Addition of Obinutuzumab to Ibrutinib Enhances Depletion of CLL Cells in the Peripheral Blood and Bone Marrow after 1 Month of Combination Therapy: Initial Results from the Bloodwise TAP Iciclle Extension Study
Authors: Rawstron Andy C , Munir Talha , Muñoz-Vicente Samuel , Brock Kristian , Yates Francesca J , Bishop Rebecca , Dalal Surita , de Tute Ruth Mary , Bloor Adrian , Sheehy Oonagh M , Pettitt Andrew R. , Fox Christopher P , Fegan Christopher , Devereux Stephen , Macdonald Donald , Hillmen Peter 
Published: October 2019

Abstract
Background: A major aim of treatment in CLL is to eradicate detectable minimal residual disease (MRD). Ibrutinib is a major step forward in the treatment of CLL but results in an immediate lymphocytosis that persists in most patients for at least several months. Obinutuzumab is a second generation anti-CD20 monoclonal antibody which appears to be highly effective in CLL resulting in a rapid eradication of peripheral blood lymphocytosis and the eradication of MRD in a proportion of patients. The IcICLLe Extension Study expands on the IcICLLe trial (ISRCTN 12695354) to examine the efficacy and safety of the combination treatment of obinutuzumab and ibrutinib.
Patients: The IcICLLetrial recruited 40 participants with CLL requiring treatment (20 treatment-naïve, 20 relapsed/refractory disease) receive continuous ibrutinib therapy until achievement of <0.01% residual disease in bone marrow or disease progression. The IcICLLe Extension Study involves 40 participants with relapsed/refractory CLL requiring treatment who will all receive continuous oral therapy with ibrutinib and 6 cycles of obinutuzumab. Of the 40 participants, >20 will have had no prior Ibrutinib treatment (ibrutinib naive), and ≤20 will have received at least 12 months of Ibrutinib monotherapy as part of the IcICLLe trial before enrolling in the Extension Study . Adverse Events (AEs) are collected from registration until 30 days after treatment cessation and reported at 1, 3 and 6 months, and 6-monthly thereafter using the Common Terminology Criteria for Adverse Events v4.0.
Results: 17 participants (12 ibrutinib naïve and 5 IcICLLe monotherapy patients) are evaluable for response assessment after one month of combination treatment. In the 12 Ibrutinib-naïve cases, the peripheral CLL counts remained at or below baseline levels in most (9/12) cases from week 1 onwards. After one month of combination therapy the peripheral B-cell count was a median 35% of baseline levels (range <1% to 174%) compared to a median 215% (range 29% to 3570%) for relapsed/refractory patients on Ibrutinib monotherapy. The percentage of CLL cells in the bone marrow aspirate for patients after 1 month of combination therapy showed a median 20% reduction (range 1% increase to 55% decrease, paired t-test P<0.001, baseline median 74% CLL cells, range 23-94%) while there was no change for relapsed/refractory patients on ibrutinib monotherapy (median 1% increase, range 39% increase to 24% decrease, paired t-test P=0.35, baseline median 85% CLL cells, range 11-96%). The reduction in bone marrow aspirate CLL percentage was also evident by morphological assessment of the trephine biopsy with all 10 evaluable patients showing improvements in the cellularity and/or extent of infiltration.
Bone marrow assessment was not mandated for the 5 patients previously on ≥12 months (range 14-20 months) continuous ibrutinib monotherapy because they had already undergone 4 biopsies in the prior year, however all five patients showed a reduction in peripheral CLL counts (median 1.3 log reduction, range 0.3 to 2.4 log) which was significantly greater than the reduction seen in the prior 6 months of ibrutinib monotherapy (median 0.5 log reduction, range -1.0 to 0.8, paired t-test P=0.043)
Of the 17 participants recruited to the IcICLLe Extension Study there have been no reports of Tumour Lysis Syndrome within the first month of combination treatment. There was a single report of a grade 2 Infusion Related Reaction (IRR) for one participant following the first infusion (100mg) of obinutuzumab. No further IRRs have been reported.
Conclusions: The data indicate that the addition of obinutuzumab to ibrutinib results in a substantial improvement in the depletion of CLL cells from the peripheral blood and bone marrow after only one month of combination therapy.
Date of Data Freeze: 19-Jul-2016

Disclosures
Rawstron: Gilead: Consultancy, Honoraria, Research Funding; BD Biosciences: Other: Remuneration; Celegene: Honoraria; Roche: Honoraria; Janssen: Research Funding; GlaxoSmithKline: Honoraria; AbbVie: Honoraria; Genzyme: Honoraria. Munir:Alexion pharmaceuticals: Honoraria. Brock:AstraZeneca: Equity Ownership; GlaxoSmithKline: Equity Ownership. Bloor:Janssen: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Gilead: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees. Pettitt:Roche: Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Infinity: Research Funding. Fox:Roche: Consultancy; Janssen: Honoraria, Other: Travel support. Fegan:Gilead Sciences: Honoraria; Roche: Honoraria; AbbVie: Honoraria. Devereux:Roche: Consultancy, Other: Travel, Accommodations, Expenses ; GSK: Consultancy; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding.