ASH 2025 | TP53-mutated myeloid malignancies: multi-hit vs single-hit disease and transplant implications

We have evaluated the outcome of myeloid malignancies with P53 mutation, and we have found distinction in how these patients behave when they have a chronic disease versus advanced MDS and acute myeloid leukemia. So, among low-risk MDS patients or those patients with chronic myelofibrosis, we have seen that the single hit, as per initial data, have a comparable outcome compared to the wild-type JAK2. Whereas, when these MPN patients or MDS patients, progress or AML patients, we didn’t find the distinction that single hit versus multi-hit have any difference in outcome. Having said that, because there are multiple pathways which have been activated when disease evolve with time, the distinction is less clear compared to when they have an indolent or low-risk disease. Having said that, come to the other point. If you have a low-risk MDS patient or chronic phase myelofibrosis with JAK2 mutation, usually these patients have a low variable frequency and most often we don’t see a complementing complex cytogenetics. So these patients tend to do better which the time interval from diagnosis of chronic phase disease to advanced phase disease is relatively longer than what we expect with a JAK2 mutated myelofibrosis. When these patients progress, they often have a complex cytogenetics such as MPN with blast phase or myelofibrosis blast phase or high-risk MDS with excess blasts or AML. Then we don’t see the distinction and at that time, the occurrence of complex cytogenetics is an independent prognostic factor that predicts their outcome in terms of event-free survival and overall survival. In terms of therapy, all compared chemotherapy regimens tend to have a comparable outcome. What we have seen, that hypomethylating agent-based combination gives you the best yield in terms of achieving the response rate with minimal toxicity and among those patients who are eligible to have a donor availability can proceed to bone marrow transplant to improve their long-term outcome. We have presented data in several cohorts of these patients, those with MPN blast phase, those with AML, as well as high-risk MDS patients. Although the proportion of patients going to bone marrow transplant is around 10 to 15%. However, among these patients, you can see a two to three year survival of more than 50%.

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