# PPM1D Mutation as a Distinct Feature of Myeloid Neoplasms in B-Cell Non-Hodgkin Lymphoma Patients: A Retrospective Analysis

## TL;DR

This study finds that PPM1D mutations are more common in myeloid cancers that develop after B-cell lymphoma treatment, and they are linked to better survival unless TP53 mutations are also present.

## Contribution

The study identifies PPM1D mutations as a distinct genetic feature in myeloid neoplasms following B-cell non-Hodgkin lymphoma.

## Key findings

- PPM1D mutations were significantly more frequent in myeloid neoplasms after B-cell lymphoma than after solid cancers.
- PPM1D mutations were associated with improved survival in the absence of TP53 mutations.
- PPM1D mutations often co-occurred with DNMT3A mutations in these patients.

## Abstract

Myeloid neoplasms are a significant complication for B-cell non-Hodgkin lymphoma survivors treated with cytotoxic therapies. This study examined the genetic profiles of myeloid neoplasms following B-cell non-Hodgkin lymphoma, finding PPM1D mutations to be significantly more frequent than in myeloid neoplasms after solid cancers. PPM1D mutations, often with DNMT3A, were associated with improved survival unless TP53 mutations were also present. This suggests the distinct role of PPM1D in myeloid neoplasms development after B-cell non-Hodgkin lymphoma.

Background/Objectives: Myeloid neoplasms are the most common secondary blood cancer in B-cell non-Hodgkin lymphoma (BNHL) patients treated with cytotoxic therapies. We aimed to characterize the genetic and clinicopathologic features of myeloid neoplasms arising after B-cell non-Hodgkin lymphoma (MN-BNHL) by comparing their features with myeloid neoplasms developing after solid cancer (MN-SC). Methods: We retrospectively analyzed the clinicopathologic and genetic data of myeloid neoplasm patients diagnosed between 2008 and 2023, categorized as MN-BNHL or MN-SC. Further NGS analysis was performed on available bone marrow samples with missing genetic data. The genetic profiles of myeloid neoplasms between BNHL and solid cancer groups were compared. Results: Sixteen patients developed MN-BNHL. Among the 11 MN-BNHL patients undergoing NGS, all harbored tier 1 mutations. PPM1D mutations (PPM1Dms) were most frequent (73%), followed by DNMT3A (46%) and TP53 (36%). PPM1Dms were significantly more prevalent than in MN-SC (n = 21), where TP53 mutations were most common (64%) (p < 0.001). PPM1Dms often co-occurred with DNMT3A. They were associated with prior radioimmunotherapy (relative risk (RR): 3.3 and RR 3.57). MN-BNHL patients with PPM1Dms exhibited improved survival compared to those without (p = 0.0376), but this benefit was negated by the presence of TP53 mutations (p = 0.0049). Conclusions: PPM1Dms are a prominent genetic feature in MN-BNHL, suggesting a distinct role in its development compared to MN-SC. Further investigation is needed to elucidate the precise contribution of PPM1D and its interaction with other mutations in BNHL-related myeloid neoplasm development and prognosis.