: Research Funding; Riegel: Honoraria; ImmuneOnc: Research Funding; GenMab: Consultancy, Honoraria, Other: data safety board; AstraZeneca: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Immunogen: Honoraria; GSK: Consultancy, Honoraria; Loxo: Research Funding; Amgen: Consultancy; Astellas: Consultancy, Honoraria; Gilead: Consultancy; Jazz: Consultancy, Honoraria; Stemline: Consultancy. Short:Stemline Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria; Autolus: Honoraria; Sanofi: Honoraria; BeiGene: Honoraria; NextCure: Research Funding; Takeda Oncology: Honoraria, Research Funding; Novartis: Honoraria; Amgen: Honoraria; Xencor: Research Funding; Astellas Pharma, Inc.: Honoraria, Research Funding; GSK: Consultancy, Research Funding; Pfizer Inc.: Honoraria. Borthakur:Catamaran Bio, AbbVie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. Daver:Menarini Group: Consultancy; Jazz: Consultancy; Celgene: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Arog: Consultancy; KITE: Research Funding; Novartis: Consultancy; Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Glycomimetics: Research Funding; Hanmi: Research Funding; Shattuck Labs: Consultancy; Syndax: Consultancy; Novimmune: Research Funding; Agios: Consultancy; Trovagene: Research Funding; Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; FATE Therapeutics: Other: Consulting Fees, Research Funding. Abbas:Alamar Biosciences: Honoraria; GlaxoSmithKline: Research Funding; Molecular Partners: Consultancy; Genentech: Research Funding; Ascentage: Research Funding; Illumina: Honoraria, Other: Inkind Support, Research Funding; Blueprint Medicines Corporation: Research Funding; Enzyme By Design: Research Funding. Yilmaz:daiichi sankyo: Honoraria, Research Funding. Garcia-Manero:Amphivena: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Astex: Other: Personal fees; Helsinn: Other: Personal fees; Janssen: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; Curis: Research Funding; Merck: Research Funding; Astex: Research Funding; AbbVie: Research Funding; Novartis: Research Funding; Aprea: Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Helsinn: Research Funding; Genentech: Other: Personal fees. Kantarjian:AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Kadia:Amgen: Research Funding; Abbvie: Consultancy, Research Funding; Rigel: Honoraria; Genentech: Consultancy, Research Funding; Novartis: Honoraria; Servier: Consultancy; Sellas: Consultancy, Research Funding; Regeneron: Research Funding; DrenBio: Consultancy, Research Funding; JAZZ: Research Funding; BMS: Consultancy, Research Funding; AstraZeneca: Research Funding; Incyte: Research Funding; Ascentage: Research Funding; ASTEX: Research Funding; Pfizer: Research Funding; Cellenkos: Research Funding.