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SOHO 2025 | The prevalence and management of TP53-mutated ALL
Nicholas Short, MD, The University of Texas MD Anderson Cancer Center, Houston, TX, comments on the prognostic impact of TP53 abnormalities in acute lymphoblastic leukemia (ALL), highlighting that TP53 mutations are relatively common, particularly in older patients, and are associated with a higher risk of relapse and therapy-related myeloid neoplasms. Dr Short advocates for a tailored approach to treatment in this patient population based on age and TP53 variant allele frequency. This interview took place at the 13th Annual Meeting of the Society of Hematologic Oncology (SOHO 2025) in Houston, TX.
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Transcript
So there’s been a lot of data publications on TP53 mutations in myeloid diseases such as MDS and AML, relatively less in ALL. And so we know that these mutations are actually relatively common, particularly in older patients. So actually older patients with Philadelphia chromosome negative B-cell ALL can have up to a 40 to 50% incidence of TP53 mutations. So they’ve actually, I would argue, been relatively underappreciated and there hasn’t been enough focus on trying to improve outcomes for these patients...
So there’s been a lot of data publications on TP53 mutations in myeloid diseases such as MDS and AML, relatively less in ALL. And so we know that these mutations are actually relatively common, particularly in older patients. So actually older patients with Philadelphia chromosome negative B-cell ALL can have up to a 40 to 50% incidence of TP53 mutations. So they’ve actually, I would argue, been relatively underappreciated and there hasn’t been enough focus on trying to improve outcomes for these patients. What we’ve seen is that the challenge of TP53-mutated ALL is twofold. We know that these patients have a higher risk of relapse, but they also are predisposed to develop therapy-related myeloid neoplasms such as MDS and AML. The risk of both relapse and therapy-related myeloid neoplasms is greatest in older patients and particularly those with a high variant allelic frequency.
So we reported that patients with TP53 VAF of over 45% have particularly poor outcomes. So in order to improve outcomes for these patients, if we have a new younger patient with Philadelphia-chromosome negative B-cell ALL that’s TP53-mutated, we treat them with intensive chemotherapy with inotuzumab and blinatumumab, we only consider them to be high-risk if they have a high VAF, and those patients we try to treat with a CAR T-cell consolidation study. For a low VAF TP53 mutation, we don’t necessarily consider it high risk, and we treat them according to the standard protocol.
Now, for older patients, we’re concerned not only about risk of relapse, but also therapy-related MDS or AML. So if they have a high burden TP53 mutation, we also try to consolidate them with CAR T-cells. And if they have a persistent TP53 mutation in remission, we’re concerned about their risk for developing a therapy-related myeloid neoplasm, so we consider them for stem cell transplant if they’re a suitable candidate. Again, if they’re older, but they have a TP53 mutation, but it’s a low VAF, we treat them according to the standard protocol, but we still would like to see the TP53 mutation as well as their NGS MRD clear, in which case, if those don’t, then we consider them for stem cell transplant.
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