Incidence of Second Primary Malignancies in Hairy Cell Leukemia: US Population-Based Study from 2000- 2021

Introduction: Hairy Cell Leukemia (HCL) is a rare B-cell lymphoproliferative disorder characterized by an indolent course but notable responsiveness to purine analog-based therapies such as cladribine and pentostatin. While these treatments have significantly improved patient outcomes, the potential for long-term complications, including the development of second primary malignancies (SPMs), remains a critical concern. Despite this, recent comprehensive population-based analyses focusing on SPM incidence in HCL are limited. Our study aims to address this gap by evaluating the incidence and risk factors associated with SPMs in HCL patients using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2021. Methodology: Utilizing the SEER database (version 8.4.3), we identified all patients with a histological diagnosis of HCL (ICD-O-3 9940/3) from 2000 to 2021. Second primary cancer sites were determined using SEER site recode- ICD-O-3 site and histology. Using multiple primary standardized incidence ratio (MP-SIR), we calculated SIR of SPM and stratified the results based on age, sex and race. Results: Our findings indicate that patients with HCL have a 31% heightened risk of developing SPMs (95% confidence interval (CI) 1.21- 1.41, p < 0.05) compared to the general population with a SIR of 1.78 in the first year (CI- 1.4- 2.22, p< 0.05). The mean interval from HCL diagnosis to the onset of an SPM was 58 months. Notable excess risk was identified for various solid tumors, including soft tissue malignancies (SIR 1.76; CI 1.36- 2.24, p< 0.05), skin (SIR 1.76; CI 1.36- 2.24, p< 0.05), melanoma (SIR 1.56; CI 1.17- 2.04, p< 0.05), brain (SIR 2; CI 1.03- 3.5, p< 0.05) and thyroid cancers (SIR 2.14; CI 1.2- 3.52, p < 0.05). Increased risks for hematological malignancies were observed, with significantly higher SIRs reported for Hodgkin's lymphoma (SIR 3.52; CI 1.13- 8.21, p< 0.05), Non- Hodgkin's lymphoma (SIR 3.69; CI 2.97- 4.55, p< 0.05) and Myeloid and Monocytic Leukemia (SIR 1.88; CI 1.03- 3.15, p< 0.05). The risks for oral cavity (SIR- 3.83, p< 0.05), cecal (SIR- 5.03, p< 0.05), renal cancers (SIR- 4.90, p< 0.05), Lymphomas (SIR- 9.60, p< 0.05) were notably elevated in the first year following HCL diagnosis, while the risks for descending colon (SIR- 5.02, p< 0.05), biliary (SIR- 5.46, p< 0.05), thyroid cancers (SIR- 3.23, p< 0.05) increased significantly after a latency period exceeding five years. Conclusion: Ourstudy contributes to the growing body of evidence emphasizing the complexity of cancer survivorship in the light of significantly increased risk of SPM in patients with HCL. It stresses the need for tailored surveillance protocols and preventive measures in the light of heightened susceptibility to specific malignancies in the critical years following their initial diagnosis. Furthermore, our results advocate for ongoing research into the mechanisms behind SPM development in this population and emphasize the integration of comprehensive long-term survivorship care into the broader framework of oncological treatment strategies.