A Polish Acute Leukemia Group Prospective Multicenter Clinical Trial to Compare the Efficacy of Two Standard Induction Therapies (DA-90 vs DAC) and Two Standard Salvage Regimens (FLAG-IDA vs CLAG-M) in Acute Myeloid Leukemia (AML) Patients ≤ 60 Years Old (PALG-AML1/2016)

Background: AML is the most common acute leukemia in adults. While most adults < 60 years achieve complete remission (CR) with intensive induction chemotherapy, approximately one third have primary refractory disease and, overall, the majority of AML patients still relapse despite having attained initial remission (Dohner et al, 2017). The combination of an anthracycline and cytarabine has been the mainstay of intensive AML induction for more than 50 years. Combined with cytarabine (AraC), high-dose daunorubicin (90 mg/m²) in induction (DA-90) resulted in a higher rate of CR (70.6% vs. 57.3%, P<0.001) and improved overall survival (OS) (median 23.7 vs. 15.7 months; P = 0.003), without increased serious adverse events compared with DA-45 (Fernandez et al, 2009). In two PALG randomized trials, the combination of cladribine with DA (DAC regimen) also resulted in significantly increased CR after a single induction course, compared with the standard two-drug induction (DA-60) (Holowiecki et al, 2012). Both regimens have a recommendation from the National Cancer Comprehensive Network (NCCN) for routine use. For patients with primary refractory disease, the commonly used FLAG-IDA (fludarabine, cytarabine, idarubicin, GCSF) regimen results in a CR rate of 52% (Pastore et al, 2003). Two previous PALG studies confirmed that another standard regimen, CLAG-M (a combination of cladribine, Ara-C, G-CSF and mitoxantrone) is also effective with tolerable toxicity in refractory/relapsed AML patients (Wierzbowska et al, 2008; Jaglal et al, 2014).

PALG-AML1/2016 aims to compare the safety and efficacy of two commonly used induction and salvage regimens in AML. This trial is also the first international randomized trial in AML induction to prospectively evaluate the impact of measurable residual disease (MRD) on overall survival, using multi-modality testing (flow-cytometry, next-generation sequencing, and PCR) of serial samples. The study is conducted in accordance with the principles of the "Declaration of Helsinki".

Study Design and Methods: PALG-AML1/2016 is a multicenter, randomized, Phase III study which will include 582 patients with newly-diagnosed AML treated at multiple centers across Poland and at Weill Cornell Medicine and The New York Presbyterian Hospital in New York City. This will allow a 10% difference in CR rate between the DAC and DA-90 induction regimens to be confirmed with a power of 80% and level of significance 0.05. Eligible patients must be 18 to 60 years of age with untreated AML, Eastern Cooperative Oncology Group performance status 0-2 and HCT-CI Index of comorbidities, ≤ 3. The trial schema is shown in Figure 1. The trial was initiated in July 2017; 408 patients have been enrolled to date and accrual is ongoing. Preliminary safety and efficacy data were reviewed by the data safety monitoring committee after 194 patients and the recommendation was to proceed without changes. The CR, CRi, CRh after single or double induction were achieved in 63.4%, 16.5% and 0.6% patients, respectively leading to an overall composite CR (cCR) rate 80.5%. Thirty-day mortality, mainly due to infectious complications in aplasia, were observed in 5% and 14.5% did not achieved cCR. Serial samples for MRD are being collected from all patients at multiple time points and analysis is ongoing.

ClinicalTrials.gov Identifier: NCT03257241

Wierzbowska:Gilead: Honoraria; Astellas: Honoraria; Janssen: Honoraria; Swixx Biopharma: Honoraria, Research Funding; Celgene/BMS: Honoraria; AbbVie: Honoraria; Novartis: Honoraria; Servier: Honoraria. Czyz:Takeda: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Pluta:Angelini: Honoraria; Novartis: Honoraria; Celgen/BMS: Honoraria; Swixx Biopharma: Honoraria, Research Funding; Astellas: Honoraria. Libura:Novartis: Honoraria; Servier: Honoraria. Stelmach:Novartis: Honoraria. Czemerska:Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Sandoz: Honoraria; Abbvie: Honoraria. Krawiec:Celgene/BMS: Honoraria. Helbig:Novartis: Honoraria. Sobas:Novartis: Honoraria; Celgene/BMS: Honoraria. Wróbel:GSK: Honoraria; Abbvie: Honoraria; Gilead: Honoraria; Celgen/BMS: Honoraria; Roche: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Beigene: Honoraria. Gil:Pfizer: Honoraria; Novartis: Honoraria; Celgene/BMS: Honoraria; Abbvie: Honoraria; Astellas: Honoraria; Gilead: Honoraria; Janssen: Honoraria. Bieniaszewska:Pfizer: Honoraria; Celgene/BMS: Honoraria. Hus:Novartis: Honoraria. Patkowska:Novartis: Honoraria. Watek:Novartis: Honoraria. Desai:Takeda, Bristol Myers Squibb, Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Research: Research Funding. Ritchie:Takeda: Consultancy; Incyte: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Jazz: Consultancy; Novartis: Consultancy. Guzman:Seq RX: Current holder of stock options in a privately-held company; Samus Therapeutics: Other: Inventor on licensed IP; BridgeMedicines: Research Funding. Roboz:Actinium: Consultancy; Karyopharm Therapeutics: Research Funding; Daiichi Sankyo: Consultancy; Sandoz: Consultancy, Other: Travel and accommodation expenses; Celgene: Consultancy, Other: travel and accommodation expenses, Research Funding; Mesoblast: Consultancy; Array BioPharma: Other: Travel and accommodation expenses; Astex Pharmaceuticals: Consultancy, Other: Travel and Accommodation expenses, Research Funding; Amphivena Therapeutics: Other: Travel and accommodation expenses, Research Funding; Bayer: Consultancy, Other: Travel and accommodation expenses; Genentech/Roche: Consultancy, Other: Travel and accommodation expenses; GlaxoSmithKline: Consultancy; Takeda: Consultancy; Jazz: Consultancy, Other: travel; Astellas: Consultancy; Novartis: Consultancy, Other: Travel and accommodation expenses, Research Funding; Sunesis Pharmaceuticals: Other: Travel and accommodation expenses, Research Funding; Roche: Consultancy; AbbVie: Consultancy, Other: travel and accommodations, Research Funding; Bristol Myers Squibb: Consultancy; MedImmune: Consultancy, Research Funding; Eisai: Other: Travel and accommodation expenses; Agios: Other: travel, Research Funding; Amgen: Consultancy, Other: travel; CTI: Research Funding; Bristol Myers Squibb: Consultancy; Agios: Consultancy, Research Funding; Amgen: Consultancy; Helsinn Therapeutics: Consultancy; MEI Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel and accommodation expenses; Clovis Oncology: Other: Travel and accommodation expenses; Onconova Therapeutics: Research Funding; Mofitt Cancer Center: Research Funding; Jasper Therapeutics: Consultancy; Janssen: Consultancy, Other: travel and accommodation expenses, Research Funding; Celltrion: Consultancy, Other: Travel and accommodation expenses; Otsuka: Consultancy; Tensha Therapeutics: Research Funding.

Cladribine in AML