Impact of Leukapheresis and Time to Chemotherapy on Outcomes of Newly Diagnosed Patients (pts) with Acute Myeloid Leukemia (AML) Presenting with Hyperleukocytosis: An Analysis from a Large International Patient Cohort
Authors: Stahl Maximilian , Wei Wei , Montesinos Pau , Lengline Etienne , Shallis Rory M , Neukirchen Judith , Bhatt Vijaya R. , Sekeres Mikkael A. , Fathi Amir T. , Konig Heiko , Luger Selina , Khan Irum , Roboz Gail J. , Cluzeau Thomas , Martínez-Cuadron David , Raffoux Emmanuel , Germing Ulrich , Manikkam Umakanthan Jayadev , Mukherjee Sudipto , Brunner Andrew M. , Miller Adam M. , McMahon Christine M. , Ritchie Ellen K. , Rodríguez-Veiga Rebeca , Itzykson Raphael , Boluda Blanca , Rabian Florence , Tormo Mar , Acuna Cruz Evelyn Gloria , Rabinovich Emma , Yoo Brendan , Podoltsev Nikolai A. , Gore Steven D. , Zeidan Amer M. 
Published: October 2019

Abstract
Introduction: Hyperleukocytosis, defined as a white blood cell count (WBC) of >50 × 109/L or >100 × 109/L, is seen in newly diagnosed AML and often results in leukostasis, increased risk of complications, and potentially early death. Those pts often require urgent evaluation and therapy. Leukapheresis is also sometimes used despite limited evidence supporting its use. There is limited data regarding the impact of time (day/night) and day (weekday/weekend) of admission and time to initiation of IC on outcomes in pts with hyperleukocytosis.
Methods: Data were collected from 12 centers in USA and Europe (EU). Eligible pts had newly diagnosed AML, presented with a WBC > 50 × 109/L, and received IC. Univariate and multivariable logistic regression models stratified by centers (EU vs. USA) estimated odds ratios for death during induction (30-day mortality) and achievement of composite complete response (CRc) defined as CR+CR with incomplete count recovery (CRi). Univariate and multivariate Cox proportional hazard models stratified by centers (EU vs. USA) estimated hazards ratios (HR) for overall survival (OS). We evaluated the impact of leukapheresis, day of presentation (weekend vs. weekday), time of presentation (nighttime = 6pm-6am vs. daytime=6am-6pm), and time to initiation of IC. Studied covariates included age, Eastern Cooperative Oncology group performance status (ECOG PS), cytogenetics and molecular abnormalities, WBC, hemoglobin, platelet count, bone marrow and blood blast percentage, and presence of clinical leukostasis, tumor lysis syndrome (TLS) or disseminated intravascular coagulation (DIC) at presentation.
Results: Among 1050 pts with AML and hyperleukocytosis whose data were collected, 787 were reported to have received IC and were included in this analysis. Of 787 pts receiving IC, 16.6% (95%CI, 13.9-19.3%) died during the first 30 days of IC. Leukapheresis was used in 117 pts (15%) in 8 of the 12 centers. In univariate analyses, neither weekend nor nighttime presentation nor use of leukapheresis impacted odds of death in the first 30 days. In multivariate analysis, higher odds of death during first 30 days were associated with age ³ 55 years (OR 3.2, p=0.015), ECOG PS ³ 2 (OR 4.4, 0.004), WBC > 100 × 109/L (OR 6.0, p=0.01) and presence of leukostasis (OR 4.5, p=0.005) and TLS (HR, 3.2, p=0.049). However, neither initiation of IC beyond 48 hours of presentation (vs. less than 48 hours) or use of leukapheresis significantly affected the odds of death in first 30 days (Figure 1A). Median OS of the entire cohort was 12.6 months (95%CI, 11.5-14.9) (Figure 2A). In multivariate analyses, age ³ 55 years (HR 2.6, p<0.001), ECOG PS ³ 2 (HR 1.5, p=0.02), poor cytogenetic risk group (vs. intermediate/good, HR 1.6, p=0.02) and clinical presence of leukostasis (HR 1.4, p=0.03) all predicted inferior OS. The use of leukapheresis showed a trend towards improved OS with borderline statistical significance in univariate analysis (HR 0.77, 95%CI 0.6-1.0, p=0.052) (Figure 2B) but this was not statistically significant in multivariate analysis (Figure 1B). Initiation of IC beyond 48 hours of presentation (vs. less than 48 hours) did not significantly impact OS. CR was achieved in 51% (95%CI, 46.9%-54.1%) of pts and 14% (95%CI, 11.4%- 16.4%) had a CRi. In multivariate analysis, age ³ 55 years (OR 0.3, p<0.001), ECOG PS ³ 2 (OR 0.5, p=0.012), adverse cytogenetic risk group (OR 0.4, p=0.007), and presence of leukostasis (OR 0.5, p=0.04) were associated with decreased odds of achieving CRc. However, initiation of IC beyond 48 hours of presentation (vs. less than 48 hours), and use of leukapheresis did not significantly impact odds of achieving CRc (Figure 1C). Day and time of presentation were not significantly associated with OS, 30-day mortality or CR/CRi rare in univariate analysis. Impact of leukapheresis in pts with clinical leukostasis and sensitivity analyses including propensity score matching are ongoing and will be presented at the meeting.
Conclusions: In this very large international cohort of newly diagnosed AML pts who presented with hyperleukocytosis and treated with IC, neither day (weekend vs weekday) nor time (day vs night) nor the use of leukapheresis had significant impact on odds of death during the first 30 days or on OS. Our data further highlight the limited evidence behind use of leukapheresis and support the urgent need to conduct randomized clinical trials to study any of its benefits.

Disclosures
Montesinos: Novartis: Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau. Bhatt:Pfizer: Consultancy; CSL Behring: Consultancy; Incyte: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Fathi:Celgene: Consultancy, Honoraria, Research Funding; Agios: Honoraria, Research Funding; Astellas: Honoraria; Boston Biomedical: Consultancy, Honoraria; Jazz: Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Khan:Teva: Speakers Bureau. Roboz:Janssen Pharmaceuticals: Consultancy; Bayer: Consultancy; Argenx: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Eisai: Consultancy; Eisai: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Orsenix: Consultancy; Novartis: Consultancy; AbbVie: Consultancy; Celltrion: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Aphivena Therapeutics: Consultancy; Jazz Pharmaceuticals: Consultancy; Orsenix: Consultancy; Jazz Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy; Daiichi Sankyo: Consultancy; Cellectis: Research Funding; Cellectis: Research Funding; Otsuka: Consultancy; Otsuka: Consultancy; Celltrion: Consultancy; Celgene Corporation: Consultancy. Cluzeau:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini: Consultancy; Sanofi: Speakers Bureau. Germing:Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Mukherjee:LEK Consulting: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Projects in Knowledge: Honoraria; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squib: Honoraria, Speakers Bureau; BioPharm Communications: Consultancy; Aplastic Anemia & MDS International Foundation in Joint Partnership with Cleveland Clinic Taussig Cancer Institute: Honoraria. Brunner:Novartis: Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. Ritchie:NS Pharma: Research Funding; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; ARIAD Pharmaceuticals: Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Podoltsev:Daiichi Snakyo: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; Celator: Research Funding; Boehringer Ingelheim: Research Funding; Pfizer: Research Funding; LAM Therapeutics: Research Funding; Sunesis Pharmaceuticals: Research Funding; Celgene: Research Funding; Genentech: Research Funding. Gore:Celgene: Consultancy, Research Funding. Zeidan:AbbVie: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.