Impact of sex on outcomes in patients with hairy cell leukemia. An HCL patient data registry analysis

To the Editor: Hairy cell leukemia (HCL) is a rare, incurable chronic hematological malignancy that makes up <1% of lymphoid neoplasms. Fewer than 2000 new cases of HCL are diagnosed annually in the United States. The median age of onset is 50–55 years and there appears to be a genetic predisposition that is sustained in people with European genetic susceptibility. Patients often present with fatigue, pancytopenia, splenomegaly, and a markedly increased risk for infection which is the leading cause of death and serious morbidity in patients with this disease. Although HCL is incurable, significant advances have been made in the treatment of this disease over the past few decades especially the advent of purine nucleoside analogs and targeted agents with improved outcomes. For reasons that remain unknown, HCL is diagnosed in female patients at a strikingly lower rate than in male patients, with a 4:1 predominance in males. To date, there have been no studies aimed at characterizing HCL in the female patient population. Although substantial advances have been made in the treatment of HCL, the rarity of the disease, especially in female patients, makes it challenging to conduct meaningful research in this population. Hence, we sought to characterize the female patients with HCL using the HCL Patient Data Registry (HCL-PDR) and evaluate their disease phenotype, response to treatment, and outcomes compared to males. The HCL-PDR is an international multicenter patient data registry that includes information regarding disease characteristics, treatment history, treatment response, comorbidities, other health outcomes, and molecular testing. The information is derived from source documents which are abstracted into discrete data elements in the patient data registry. The HCL Foundation has sponsored the development of the HCL-PDR to characterize the clinical features and outcomes of these diseases. The study was approved by the institutional review boards at all the participating sites and performed in compliance with the Declaration of Helsinki. This analysis included adults (aged ≥ 18 years) with HCL. Female patients with HCL were the study population, with male patients with HCL as the comparator group. The study included patients with both classical HCL (cHCL) and HCL variant (HCLv) with majority of the patients having cHCL. The primary endpoint was the time to next treatment (TTNT) in female HCL patients compared to male HCL patients. Secondary endpoints included response rate to first-line therapy and predictors of TTNT. Patient outcomes and responses were analyzed according to consensus criteria. Responses were categorized as complete response (CR) and partial response (PR). CR included those achieving CR, CRu (CR unconfirmed), and HR (hematologic response). PR included those achieving PR, PRu (PR unconfirmed), and pHR (partial HR). See Suppl appendix (Table S1) for the definitions of the response criteria. The TTNT was calculated from the first HCL treatment to the second HCL treatment, estimated using the Kaplan–Meier method, and compared between groups using the Log-rank test. Cox proportional hazard regression models were used to estimate the hazard ratios for the risk of TTNT. Analyses were performed using Stata software (version 16; StataCorp, College Station, Texas), and all statistical tests were two-sided with a type-1 error of 0.05. A total of 357 patients were included in the study. Of these, 265 were males and 92 were female patients. The median age at diagnosis was 52 years (19–80 years) and was comparable between male (53 years) and female patients (51 years). The study included Caucasians (98%) predominantly consistent with previously reported patient demographics, with a greater proportion of patients being never smokers (74%) and having had no prior chemical or radiation exposure (89%). The majority of the patients (95%, n = 337) had classical HCL with 87% of these being BRAF mutated (among those with available BRAF mutation status). Female patients had significantly higher median platelet count (92 K/μL vs. 77 K/μL, p = .04) but lower median hemoglobin (11.5 gm/dL vs. 12.5 gm/dL, p = .01) compared to male patients. The most common therapy administered was cladribine (61%) followed by pentostatin (17%). There were no differences in the immunophenotypic features (CD11c, CD25, CD103, CD123, and CD200) among those with available data between male and female patients with HCL. The median follow-up time from the start of first HCL treatment was 6.3 years (overall), 6.2 years in male, and 6.3 years in female patients. Table S2 shows pertinent baseline characteristics stratified by sex. Among the patients who had disease status assessed after the first treatment, n = 224 (males 169, females 55), there was no significant difference in response rates (see Table S3). Female patients had a significantly longer median TTNT (17.6 years, 95%CI = 7.6 to not reached [NR]) compared to males (8 years, 95% CI = 6.3–14.1), p = . 02 (Figure 1). Patients who achieved CR after first-line therapy had significantly longer median TTNT (14.1 years, 95% CI = 10.4-NR) compared to those who achieved PR (6.9 years, 95% CI = 2.9-NR) and SD (0.7 years, 95% CI = 0.5-NR), p < . 01 (Figure S1). On subgroup analysis based on age at diagnosis, female patients with HCL had significantly longer median TTNT compared to males (NR vs. 7.2 years, p = .01, Figure S2) for those who were ≤ 60 years, Received: 11 January 2023 Revised: 22 January 2023 Accepted: 13 February 2023