Obinutuzumab Triplet Achieves Deep Remissions in Chronic Lymphocytic Leukemia

The combination of obinutuzumab (Gazyva), ibrutinib (Imbruvica), and venetoclax (Venclexta) led to deep remissions as a time-limited treatment for patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL), according to the results of a phase 2 study.

Among patients with either treatment-naïve or relapsed/refractory CLL, the rate of complete remission (CR) with undetectable minimal residual disease (MRD) by flow cytometry in both the blood and bone marrow 2 months following completion of study treatment was 28% in both groups (95% CI, 12%-49%), which was the primary end point of the study. The overall response rate (ORR) was 84% among the treatment-naïve group and 88% among the relapsed/refractory group.

“The regimen of obinutuzumab, ibrutinib, and venetoclax met its primary goal of achieving deep remissions with a fixed-duration combination of targeted agents,” wrote the study authors, led by Kerry A. Rogers, MD. “The ORR compares favorably to that achieved with fludarabine, cyclophosphamide, and rituximab or obinutuzumab and venetoclax, which are also fixed-duration regimens.”

Also at this time point, 67% of the patients in the treatment-naïve group and 50% in the relapsed/refractory group had undetectable MRD in both the blood and bone marrow. The median progression-free survival (PFS) at 24.2 months was not reached in either arm nor was the median overall survival (OS). Only 1 patient experienced progression and 1 died at this time.

Overall, 50 patients were enrolled between August 2015 and April 2017, in which they were divided into the 2 cohorts of treatment-naïve patients (n = 25) and relapsed/refractory patients (n = 25). Eighty-six percent of patients completed treatment with the regimen and underwent response assessment, while 7 patients (14%) discontinued treatment. Three patients discontinued due to patient or investigator preference, including 2 patients from the treatment-naïve cohort and 1 from the relapsed/refractory cohort, and 3 patients discontinued due to adverse events (AEs), including 2 in the treatment-naïve cohort and 1 from the relapsed/refractory cohort.

The mid-therapy ORR was 96% in the treatment-naïve cohort (95% CI, 80%-100%) and 92% in the relapsed/refractory cohort (95% CI, 74%-99%), and by the end of therapy, the ORRs were 84% (95% CI, 64%-95%) and 88% (95% CI, 69%-97%), respectively. The most common responses were partial responses (PRs), and all PRs were due to small residual lymph nodes of > 1.5 cm. By the assessment at the end of treatment, the median greatest lymph node diameters were 2 cm (range, 1.6-3.5) in the treatment-naïve arm and 2 cm (range, 1.6-3.4) in the relapsed/refractory arm.

In terms of safety, the investigators found the regimen to be tolerable. Only 6% of patients discontinued treatment due to AEs. The most common AEs were hematologic. Neutropenia occurred in 94% of patients and thrombocytopenia in 90% of patients. Neutropenia was also the most common grade 3/4 AE, which occurred in 66% of patients. Only 1 patient experienced febrile neutropenia. Cytopenias appeared to occur more commonly in earlier treatment cycles.

The most common any grade nonhematologic AEs were hypertension (82%), hypocalcemia (82%), fatigue (78%), bruising (74%), infusion-related reactions (74%), myalgia (72%), hyperglycemia (66%), diarrhea (64%), hyperuricemia (64%), oral mucositis (64%), nausea (62%), weight gain (62%), dyspepsia (58%), arthralgia (56%), headache (52%), and increased AST (50%). Mucositis was limited to oral ulcers. The only grade 3/4 nonhematologic AEs that occurred in ≥ 10 patients included hypertension (38%) and hyponatremia (10%). Atrial fibrillation occurred in 10% of patients, and no patients experienced clinical or laboratory TLS.

Overall, there was a significant decrease in the mean natural killer (NK) cells in the blood by the end of study treatment with an average decrease of -675,000/µL (95% CI, -861,000/ µL to -488,000/ µL; P = .0001). By 8 months following the study treatment, there was some increase (P =.002), but the NK cells maintained an average of 628,000/µL below the pretreatment number (95% CI, -809,000/µL to -447,000/µL; P =.0001).

On average, as well as overtime, the relapsed/refractory cohort has lower NK cells in the blood compared with the treatment-naïve cohort, with a mean difference of -176,000/µL (95% CI, -325,000 to -28,000; P =.0), but there was no strong evidence that the NK cell changes were observed between the 2 cohorts (P =.052).

CD4 and CD8 T cells decreased overtime. At baseline, the mean CD4-positive T-cell absolute number appeared to be lower than by end of treatment, with an average decrease of 1,356,000/ µL (95% CI, -1,685,000/ µL to -1,026,000/ µL; P =.0001). At 8 months after treatment, the T-cell level remained decreased (P =.0001). The mean CD8-positive T-cell absolute number decreased by 901,000/ µL on average at the end of treatment from baseline (95% CI, 21,236,000/µL to 2566,000/ µL; P =.0001), and 8 months after treatment (95% CI, 21,237,000/ µL to 2564,000/ µL; P =.0001).

On average, in the relapsed/refractory group, the CD4-positive T cells were 503,000/ lower (95% CI, -822,000/ to -183,000; P =.002), but there was not a significant difference in CD8-positive T cells between the 2 groups.

In conclusion, the study authors noted, “The combination of obinutuzumab, ibrutinib, and venetoclax for a fixed course was tolerable and resulted in high rates of response and undetectable MRD.”

At this time, the regimen should not be used in patients outside of a clinical trial, but it is currently being compared with ibrutinib and obinutuzumab in 2 clinical trials, which are both phase 3 cooperative group trials (NCT03701282 and NCT03737981).

_Reference

_{Rogers KA, Huang Y, Ruppert AS, et al. Phase II study of combination obinutuzumab, ibrutinib, and venetoclax in treatment-naïve and relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. doi: 10.1200/JCO.20.00491}