Long-term outcomes of patients with hairy cell leukemia treated with first-line cladribine in British Columbia

Abstract Background Hairy cell leukemia (HCL) is a rare indolent B-cell malignancy. First-line (1L) treatment typically includes a purine analog (PA), most commonly cladribine, which has shown high response rates and durable remissions. Despite excellent long-term outcomes, HCL remains incurable and patients (pts) can relapse many years after initial remission. Second-line (2L) options include re-treatment with cladribine or alternate PAs, or combination treatments with PA plus anti-CD20 monoclonal antibodies (mAbs). More recently, with the discovery of clonal somatic BRAF V600E activating mutations in more than 95% of HCL cases, BRAF inhibitors in combination with anti-CD20 mAbs are under investigation in relapsed disease. This study aims to evaluate long-term outcomes of HCL pts treated with 1L cladribine over 3 decades to serve as a benchmark for outcomes with novel combinations. Methods We conducted a population-based analysis of patients diagnosed with HCL from 1990-2023 in British Columbia (BC) who were treated with 1L cladribine ± anti-CD20 mAb, identified through the BC Cancer Centre for Lymphoid Cancer Clinical Database. Key outcomes included overall survival (OS), progression-free survival (PFS), time to progression (TTP), treatment patterns at relapse, OS and PFS after 2L therapy (OS2 and PFS2), and cause of death. For patients who progressed after 1L cladribine, we compared outcomes between those re-treated with PA alone versus PA plus anti-CD20 mAb. Results We identified 279 pts diagnosed with HCL or HCL variant between 1990-2023, of which 205 pts were diagnosed with classic HCL and treated with 1L cladribine (200 cladribine alone; 5 cladribine+rituximab [R]). Median age at diagnosis was 56 years (y) (range 30–88 y) and 79% were male. With a median follow-up of 21.2 y (range 0-33 y), median OS from 1L cladribine for the whole cohort was 26.6 y, with no significant difference between males and females (P=0.2). 5- and 10-y OS were 93% and 85%, respectively. Median PFS after 1L cladribine was 13.6 y, with 5- and 10-y PFS 78% and 61%, respectively. Median TTP after 1L cladribine was not reached, with 5- and 10-y TTP 83% and 69%, respectively. 65 pts (32% of the cohort) progressed after 1L therapy. With a median follow-up of 15.5 y (range 0.1 – 29 y), median OS2 was not reached, with 5- and 10-y OS2 81% and 72%, respectively. Median PFS2 was 16.2 y, with 5- and 10-y PFS2 68% and 53%, respectively. Of these 65 pts, 45 (69%) were re-treated with PA alone (cladribine 40; fludarabine 5), 14 (22%) with a PA (14 of which received fludarabine) plus R, 2 with single-agent R, 1 with RCHOP, and 3 were observed. When comparing those re-treated with PA alone versus PA plus R, median PFS2 was 8.6 y vs. not reached (P=0.03), and median OS2 was 23.7 y vs. not reached (P=0.62), respectively. During the follow-up period, 17/62 pts received 3L therapy including: re-treatment with cladribine monotherapy in 3 pts, fludarabine plus R in 8, bendamustine plus R in 1, single-agent R in 4, and 1 patient each received ibrutinib and vemurafenib with R. 5/17 pts went on to receive 4L therapy and 2/5 pts received 5L therapy, primarily with alternate PAs and other novel agents such as anti-CD22 mAbs, Bruton's tyrosine kinase or BRAF inhibitors. A total of 74 pts (36% of the entire cohort) died. The most common cause of death was due to second primary malignancies (SPM) in 24 pts (32% of all deaths), with the most common SPM originating in the gastrointestinal tract (8 pts) followed by lung, bladder, melanoma and hematological (2 pts each). Other causes of death included cardiovascular in 22 pts (30% of all deaths), HCL progression in 14 pts (19%), sepsis in 4 pts (5%), and 10 ps (14%) died from other causes. Conclusions With over 20 years of follow-up, we confirm that cladribine provides durable disease control in many HCL pts with prolonged survival. However, 1 in 3 HCL pts ultimately relapses, highlighting the need for effective 2L treatment strategies. Our study suggests that combining a PA with an anti-CD20 mAb (most commonly fludarabine and R in this cohort) at progression results in a longer PFS after 2L therapy compared to retreatment with a PA alone. Mortality data further highlights the potential long-term complications of pts with HCL undergoing treatment with PAs, particularly SPM, reinforcing the need for more targeted and disease-specific treatments.

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