Abstract P063: Risk factors beyond chemotherapy exposure for therapy-related myelodysplastic syndrome (tMDS) and Acute Myeloid Leukemia (tAML) development in lymphoma survivors: a 15-year SEER-Medicare analysis
Authors: Singh Abhay , Herr Megan M. , Hahn Theresa E. , Thota Swapna 
Published: January 2023

Therapy-related Myeloid Neoplasms (tMNs) constitute 10-20% of newly diagnosed myeloid neoplasms and carry poor prognosis. tMNs develop in a small percentage of patients who receive chemoradiotherapy (CRT), thereby suggesting role of additional factors that may facilitate leukemic transformation. Clonal hematopoiesis (CH) represents a precursor state to overt myeloid neoplasm. CH surviving CRT/genotoxic stress may give rise to tMNs. Do factors beyond CRT aid in the clonal evolution and facilitate leukemia development? We hypothesized that CH-associated comorbidities (cardiovascular disease, infections, autoimmunity etc.) may facilitate CH’s evolution to tMN, beyond CRT. A population-based retrospective cohort study was conducted using cancer registries from the Surveillance, Epidemiology, and End Results (SEER) Program and Medicare claims database. Descriptive analyses included adults aged 66-84 who were diagnosed with first primary lymphoma (Diffuse Large B-Cell Lymphoma; DLBCL and Follicular Lymphoma; FL) during 2000 to 2014 (followed up through 2015), and survived at least 1 year, as reported to SEER. Chi-square tests were used to examine associations between comorbidity of interest/potential risk factors and tMDS/AML. Factors associated with tMDS/AML were then included in the multivariable logistic regression model with significance set at p&lt;0.05. Among the 33,520 lymphoma patients (pts), 293 tMDS/AML cases were identified. tMDS/AML occurred more often after initial chemotherapy vs none (DLBCL-Odds Ratio; OR=1.87 95% CI=1.23-2.83; FL-OR=2.15 95% CI=1.29-3.61). Prior history of autoimmune conditions significantly increased the risk of subsequent tMDS/AML (DLBCL-OR=2.10 95% CI=1.51-2.91; FL-OR=3.46 95% CI=2.30-5.20). Though infection was not directly associated with increased risk, methods of infection prophylaxis often used in treatment of lymphomas, i.e., use of granulocyte colony-stimulating factor (GCSF) significantly increased the risk of subsequent tMDS/AML (DLBCL-OR=2.94 95% CI=2.03-4.26; FL-OR=3.97 95% CI=2.51-6.28). No other comorbidities of interest (hypertension, dyslipidemia, diabetes etc.) were associated with increased risk of subsequent tMDS/AML. Findings in our study suggest role of other mediators/selection pressures in clonal evolution/leukemic transformation of CH after CRT exposure. These factors include immunosuppressed state (as therapy for autoimmunity) and GCSF exposure, with former conceivably leading to clonal expansion via immune escape and latter via direct stimulation and clonal expansion. The findings warrant reconsideration and modifications to common clinical practices such as the use of GCSF during lymphoma treatment as primary prophylaxis to limit neutropenia. In addition, future research efforts should focus on replicating these findings at molecular level and designing CH screening strategies in pts with autoimmune conditions and those who receive GCSF. This knowledge may inform future clinical practice to avoid exposure in pts with underlying CH and thereby prevent future myeloid malignancy development.

Citation Format: Abhay Singh, Megan M. Herr, Theresa E. Hahn, Swapna Thota. Risk factors beyond chemotherapy exposure for therapy-related myelodysplastic syndrome (tMDS) and Acute Myeloid Leukemia (tAML) development in lymphoma survivors: a 15-year SEER-Medicare analysis. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P063.