Role of Bruton Tyrosine Kinase Inhibitors (BTKi) in Relapsed Refractory (r/r) Hairy Cell Leukaemia Patients: A Single-Centre Real-World Data Set from the Royal Marsden Hospital
Authors: Sillito Francesca Emily , Pickard Lucy , Miriam Ravindi , Shah Paras , Iyengar Sunil , El-Sharkawi Dima 
Published: December 2024

Background:
Hairy cell leukemia (HCL) is a rare B-cell malignancy, encompassing classic HCL (cHCL) and variant HCL (vHCL), vHCL is BRAF p.V600E unmutated and represents a more aggressive disease with shorter progression-free survival (PFS) compared to cHCL 1. Purine analogues (PA) such as pentostatin are highly effective in cHCL, however 36-44% of patients relapse post PA and require further treatment 2. Hence, there is a need for less immunosuppresive treatments for patients who do not respond or lose response to PAs. Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signalling pathway, is highly effective in several malignancies and has been evaluated in a phase II clinical trial showing a 36-month PFS of 73% and overall survival of 85% in a heavily pre-treated HCL patient cohort 3 . We evaluated single centre data of patients with HCL receiving BTKi from the Royal Marsden Hospital (RMH) UK, to help inform real-world treatment decisions in this patient group.
Methods: We retrospectively analysed case notes for all r/r HCL patients treated at RMH between 2020-2024. We collected data on patient demographics, histological subtype, response as per international criteria 4, duration of response to BTKi including clinical benefit such as improvement in transfusion frequency.
Results: We identified 7 patients, 5/7 male (67%), median age 69 (range 53-78 years). 6/7 (71%) had cHCL, 1/7 (14%) vHCL. 6/7 (71%) had a BRAF p.V600E mutation. 4/7 (57%) had splenectomy prior to BTKi. Median prior lines of therapy was 6 (range 3-7). 5/7 (71%) had been treated with a targeted BRAF inhibitor prior to BTKi initiation. Median time from HCL diagnosis to BTKi treatment was 19 years (range 4-30 years). 4/7 (57%) were treated with Ibrutinib, 3/7 (43%) were treated with Zanubrutinib. Median duration of response (DOR) to therapy prior to BTKi was 3 months (range 0-36 months). 2/7 (29%) patients had confirmed bony disease. 1/7 (14%) patients had a partial response (PR) to BTKi, with a DOR of 16 weeks, 1/7 had a complete response (CMR), assessed by radiological rather than international criteria, with DOR of 26 months. Post BTKi, 3/7 (43%) had progressive disease (PD), 2/7 (29%) patients had stable disease (SD). 57% of patients achieved a clinical benefit with reduced transfusion frequency or resolution of bony pain, despite not meeting the criteria for response as per international criteria. In 2/7 (29%) patients the BTKi was stopped due to infections, 1 patient developed myelodysplastic syndrome (MDS). 4/7 (57%) patients in this cohort are now deceased.
Conclusions: We describe real-world data on the efficacy of BTKi treatment in the r/r setting for HCL in a heterogenous patient group with multiple pauses in treatment and complications including infections, making comparison to response rates observed in the trial setting challenging. This cohort has aggressive r/r disease with limited response to prior therapies, highlighting a biological variance compared to PA-responsive disease. In addition, our cohort included a patient with confirmed bony disease, which is a rare complication of HCL; this patient achieved a complete response to his bony disease, which has not to our knowledge been previously documented. Although only 28% of patients responded to BTKi, 57% achieved a clinical benefit, suggesting a rationale for considering treatment with BTKi in this setting. There is a critical need to collect further real-world data on BTKi in the r/r setting due to dismal outcomes in this patient group. Furthermore, BTKi should be evaluated in combination with other HCL-active agents in clinical trials.
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