As the first Bruton tyrosine kinase inhibitor (BTKi) approved for clinical use, ibrutinib has transformed the treatment of chronic lymphocytic leukemia (CLL). Unfortunately, the risk of cumulative toxicity and acquired resistance have restricted ibrutinib's application. Moreover, time-limited combination therapies have been shown to produce high overall response rates and durable responses for patients with CLL. However, this approach has also been associated with high rates of adverse events and possibly overtreats many favorable-risk patients.
To address these challenges, investigators in a new study utilized an "add-on" time-limited treatment approach for patients with CLL with detectable minimal residual disease (MRD) who received treatment with ibrutinib monotherapy in the frontline or relapsed/refractory settings. Results of the Phase II, multicenter, open-label clinical trial (NCT04016805) were published in the AACR journal Clinical Cancer Research (2022; https://doi.org/10.1158/1078-0432.CCR-22-0964).
Umbralisib, an oral selective PI3K[delta] and casein kinase-1-[epsilon] (CK1[epsilon]) inhibitor, and ublituximab, which is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity (U2), were "added on" to ibrutinib. Individuals were treated until they achieved undetectable MRD (U-MRD; MRD negativity), at which point they began treatment-free observation (TFO).
With this strategy, researchers hoped to induce uMRD, curtail the risk of developing BTKi resistance mutations, stop all CLL-directed therapy, and attain a durable TFO period in CLL patients who would most benefit from combination therapy.
To be eligible for enrollment, patients had to be receiving ongoing ibrutinib for >=6 months in any line of therapy and have measurable MRD (flow cytometry, one cell in 10-4 cutoff for uMRD). Umbralisib (daily at 800 mg) and ublituximab (intravenously at 900 mg on Days 1/2 [split 150/750 mg], 8, and 15 of Cycle 1, Day 1 of Cycles 2-6, and on Day 1 every 3 cycles after Cycle 6) were added to ibrutinib and accompanied by serial assessments of MRD starting on Cycle 3, Day 1.
Once U-MRD was achieved or a total of 24 cycles were administered, patients entered a period of TFO. This research was conducted with the rate of U-MRD as its primary endpoint, with a prespecified MRD conversion rate of 25 percent defined as promising. Secondary endpoints included safety and durability of clinical benefit after treatment cessation.
Twenty-eight patients were enrolled with 27 evaluable for efficacy; the median age was 64 years and 79 percent were male. Patients received ibrutinib for a median of 21 months (range 7-67) prior to study enrollment. Fourteen patients (52%) have been deemed uMRD-compliant with the methodology, and 78.0 percent have undergone at least one uMRD evaluation. Seventeen patients (63%) have entered TFO after a median of 6.4 months on triplet therapy. Progression-free survival at 12 months was estimated at 95 percent.
The triplet regimen was well-tolerated. Grade >=3 adverse events were rare and included hypertension in 7 percent, diarrhea in 4 percent, and elevated alanine aminotransferase/aspartate aminotransferase in 4 percent of the patients. Two patients discontinued treatment due to rash (n=1) and rash plus arthralgia (n=1). Both individuals were uMRD at the time of treatment discontinuation and remain uMRD. One patient died from COVID-19 complications.
Limitations of the study were the small sample size and, as a single-arm study, the researchers were not able to have a comparative continuous strategy or other time-limited approaches. Additionally, the application of this strategy is unexplored as patients have not yet required retreatment per protocol.
According to the study, "this is the first MRD-driven approach utilizing the combination of BTKi, PI3Ki, and anti-CD20 monoclonal antibody." The addition of ublituximab and umbralisib for patients on continuous ibrutinib resulted in deep remissions that permitted personalized, time-limited therapy and sustained treatment-free observation.
Dibash Kumar Das is a contributing writer.