• Multi-hit TP53MT represents a novel very high-risk group in patients with myelofibrosis undergoing hematopoietic cell transplantation.

  • Multi-hit TP53MTwas associated with high rates of leukemic transformation early after transplantation.

TP53 mutations (TP53MT) have been associated with poor outcomes in various hematologic malignancies, but no data exist on 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 TP53MTin this setting. Among 349 included patients, 49 (13%) had detectable TP53MT, of whom 30 showed a multi-hit 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 TP53MT patients was 1.5 years vs 13.5 years for the TP53WT group (P<0.001). Outcome was driven by multi-hit TP53MT constellation (P<0.001), showing 6-year survival of 56% for single-hit vs 25% for multi-hit TP53MT carriers vs 64% for TP53WT. Outcome was independent of current transplant-specific risk factors and conditioning intensity. Similarly, cumulative incidence of relapse was 17% for single-hit vs 52% for multi-hit vs 21% for TP53WT. Ten patients with TP53MT (20%) presented as leukemic transformation vs only 7 (2%) in the TP53WT group (P<0.001). Out of the 10 patients with TP53MT, 8 showed multi-hit constellation. Median time to leukemic transformation was shorter for multi-and single-hit TP53MT (0.7 and 0.5 years, respectively) vs 2.5 years for TP53WT. In summary, multi-hit TP53MT represents a very high-risk group in myelofibrosis patients undergoing HSCT, whereas single-hit TP53MTalone showed similar outcome to non-mutated patients, informing prognostication for survival and relapse together with current transplant-specific tools.

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