Allogeneic HCT Improves Survival Rates for TP53-Mutated MDS

This article was originally published by Targeted Oncology. This version has been edited.

Allogeneic hematopoietic cell transplantation (HCT) improved overall survival (OS) vs non-HCT treatment in patients with myelodysplastic syndrome (MDS) harboring TP53 mutations.¹

The findings come from a study performed at Dana-Farber Cancer Institute and published in the Journal of Clinical Oncology in which DNA sequencing was used to assess samples from the multicenter BMT CTN 1102 study (NCT02016781).^1,2 In the study, patients with MDS with TP53 mutations had better OS rates irrespective of TP53 allelic status vs those treated with best available supportive care. Patients with IPSS-M very high risk without a TP53 mutation also had favorable outcomes when a donor was available.

“[O]ur data indicate that the benefit of HCT in patients with IPSS intermediate-2 and high-risk MDS extends to high-risk genetic subgroups. Moreover, patients with TP53-mutated MDS, irrespective of additional clinical or genetic variables, including allelic state, VAF, and pre-HCT mutation clearance, have superior survival with RIC allogeneic HCT compared with non-HCT treatment approaches, indicating that these patients should not be excluded for HCT on the basis of genetic findings alone, further reinforcing the conclusion that such patients should be offered transplantation when a donor is available,” the study authors wrote.

Targeted sequencing was performed on samples from 309 patients enrolled in the BMT CTN 1102 study. To evaluate the impact of MDS genetics on the benefit of HCT, a biological assignment study was conducted. Patients were aged 50-75 years and had International Prognostic Scoring System (IPSS) intermediate-2 or high-risk MDS, and patients with TP53 mutations were classified as TP53^multihit if 2 alleles were altered.

A total of 229 patients were assigned to the donor arm and 80 to the no donor arm. The baseline characteristics between patients with an available sample and those without were not significantly different. Among patients with samples, characteristics were similar in the donor and no donor group.

At the time of enrollment, targeted DNA sequencing was performed on 113 genes that are known to be recurrently mutated in myeloid malignancies or associated with germline predisposition to develop myeloid malignancies. Additionally, 17 genes that were mutated in at least 10 patients in the study cohort were evaluated to identify mutations associated with OS in the whole study cohort.

Two methods were used to assess the impact of allogeneic HCT. The first was a time-dependent analysis allowing the HCT covariate to change at the time of HCT, and the second was a dynamic landmarking analysis at 3, 6, and 9 months from consent where patients were assigned to no HCT group if they were not transplanted at the landmark time. The median follow-up in survivors was 32 months (range, 6-38).

Findings showed that at least 1 mutation was identified in 272 of 309 (88%) patients. The overall distribution of gene mutations was similar between the donor and no donor arms, with the most common being TP53 (28% v 29%; P = .89), ASXL1 (23% v 29%; P = .37), and SRSF2 (16% v 16%; P = .99). Patients with a TP53 mutation had shorter OS rates compared with patients without TP53 mutation (21% ± 5% [SE] v 52% ± 4% at 3 years; P < .001). For patients with a TP53 mutation, OS was similar between TP53 single vs TP53^multihit (22% ± 8% v 20% ± 6% at 3 years; P = .31).

Among patients with a TP53 mutation who received RIC HCT, OS was improved compared with non-HCT treatment (OS at 3 years: 23% ± 7% v 11% ± 7%; P = .04). This was associated with a hazard ratio of 3.89; 95% CI, 1.87 to 8.12; P <.001 after adjustment for covariates. Patients with molecular IPSS very high-risk without a TP53 mutation had an OS rate that was significantly improved if they had a donor (68% ± 10% v 0% ± 12% at 3 years).

These data show that even after adjustment for genetic variables, the survival rates of patients after allogeneic HCT remained superior vs with non-HCT treatment with no interaction between genetic subtype and treatment effect.

“Moreover, we show that the benefit of HCT over non-HCT treatment was independent of TP53 allelic state and not restricted to specific subgroups of TP53 mutated MDS, including VAF, complex karyotype, or mutation clearance after pre-HCT hypomethylating agent treatment,” concluded the study authors.

References

1. Versluis J, Saber W, Tsai HK, et al. Allogeneic hematopoietic cell transplantation improves outcome in myelodysplastic syndrome across high-risk genetic subgroups: genetic analysis of the blood and marrow transplant clinical trials network 1102 study. Published online August 22, 2023. J Clin Oncol. doi:10.1200/JCO.23.00866

2. Allo vs hypomethylating/best supportive care in MDS (BMTCTN1102). ClinicalTrials.gov. Updated March 3, 2023. Accessed August 28, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT02016781