Acute Promyelocytic Leukemia in the Molecular Age

Background: Acute Promyelocytic Leukemia (APL) is a rare form of leukemia defined by the PML::RARA translocation; with recent advances, including aggressive supportive care and the widespread adoption of ATRA and arsenic trioxide (ATO) regimens, survival rates have greatly improved. The use of next-generation sequencing (NGS) panels has transformed the diagnosis and treatment of AML, but there is little known regarding how somatic mutations affect clinical features in APL.

Methods: We retrospectively reviewed all adult patients >18 years-old diagnosed and/or treated for APL at our multi-hospital institution from 2014-2022. FLT3-ITD status was assessed by PCR amplification done locally and/or by the below commercial vendors. NGS panels were performed by Genoptix/Neogenomics Laboratories and Foundation Medicine, which included panels assessing for mutations from 21-406 genes. High-risk APL was defined as patients with a white blood cell (WBC) count of >10x10⁹/L at initial diagnosis. The Z-score test was used to assess for statistical differences in proportions between groups. The Kaplan-Meier method was used to calculate overall survival.

Results: We identified 47 patients during the time-period with APL. The median age at diagnosis was 53 years (range, 19-91) and 23 patients were female. Ten patients (21.3%) had high-risk APL. 41 patients (87.2%) presented with absolute neutrophil count (ANC) of <1x10⁹/L (range, 0-9.89). Ten of 47 patients (21.3%) were FLT3-ITD positive, with n=5 (50.0%) presenting as high-risk. Nineteen of 45 patients (42.2%) with complete cytogenetics had additional cytogenetic abnormalities and/or atypical PML::RARA translocations. Notably, none of the patients in the cohort relapsed, though nine patients (18.4%) had APL-related early mortality within 60-days of diagnosis. The median overall survival (mOS) for the cohort was not reached; the 12-, 60-month OS was 79.5% and 76.2%, respectively. Treatment included: 32 patients (68.1%) received ATRA/ATO, ten patients (21.3%) received ATRA + ATO + chemotherapy combinations (Anthracycline, GO, and/or cytarabine), two patients (4.3%) received ATRA monotherapy, two patients (4.3%) received ATRA + chemotherapy, and one (2.1%) received no treatment.

Thirty-three patients (70.2%) underwent molecular profiling via NGS testing. Eighteen of the 33 patients (54.5%) had a FLT3-ITD and/or pathogenic mutation identified (NGS+), whereas 15/33 patients (45.5%) had no mutations (NGS-). The most common mutations were FLT3-ITD (n=9), WT1 (n=4), RUNX1 (n=2), PPM1D (n=2), and FLT3-TKD (n=2). Clinical presentations and courses were relatively similar between the two groups. Rates of high-risk disease were 5/18 (27.8%) NGS+ patients (all FLT3-ITD+, 1/5 patients had additional PPM1D and KIT mutations) and 3/15 (20.0%) NGS- patients (p=0.60). Eight of 17 (47.1%) NGS+ patients had an atypical PML::RARA rearrangement or additional chromosomal abnormalities, compared to 7/14 (50.0%) NGS- patients (p=0.87). Rates of neutropenia with an ANC <1x10⁹/L at diagnosis were similar in patients who were NGS+ (16/18; 88.9%) and NGS- (13/15; 86.7%) (p=0.85). Rates of differentiation syndrome were also similar: 12/18 (66.7%) NGS+ patients and 9/15 (60.0%) NGS- patients (p=0.69). DIC occurred in 6/18 (33.3%) NGS+ and 8/15 (53.3%) NGS- patients (p=0.25). The mOS of NGS+ and NGS- patients was not reached and not statistically different (HR 1.14, 95%CI 0.22-5.87, p=0.87). The 12-, 60-month OS was 83.3% for NGS+ patients and 93.3%, 84.9% respectively for NGS- patients; 2/18 (11.1%) NGS+ and 1/15 (6.7%) NGS- patients died within 60 days of diagnosis (p=0.66).

Discussion: This is the first report correlating mutational profiles with clinical features and outcomes, including high-risk disease, differentiation syndrome, and DIC in APL. There was no significant difference in the clinical features and outcomes between patients who had mutations and those who did not. Larger studies may be able to discern differences between patients with individual mutations to better understand their clinical impact.

Levavi:Sobi: Consultancy, Other: Advisory Board. Kremyanskaya:AbbVie: Consultancy; Incyte: Consultancy; Agios: Consultancy; Silence Therapeutics: Consultancy; Protagonist Therapeutics: Consultancy; Constellation/MorphoSys: Consultancy; Disc Medicine: Consultancy. Marcellino:Cellarity: Consultancy. Silverman:BMS: Research Funding; Celgene: Research Funding. Mascarenhas:MorphoSys: Consultancy; Blueprint Medicines: Consultancy; Karyopharm: Consultancy; Merck: Consultancy; Pfizer: Research Funding; GSK: Consultancy; Keros: Consultancy; Bristol Myers Squibb: Research Funding; AbbVie: Consultancy, Research Funding; Icahn School of Medicine at Mount Sinai: Current Employment; Ajax: Research Funding; Geron: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Disc: Consultancy; Roche: Consultancy; CTI BioPharma/SOBI: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel Support, Speakers Bureau; Novartis: Consultancy, Other: Travel Support , Research Funding, Speakers Bureau; PharmaEssentia: Consultancy, Research Funding; Sumitomo: Consultancy; Ariad: Speakers Bureau; NS Pharma: Research Funding; Incyte Corporation: Consultancy, Speakers Bureau; Astellas: Research Funding. Tremblay:Sobi: Consultancy, Research Funding; Sumitomo: Research Funding; Cogent Biosciences: Consultancy, Research Funding; Gilead: Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Pharmaessentia: Consultancy; Sierra Oncology: Consultancy; GSK: Consultancy. Feld:Syros Pharmaceuticals: Research Funding; Oryzon Genomics: Research Funding; Taiho Pharmaceutical: Research Funding.