Older Age and TP53 Mutations Are Predictors for the Development of Therapy-Related Myeloid Neoplasms in Adults Undergoing Frontline Therapy for Acute Lymphoblastic Leukemia

Background: With contemporary treatment regimens, most adults with acute lymphoblastic leukemia (ALL) can be cured. However, some patients (pts) develop therapy-related myeloid neoplasms (t-MNs) after ALL therapy, which is associated with a poor prognosis. We sought to determine the frequency of t-MNs following ALL therapy, the risk factors for their development, and the cytomolecular characteristics and outcomes of these t-MNs.

Methods: This is a retrospective analysis of pts with de novo ALL diagnosed between 1992 and 2022 who were treated with a frontline hyper-CVAD or mini-hyper-CVD-based regimen. Pts with refractory disease to frontline therapy or who had a follow-up of <6 months from their ALL diagnosis were excluded from this analysis.

Results: 875 pts with newly diagnosed ALL meeting the inclusion criteria were analyzed. The median age at ALL diagnosis was 45 years (range, 18-87); 212 pts (24%) were ≥60 years. 716 pts (82%) had B-cell ALL, 114 pts (13%) had T-cell ALL, and 45 pts (5%) had unspecified immunophenotype (all diagnosed early in the study period). 239 pts (27%) had Ph-positive ALL. TP53 mutation was detected in 19% (53/283 pts). 792 pts (91%) received hyper-CVAD, and 83 pts (9%) received mini-hyper-CVD as the treatment backbone. Allogeneic stem cell transplant (ASCT) was performed in 121 pts (14%) in first remission. The median follow-up for the cohort was 46.1 months (range, 6.0-312.6).

Overall, 35 pts (4%) developed a t-MN, with a median interval between ALL and t-MN diagnosis of 38.2 months (range, 2.9-178.9). The median age at time of t-MN diagnosis was 59 years (range, 26-87). 24 of the t-MN cases (68%) were myelodysplastic syndrome (MDS), 10 (29%) were acute myeloid leukemia (AML), and 1 (3%) was chronic myelomonocytic leukemia (CMML). 4 pts (11%) had a second neoplasm diagnosed between ALL and t-MNs that was treated with chemotherapy and/or radiotherapy. Predictors for development of a t-MN were age (t-MN incidence for pts aged ≥60 vs <60 years: 7% vs 3%, respectively, p=0.009) and TP53 mutation at ALL diagnosis (TP53-mutated vs wild-type: 9% vs 1%, p=0.008). Immunophenotype, karyotype, and Ph-like status were not associated with t-MNs.

Among the 33 t-MN pts who had cytogenetic/molecular testing performed, 30 (91%) had at least 1 adverse risk factor, including complex karyotype in 22 pts (67%), KMT2A rearrangement in 3 pts (9%), and TP53 mutation in 10/15 tested pts (67%). Among 28 pts who had an evaluable karyotype at both ALL and t-MN diagnoses, only 4 (14%) shared at least one cytogenetic abnormality between the 2 time points. However, among 7 pts who had molecular testing performed at both ALL and t-MNs diagnosis, 6 (86%) shared at least one mutation between the 2 time points. Notably, 5 of these 6 pts shared a TP53 mutation, including 1 pt who also acquired a second TP53 mutation with low VAF (2%) at the time of t-MN diagnosis. The other pt shared ASXL1, RUNX1, SRSF2, and TET2 mutations.

Following t-MN diagnosis, 13 pts (37%) received intensive chemotherapy, 20 (57%) received low-intensity therapy; 2 pts (6%) proceeded directly to ASCT without intervening treatment. 61% of pts (20/33) responded to frontline therapy for t-MN, and 10 pts (29% overall; 50% of responders) were bridged to ASCT. The median OS after diagnosis of t-MN was 8.9 months, and the 2-year OS rate was 20%. OS was similar between pts with AML and MDS/CMML (p=0.31). In a landmark analysis among responding pts, there was a trend towards superior OS in pts who underwent subsequent ASCT vs. those who did not (2-year OS 36% vs. 18%, respectively; p=0.17). Only one pt experienced relapse of ALL after diagnosis of t-MN (occurring 38 months after the initial ALL diagnosis and 9 months after AML diagnosis).

