LENALIDOMIDE AND OBINUTUZUMAB WITH CHOP FOR NEWLY DIAGNOSED DIFFUSE LARGE B‐CELL LYMPHOMA: PHASE I/II RESULTS

Abstract

Introduction: Standard initial therapy for diffuse large B‐cell Lymphoma (DLBCL) is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) which cures ~65% of patients. Obinutuzumab (O) is a CD20 monoclonal antibody with increased antibody dependent cell‐mediated cytotoxicity in comparison with rituximab. Lenalidomide (L) is toxic to DLBCL via interferon signaling and immunomodulation. The GOYA study found RCHOP was as effective as OCHOP in patients with unselected newly diagnosed DLBCL. We hypothesize the combination of OLCHOP will be well tolerated and have a complete response (CR) rate ≥ to OCHOP (57% in GOYA trial, Vitolo et al., ASH 2016). We performed a phase Ib/II study of OLCHOP in patients with newly diagnosed DLBCL to assess the safety and efficacy of this combination. Methods: Patients with newly diagnosed, CD20+ DLBCL were eligible if they have measurable disease, age ≥ 18 years, and adequate organ function. In the Phase Ib trial, Obinutuzumab was dosed at 1000 mg IV days 1, 8, and 15 during cycle 1, and day 1 on cycles 2–6. CHOP was dosed in a standard fashion. The initial cohort in Phase Ib (PhIb) tested the safety of lenalidomide dose at 15 mg daily days 1–14 cycles 1–6, with lower dose cohorts only if dose limiting toxicities (DLT) occurred in the first cycle. An additional 44 patients were enrolled in Phase II (PhII) at the maximum tolerated dose (MTD). The primary objectives of this phase Ib/II trial were to determine the MTD and efficacy of LOCHOP. Correlative studies, including minimal residual disease, cell of origin determination, and immune profiling are planned on blood and tumor samples. Results: In the six patients treated in PhIb, no DLT were identified at lenalidomide dose 15 mg. An additional 44 patients were enrolled in PhII, and as of 3/15/17 all are evaluable for safety and 33 for efficacy with an end of therapy assessment. The median age was 62.5 years (26–83), with 44% males and a median IPI of 2 and NCCN IPI of 2.5. Five patients had double hit DLBCL, 5 patients had Double Expressor DLBCL, and 24 patients had non‐GCB DLBCL. Common toxicities encountered in PhIb include neutropenia (Grade 3: 50%, Grade 4: 33%), thrombocytopenia (grade 3: 17%), and rash (grade 2: 17%), with similar findings in PhII. All six patients in PhIb achieved a CR. In the PhII trial, of 27 patients with response data available at submission, 25 have a CR, 1 has a partial response, and 1 has progression. In the combined evaluable patients, the overall response rate is 97%, with CR rate of 94%. Conclusions: The combination of OLCHOP is well tolerated, with no DLT encountered in the PhIb trial, and impressive efficacy in this single center single arm Phase Ib/II trial. Adverse events do not appear to be different than expected with standard RCHOP. Results from additional patients will be presented at the ICML meeting.