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

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.

References

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2. Dearden CE, Else M, Catovsky D. Long-term results for pentostatin and cladribine treatment of hairy cell leukemia. Leuk Lymphoma. 2011 Jun;52(sup2):21-4.

3. Rogers KA, Andritsos LA, Wei L, McLaughlin EM, Ruppert AS, Anghelina M, et al. Phase 2 study of ibrutinib in classic and variant hairy cell leukemia. Blood. 2021 Jun 24;137(25):3473-83.

4. Parry‐Jones N, Joshi A, Forconi F, Dearden C, BSH guidelines committee. Guideline for diagnosis and management of hairy cell leukaemia (HCL) and hairy cell variant (HCL‐V). Br J Haematol. 2020 Dec;191(5):730-7.

Sillito:Kite, Gilead: Honoraria. Iyengar:Astra Zeneca: Honoraria; Beigene: Honoraria; Kite/Gilead: Honoraria; MSD: Honoraria; Takeda: Honoraria.

Bruton Tyrosine kinase inhibitors are highly selective in several B cell malignancies. They are available through compassionate access schemes for treatment of Hairy Cell Leukaemia in the united kingdom. They have been evaluated in phase II clinical trial in r/r HCL showing 36 month PFS and OS 85% in this difficult to treat and refractory patient group, not responsive to purine anaolgues. (Rogers et al, Phase 2 study of ibrutinib in classic and variant hairy cell leukaemia. Blood June 2021- see abstract for full citation).