People with myelofibrosis (MF) who undergo hematopoietic stem cell transplantation (HSCT) may have a greater risk of adverse outcomes if they have multiple TP53 mutations, according to a new study.

Those risks include a significantly higher likelihood of leukemic transformation shortly after transplantation, according to the report, which was published in Blood.

The study authors explained that mutations of the TP53 gene have long been associated with inferior outcomes in patients with hematologic malignancies. However, they wrote that there is little scientific evidence regarding the prognostic effects of TP53 mutations in people with MF.

To help fill the gap, the investigators used a large, multicenter cohort of 349 patients with MF who underwent their first HSCT between 1997 and 2001. Of those, 49 patients (13%) had mutations of TP53. Thirty of those patients had a multi-hit mutational configuration, and the rest had single-hit configurations.

The investigators used the International Consensus Classifications to categorize patients as single- or multi-hit cases. Multi-hit constellations were defined as the presence of 2 or more distinct mutations of TP53 with variant allele frequency of equal to or greater than 10%, one mutation plus 1 deletion involving the TP53 locus at 17p, 1 mutation with a variant allele frequency equal to or greater than 50%, or 1 mutation plus complex karyotype. Single-hit cases were defined as the absence of multi-hit constellations and a variant allele frequency of less than 50%.

Most of the people in the study cohort had a favorable cytogenetic risk profile (71%), while 23% had unfavorable cytogenetic risk and 6% were classified as very high risk. Thirty-six patients (10%) had a complex karyotype.

The data showed patients with TP53 mutations had significantly shorter median survival compared with patients with wild-type TP53: 1.5 vs 13.5 years, respectively. However, that gap seemed to be largely based upon whether the patient was categorized as multi-hit or single-hit. Among patients with multi-hit TP53 mutations, the 6-year survival rate was 25%, but for patients with single-hit mutations, the survival rate was 56%. The latter figure was similar to that of people with wild-type TP53, who had a survival rate at 6 years of 64%.

People with multi-hit constellations also had a much higher cumulative incidence of relapse (52% vs 17% for single-hit mutations vs 21% for people with wild-type TP53). Likewise, of the 10 people with TP53 mutations who experienced leukemic transformation, 8 had mult-hit constellations. In the wild-type cohort, 7 patients had leukemic transformation.

Our data, in line with previous reports in the nontransplant setting investigating patients with myelodysplastic syndromes and acute myeloid leukemia, clearly show that multi-hit TP53MT significantly increases the risk of relapse and, more importantly, leukemic relapse, in patients with myelofibrosis receiving HSCT, the study investigators wrote.

Clinically, they noted that people with multi-hit TP53 mutations were more likely to have severe anemia and thrombocytopenia at baseline, although other disease-specific and patient-specific characteristics were generally balanced between the cohorts.

The investigators also noted that posttransplant relapse remains the major cause of treatment failure, and they said more research is needed to better understand the role next-generation sequencing might play in monitoring patients and making treatment decisions.

Our data are not only of immediate clinical relevance for the transplant and nontransplant community, but also highlight the need for translational and clinical studies focused on understanding the mechanism of TP53MT specifically in patients with myelofibrosis, they concluded.

Reference

Gagelmann N, Badbaran A, Salit RB, et al. Impact of TP53 on outcome of patients with myelofibrosis undergoing hematopoietic stem cell transplantation. Blood. Published online March 20, 2023. doi:10.1182/blood.2023019630

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