Clonal Hematopoiesis and Venous Thromboembolism Risk in Lymphoma Patients Surviving Autologous Transplantation
Authors: Gangaraju Radhika , Chen Yanjun , Hageman Lindsey , Ross Elizabeth , Francisco Liton , Crossman David K , Singh Purnima , Bosworth Alysia , Weisdorf Daniel , Bhatia Ravi , Armenian Saro , Forman Stephen J. , Bhatia Smita 
Published: December 2024

BACKGROUND
Peripheral blood stem cell transplantation (PBSCT)recipients are at increased risk of venous thromboembolism (VTE) and subsequent mortality (Gangaraju et al. Br J Haematol, 2019). Clonal hematopoiesis (CH) is associated with increased risk of VTE in the general population (Zon et al. Blood, 2024) and in myeloid malignancies such as JAK2 positive myeloproliferative neoplasms, but less is known about the association between presence of CH in the infused peripheral blood stem cell (PBSC) product and subsequent post-PBSCT VTE risk.

METHODS
This study included Hodgkin lymphoma and non-Hodgkin lymphoma patients who received autologous PBSCT between 1999 and 2014 at City of Hope, CA, had available cryopreserved PBSC product, survived ≥2 years after PBSCT and had completed a comprehensive survey detailing socio-demographics and health outcomes (including VTE). We performed targeted sequencing by enriching target DNA regions of 91 genes selected based on pathogenic involvement in CH or myeloid malignancies. Our methodology allowed detection of CH clones present at a variant allele frequency (VAF) of ≥1%. We classified variants as pathogenic driver mutations based on mutation type and position, and on frequency in publicly available single nucleotide polymorphism databases. Information regarding primary cancer diagnosis, therapeutic exposures (pre- PBSCT and conditioning) and PBSCT-specific variables were abstracted from the medical records. Subdistribution hazard regression analysis (accounting for death as competing risk) was used to examine the association between specific CH mutations in the PBSC product and post-PBSCT VTE, adjusting for the following variables (if significant at p &lt;0.1 on univariate analysis): age at PBSCT, sex, race, income and education, PBSCT year, smoking, conditioning intensity, total body irradiation and pre-PBSCT chronic health conditions.

RESULTS
The study included 557 patients. Median age at autologous PBSCT was 54 years (range 18-78 years); 62% were males and 70% were non-Hispanic whites. The median length of follow-up was 5.4 years. Post-PBSCT VTE developed in 24 participants (4.3%) at a median latency of 2 years from transplantation. CH was present in the PBSC product of 201 patients (36.1%); 22.3% with 1 CH mutation and 13.8% with ≥2 mutations. PPM1D mutations were present in 11%, TET2 in 5.9% and TP53 in 3.8%. Multivariable analysis revealed that presence of PPM1D mutations (hazard ratio [HR]=2.8, 95% confidence intervals [CI] =1.1-7.1; ref: no CH) was associated with subsequent VTE. Similarly, presence of TP53 mutations (HR=3.7, 95%CI=1.1-12.2; ref: no CH) was associated with subsequent VTE risk. JAK2 mutation was not specifically examined as the prevalence was low. The only other factor associated with VTE was the presence of pre- PBSCT chronic health conditions (PPM1D model: HR=3.89, 95%CI=1.5-10.3; TP53 model: HR=4.11, 95%CI=1.5-11.2).

CONCLUSION
Presence of PPM1D or TP53 mutations in the PBSC product and chronic comorbidities were associated with increased risk of VTE post- PBSCT in lymphoma patients, providing evidence for future targeted interventions.