BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax

Abstract

Highly active BTK inhibitors (BTKis) and the BCL2 inhibitor venetoclax have transformed the therapeutic landscape for chronic lymphocytic leukemia (CLL). Results of prospective clinical trials demonstrate the efficacy of venetoclax to salvage patients with disease progression on BTKis, but data on BTKi therapy after disease progression on venetoclax are limited, especially regarding durability of benefit. We retrospectively evaluated the records of 23 consecutive patients with relapsed/refractory CLL who received a BTKi (ibrutinib, n = 21; zanubrutinib, n = 2) after stopping venetoclax because of progressive disease. Median progression-free survival (PFS) and median overall survival after BTKi initiation were 34 months (range, <1 to 49) and 42 months (range, 2-49), respectively. Prior remission duration ≥24 months and attainment of complete remission or undetectable measurable residual disease on venetoclax were associated with longer PFS after BTKi salvage (P = .044 and P = .029, respectively). BTKi therapy achieved durable benefit for patients with the BCL2 Gly101Val venetoclax resistance mutation (estimated 24-month PFS, 69%). At a median survivor follow-up of 33 months (range, 2-53), 11 patients remained on BTKi and 12 had stopped therapy because of disease progression (n = 8) or toxicity (n = 4). Our findings indicate that BTKi therapy can provide durable CLL control after disease progression on venetoclax.

Graphical abstract

Figure 1.

Outcomes of BTKi therapy for CLL after progression on venetoclax (VEN). (A) Individual patient characteristics and timelines of outcomes and treatments after BTKi initiation. Arrows at the ends of lanes indicate ongoing response to treatment at last follow-up, circles indicate death, and other treatments have specific symbols as indicated. The columns on the left indicate relevant pre-BTKi features. Gray fill indicates presence of a variable; white fill indicates absence. Where a TP53 abnormality or CK was first detected after progression on VEN, the cells have a diagonal line. In all other cases, the CLL patient had these genetic features before treatment with VEN. Patients who were treated for RT before BTKi are denoted by a red fill. Ibrutinib was the BTKi used in all patients except where zanubrutinib (ZANU) is indicated. Histology, treatment, and response of RT were as follows: lanes 1 and 5: diffuse large B-cell lymphoma (DLBCL): rituximab, ifosfamide, carboplatin, and etoposide followed by autologous (auto) SCT (CR in both cases); lane 6: DLBCL: rituximab, methotrexate, vincristine, and procarbazine followed by radiotherapy (partial remission [PR]); lane 13: Hodgkin variant: doxorubicin, bleomycin, vinblastine, and dacarbazine (CR); and lane 14: Hodgkin variant: cyclophosphamide, doxorubicin, etoposide, and prednisolone followed by radiotherapy (CR). (B) PFS (blue) and overall survival (OS) on BTKi (red) from initiation of BTKi after disease progression on VEN. In both, patient data were censored at allogeneic (allo) SCT if this occurred in first response to BTKi. (C) PFS on BTKi stratified by prior remission to VEN ≥24 (blue) or <24 months (red). HR, hazard ratio; UNK, unknown.