Older Age and TP53 Mutations Are Predictors for the Development of Therapy-Related Myeloid Neoplasms in Adults Undergoing Frontline Therapy for Acute Lymphoblastic Leukemia
Authors: Santos Azevedo Roberta , Kantarjian Hagop M. , Takahashi Koichi , Christophe Nasnas Cedric , Loghavi Sanam , Jain Nitin , Haddad Fadi G. , Senapati Jayastu , Issa Ghayas C. , Abbas Hussein A. , Kadia Tapan M. , Chien Kelly S. , Montalban-Bravo Guillermo , Garris Rebecca , Ravandi Farhad , Jabbour Elias , Short Nicholas J. 
Published: December 2024

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 &lt;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 &lt;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.