Incidence of Secondary Hematological Malignancies in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: An Analysis of SEER Database

Background: Patients with Chronic lymphocytic leukemia/ Small lymphocytic lymphoma (CLL/SLL) are at risk of experiencing transformation to aggressive hematological malignancies and can develop second primary malignancies. With a dramatic change in the treatment landscape of CLL/SLL, there is paucity of literature on real-world incidence of second hematological malignancies (SHM) in the era of targeted therapy. We analyzed data obtained from Surveillance, Epidemiology, and End Results (SEER) database to estimate the incidence of SHM in patients with CLL/SLL.

Method We used SEER 17 registry to identify adult patients with an index diagnosis of CLL/SLL between January 2000- December 2019, and subsequent diagnosis (>2months after index diagnosis) of any SHM. International Classification of Disease code for Oncology (ICD-O-3) was used to identify codes assigned to CLL/SLL (9823/3) and 11 types of SHM [9650/3: Classical Hodgkin lymphoma(HL), 9673/3: Mantle cell lymphoma(MCL), 9680/3: Diffuse large B-cell lymphoma (DLBCL), 9687/3: Burkitt lymphoma (BL), 9689/3: Splenic marginal zone lymphoma (SMZL), Acute lymphoblastic leukemia/lymphoma (ALL: consisting of 9811/3: B lymphoblastic leukemia/lymphoma, 9728/3: Precursor B-lymphoblastic lymphoma, 9836/3: Precursor B-cell lymphoblastic leukemia and 9837/3: T lymphoblastic leukemia/lymphoma), 9833/3: B-cell prolymphocytic leukemia(B-PLL), 9834/3: T-cell prolymphocytic leukemia(T-PLL), 9861/3: Acute myeloid leukemia (AML), 9863/3: Chronic myeloid leukemia (CML), 9989/3: Myelodysplastic syndrome (MDS)]. We considered SHM as any blood malignancy with diagnosis after treated or untreated CLL/SLL. Patients with CLL/SLL who had unknown survival time or a simultaneous diagnosis of another hematological malignancy were excluded. A data cut-off time point (December, 2019) was used to estimate survival duration (in months) and vital status (dead or alive). Additional data including demographics and treatment details were extracted using SEER Stat v 8.4.0.1 software. Statistical analyses were performed using IBM-SPSS Statistics v 28.0.1.1(15). The reverse Kaplan Meier method was used to calculate median follow-up duration. Chi-squared test was used to calculate difference between categorical variables. Kaplan Meier method and log rank test were used to estimate overall survival (OS).

Result 1.8% of adult patients with CLL/SLL (1390 of 78,943) had SHM during the study period. 1255 patients met eligibility criteria (CLL/SLL patients with unknown survival duration (n=3), simultaneous diagnosis of other hematological malignancy (n=3) and a gap of <2months between SHM diagnosis and index diagnosis (n=129) were excluded). Of the 1255 patients, 63.7% (799) were males and 90% (1130) had White race. Median ages at the time of diagnosis of CLL/SLL and SHM were 65 and 70 years respectively. DLBCL (57.2% [n=718]), MCL (10.8% [n=136]), and MDS (8.69% [n= 109]) were the most frequently reported SHMs. Median (95% Confidence Interval) follow-up duration after CLL/SLL and SHM diagnosis were 153 (145.0-160.9) and 58 (53.4-62.6) months respectively. Gender association with SHM was not statistically significant (p =0.146). 394 (31.4%) patients received chemotherapy (CT) for CLL/SLL, while 861 (68.6%) patients either did not receive treatment or status was unknown. OS subsequent to any SHM diagnosis was 12 (95%CI 10.1-13.9) months. OS was lowest for AML [3(1.3-4.6)], and highest for SMZL [113(82.7-143.3)]. Patients who did not receive chemotherapy (for CLL) or details were unknown lived longer subsequent to SHM diagnosis compared to patients who received chemotherapy for CLL/SLL (Median survival months (95%CI): 13(10-16) vs 10(8-12), p =0.034, hazard ratio = 1.159 (95% CI: 1.007-1.334) (Figure).

Conclusion SHM were seen in approximately 2% of CLL/SLL patients, predominantly among males and white race. Overall survival after the diagnosis of SHM is around 1 year. Improvement in overall survival with newer targeted therapies for CLL/SLL necessitates robust strategies for surveillance of SHM.

Caimi:Janssen: Consultancy; MEI Pharma: Honoraria; Incyte: Consultancy; Novartis: Consultancy; Kite: Consultancy; Genentech: Consultancy; BMS: Honoraria; GenMab: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Research Funding. Jagadeesh:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Debio pharma: Research Funding; LOXO Pharmaceuticals: Research Funding; Trillium Pharmaceuticals: Research Funding; Seagen: Research Funding; ATARA Biotherapeutics: Research Funding; Affimed: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Regeneron Pharmaceuticals, Inc.: Research Funding; MEI Pharma: Research Funding.