Zahra Mahmoudjafari, PharmD, BCOP, DPLA: CAPTIVATE was an international phase 2 study in patients less than 70 years old with previously untreated CLL [chronic lymphocytic leukemia]. The trial had 2 cohorts. Patients in the first [cohort] received fixed-duration ibrutinib plus venetoclax for a year and were then observed. Patients in the second cohort received ibrutinib plus venetoclax before being stratified by minimal residual disease [MRD] status and randomized to receive additional treatment. Patients received 2 cycles of ibrutinib as a lead-in and then 12 cycles of the combination of ibrutinib plus venetoclax. The ibrutinib was dosed at 420 mg per day. This was before drug interactions. Oral venetoclax had a 5-week ramp-up to 400 mg per day. The primary end point of this trial was complete response [CR] and secondary end points included undetectable minimal residual disease, progression-free survival, overall survival, and safety. Of the 159 patients enrolled and treated, the median time on study was 27.9 months, and 92% of the patients completed all planned treatments. The primary end point in this trial was met, with a CR rate of 56% in patients without deletion 17p. This was significantly higher than the prescribed 37% minimum rate.

In the all-treated patient population, the CR rate was 55%, and the best undetectable minimal residual disease rates were 77%. The 24-month progression-free survival and overall survival rates were 95% and 98%, which is fairly remarkable. At baseline, 21% of these patients were in the high tumor burden category for tumor lysis syndrome risk. After the ibrutinib lead-in, only 1% remained in this category, which is significant given the tumor lysis toxicities that we often can see with venetoclax in patients with high tumor burden.

The most common grade 3 or higher adverse events were neutropenia and hypertension, which is no surprise given the agents that were used. This study ultimately demonstrated that the combination of ibrutinib plus venetoclax was effective in these patients and that the patients achieved deep, durable responses and promising progression-free survival, including patients with high-risk features.

One thing to note is the MRD, which is an extremely popular marker these days in the world of hematology. In CLL, MRD is defined as less than 1 CLL cell in 10,000 leukocytes. It may also be referred to as less than 0.01% of the cells or less than 10-4. With fixed-duration therapies, which seems to be the direction we’re going in the management of CLL, undetectable minimal residual disease is associated with longer progression-free survival. MRD assessment may be useful in clinical practice to provide insight into anticipated progression-free duration, following fixed-duration treatment. But it’s not reliably recommended to understand treatment duration or treatment decisions for patients on targeted therapy. A benefit of CAPTIVATE was that an all-oral therapy approach means a patient wouldn’t have to come to an infusion center for treatment. In theory, it’s a major win for patient convenience.

The GLOW study was a phase 3 trial that randomly assigned patients in a 1:1 fashion. The study evaluated fixed-duration ibrutinib plus venetoclax compared with chlorambucil plus obinutuzumab for first-line treatment of older or unfit patients with CLL. Of note, this study excluded patients with deletion 17p or known TP53 mutations. Randomization to fixed-duration ibrutinib and venetoclax for a standard 6 cycles of chlorambucil plus obinutuzumab was stratified by immunoglobulin heavy chain variable region genes, or IGHV mutational status, and deletion 11q status. Patients in the IMV [MB1] arm received 3 months of ibrutinib lead-in, just like in the other trial, followed by 12 months of the combination ibrutinib plus venetoclax. All patients stopped therapy regardless of MRD status.

In the study, 106 patients received ibrutinib plus venetoclax, and 105 received chlorambucil plus obinutuzumab. The median age in this trial was 71 years. The primary end point was progression-free survival, and secondary end points included undetectable minimal residual disease, response rate, and overall safety. The study enrolled 211 patients and had a median follow-up of 27.7 months. There were 22 progression-free survival events for ibrutinib and venetoclax and 67 events for the chemotherapy arm. Progression-free survival was significantly longer for the ibrutinib-venetoclax arm than for chlorambucil-obinutuzumab. This improvement was consistent across the predefined subgroups.

The best-undetected minimal residual disease rate in bone marrow was significantly higher for the ibrutinib-venetoclax group than for chlorambucil-obinutuzumab. The proportion of patients with sustained undetectable minimal residual disease in peripheral blood from 3 to 12 months after the end of treatment was 84.5% for ibrutinib-venetoclax and 29.3% for chlorambucil-obinutuzumab. Only 4 patients treated with ibrutinib-venetoclax required subsequent therapy, compared with 27 patients who receive chlorambucil-obinutuzumab.

In the adverse effects, we did see a bit of a difference. For grade 3 or higher, this occurred in 75% of the ibrutinib-venetoclax patients but only 69% of chlorambucil-obinutuzumab. That’s pretty close, but there was a slight trend toward a higher rate of adverse events in the ibrutinib-venetoclax arm. Typically the most common adverse events in this study were neutropenia in both arms. The study basically concluded that the combination of ibrutinib-venetoclax, which was all oral, once daily, and fixed duration, demonstrated superior progression-free survival and deeper and sustained responses vs chlorambucil-obinutuzumab as first-line treatment in older patients.

One thing that has caught my attention with the GLOW study is that chlorambucil-obinutuzumab is no longer a standard-of-care regimen for most patients. It’s difficult to compare the efficacy of this newer regimen with current standards, but we still see a very remarkable progression-free survival with the fixed-duration ibrutinib-venetoclax.

Transcript edited for clarity.