Urgent Cytoreductive Chemotherapy for Newly Diagnosed Patients with AML Is Safe and Feasible and Facilitates Enrollment on Investigational Clinical Trials
Authors: Kim Kunhwa , Konopleva Marina , DiNardo Courtney D. , Borthakur Gautam , Garcia-Manero Guillermo , Pemmaraju Naveen , Daver Naval , Jabbour Elias , Kornblau Steven M. , Yilmaz Musa , Ohanian Maro , Ferrajoli Alessandra , Jain Nitin , Short Nicholas J. , Rausch Caitlin R. , Brandt Mark , Pierce Sherry A. , Estrov Zeev E. , Ravandi Farhad , Kantarjian Hagop M. , Kadia Tapan M. 
Published: November 2020

Background : AML is a life-threatening, rapidly progressive malignancy that frequently presents with uncontrolled leukocytosis, organ infiltration, and the need for urgent chemotherapy. Recent advances in genomic profiling have identified significant heterogeneity in AML, that is best addressed with individualized, targeted approaches, often on clinical trials. The requisite cytogenetic and molecular data to inform definite treatment, however, is not rapidly available. Studies have suggested that delaying initial therapy in newly diagnosed AML may worsen OS. Implementing formal cytoreduction strategies may allow time for treatment selection and clinical trial enrollment without adversely affecting outcomes.
Methods: We piloted an approach with our frontline clinical trials in AML to allow cytoreductive therapy with hydroxyurea (HA) and/or higher doses of Cytarabine (Ara-C) for disease control prior to definitive therapy. 3 frontline chemotherapy protocols were designed to allow HA and up to 2 grams/m2 of Ara-C for urgent disease control prior to starting therapy. We reviewed the feasibility and outcomes of this approach in older and younger pts with newly diagnosed AML treated between April 2014 and May 2020.
Results: We reviewed 276 patients, 97 (35%) which received cytoreductive therapy prior to starting definitive therapy. Baseline characteristics of patients who did or did not receive cytoreductive therapy are summarized in Table 1. The median time from presentation to definitive treatment was 6 days (range 1-21 days) and 6 days (1-46 days) in patients with or without cytoreduction, respectively. Patients with cytoreduction had higher median peripheral blasts 44% (Interquartile Range, IQR : 46-79) vs. 6% (IQR: 4-7) than patients without cytoreduction. More patients with cytoreduction were female (64%; p=0.007), ECOG performance status (PS) &gt;1 (27%; p&lt;0.001), and adverse ELN 2017 risk (36%, p=0.008) compared to patients without cytoreduction. Patients receiving cytoreduction more frequently had mutations in NPM1 (p&lt;0.001), FLT3 (p&lt;0.001) and RAS (p=0.006). In multivariate logistic regression, patients with high peripheral blasts (over 20%) were 5.0 times more likely to receive cytoreductive therapies (OR 5.0, CI 2.6-9.5 p&lt;0.001). ECOG &gt; 1(OR 3.5, 95% CI 1.6-8.0), FLT3 mutation (OR 2.7, p=0.006), female gender (OR 2.4, CI 1.3-4.3) were also associated with a higher likelihood to get cytoreductive therapeutics.
Response rates and outcome are summarized in Table 2. There was no difference in rate of CR/CRi (89% vs. 87%; P=0.72) among patients with or without cytoreduction, respectively. Similarly, there was no difference in 30- and 60-day mortality between the groups. When stratified with cytoreduction treatment regimen, there was no significant difference in CR and/or CRi. Of the 16 patients who died within 60 days of diagnosis, only 5 (31%) had documented CR or CRi at the time of death.
Median overall survival among patients with or without cytoreduction was 11.3 vs. 11.5 months, respectively (P=0.57) (Figure 1). There remained no difference in OS after adjustment of age, secondary AML, ECOG, ELN, TP53, and type of frontline treatment: Hazard Ratio of 1.1 (95% CI 0.7-1.7). Similarly, there was also no difference in progression free survival between the 2 groups (p=0.59).
Conclusions: Pretreatment cytoreductive therapy was safe and feasible in pts with newly diagnosed AML who are in need of urgent therapy, allowing collection of genomic data and enrollment on clinical trials. Despite having higher baseline WBC, blast %, incidence of FLT3 mutations, advanced PS, and higher ELN risk among pts who received cytoreduction, there was no difference in OS, PFS, or early mortality between the 2 groups. These data suggest that urgent cytoreduction may be reasonable alternate option to immediate induction.

Disclosures
Konopleva: AstraZeneca: Research Funding; AbbVie: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Ascentage: Research Funding; Amgen: Consultancy; Kisoji: Consultancy; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Cellectis: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Sanofi: Research Funding; Rafael Pharmaceutical: Research Funding; Agios: Research Funding; Genentech: Consultancy, Research Funding; Ablynx: Research Funding; Calithera: Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Research Funding. DiNardo:MedImmune: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; Takeda: Honoraria; Calithera: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Novartis: Consultancy; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria, Research Funding; Syros: Honoraria. Borthakur:Treadwell Therapeutics: Consultancy; Nkarta Therapeutics: Consultancy; AstraZeneca: Research Funding; FTC Therapeutics: Consultancy; PTC Therapeutics: Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Jannsen: Research Funding; GSK: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Curio Science LLC: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BioTherix: Consultancy; Polaris: Research Funding; Cyclacel: Research Funding; Novartis: Research Funding. Garcia-Manero:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Amphivena Therapeutics: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Pemmaraju:Affymetrix: Other: Grant Support, Research Funding; MustangBio: Honoraria; Pacylex Pharmaceuticals: Consultancy; Novartis: Honoraria, Research Funding; Incyte Corporation: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Cellectis: Research Funding; Blueprint Medicines: Honoraria; DAVA Oncology: Honoraria; Plexxikon: Research Funding; SagerStrong Foundation: Other: Grant Support; Roche Diagnostics: Honoraria; Samus Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Honoraria; Daiichi Sankyo: Research Funding. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jabbour:Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding. Yilmaz:Pfizer: Research Funding; Pint Pharma: Honoraria; Daicho Sankyo: Research Funding. Jain:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; ADC Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; BMS: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; Pharmacyclics: 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; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Aprea Therapeutics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Short:Astellas: Research Funding; Amgen: Honoraria; Takeda Oncology: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy. Ravandi:Astellas: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Kantarjian:BMS: Research Funding; Pfizer: Honoraria, Research Funding; Astex: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding. Kadia:JAZZ: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cellenkos: Research Funding; Novartis: Honoraria; Amgen: Research Funding; Pulmotec: Research Funding; Astra Zeneca: Research Funding; Abbvie: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Astellas: Research Funding; Pfizer: Honoraria, Research Funding; Celgene: Research Funding; Incyte: Research Funding; Ascentage: Research Funding; Cyclacel: Research Funding.