Phase 1b results indicate no benefit when chemotherapy is added to novel regimens for chronic lymphocytic leukemia.
Adding bendamustine to venetoclax (Venclexta) plus rituximab (Rituxan), or Ven-BR, appeared to increase toxicity in patients with chronic lymphocytic leukemia (CLL) and did not show efficacy benefit when compared with venetoclax plus bendamustine and obinutuzumab (Gazyva), or Ven-BG, according to results from a phase 1b study published in Haematologica.
Over the past decade, survival outcomes for patients with CLL have greatly improved. This improvement is mainly due to the expansion of the treatment landscape to include agents that targeted the B-cell receptor signaling pathway as well as other pathways involved in CLL cell proliferation. BCL-2 inhibitors have also become standard treatment options for the patient population. Still, disease relapse and resistance/intolerance are issues with these patients that call for novel combination regimens.
Executing the phase 1b, open-label study of Ven-BR versus Ven-BG was an effort to see if combining chemotherapy with novel combinations could fill the treatment gap for the relapsed/refractory population.
To test the theory, 84 patients were enrolled at 11 sites across the United States. Those included were 81 years of age or older with a diagnosis of CLL per the International Workshop on CLL 2008 guidelines. Patients were required to have an ECOG performance status of 0 or 1, adequate hematologic function, and prior treatment with at least 3 lines of therapy. These patients were primarily evaluated for determining the maximum-tolerated dose (MTD) of the investigational triplet and the safety and efficacy of the triplet in patients with relapsed or refractory CLL undergoing treatment in the frontline setting. Secondary end points of the study included complete response rate, objective response rate, duration of response, and progression-free survival (PFS). Exploratory end points in the study included determining the MTD of the investigational triplet, as well as safety/efficacy in the subgroup of patients with undetectable minimal residual disease (MRD).
The study was executed in 2 phases, in which a dose-finding and standard 3 + 3 dose-escalation design was followed. Venetoclax treatment was dosed at 100 mg to 600 mg daily in combination with standard doses of bendamustine plus rituximab or bendamustine plus obinutuzumab. Venetoclax was also started as a weekly ramp-up to the target dose to prevent patients from developing tumor lysis syndrome (TLS). Treatment in the study went on for 28 cycles or until disease progression, death, or unacceptable toxicity.
Of the patients included in the study, 33 had relapsed/refractory CLL and 50 were receiving first-line therapy. In the Ven-BR arm, 27 patients were included and compared with the 23 patients in the Ven-BG arm.
According to baseline information, the relapsed/refractory Ven-BR cohort had a median age of 62 years (range 38-77) with the majority of patients (68%) being above 65 years of age. Ninety-seven percent of the cohort had an ECOG performance status of 0 or 1. The most common Rai stage at baseline in the relapsed/refractory CLL population was stag IV (46%). Twenty-four percent of the cohort had a creatinine clearance of < 70 mL/min. Based on prior treatment the TLS risk in the relapsed/refractory Ven-BR group was predominantly medium, although 30% had a high risk of developing TLS. Other characteristics screened at baseline included cytogenetics, IGHV mutation status, and prior therapies. Information from the relapsed/refractory Ven-BR cohort showed that most patients had a del(17p) and/or tP53 mutation, 67% had an IGHV mutation, and fludarabine-based treatment was a common prior therapy observed in 79% of patients. It was also noted that 50% of patients in this group have a Serum b -2 microglobulin ≥ 3.5 mg/mL.
In the 27 patients treated with Ven-BR in the frontline setting, the median age was 65 years (range, 27-73). The majority of patients in the group (56%) were 65 years old or younger, and 52% were male. All patients in the frontline Ven-BR group had the required ECOG performance status, and Rai stage was most commonly stage III. Forty-one percent of patients had a creatinine clearance of < 70 mL/min. Based on prior treatment, 70% of patients were identified as having a medium risk of developing TLS. In terms of cytogenetics del(13q) was found in 62% of the cohort. Further, 50% of patients in the frontline Ven-BR cohort had an IGHV mutation. The Serum b -2 microglobulin was ≥ 3.5 mg/mL in 63% of patients.
Among the 22 patients in the frontline Ven-BG cohort, the median age was 64 years (range, 38-74) with 55% of patients being below the age of 65 years. Sixty-eight percent of the patients were male, and all had an ECOG performance status or either 0 or 1. Baseline Rai stage was notable unknown for 36% of patients of those whose status was known, 27% were stage II. Twenty-three percent of the cohort had a creatinine clearance of < 70 mL/min. There was mixed TLS risk in the cohort with 32% being at low risk, 46% being medium risk, and 23% being high risk. Similar to the frontline Ven-BR arm, patient in the frontline Ven-BG arm had del(13q) more often than other alterations (50%). Seventy-one percent of them had IGHV mutated tumors.
In relapsed/refractory patients with CLL treated with Ven-BR, the ORR was 91%, which included CRs or CRs with hematologic recovery (CRi) in 42% of patients. For the frontline CLL population treated with Ven-BR in the study, the ORR was 100%, 44% of which were CRs or CRis. Moreover, responses were not impacted by cytogenetics, IGHV status, or prior therapy type.
Overall, 58% of patients with relapsed/refractory disease had undetectable MRD and were included in the exploratory analysis, and 89% of patients in the frontline setting had undetectable MRD. Following the last dose of rituximab in each cohort, 37% of the relapsed/refractory population sustained MRD negativity compared with 67% of the frontline Ven-BR group and 92% of the frontline Ven-BG group.
The 24-month PFS rate was 87% (95% CI, 74%-99% Ven-BG) in the relapsed/refractory arm compared with 96% (95% CI, 89%-100%) in the frontline Ven-BR arm and 100% (95% CI, 100%-100%) in the Ven-BG arm.
No dose-limiting toxicities were observed during the study and the MTD was not reached in the doses explored during the study. Further, no cases of TLS were reported. Overall, all patients in the study experienced adverse events. Further, 82% of the relapsed/refractory Ven-BR cohort, 93% of the frontline Ven-BR cohort, and 91% of the frontline Ven-BG cohort experienced grade 3 or 4 AEs.
“Neutropenia was the most important toxicity in triplet combinations in both 1L and R/R CLL populations. Rates of grade 3–4 neutropenia, however, were generally consistent with those observed with Ven-R in R/R CLL in the MURANO trial [NCT02005471],” wrote the study authors.
Based on the discoveries in the early-phase study, investigators believe there is no need to add chemotherapy to novel regimens.
Stilgenbauer S, Morschhauser F, Wendtner CM, et al. Venetoclax plus bendamustine-rituximab or bendamustine-obinutuzumab in chronic lymphocytic leukemia: final results of a phase Ib study (GO28440). Haematologic. 2021;106(11): 2831-2844. doi: 10.3324/haematol.2020.261107