Ibrutinib and Obinutuzumab in CLL: Improved MRD Response Rates with Substantially Enhanced MRD Depletion for Patients with >1 Year Prior Ibrutinib Exposure
Authors: Rawstron Andy , Munir Talha , Brock Kristian , Webster Nichola , Munoz Vicente Samuel , Yates Francesca , Cramp Sophie , Bishop Rebecca , Dalal Surita , De Tute Ruth M , Sheehy Oonagh , Pettitt Andrew , Fox Christopher P. , Devereux Stephen , Fegan Christopher , MacDonald Donald , Bloor Adrian , Hillmen Peter 
Published: October 2019

Abstract
Background: Ibrutinib inhibits CLL cell proliferation and results in prolonged remission, but MRD responses are rare. Obinutuzumab is a second generation anti-CD20 monoclonal antibody that is effective in CLL and can result in MRD responses. In the IcICLLe study (ISRCTN12695354), 40 participants with CLL requiring treatment (20 treatment-naïve, 20 with relapsed/refractory [R/R] disease) received ibrutinib until complete remission with <0.01% Minimal Residual Disease (MRD) in the bone marrow or disease progression. The IcICLLe Extension Study expanded IcICLLe to examine the efficacy and safety of the combination of obinutuzumab and ibrutinib in 40 patients with R/R CLL, of which 10/40 had received prior ibrutinib on the IcICLLe trial. Initial results after 1 month of combination treatment indicated that adding obinutuzumab to ibrutinib improved CLL depletion, and 18 month follow-up data is now available.
Aim: to determine the MRD response rates for patients with R/R CLL treated with ibrutinib and obinutuzumab in ibrutinib-naïve trial participants compared to those treated with >1 year prior ibrutinib.
Patients: The IcICLLe Extension Study recruited 40 participants with relapsed/refractory CLL requiring treatment. They received continuous ibrutinib (420mg OD) with 6 cycles of obinutuzumab given over 6 months (M). Ten participants had >1 year of prior ibrutinib monotherapy in IcICLLe and 30 were ibrutinib-naïve with obinutuzumab started 24 hours after first ibrutinib dose. Patient characteristics and Adverse Events (AEs, collected from registration until 30 days after treatment cessation and reported at 1, 3, and 6M, and 6-monthly thereafter using the Common Terminology Criteria for Adverse Events v4.0) are shown in Table 1. MRD assessment was performed according to ERIC guidelines with a maximum detection limit of 0.001%/10-5.
Results: In the 20 R/R patients treated with ibrutinib monotherapy there were no IWCLL CR/CRi responses and no patients achieved <0.01% CLL in the PB or BM at the 6 month response assessment. PB MRD levels either remained stable or improved at subsequent timepoints, with 1/20 achieving <0.01% PB MRD at 18M. The addition of obinutuzumab did not have a discernible impact on safety but was associated with a higher response rates and greater depth of MRD depletion than observed in patients treated with ibrutinib monotherapy, particularly in patients who had received ibrutinib for >1 year prior to combination with obinutuzumab (see Table 1).
Patients receiving obinutuzumab after >1 year prior ibrutinib monotherapy achieved a higher response rate compared to ibrutinib-naive patients (IWCLL CR/CRi 50% vs. 30%), with a higher proportion of patients achieving <0.01% BM MRD (50% vs. 6%) and a greater depth of disease depletion (3.1 vs. 1.5 log reduction).
PB MRD levels continued to improve in ibrutinib-naïve patients after cessation of obinutuzumab with 30% (9/30 with 4/30 inevaluable) achieving PB MRD <0.01% rate at 12 months post-obinutuzumab, compared to 60% (6/10 with 2/10 inevaluable) of patients at the same timepoint (12 months post-obinutuzumab) who had received ibrutinib for >1 year prior to starting obinutuzumab. The difference in extent of disease depletion observed with obinutuzumab may be related to the pre-obinutuzumab disease bulk because the majority of patients (7/10) with >1 year prior ibrutinib treatment had already resolved any lymphadenopathy prior to receiving obinutuzumab.
Conclusions: The results suggest that the addition of obinutuzumab to ibrutinib may result in a substantial improvement in the depletion of CLL cells from the PB and BM for ibrutinib-naïve patients. However, a greater impact in MRD response rate and depth of depletion was seen when obinutuzumab was introduced after >1 year of ibrutinib treatment and tumour 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.

Disclosures
Rawstron: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BD Bio-sciences: Research Funding; Beckman Coulter: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Munir:MorphoSys: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Brock:GlaxoSmithKline: Equity Ownership; AstraZeneca: Equity Ownership; Merck Sharp Dohme: Other: Reimbursement of conference fees; Roche: Other: Reimbursement of expenses; Lilly: Honoraria. Pettitt:AstraZeneca: Research Funding; Celgene: Research Funding; Chugai: Research Funding; Roche: Research Funding; GSK/Novartis: Research Funding; Gilead: Research Funding; Napp: Research Funding. Fox:Celgene: Consultancy, Other: Travel support, Speakers Bureau; Janssen: Consultancy, Other: Personal fees and non-financial support, Speakers Bureau; Gilead: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Sunesis: Consultancy. Devereux:Janssen: Other: Personal fees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Fegan:Janssen: Honoraria; Gilead Sciences, Inc.: Honoraria; Abbvie: Honoraria; Roche: Honoraria; Napp: Honoraria. Bloor:Janssen: Research Funding; AbbVie: Research Funding. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Acerta: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.