BTK Inhibitor Therapy Can Be Stopped in CLL

Histologic image of chronic lymphocytic leukemia (CLL) cells

The decision to discontinue treatment of chronic lymphocytic leukemia (CLL) with Bruton tyrosine kinase (BTK) inhibitors is a complex one. Traditionally, BTK inhibitors were developed as continuous therapy. Because BTK inhibitors rarely achieve deep responses as monotherapy and have relatively short half-lives, treatment break has been traditionally discouraged due to concerns of disease flare.¹

However, emerging data challenge the notion of continuous BTK inhibition. In a post hoc analysis of 84 patients with CLL treated with ibrutinib (Imbruvica) in a phase 2 study, there were no statistically significant differences in progression-free survival (PFS) or overall survival (OS) among subgroups divided by various dose-intensity cutoffs (95%, 90%, or 80%) and dose-interruption time points (within 6 or 12 months of starting ibrutinib).² Similarly, a retrospective analysis of 209 patients with CLL at Mayo Clinic showed no differences in OS between groups with or without ibrutinib interruptions.³ Although other investigators reported less favorable outcomes with BTK inhibitor interruptions,^4,5 these data were from studies that assessed early drug holds and lacked consideration of dose intensity as a time-dependent covariate, which is a critical factor given that treatment toxicities can be cumulative and prolonged therapy increases the likelihood of dose interruptions.

Long-term data from prospective trials of ibrutinib reported surprisingly durable disease control after stopping BTK inhibitors for reasons other than disease progression. In the ECOG-E1912 study (NCT02048813) testing ibrutinib plus rituximab (Rituxan) in younger treatment-naive (TN) patients with CLL, 101 patients who stopped ibrutinib had a median of 25 months from treatment cessation to disease progression or death.⁶ Similar findings were reported from the Alliance A041202 study (NCT01886872) testing ibrutinib with or without rituximab in older adults with TN CLL; the median time from ibrutinib cessation until disease progression was 24 months among 75 patients who stopped taking ibrutinib for reasons other than progression.⁷

Time-Limited Targeted Therapy

Combinations of a BTK inhibitor with other targeted agents, particularly B-cell lymphoma 2 (BCL-2) inhibitors, can achieve high rates of undetectable minimal residual disease (uMRD) and durable, treatment-free remission. For instance, The University of Texas MD Anderson Cancer Center phase 2 study (NCT02756897) of ibrutinib plus venetoclax (Venclexta; I + V) reported a 5-year PFS rate of 90% in TN patients with CLL who had high-risk markers or who were older.⁸ Triplet regimens combining a BTK inhibitor, a BCL2 inhibitor, and an anti-CD20 monoclonal antibody (mAb) are also highly efficacious.^9-11 Data from the ongoing CLL17 study comparing 2 fixed-duration regimens (I + V; venetoclax plus obinutuzumab [Gazyva]) and continuous treatment with ibrutinib will provide valuable insight into the comparative efficacy and safety of time-limited vs continuous treatment approaches in TN CLL (NCT04608318).

Is Time-Limited Therapy Feasible Without a BCL2 Inhibitor?

Histologic image of chronic lymphoblastic leukemia (CLL) cells

BCL2 inhibitor–free, fixed-duration regimens are being actively investigated in CLL. Findings from previous studies demonstrated that the addition of CD20 mAb to a BTK inhibitor improved rates of uMRD (eg, 38% with ibrutinib plus obinutuzumab [I + O])¹² and complete response (CR; eg, 13% with acalabrutinib plus obinutuzumab [A + O]),¹³ although these studies used continuous BTK inhibitors. Time-limited BTK inhibitor plus mAb regimens being tested in ongoing trials include A + O (NCT04505254 and NCT04722172), I + O (NCT04908228), and pirtobrutinib plus obinutuzumab (NCT06333262). Another interesting approach is intermittent BTK inhibitor dosing without mAb as in the IbruOnOff study (NCT04771507). Most of these trials are being conducted in patients with TN CLL and utilize uMRD or CR as the primary end point, suggesting that the treatment setting and responses achieved at the end of therapy may inform patient selection.

Strategic and Tactical Decision-Making

Factors to consider when stopping BTK inhibitor therapy include long- and short-term factors relevant to the host, the disease, and the treatment. Durability of remission after stopping BTK inhibitors likely varies by genetic markers of the disease (eg, TP53 aberration, IGHV mutation, and mutations associated with treatment resistance, such as BTK mutations), prior treatment status (TN vs relapsed/refractory), and depth of response to BTK inhibitor therapy at time of treatment cessation (eg, with or without uMRD). Also necessary are considerations of patient preference, tolerance of BTK inhibitors, treatment adherence, and cost. More research is needed to understand the long-term impact of BTK inhibitor cessation on disease biology and to define monitoring and subsequent treatments after time-limited BTK inhibitor therapy.

REFERENCES:

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9. Rogers KA, Huang Y, Ruppert AS, et al. Phase II study of combination obinutuzumab, ibrutinib, and venetoclax in treatment-naive and relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(31):3626-3637. doi:10.1200/JCO.20.00491

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11. Soumerai JD, Mato AR, Dogan A, et al. Zanubrutinib, obinutuzumab, and venetoclax with minimal residual disease–driven discontinuation in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2021;8(12):e879-e890. doi:10.1016/ S2352-3026(21)00307-0

12. Moreno C, Greil R, Demirkan F, et al. First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase III iLLUMINATE trial. Haematologica. 2022;107(9):2108-2120. doi:10.3324/haematol.2021.279012

13. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S01406736(20)30262-2