Combination treatment with obinutuzumab, ibrutinib improves outcomes in CLL

Adding obinutuzumab to ibrutinib enhances the depletion of chronic lymphocytic leukemia cells from the peripheral blood and the bone marrow in both ibrutinib-naive patients and patients treated with ibrutinib for 1 year, according to findings presented at the ASH Annual Meeting and Exposition.

Patients treated with ibrutinib (Imbruvica, Janssen) for 1 year experienced a more pronounced reduction in the depletion of CLL cells when compared with ibrutinib-naive patients.

“Ibrutinib inhibits CLL cell proliferation and results in prolonged remission, but minimal residual disease responses are rare,” the researchers wrote. “Obinutuzumab [Gazyva, Genentech] is a second-generation anti-CD20 monoclonal antibody that is effective in CLL and can result in MRD responses. The IcICLLe Extension Study [examined] the efficacy and safety of the combination of obinutuzumab and ibrutinib ... in relapsed, refractory CLL.”

In the IcICLLe study, 40 patients with CLL were treated with ibrutinib until they achieved complete remission, defined as <0.01% MRD in the bone marrow, or experienced disease progression. The cohort was evenly split between patients with treatment-naive disease (n = 20) and patients with relapsed, refractory disease (n = 20).

Andy Rawstron, PhD, of Leeds Teaching Hospitals in England, and colleagues conducted the IcICLLe Extension Study, which studied the safety and efficacy of obinutuzumab in combination with ibrutinib in the same cohort of patients. Preliminary results from IcICLLe after 1 month demonstrated that the addition of obinutuzumab to ibrutinib enhanced CLL depletion. The researchers presented 18-month follow-up data.

Treatment in the extension study involved continuous ibrutinib (420 mg once daily) with 6 cycles of obinutuzumab given over 6 months. Ten patients received ibrutinib monotherapy for more than 1 year while enrolled in the original study. Among 30 ibrutinib-naive patients, obinutuzumab therapy began 24 hours after the first ibrutinib dose.

The researchers examined patient characteristics and the incidence of adverse events, from the time the study began until 30 days after treatment stopped. Adverse events were reported at months 1, 3 and 6 followed by every 6 months thereafter using Common Terminology Criteria for Adverse Events version 4.0. MRD assessments were conducted using the European Research Initiative on CLL (ERIC) guidelines, with a maximum detection limit of 0.001%/10-5.

At 6 months, none of the patients with relapsed, refractory disease who received ibrutinib monotherapy achieved complete response or complete response with incomplete blood count recovery according to the International Workshop on CLL criteria. No CLL counts of less than .01% in the peripheral blood or bone marrow were observed among patients in this group. Peripheral blood MRD levels were consistent or improved at later points; one of the 20 patients achieved <0.01% peripheral blood MRD at 18 months.

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Adding obinutuzumab did not noticeably influence safety outcomes, though it did correlate with higher response rates and an increased depth of MRD depletion when compared with the results seen in patients treated with ibrutinib alone. This was especially true among patients treated with ibrutinib for more than 1 year before combination treatment with obinutuzumab.

Patients treated with obinutuzumab following at least 1 year of ibrutinib monotherapy experienced an increased response rate when compared with ibrutinib-naive patients; the response according to International Workshop on CLL criteria for complete response or complete response with incomplete blood count recovery was 50% in the monotherapy group and 30% in the ibrutinib-naive group. More patients in the monotherapy group attained <0.01% bone marrow MRD (50% vs. 6%) and a greater depth of disease depletion (3.1 vs. 1.5 log reduction).

Nine of 30 patients (30%) in the ibrutinib-naive arm achieved peripheral blood MRD <0.01% 12 months after the end of obinutuzumab treatment compared with 60% of patients at the same time period who had received ibrutinib for more than 1 year before treatment with obinutuzumab. Four of 30 patients in the ibrutinib-naïve group and two of 10 in the group of patients treated with ibrutinib for at least 1 year could not be evaluated.

Variance in the depth of disease depletion with obinutuzumab may be due to disease bulk prior to starting obinutuzumab, the researchers noted, as lymphadenopathy had resolved in most patients (7 out of 10) who received 1 year or more of prior treatment with ibrutinib before beginning obinutuzumab.

“The addition of obinutuzumab to ibrutinib may result in a substantial improvement in the depletion of CLL cells from the peripheral blood and bone marrow” among patients who are ibrutinib-naive, the researchers wrote. “However, a greater impact in MRD response rate and depth of depletion was seen when obinutuzumab was introduced after [more than 1 year] of ibrutinib treatment and tumor bulk was low. For patients with persistent disease during/following pathway inhibition treatments, the addition of anti-CD20 antibody therapy may be effective at improving MRD response rates.” - by Julia Ernst, MS

Reference:

Rawstron A, et al. Abstract 181. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.

Disclosures: Rawstron reports advisory committee/consultant roles and board of directors’ membership with AbbVie, Celgene, Gilead Sciences, Janssen, Pharmacyclics and Roche and receiving research funding from AbbVie, BD Biosciences, Beckman Coulter, Celgene, Gilead Sciences, Janssen, Pharmacyclics and Roche. Please see the abstract for all other authors’ relevant financial disclosures.