A Simplified Patient Care Strategy to Decrease Early Deaths in Acute Promyelocytic Leukemia (APL): Results of the ECOG-ACRIN EA9131 Trial

BACKGROUND Clinical trials have reported rates of >95% durable remissions (i.e., cure) for patients diagnosed with acute promyelocytic leukemia (APL) when treated on a clinical trial. In contrast, population studies from national registries report 1-year survival far less at 70% and 5-year survival between 55 to 70%. The conflicting survival rates may be related to patient selection as patients on trials are younger (median age 34-47 years) and exclude those with co-morbid conditions. Of particular importance is the under appreciation among physicians of a high rate of early deaths (ED) of 17-29% in the general population within the first 30 days of treatment. ED is the commonest cause of treatment failure in APL. Possible causes include rarity of the disease, advanced age, comorbid conditions, complexity at presentation, lack of institutional pathways for management and provider inexperience. In this multi-center cooperative group, prospective trial, we proposed that prompt access to APL experts at academic centers and for remote guidance in management of APL in community centers would decrease ED. The primary objective of the study was to decrease induction mortality from an estimated 30% to <15%. Secondary objectives included comparing treatment outcomes between academic and community programs and to assess overall survival of enrolled patients 1 year following completion of trial accrual.

METHODS Based on a previous pilot project, we created a simplified treatment algorithm in collaboration with 7 APL experts at 6 academic lead centers (LC). The trial was opened at the 6 LC and 293 community centers (CC). All CC were part of the NCI Community Oncology Research Network (NCORP). Patients who presented to one of the 6 LC were managed with input from the local expert. Physicians at the CC contacted one of the 7 LC experts as soon as a patient presented with suspected APL either by email or phone. Expert support was available 24/7 and the patient was eligible for enrollment if the contact was made within 72 hours of initiation of APL-directed therapy. All referred patients were enrolled except those refusing treatment or blood transfusion support. An initial work up and treatment plan was provided to the CC physician. Therapy was based on standard of care with dose reductions for patient age and comorbidities. More complex patients at LC and CC were discussed with all LC experts for a consensus recommendation. Ongoing communication was maintained for anticipated problems, treatment modifications and continued throughout induction therapy and was more frequent during the first 2 weeks as most complications occur during this period. Overall survival data was evaluated using the method of Kaplan-Meier (KM) and one-month and one-year OS rates estimated based on the KM estimate.

RESULTS A total of 202 patients were enrolled in 43 centers between August 2017 and July 2021; 62 at 6 LC and 140 at 37 CC with a median of 2 patients per site (range 1-16). The median age was 53 (range: 18-91 years) representative of the general population, 72 (35.6%) were elderly and ≥60 years of age and 105 (52%) male. Patient race included 79.7% White, 13.2% African American, 5.7% Asian, 1.4% Native American/Hawaiian. 18.8% identified as Hispanic. 25.7% (52/202) were high-risk APL at presentation. The primary objective was met with only 7 deaths (3.5%) attributed to induction (days 2-35) and all deaths were due to differentiation syndrome. 6 of 7 deaths were among the elderly (69-91 years) with 4 at LC (6.5%) and 3 (2.1%) at CC. There were 4 additional deaths during year one (days 52, 189, 256 and 293) due to refusal of further therapy, ovarian cancer, myocardial infarction and COVID respectively. The induction survival (one-month) was 97.0% (95% CI: 93.4-98.7) and one-year survival was 94.5% (95% CI: 90.3-96.9) with no difference between LC and CC. During the COVID pandemic, there was a trend towards increased high-risk disease 36.5% (19/52) with 2 COVID related deaths but after induction.

CONCLUSIONS Use of a simplified treatment algorithm, management recommendations provided by a limited and dedicated group of APL experts and collaborative care results in a dramatic improvement in 1-year survival. Awareness among providers regarding induction mortality is an important barrier to long-term survival. Availability of a core group of APL experts to co-manage with physicians is crucial given the acuity and complexity of early disease-related mortality.

Altman:Astellas: Honoraria, Research Funding; Aptos: Research Funding; Aprea: Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding; ALX Oncology Inc: Research Funding; Kura Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujifilm: Research Funding; Glycomimetics: Other: Data Monitoring Committee; Loxo: Research Funding; Celgene: Research Funding; Kartos Therapeutics: Research Funding; ImmunoGen: Research Funding; Biosight: Membership on an entity's Board of Directors or advisory committees, Other: reumbursement for travel, Research Funding. Luger:Onconova, Celgene, Biosight, Hoffman LaRoche, and Kura: Research Funding; Syros, Agios, Daiichi Sankyo, Jazz Pharmaceuticals, Brystol Myers Squibb, Acceleron, Astellas, and Pfizer: Honoraria. Tallman:UpToDate: Patents & Royalties; Syros Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees; Innate Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Ipsen Biopharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR-Adv Bd: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Membership on an entity's Board of Directors or advisory committees, Research Funding; Orsenix: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Foran:Novartis, Servier, Pfizer, BMS, Taiho: Other: Formal Advisory Activities; AbbVie, Actinium, Aptose, Astex, H3Biosciences, Kura Oncology, Trillium, Xencor: Research Funding. Perl:Astellas, Daiichi Sankyo, AbbVie, Forma, Sumitomo Dainippon, BeatAML LLC: Consultancy; Astellas, Abbvie, Daiichi Sankyo, FujiFilm, Syndax: Research Funding; Astellas, Daiichi Sankyo, Abbvie, Genentech, BerGenBio, Immunogen, BMS/Celgene, Actinium: Membership on an entity's Board of Directors or advisory committees. Vadakara:Mallinckrodt Pharmaceuticals: Research Funding. Wagner:Celgene/Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Litzow:Abbvie: Research Funding; Amgen: Research Funding; Astellas: Research Funding; Novartis: Research Funding; Syndax: Research Funding; Jazz: Consultancy; Actinium: Research Funding; Pluristem: Research Funding; Biosight: Other: Data Monitoring Board. Kota:Xcenda: Honoraria; Pfizer Inc: Honoraria, Research Funding; Ariad: Honoraria; Incyte: Honoraria; Novartis: Honoraria.