Background. Higher white blood cell (WBC) count at diagnosis is associated with specific gene lesions and higher early death rates in AML patients (pts) treated intensively. Whether higher WBC count at diagnosis affects outcome beyond remission independently of genetics is unknown.

Methods. 1,371 AML pts treated intensively in 3 ALFA trials (0702 18-60y, 0701 50-70y, 1200 60y+) with centralized genetics were studied. Genetic alterations found in >5% of pts (n=22) were analyzed. Hyperleukocytosis (HL) was defined as WBC > 50 x10 9/L. NPM1 MRD was stratified as published (Balsat, J Clin Oncol 2017). All prognostic analyses were stratified on trial. Time-dependent effects were introduced in multivariable Cox models when the proportional hazard (PH) assumption was violated.

Results. The median WBC count at diagnosis was 7.1 x10 9/L (range 0.3-546.6), and 235 pts (17.1%) had HL. HL pts had poorer performance status (p<0.001), lower platelet counts (p=0.003), higher frequency of de novo AML (p=0.006) and more favorable genetic risk (ELN 2022 criteria, p<0.001). In a multivariable model, HL was independently associated with more frequent NPM1, FLT3-ITD and -TKD mutations, and less frequent STAG2 and -17/17p- alterations (all p<0.05, Figure 1A).

Complete remission (CR [including CR with incomplete platelet recovery, CRp]) and early death (ED) rates were 77.4 vs 80.0% (p=0.38) and 8.9 vs 5.0% (p=0.03) in pts with and without HL, respectively (resp). In a multivariable model accounting for ELN22 risk and age, HL was independently associated with more frequent ED (OR =2.20, 95%CI 1.26-3.75, p=0.004), and a trend to more frequent primary induction failure (OR=1.40, 95%CI 0.95-2.05, p=0.08).

In the 1,091 pts achieving CR/CRp (182 and 909 with and without HL resp), 1-y and 2-y cumulative incidence of relapse were 39.0% vs 26.1% and 44.0% vs 40.2% resp, suggestive of a time-dependent effect of HL on post-remission outcome ( Figure 1B). Considering relapse and death as competing events, a multivariable model revealed a significant impact of HL on relapse (subdistribution hazard ratio, sHR=1.59, p=0.0003), independent of ELN22 risk and age, but not on non-relapse mortality (sHR=0.69, p=0.23). HL violated the PH assumption in a univariable Cox model for DFS (p=0.0003). We thus performed multivariable Cox models for DFS separating early (< 1 year from CR) and late (≥1 year) effects for HL. In a multivariable time-dependent model, HL significantly impaired early (HR=1.89, p<10 -4), but not late (HR=0.79, p=0.29) DFS, independently of ELN risk and age.

These results were confirmed considering WBC count as a (log-transformed) continuous variable, accounting for all differentially represented genetic lesions instead of ELN22 risk or censoring at allogeneic HCT. In a validation cohort of 1,089 pts <60y reaching CR after intensive chemotherapy in the BIG-1 trial (NCT02416388) where median WBC was 7.7 x10 9/L and 16.1% of pts were HL, the adverse risk of HL on CIR (sHR=1.39, p=0.007) but not NRM (sHR=1.02, p=0.95) and on early (HR=1.42, p=0.01), but not late (HR=1.24, p=0.23) DFS independent of ELN22 risk and age was validated. Finally, to explore the mechanism underlying the higher early relapse rate of HL pts, we analyzed NPM1 MRD (n=152) and LSC17 (n=504) data from the 0702 trial. A higher WBC count was predictive of suboptimal MRD (OR=1.97, p=0.05) independently of FLT3-ITD status. A higher WBC count was significantly correlated to lower LSC17 score (Spearman rho=0.23, p<10-5).

Conclusion. A high WBC count at diagnosis predicts higher rates of early, but not late relapse, independent of genetic risk. Our results strengthen the hypothesis that distinct biological mechanisms underpin early vs late chemoresistance in AML.

Lambert:AbbVie: Honoraria; Bristol Meyers Squibb: Honoraria; Gilead: Honoraria; Jazz Pharmaceuticals: Honoraria; Pfizer, Inc.: Honoraria. Heiblig:Jazz Pharmaceuticals: Honoraria; AbbVie: Honoraria; Pfizer Inc.: Honoraria; Astellas: Honoraria; Servier: Honoraria. De Botton:Pfizer: Honoraria; Novartis: Honoraria; FORMA Therapeutics: Research Funding; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria; Astellas Pharma a/s Nordic Operations: Honoraria; Abbvie: Honoraria; Agios: Research Funding. Pigneux:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings; Roche: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings, Research Funding; Novartis: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Recher:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Iqvia: Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharamceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Itzykson:Novartis: Honoraria; Gilead: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Servier: Honoraria; Jazz Pharma: Honoraria, Research Funding.

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2023
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