Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition

Abstract

Covalent Bruton tyrosine kinase inhibitors (BTKi's) and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes for patients with chronic lymphocytic leukemia (CLL), especially those with biologically adverse disease. Patients with CLL resistant to their first targeted agent (TA) can be effectively treated with the alternative class. However, relapses are expected with second-line TA therapy, and the clinical challenge of double class-resistant disease is now emerging with increasing frequency. To define the characteristics and outcomes of patients with double class-resistant disease, we retrospectively analyzed 17 patients who developed progressive disease (PD) on both TA classes for CLL (venetoclax, then BTKi, n=12; BTKi, then venetoclax, n = 5). The cohort was heavily pretreated (median lines of prior therapy, 4) and enriched for adverse disease genetics (complex karyotype, 12 of 12 tested [100%]; del(17p)/TP53 mutations, 15 of 17 [88%]). The median time to progression on prior venetoclax was 24 months (range, 6-94 months) and was 25 months (range, 1-55 months) on prior BTKi. Progression on second-line TA was manifest as progressive CLL in 11 patients and as Richter transformation in 6. The median overall survival after progression on second-line TA was 3.6 months (95% confidence interval, 2-11 months). Patients with double class-resistant CLL have a dismal prognosis, representing a group of high unmet need.

Figure 1.

Outcomes for patients who developed PD on a second-line TA (BTKi or venetoclax). (A) Individual patient characteristics and timelines of outcomes and treatments after the development of PD on either BTKi or venetoclax used sequentially as a second-line TA. Arrows at the end of lanes indicate ongoing survival at last follow-up, circles indicate death, and other treatments have specific symbols as indicated. The columns on the left indicate clinicopathological variables at time of progression on the second-line agent. Gray fill indicates presence of a variable; gray horizontal line indicates new genetic lesion at time of progression on second-line TA; white fill indicates absence; patients who were treated for RT prior to the second-line TA are denoted by a red fill. ^The patient in lane 14 ceased venetoclax in measurable residual disease–positive CR after 6 months, resumed for progressive CLL 12 months later, then subsequently progressed while on drug with a total duration of disease control with venetoclax of 51 months. *Gray fill indicates detection of resistance mutation at any time after exposure to TA; white fill, untested or not detected. (B) OS after the development of PD on a second-line TA. Curves represent outcomes for the overall cohort (green), patients with progressive CLL on a second-line TA (blue, dashed), and patients with RT on second-line TA (red, dashed). (C) OS after the development of PD on a second-line TA, stratified by prior sequencing of TAs. Curves represent the outcomes for patients who receiving BTKi’s then venetoclax (blue) or venetoclax then BTKi’s (red). AutoSCT, autologous stem cell transplant for RT prior to second-line TA; AZA, azacitidine; B, BTKi; IBR, ibrutinib; IFRT, involved-field radiotherapy for RT prior to second-line TA; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-EPOCH, rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin; R-GV, rituximab, gemcitabine, vinorelbine; R-ICE, rituximab, ifosfamide, carboplatin, etoposide; Rx, treatment; tMDS, treatment-associated myelodysplasia; TOX, toxicity; TTP, time to progression; UNK, unknown; V, venetoclax; VEN, ventoclax.