Leukemia Physician's Perspective on Transplant in Patients with <i>TP53</i> Mutated Acute Myeloid Leukemia

Background Acute myeloid leukemia (AML) with TP53 mutation (m) has poor outcomes even in the contemporary era with median overall survival (OS) of 6-9 months. The only factor that has been shown to improve outcomes is allogeneic hematopoietic cell transplantation (allo-HCT) (Badar et al AJH 2022; Leukemia 2023). However, the role of allo-HCT for TP53-m AML continues to be a matter of debate given high rates of relapse after allo-HCT particularly in TP53-m AML with complex cytogenetics (CG). We used the COMMAND consortium database to investigate the factors that influenced physician's decision for allo-HCT in TP53-m AML. Method We conducted a multicenter observational study in collaboration with 7 U.S. academic centers under COMMAND consortium. We reviewed electronic medical records of 369 TP53-m AML patients to analyze reasons for not pursuing allo-HCT including refractory disease, donor availability, advanced age/co-morbidities, physician perspective on ineffectiveness of allo-HCT in improving outcome and patient's decision. Diagnostic criteria for TP53 allelic state were according to the International Consensus Classification (ICC) (Blood 2022; 140:1200). Next-generation sequencing and cytogenetic studies were performed according to institutional standard protocols. Results The median age at diagnosis was 68 years, with 222 (60.5%) patients being male. The majority of patients were diagnosed with de novo AML 179 (48.8%), followed by secondary AML (sAML) in 103 (28%) patients, and therapy-related (t)AML in 85 (23.2%) patients. Ninety-four percent of evaluable patients had complex cytogenetics (CG) and 192 (52%) had multi-hit TP53-m. One-hundred forty-seven (42%) patients received intensive chemotherapy (CPX 351 [66 (44%)], 7+3 [78 (53%)]), while 205 (58%) patients received low-intensity regimens including hypomethylating agents (HMA) plus venetoclax (137 [66%]) and HMA +/- investigational agents (68 [33%]). The rate of complete remission (CR)/CR with incomplete count recovery (CRi) was 34.4% and overall response rate (CR/CRi + partial remission [PR] + morphologic leukemia free state [MLFS]) was 52%. Forty-seven (13%) patients received allo-HCT in CR1 and 17 (5%) patients received allo-HCT in CR2. Of the 294 patients for whom data on allo-HCT decision-making was available, the most common reason for not proceeding to allo-HCT was refractory disease in 126 (43%) patients. Other significant reasons included advanced age/comorbidities (n=78 [30.6%]), physician recommendation (n=7 [2%]), patient's decision (n=24 [9.4%]), and patient relocation or changing healthcare providers (n= 9 [3.5%]). Two (0.4%) patients had no suitable donor available for allo-HCT. Amongst the 7 patients for whom allo-HCT was not pursued due to physician's decision, the median age of the patients was 69 years (R, 59-70), 3 (25%) patients had sAML, and all of them had multi-hit TP53-m associated with complex CG. Six out of seven (86%) patients received HMA plus venetoclax and 1 (14%) patient received HMA-based induction. Six patients achieved CR/CRi after induction and 1 patient had partial remission. The median survival of these patients was 11 months (R, 10.7-11.3), eventually all patients died from progressive AML. Conclusion Our survey suggests that the primary reason for not proceeding with allo-HCT was refractory disease, underlying the difficulty in achieving the disease control needed for allo-HCT. There is an urgent need for better frontline therapies tailored specifically for TP53-m AML, along with refined patient selection criteria to better identify candidates who would benefit most from allo-HCT to potentially improve their long-term outcomes.