Second Primary Malignancies in Hairy Cell Leukemia Survivors

Hairy cell leukemia (HCL) is a rare, indolent B cell leukemia, usually diagnosed in the sixth decade of life, more commonly in men. Although therapeutic options include purine analogs such as cladribine, these patients may not always require treatment. There is limited information about the risk of second primary malignancies (SPM) in HCL, although there is a chance of development of SPMs given high rates of cure, immunosuppression, use of chemotherapy. We aim to investigate the development of SPMs in these patients.

We conducted a retrospective analysis of the Surveillance, Epidemiology and End Results (SEER) 17 registries database and identified the cases diagnosed with HCL as their primary malignancy between the years 2000 to 2021 using the International Classification of Diseases (ICD) code 9940/3. These cases were followed for several years, and the standardized incidence ratio (SIR = Observed/expected cases) and absolute excess risk (AER) for development of SPMs in HCL were calculated. The analysis was stratified by the receipt of chemotherapy (CT).

A total of 4492 patients were included in the SPM analysis, of which 3558 were males and 934 were females. The median age at diagnosis of HCL was 58.64y overall (58.17y in males and 60.43y in females).

SPM analysis of the 4492 HCL cases revealed that 3100 received CT and 1392 were in the No/unknown CT category. Both groups had a statistically significant SIR for SPM lymphomas (No/Unknown CT - 3.45, CT - 3.96, p<0.05). In the no/unknown CT group, the SIR peaked at 4.47 (p<0.05) at a latency of 5 to 10 years (y) from the diagnosis of HCL. In CT recipients, the SIR for SPM lymphomas was highest at 2-11months (13.87, p<0.05), but continued to be elevated at all latencies of 1-5 y, 5-10 y and beyond 10 y with SIR 3.33, 2.34 and 3.99 respectively (p<0.05). Both CT and no/unknown CT groups were at increased risk for Non-Hodgkin lymphoma (NHL) with overall SIR at 3.96 and 3.5 respectively (p<0.05). In the No/unknown CT group, this risk peaked at 5-10 y with SIR 4.27 (p<0.05). In the CT group, the SIR for NHL peaked at 14.01 (p<0.05) at latency 2-11 months allowing for the possibility of some synchronous NHLs which may even have been the indication for CT rather than HCL. However, the CT recipients continued to demonstrate elevated risk for NHL at 1-5 y, 5-10y and beyond 10y with SIRs 3.36, 2.49 and 3.79 respectively (p<0.05). The CT group demonstrated elevated risk for nodal Hodgkin Lymphoma (SIR 4.21, p<0.05).

HCL survivors also demonstrated increased risk for certain solid tumor SPMs with some variations between the No/unknown CT group and the CT group. The CT recipients developed melanoma of the skin more frequently with overall SIR 1.9 (p<0.05), particularly at a latency of 1-5y (SIR 2.2, p<0.05). They are also at elevated risk for “skin cancers excluding basal and squamous” with overall SIR 2.09 (p<0.05), particularly 10y out from diagnosis (SIR 2.3, p<0.05). CT recipients also developed prostate cancer more frequently with overall SIR 1.49 (p<0.05), particularly at a latency of 1-5y (SIR 1.94, p<0.05). Further, the CT group also demonstrated elevated risk for “Intrahepatic and extrahepatic bile duct and other biliary cancers” with overall SIR 2.7 (p<0.05). Regardless of receipt of CT, HCL survivors are at elevated risk for “other non-epithelial skin cancers” with overall SIR 4.37 for CT group and 3.89 for No/unknown CT group (p<0.05). Patients in the No/unknown CT group developed certain other solid tumors more frequently: colon, rectum and anus (overall SIR 1.58, p<0.05), “soft tissue including the heart,” (overall SIR 4.59, p<0.05), brain (overall SIR 3.88, p<0.05).

Interestingly, the HCL survivors who received CT had lower risk for respiratory system malignancies than the general population, particularly at 1-5y from diagnosis, with SIR for lung and bronchus cancer being 0.42 (p<0.05).

Hairy cell leukemia is a rare, indolent B cell leukemia, which may be managed by active surveillance or chemotherapy depending on the severity. However, in our study both CT and no/unknown CT groups seem to be at an elevated risk for secondary lymphomas, with the SIR being slightly higher in the group that received CT. The development of SPM even after 10 years of diagnosis of HCL warrants strict surveillance evaluations. Further both groups may be at elevated risk for certain types of skin cancers and hence may be candidates for annual dermatology screening.

No relevant conflicts of interest to declare.