Clonal Hematopoiesis May Link T-Follicular Helper Cell Lymphoma With Subsequent Myeloid Neoplasms

Patients with nodal T-follicular helper cell lymphoma (TFHL) had a 5-year cumulative incidence of subsequent myeloid neoplasms (MNs) of 5.3%, with genomic findings suggesting that the lymphoid and myeloid malignancies may arise through divergent evolution of shared clonal hematopoiesis (CH), according to findings published in Haematologica.¹

Among 208 patients with TFHL treated at Memorial Sloan Kettering Cancer Center, 10 subsequently developed an MN, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), or chronic neutrophilic leukemia (CNL). Although all affected patients had previously received anthracycline-based treatment, investigators did not identify significant associations between MN development and age, sex, autologous stem cell transplant (ASCT), or exposure to etoposide, suggesting that treatment exposure alone may not account for the observed risk.¹

Instead, molecular profiling demonstrated shared mutations—most prominently in TET2—between TFHL and later MNs, supporting an emerging model in which both malignancies can develop from a common CH-containing progenitor.¹ Previous studies have similarly demonstrated that CH-associated mutations can be present across both malignant T-cell and myeloid compartments in patients with TFH-derived lymphomas.²

Subsequent Myeloid Neoplasms Developed in 5.3% of Patients by 5 Years

Investigators retrospectively evaluated 208 patients with nodal TFHL who were sequentially treated at Memorial Sloan Kettering between 2012 and 2023. All diagnoses underwent pathology review and were classified according to World Health Organization and International Consensus Classification criteria.¹

The median age at lymphoma diagnosis was 69 years. Most patients received anthracycline-based induction therapy, with 96 patients (46%) receiving an etoposide-containing regimen such as cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone. Eighty-one patients (39%) underwent ASCT during first remission.¹

During a median follow-up of 2.7 years among survivors, 10 patients developed a subsequent MN. The cumulative incidence was approximately 1.5% at 2 years and 5.3% at 5 years, and the median interval between TFHL and MN development was 2.2 years.¹

The subsequent malignancies included were AML in 4 patients, MDS in 4 patients, CMML in 1 patient, and CNL in 1 patient. Importantly, baseline bone marrow examinations were available for 8 of the 10 affected patients, and none showed evidence of the subsequent MN at TFHL diagnosis. Most also had largely unremarkable peripheral hematologic parameters at baseline.¹

Shared TET2 Mutations Point Toward a Common Clonal Origin

Genomic findings provided further insight into how these secondary malignancies may develop.

Among patients with sequencing available from both the lymphoma and subsequent MN, every patient shared at least 1 TET2 mutation between the 2 malignancies. DNMT3A was the only other gene with mutations shared between TFHL and the subsequent MN.¹

TET2 and DNMT3A are among the genes commonly involved in CH, an age-associated process in which hematopoietic stem cells carrying acquired somatic mutations expand without meeting criteria for a hematologic malignancy. CH is itself associated with an increased risk of developing myeloid malignancies.³

Earlier research in TFH-derived lymphoma demonstrated identical CH-associated mutations in malignant T cells and myeloid cells, supporting the idea that an ancestral hematopoietic clone can acquire additional mutations and subsequently diverge into separate lymphoid and myeloid cancers.²

The current findings extend that model by estimating how frequently a subsequent MN developed within a comparatively large TFHL cohort.

One patient's longitudinal molecular findings were particularly illustrative. Several years before the patient formally developed MDS, bone marrow sequencing detected U2AF1 and ASXL1 mutations without definitive morphologic evidence of MDS. At diagnosis 3 years later, the same variants remained detectable, and the variant allele frequency of U2AF1 had increased substantially.¹

Treatment Exposure Was Not Significantly Associated With MN Risk

Because patients with TFHL frequently receive cytotoxic chemotherapy and transplantation, treatment-related selective pressure represents a potential mechanism through which preexisting CH clones could expand and progress toward an MN. Cancer therapy has previously been shown to alter the fitness landscape of CH and preferentially select particular mutant clones.⁴

However, investigators did not identify a statistically significant association between subsequent MN development and any of the patient- or treatment-related variables evaluated. Age older than 60 years, male sex, CHOP vs etoposide-containing induction, ASCT, and etoposide exposure were not significantly associated with MN development in univariate analyses.¹

The authors cautioned that only 10 MN events occurred, limiting the statistical power to identify potential risk factors. The genomic profile of TFHL may also help explain why the incidence was not higher. TET2 and DNMT3A mutations, which predominate in TFHL, generally confer substantially lower myeloid malignancy risk than mutations involving genes such as SRSF2, SF3B1, ZRSR2, FLT3, or RUNX1.^1,3

This contrasts with findings from patients undergoing autologous transplantation for Hodgkin lymphoma, in whom CH involving TP53 or PPM1D has been associated with a particularly high risk of therapy-related MN.⁵

Findings May Support Longitudinal Molecular Surveillance Research

The study was retrospective and included relatively few MN events. Molecular profiling was also unavailable for every patient, preventing investigators from systematically comparing baseline CH features between patients who did and did not subsequently develop an MN.¹

As a result, the findings do not establish which patients with TFHL require additional molecular surveillance beyond established clinical follow-up.

However, the combination of shared mutations, changing variant allele frequencies, and development of MNs despite initially normal bone marrow findings underscores the potential value of studying CH longitudinally in this population.¹

The investigators suggested that prospective studies incorporating sequential sequencing could help determine whether changes in variant allele frequency or acquisition of additional mutations can identify patients at greatest risk for clonal progression.¹ Such work may ultimately clarify the relative contributions of underlying genetic susceptibility and treatment-related selective pressure to the development of subsequent myeloid malignancies after TFHL.

REFERENCES

1. Lin KS, Yan M, Ganesan N, et al. Cumulative incidence and factors associated with subsequent myeloid neoplasms in patients with nodal T-follicular helper cell lymphomas. Haematologica. Published online November 27, 2025. doi:10.3324/haematol.2025.288615

2. Lewis NE, Petrova-Drus K, Huet S, et al. Clonal hematopoiesis in angioimmunoblastic T-cell lymphoma with divergent evolution to myeloid neoplasms. Blood Adv. 2020;4(10):2261-2271. doi:10.1182/bloodadvances.2020001636

3. Weeks LD, Niroula A, Neuberg D, et al. Prediction of risk for myeloid malignancy in clonal hematopoiesis. NEJM Evid. 2023;2(5):10.1056/evidoa2200310. doi:10.1056/evidoa2200310

4. Bolton KL, Ptashkin RN, Gao T, et al. Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nat Genet. 2020;52(11):1219-1226. doi:10.1038/s41588-020-00710-0

5. Yan C, Richard MA, Gibson CJ, et al. Clonal Hematopoiesis and Therapy-Related Myeloid Neoplasms After Autologous Transplant for Hodgkin Lymphoma. J Clin Oncol. 2024;42(20):2415-2424. doi:10.1200/JCO.23.02547