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

Program: Oral and Poster Abstracts
Type: Oral
Session: 612. Acute Lymphoblastic Leukemias: Clinical and Epidemiological: Look into the Crystal B-ALL: Genetic, Phenotypic and Dynamic Outcome Predictors in Lymphoblastic Leukemia
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, ALL, Diseases, Lymphoid Malignancies
Monday, December 9, 2024: 10:45 AM

Roberta Santos Azevedo1*, Hagop M. Kantarjian, MD1, Koichi Takahashi, MD, PhD1, Cedric Christophe Nasnas, MD1*, Sanam Loghavi, MD2, Nitin Jain, MD1, Fadi G. Haddad, MD1, Jayastu Senapati, MD, DM, MBBS1, Ghayas C. Issa, MD1, Hussein A. Abbas, MD, PhD1, Tapan M. Kadia, MD1, Kelly S. Chien, MD1, Guillermo Montalban-Bravo, MD1, Rebecca Garris1*, Farhad Ravandi, MBBS1, Elias Jabbour, MD3 and Nicholas J. Short, MD1

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Leukemia, University of Texas M.D. Anderson Cancer Ctr., Houston, TX

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.

Disclosures: 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: Amgen: Research Funding; Syros: Consultancy, Honoraria, Research Funding; Syndax: Honoraria; Xencor: Research Funding; Prelude: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Astyex/Taiho: 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.

*signifies non-member of ASH