A nonrandomized phase 2 trial of ibrutinib plus venetoclax in patients with treatment naïve chronic lymphocytic leukemia showed durable remissions after more than 3 years of follow-up.
A nonrandomized phase 2 trial (NCT02756897) of ibrutinib (Imbruvica) plus venetoclax (Venclexta) in patients with treatment naïve chronic lymphocytic leukemia (CLL) showed durable remissions after more than 3 years of follow-up, according to data published in JAMA Oncology.1
“CLL is the most common leukemia in the United States and was originally treated with chemoimmunotherapy,” Nitin Jain, MD, one of the lead investigators on the trial, said in a statement.2 “These long-term results show that 2 years of oral targeted therapy can achieve lasting disease remission for patients with CLL.”
This single-center trial investigated 420 mg daily of ibrutinib monotherapy for 3 cycles, then added venetoclax at a standard weekly dose ramp-up starting at 20 mg daily up to 400 mg daily for 24 cycles of combination therapy. Patients with previously untreated CLL on this trial had to have at least 1 of the following: deletion 17p (del[17p]), a TP53 mutation, del(11q), unmutated immunoglobulin heavy-chain variable gene, or be age 65 years or older.
For the 80 patients on the trial, the primary end point was best response of either complete remission (CR) or CR with incomplete count recovery (CRi) achieved any time throughout treatment, up to 2 months after completion of ibrutinib plus venetoclax. Five patients discontinued treatment while receiving ibrutinib monotherapy for reasons other than CLL progression. The 75 remaining patients started combination treatment. There was a median follow-up for all 80 patients of 38.5 months (range, 5.6-51.1 months).
After 12 cycles of combination treatment, 55 patients (69%) achieved CR/CRi; there were 14 patients (18%) with partial remission (PR). There was the same amount of patients with CR/CRi at 24 cycles and 10 patients (13%) with PR. CR/CRi as best response during the trial was observed in 62 patients (78%).
While on the combination, patients’ MRD was assessed in bone marrow. Then patients were monitored for MRD in peripheral blood samples after the completion of combination therapy every 6 months. Multicolor flow cytometry with a sensitivity of 10-4 was used to assess measurable residual disease.
There were 60 patients (75%) who achieved bone marrow undetectable measurable residual disease (U-MRD) remission as their best response at any time during the trial.
After 12 cycles of combination therapy, 45 patients (56%) achieved bone marrow U-MRD remission. Another 19 (24%) experienced low MRD-positive response (0.01% to <1%), 5 (6%) had high MRD-positive response (≥1%), and 11 (14%) discontinued the trial before the cycle 12 assessment. After 24 cycles of ibrutinib and venetoclax, 53 patients (66%) achieved bone marrow U-MRD remission; investigators observed 13 patients (16%) with low MRD-positive response and 1 (1%) with high MRD-positive response. Thirteen patients (16%) discontinued the study before the cycle 24 assessment.
“MRD is one of the most important prognostic markers at the end of leukemia treatment,” Jain, an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, said in a press release. “The majority of patients achieved bone marrow MRD remission and no patients on the trial had CLL disease progression.”
The investigators observed that bone marrow U-MRD remission by the completion of 12 cycles of combination treatment was more likely in patients who achieved less than 1% bone marrow MRD by the first response assessment after starting combination therapy (41 of 53 [77%] vs 3 of 15 [20%]; P < .001). Patients with more than a 2-log reduction in bone marrow MRD at cycle 3 of ibrutinib plus venetoclax were also more likely to achieve bone marrow U-MRD remission by the end of cycle 12 of combination therapy (40 of 48 [83%] vs 4 of 20 [20%]; P < .001). These results were similar for those with early bone marrow response and who achieved U-MRD remission by the end of 24 combination treatment cycles.
Out of 24 patients with bone marrow MRD-positive disease after 12 combination cycles, 12 (50%) achieved bone marrow U-MRD remission by the end of 24 combination cycles. Fourteen patients had bone marrow MRD positivity after 24 cycles of combination therapy, 1 of which had high MRD-positive disease; this patient had Richter transformation at that time.
Patients who had MRD positivity at the end of combination therapy could originally continue on ibrutinib alone, but an amendment was made to allow 12 additional cycles on combination therapy for these patients instead. The 13 patients with low MRD-positive disease initially continued ibrutinib monotherapy after the combination, then 9 of the 13 reinitiated venetoclax and ibrutinib after the protocol amendment. There were 51 patients who discontinued both at the end of 24 combination cycles.
After 12.4 months of median follow-up, there were 8 patients with MRD recurrence detected in their blood samples. Five of these patients had achieved U-MRD for the first time after completing 24 cycles of combination therapy. None of the patients had clinical progression.
All of the high-risk subgroups on the trial had responses. Of the 18 patients with del(17p) and/or TP53-mutated CLL, 4 discontinued ibrutinib alone before receiving the combination and 1 discontinued soon after completing the venetoclax ramp-up; all discontinuations were for reasons other than CLL progression. Nine of the 13 (69%) remaining patients who completed combination therapy had bone marrow U-MRD at cycle 12 and 10 (77%) had U-MRD at cycle 24.
There were 57 men (71%) on the trial and the median age was 65 years (range, 26-83). Fourteen patients (18%) had del(17p), 11 (14%) had TP53-mutated CLL, and 18 (23%) had del(17p) and/or TP53-mutated CLL.
“I think this will be one of several standard of care treatments available for patients with CLL,” Jain said. “There are pros and cons to each of those approaches, and physicians will have to decide which option is best for their patient.”
1. Jain N, Keating M, Thompson P, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia: a nonrandomized phase 2 trial. JAMA Oncol. Published online June 10, 2021. doi:10.1001/jamaoncol.2021.1649
2. Combination targeted therapy provides durable remission for patients with chronic lymphocytic leukemia. News release. MD Anderson. Published June 10, 2021. Accessed June 18, 2021. https://bit.ly/2SeC3dC