A Phase Ib/II Study of Ibrutinib in Combination with Obinutuzumab-Gazyva As First-Line Treatment for Patients with Chronic Lymphocytic Leukemia > 65 Years Old or with Coexisting Conditions

Standard treatment for patients (pts) with chronic lymphocytic leukemia (CLL) is rapidly evolving and gradually has incorporated the use of monoclonal antibodies (mAbs) and targeted therapy with small molecules. Single agent Ibrutinib (a first-in-class BTK inhibitor) has shown to be effective in previously untreated (PU) pts including those that are older than 65 or considered unfit to receive chemotherapy-based combinations. The response rate could be higher in pts receiving ibrutinib (overall response of 71% and complete response of 13%) but the mobilization of lymphocytes, which is typically asymptomatic, decreases the response rate due to lack of complete fulfillment of iwCLL criteria. Ibrutinib-induced lymphocytosis could be ameliorated by using mAbs like rituximab or obinutuzumab-Gazyva (G), a third-generation anti-CD20 mAb, and consequently increased the overall response rate. However, there are no data available assessing the combination of ibrutinib and G in the elderly population (> 65 years old) or in those pts < 65 years old where chemotherapy based agents are not indicated. Accordingly, we initiated an open-label phase Ib/II clinical study of Ibrutinib in combination with G for therapy of PU pts with CLL.

The study will enroll 32 PU pts with CLL. Pts receive G administered based on FDA dosing recommendations for 6 cycles (28 days/cycle) and Ibrutinib 420mg po. qd for up to 3 years. All pts receive prophylactic medications (acyclovir, allopurinol and low dose glucocorticoids). Pts will undergo response assessment two months after completion of the study treatment by iwCLL criteria, and will be followed for survival during 3 years until initiation of new treatment for CLL, disease progression, consent withdrawal or death, whichever occurs first. Here we present a preliminary analysis of safety / tolerability with the first 9 pts treated with this regimen.

The median age of the pts was 63 years ± 8.6. 78% of the pts had a CIRS > 6, 44% had a Rai stage III-IV and 33% had an ECOG performance >2. The median baseline absolute lymphocyte count (ALC) was 96.6 ± 20.2 x10³/mm³. Pts showed the following cytogenetic abnormalities: del(13q) in 67%, trisomy 12 in 22% and del(11q) in 11%. None of these pts showed del(17p).

Most adverse events (AEs) were grade 1-2 (94%) without development of dose-limiting toxicities. Only one pt (11%) had a grade 1 G-infusion-related reaction (IRR). We did not observe grade 3-4 IRR. We observed neutropenia (all grades: 33%, grade 3-4: 22%), thrombocytopenia (all grades: 78%, grade 3-4: 11%) and anemia (all grades: 44%). 78% of the pts had a decrease in ALC during the first cycle of treatment and two pts had persistent lymphocytosis up to cycle three. There were no cases of febrile neutropenia. Two pts (22%) had grade 1-2 bleeding (one pt with asymptomatic lower gastrointestinal bleeding and the second pt with epistaxis) that resolved spontaneously without requirement of blood transfusion or study treatment discontinuation. One pt (11%) developed community-acquired pneumonia requiring inpatient treatment with IV antibiotics; the study treatment was held until resolution of symptoms and re-initiated at full dose. The most frequent non-hematological AEs were diarrhea, transaminitis, hyperbilirubinemia, hyperglycemia, and electrolyte alterations (grade 1-2).

Two pts were evaluable for response assessment by iwCLL criteria. One pt achieved a complete remission with MRD^positivein the bone marrow by multiparameter flow cytometry and the other pt had a partial response due to small residual lymph nodes > 1.5 cm.

Overall, Ibrutinib-G combination has been well tolerated. All 9 pts have had favorable clinical and hematological responses. We observed a resolution of the lymphocytosis in 78% of the pts during the first cycle of treatment. We did not observe unexpected AEs with this regimen allowing all 9 pts to continue in the study. The most important finding thus far has been the very low rate of IRR, only one pt (11% - grade 1), and the absence of grade 3-4 IRR, suggesting that ibrutinib can strongly mitigate the incidence and severity of IRR with G. Pt enrollment continues and updated information will be presented at the meeting.