Impact of TP53 on outcome of patients with myelofibrosis undergoing hematopoietic stem cell transplantation

• Multihit TP53^MT represents a novel very high-risk group in patients with myelofibrosis undergoing HSCT.

• Multihit TP53^MT was particularly associated with high rates of leukemic transformation early after transplantation.

TP53 mutations (TP53^MTs) have been associated with poor outcomes in various hematologic malignancies, but no data exist regarding its role in patients with myelofibrosis undergoing hematopoietic stem cell transplantation (HSCT). Here, we took advantage of a large international multicenter cohort to evaluate the role of TP53^MT in this setting. Among 349 included patients, 49 (13%) had detectable TP53^MT, of whom 30 showed a multihit configuration. Median variant allele frequency was 20.3%. Cytogenetic risk was favorable (71%), unfavorable (23%), and very high (6%), with complex karyotype present in 36 patients (10%). Median survival of patients with TP53^MT was 1.5 vs 13.5 years for those with wild-type TP53 (TP53^WT; P < .001). Outcome was driven by multihit TP53^MT constellation (P < .001), showing 6-year survival of 56% for individuals with single-hit vs 25% for those with multihit TP53^MT vs 64% for those with TP53^WT. Outcome was independent of current transplantation-specific risk factors and conditioning intensity. Similarly, cumulative incidence of relapse was 17% for single-hit vs 52% for multihit vs 21% for TP53^WT. Ten patients with TP53^MT (20%) presented as leukemic transformation vs only 7 (2%) in the TP53^WT group (P < .001). Out of the 10 patients with TP53^MT, 8 showed multihit constellation. Median time to leukemic transformation was shorter for multihit and single-hit TP53^MT (0.7 and 0.5 years, respectively) vs 2.5 years for TP53^WT. In summary, multihit TP53^MT represents a very high-risk group in patients with myelofibrosis who are undergoing HSCT, whereas single-hit TP53^MT alone showed similar outcome to patients with nonmutated TP53, informing prognostication for survival and relapse together with current transplantation-specific tools.