Conclusion: t-MNs occur in approximately 4% of pts after frontline ALL therapy. The strongest predictor for t-MNs were older age (i.e. age ≥ 60 years) at time of ALL and TP53-mutated ALL. t-MNs after ALL therapy are enriched with adverse-risk features and have a poor outcome. Molecular mutations are commonly shared between the ALL and t-MN (particularly TP53 mutations) suggesting a common preleukemic clone that is shared between these diseases and predisposes to development of t-MN.

Kantarjian:AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Loghavi:Pathology Education Partners; VJ HemeOnc, College of American Pathologists, OncLive, ICCS, MD Education, NCCN, MashUp Media, NCTN, Aptitude Health: Honoraria; Guidepoint; QualWorld; Gerson Lehrman Group, AlphaSight, Arima, Qiagen, Opinion Health: Consultancy; Astellas, Amgen: Research Funding; Abbvie: Current holder of stock options in a privately-held company; Syndx, Servier, BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie, Daiichi Sankyo, BluePrint Medicine, Caris Diagnostics, Recordati, Servier: Consultancy. Jain:ADC Therapeutics: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support, Research Funding; MEI Pharma: Consultancy, Honoraria, Other: Travel Support; NovalGen: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel Support, Research Funding; Newave: Research Funding; BeiGene: Consultancy, Honoraria, Other: Travel Support; TG Therapeutics: Consultancy, Honoraria, Other: Travel Support; Incyte: Research Funding; CareDx: Consultancy, Honoraria, Other: Travel Support; Dialectic Therapeutics: Research Funding; Takeda: Research Funding; Medisix: Research Funding; Pfizer: Research Funding; MingSight: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel Support; Genentech: Consultancy, Honoraria, Other: Travel Support, Research Funding; Fate Therapeutics: Research Funding; Cellectis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Ipsen: Consultancy, Honoraria, Other: Travel Support; TransThera Sciences: Research Funding; Loxo Oncology: Research Funding; Aprea Therapeutics: Research Funding; Servier: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding. Issa:Kura Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Astex: Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Merck: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Celgene: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Syndax Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; NuProbe: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding. Abbas:Ascentage: Research Funding; Enzyme By Design: Research Funding; Blueprint Medicines Corporation: Research Funding; GlaxoSmithKline: Research Funding; Genentech: Research Funding; Alamar Biosciences: Honoraria; Molecular Partners: Consultancy; Illumina: Honoraria, Other: Inkind Support, Research Funding. Kadia:Genentech: Consultancy, Research Funding; Sellas: Consultancy, Research Funding; DrenBio: Consultancy, Research Funding; JAZZ: Research Funding; Servier: Consultancy; BMS: Consultancy, Research Funding; Regeneron: Research Funding; Abbvie: Consultancy, Research Funding; Rigel: Honoraria; Ascentage: Research Funding; Pfizer: Research Funding; Amgen: Research Funding; Novartis: Honoraria; Cellenkos: Research Funding; Incyte: Research Funding; ASTEX: Research Funding; AstraZeneca: Research Funding. Chien:AbbVie: Consultancy; Rigel Pharmaceuticals: Consultancy. Montalban-Bravo:Rigel: Research Funding; Takeda: Research Funding. Ravandi:Syros: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Prelude: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Astyex/Taiho: Research Funding; Astellas: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Xencor: Research Funding. Jabbour:AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy; AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding. Short:Astellas Pharma, Inc.: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria; Takeda Oncology: Honoraria, Research Funding; BeiGene: Honoraria; Xencor: Research Funding; Autolus: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Stemline Therapeutics: Research Funding; GSK: Consultancy, Research Funding; Pfizer Inc.: Honoraria; NextCure: Research Funding.