Acute Myeloid Leukemia (AML) with TP53 alteration and outcomes after allogeneic hematopoietic stem cell transplantation: A CIBMTR registry study Free

Background: Acute myeloid leukemia (AML) with TP53 alteration (TP53^alt), including deletion (TP53^del) detected by cytogenetics (CG) (karyotype, FISH, or genomic microarray) and/or TP53 mutation (TP53^mut) identified by next-generation sequencing, is associated with poor prognosis. However, a subset of patients may achieve long-term survival after allogeneic hematopoietic cell transplantation (allo-HCT). Patient-, disease-, and transplant-related variables may inform risk stratification and improve treatment decision-making in this high-risk population. We used the CIBMTR registry to investigate outcomes of patients with TP53^alt AML undergoing allo-HCT.

Methods: We included adult patients with 2017 ELN adverse-risk AML who underwent first allo-HCT between 2013–2019 and had available CG and molecular data. TP53^del was centrally reviewed by expert cytogeneticist. Patients were stratified into three TP53^alt groups: Group 1 (TP53^mut+/ TP53^del+), Group 2 (TP53^mut −/ TP53^del+), and Group 3 (TP53^mut+/ TP53^del −). The control group comprised patients with 2017 ELN adverse-risk AML negative for both TP53^mut and TP53^del. Patients from embargoed centers, lacking consent or comprehensive research data, or missing CG and molecular information were excluded.

Results: Of 6,474 patients with adverse-risk AML, 703 patients with TP53^alt met inclusion criteria: Group 1 (n=203), Group 2 (n=271), Group 3 (n=229). The control group included 2,763 patients. Median age was 58 years (44% ≥60); 44% were female; 16% had Karnofsky score <90, and 52% had HCT-CI ≥3. Secondary AML was more frequent in TP53^alt groups (32%, 27%, 27%) versus control (21%) (p<.01). Complex and monosomal karyotypes were most common in Group 1 (61%), followed by Group 2 (54%), Group 3 (31%), and control (6%), p<.01. More patients in Groups 1 and 2 (28% each) underwent HCT in primary induction failure/relapse (PIF/Rel) versus Group 3 (19%) and control (19%), p<.01. Median time from diagnosis to transplant was 5 months (1-331). Donor type was matched related in 23%, matched or mismatched unrelated in 50%, haploidentical in 18%, and umbilical cord blood in 7%. Conditioning intensity was myeloablative (MA) in 51%; reduced-intensity (RIC) in 36% , and 13% non-MA (NMA). Post-transplant cyclophosphamide (PTCy) was used in 27%; and in vivo T-cell depletion (ATG or alemtuzumab) in 26%.

After median follow-up of 66 months (3-130), 5-yr OS was 18% (Group 1), 18% (Group 2), 35% (Group 3) vs 46% in controls (p<0.001). 5-yr LFS was 14%, 15%, and 28%, respectively, vs 38% (p<0.001). 5-yr CIR was 69%, 66%, and 52% vs 43% (p<0.001). Transplant-related mortality (TRM) was similar across groups (1-year: 12–16%).

On multivariate analysis, compared with controls, TP53^del (with or without TP53^mut) was independently associated with higher relapse risk: Group 1 HR 1.97, Group 2 HR 1.91, Group 3 HR 1.45 (all p<0.001). These findings translated into inferior OS (HR 1.94, 1.87, and 1.45, respectively, p<0.001). PIF/Rel and CR2+ were also associated with worse survival (HR 2.58 (p<0.001) and 1.18 (p<0.001, respectively). No significant difference was observed between MA and RIC for relapse, while non-myeloablative regimens (HR 1.65; p<0.001) were associated with higher CIR. In vivo T-cell depletion increased relapse risk (HR 1.22; p=0.004). TRM was not influenced by TP53^alt status; it was impacted by age, KPS, time from diagnosis to HCT, and GVHD prophylaxis regiment (non-PTCy).

Conclusions: This large, registry-based study with long term median follow-up showed that among patients with adverse-risk AML, TP53^alt is a strong independent predictor of poor post-HCT outcomes in AML, particularly when TP53^del is present. Patients with TP53^del , with or without concurrent TP53^mut, experienced the worst outcomes, followed by those with isolated TP53^mut. Despite the limitations of registry data including lack of information on timing of TP53^mut, variant allele frequency (VAF), number of mutations, or accurate information on measurable residual disease (MRD), these findings reinforce the adverse prognostic impact of TP53^alt and support its inclusion in risk stratification frameworks. While some patients with TP53^alt —particularly those with isolated mutations—may benefit from allo-HCT, relapse remains the dominant cause of failure. Future studies incorporating TP53 functional status, VAF, clonal architecture, specific CG, MRD, and novel transplant approaches are warranted.