According to findings published in Blood Advances, researchers have determined the optimal dosing combination of ibrutinib with venetoclax, that having the highest response and lowest toxicity, in relapsed or refractory mantle cell lymphoma (MCL).

“Adding [venetoclax] to [ibrutinib] has shown synergy in preclinical MCL models. Prior MCL studies of the combination show promising efficacy but have conducted limited dose finding,” the authors stated in their report.

The researchers conducted a phase 1 dose-finding study to identify the optimal dosing combination of ibrutinib and venetoclax in adult patients (≥18 years) with relapsed or refractory MCL ( Identifier: NCT02419560).

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The team used a continual reassessment method of 6 combinations of ibrutinib (280 mg, 420 mg, and 560 mg by mouth daily) and venetoclax (max dose of 200 mg and 400 mg by mouth daily), for up to 6 28-day cycles. For inclusion, patients could not have previous exposure to Bruton tyrosine kinase inhibitors (BTKi) or high risk for tumor lysis syndrome (TLS). Venetoclax was initiated first, 1 week before ibrutinib, at 100 milligrams then ramped-up to the assigned dose level. If a TLS event occurred during ramp up, patients were restarted on venetoclax at 20 mg. The optimal dosing combination was determined based on efficacy and toxicity.

A total of 35 patients (mean age, 63 years; range, 49-82; 83% male and 17% female) participated in the study. Among them, 43% had prior autologous stem-cell transplantation, and most patients had 1 line (57%) or 2 lines (37%) of prior therapy. Over 50% of patients were refractory to their last line of therapy.

The researchers reported 1 TLS event with the 100-mg starting dose of venetoclax and no TLS events with the 20-mg starting dose. All participants were able to transition from venetoclax only (cycle 0) to ibrutinib with venetoclax (cycle 1). The 6 cycles of combination treatment were completed by 71.4% of patients. Disease progression or relapse before finishing therapy was reported for 7 patients (17.1%).

Adverse events (AEs) causing treatment discontinuation were reported for 3 patients (8.6%). The researchers reported 3 DLTs: persistent grade 4 neutropenia (n=1; ibrutinib 420 mg, venetoclax 400 mg arm), persistent grade 3 diarrhea (n=1; ibrutinib 420 mg, venetoclax 400 mg arm), and grade 3 respiratory disorder (n=2; ibrutinib 420 mg, venetoclax 200 mg arm). No patients were assigned to receive ibrutinib 560 mg and venetoclax 400 mg.

The study revealed the optimal dosing combination to be venetoclax 200 mg and ibrutinib 420 mg, which yielded an overall response rate (ORR) of 93.8% (95% CI, 73.6-99.7%) and dose-limiting toxicity (DLT) incidence of 6.2% (95% CI, 0.3-26.4%). The researchers reported an ORR for all arms of 82.3% (28/34; 95% CI, 65.5-93.2%), with a complete response rate of 42.4% (14/33; 95% CI, 25.5-60.8%). They did not observe ORR benefit with higher dosing combinations, which demonstrated higher toxicity.

“The 2 drugs’ interaction was hypothesized to increase effective drug levels that may allow for a lower dose without negative effects on efficacy. Our finding of an optimal combination of [ibrutinib] and [venetoclax] that is lower than both drugs used as single agents would support this hypothesis,” concluded the researchers. “Our study would suggest that [ibrutinib] 420 mg by mouth daily and [venetoclax] 200 mg by mouth daily has a similar response rate to other studies of the combination.”

Limitations of the study included exclusions of participants deemed to be at high risk for TLS and those with prior BTKi exposure, limited information regarding the biologic determinants of MCL, inability to match arm by clinical characteristics in a trial using the continual reassessment method, and limitation of the combination to 6 28-day cycles.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Portell CA, Wages NA, Kahl BS, et al. Dose-finding study of ibrutinib and venetoclax in relapsed or refractory mantle cell lymphoma. Blood Adv. 2022;6(5):1490-1498. doi:10.1182/bloodadvances.2021005357