Factors Predicting Survival in Patients with TP53-Mutated Myeloid Neoplasms Following Allogeneic Stem Cell Transplant

Introduction Allogeneic stem cell transplant (alloSCT) is considered the therapeutic modality of choice for patients with TP53 mutated (TP53mut) myeloid neoplams (MN). However, outcomes remain poor and factors associated with post-alloSCT survival, in this high-risk cohort, are not known. Methods We retrospectively reviewed TP53mut MN patients undergoing alloSCT at Mayo Clinic Enterprise and CALHN, Adelaide, South Australia. TP53mut MN were defined per 2022 ICC guidelines. Multi-hit TP53mut was defined as: 2 distinct TP53mut (each VAF ≥10%) or a single TP53mut with (1) 17p deletion on cytogenetics; (2) VAF of ≥50%; or (3) copy-neutral LOH at the 17p TP53 locus. With an aim to evaluate the impact of complex karyotype (CK) on post-alloSCT outcomes, CK was not considered a multi-hit equivalent. Overall survival (OS) was calculated from the time of alloSCT using Kaplan Meier method. Non-relapse mortality (NRM) and relapse incidence (RI) was determined using competing risk analysis. Results Of 87 TP53mut MN patients 32 (36.8%) had AML, 13 (14.9%) had MDS/AML and 42 (48.3%) had MDS. At diagnosis, 73 (83.9%) had CK and 17 (19.5%) patients had two TP53mut. Median TP53 variant allele frequency (VAF) was 38.5% (IQR 17.2–62). Forty-nine (56.3%) patients had multi-hit TP53mut (mhTP53). Median age at alloSCT was 64 (IQR 59-68) years. Median follow-up was 2.9 years. Median OS was 11.7 months, driven primarily by relapse (1-year RI 51.3% and NRM 13.9%). Multivariate analysis (MVA) confirmed mhTP53 (HR 2.37, 95% CI 1.1 – 3.9, P = 0.024) and CK (HR 2.37, 95% CI 1.3 – 4.3, P = 0.005) to be associated with inferior OS, whereas there was a trend towards improved OS with melphalan-based conditioning (HR 0.57, 95% CI 0.32 – 1.04, P = 0.067, Figure 1A). Melphalan-based conditioning was associated with a decreased RI (HR 0.32, 95% CI 0.17–0.60, P <0.001, Figure 1B). In contrast, myeloablative conditioning (HR 2.2, 95% CI 1.13–4.34, P = 0.02) and post-transplant cyclophosphamide (HR 1.84, 95% CI 1.03 – 3.3, P = 0.04) were associated with an increased risk of relapse. Late NRM partially abrogated the benefit of decreased RI seen with melphalan-based conditioning (Figure 2).Given that melphalan was the only modifiable factor associated with a decreased relapse risk, we considered patients with neither mhTP53 nor complex karyotype, but receiving melphalan based conditioning, to have comparatively favorable OS (“standard-risk”). Twelve (13.8%) patients had standard risk, while the remaining 71 (81.6%) patients were considered high-risk. The standard-risk cohort had a significantly longer 3-year OS compared to the high-risk cohort (51.9% vs. 22.3%, P = 0.038, Figure 3). Conclusion Melphalan-based conditioning in patients without mhTP53mut and without complex karyotype may identify a small subset of patients with favorable outcomes in this otherwise high-risk cohort. Larger studies are needed to confirm these findings.