Spectrum, molecular features, and clinical outcomes of hematologic malignancies and clonal hematopoiesis in li fraumeni syndrome

Abstract Background: Li Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by germline pathogenic variants in the TP53 gene. The classic LFS tumor spectrum includes sarcoma, breast, brain, and adrenocortical cancers. Hematologic malignancies (HMs), specifically low hypodiploid acute lymphoblastic leukemia (ALL) and therapy-related myeloid malignancies, are thought to be less common cancer types in LFS. Within a large single-institution LFS cohort, we sought to define the full HM spectrum, molecular features, precursor states, and overall clinical outcomes. Methods: Patients with germline pathogenic/likely pathogenic (P/LP) variants in TP53 were identified through a retrospective review of multiple IRB-approved institutional protocols. Patients with variants of uncertain significance (VUS) were included if their personal and/or family history was consistent with LFS and were therefore being followed clinically as having LFS. Patients with mosaic TP53 results were excluded. Clinical, pathologic, and molecular data were collected from medical records. Results: 148 patients from 130 families with LFS were identified between the years of 2007 and 2025. 136 patients had P/LP variants, and 12 patients had a VUS. Overall, 19 HMs were diagnosed in 18 patients (12.2%). Specific HM types included therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (n=7, 37%), B-cell ALL (n=3, 16%), diffuse large B-cell lymphoma (DLBCL) (n=2, 11%), chronic lymphocytic lymphoma (CLL) (n=2, 11%), marginal zone lymphoma (n=1, 5%), follicular lymphoma (n=1, 5%), Hodgkin lymphoma (n=1, 5%), multiple myeloma (n=1, 5%), and T-prolymphocytic leukemia (T-PLL) (n=1, 5%). The patient with 2 HMs was diagnosed metachronously with CLL and multiple myeloma. The median age of HM diagnosis was 41 (range 7-67). In 8 patients, their HM was the first cancer diagnosis. Molecular data was available for 12 HMs. Seven tumors (58%) had evidence of biallelic TP53 inactivation, either through a second somatic TP53 hit or chromosome 17p loss, including both myeloid (n=4) and lymphoid (n=3) tumors. Of 6 cases of MDS/AML with evaluable cytogenetics, 4 (67%) demonstrated a complex karyotype. Of the 7 patients with MDS/AML, 3 died from non-hematologic cancers, 2 died from refractory disease, 1 underwent allogeneic stem cell transplantation (alloSCT) and died from early relapse, and 1 underwent alloSCT and died from severe graft-versus-host disease. The three patients with ALL are all living without evidence of disease, one of whom underwent alloSCT. Of the 7 patients with lymphoma, CLL, and/or multiple myeloma, 5 achieved remission with systemic therapy but died from non-hematologic cancers, 1 is under observation with no evidence of recurrent lymphoma, and 1 patient is on therapy for relapsed/refractory multiple myeloma and CLL. The patient with T-PLL is receiving investigational therapy for refractory disease. Eight patients without HM were incidentally diagnosed with clonal hematopoiesis (CH), 2 of whom did not have prior exposure to cytotoxic therapy. The median age of CH diagnosis was 52 years. The most common CH finding was an isolated DNMT3A clone; there were no cases of TP53-driven CH. No patient with CH developed a HM with a median of 16 months of follow-up. Conclusions: LFS is classically recognized as a solid tumor cancer predisposition syndrome. However, our data show that up to 12% of patients with LFS develop a HM, which is frequently the initial cancer diagnosis, underscoring the importance of germline genetic testing in patients with HM. Additionally, we show that the HM spectrum is heterogeneous, including the hallmark HMs of hypodiploid ALL and therapy-related MDS/AML, but also indolent and aggressive lymphomas, multiple myeloma, and T-cell malignancies. The high rate of biallelic TP53 loss observed across both myeloid and lymphoid malignancies suggests causality of the germline LFS variant in HM development. Importantly, we show that non-hematologic cancer remains a significant competing risk to mortality, highlighting the importance of solid tumor LFS screening even after diagnosis of an HM. The clinical significance of CH in LFS remains unclear, and more studies are needed to determine the exact prevalence and clone dynamics.