A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL

Abstract

Richter transformation (RT) is a rare complication of CLL with dismal outcomes. Upregulation of PD-1/PD-L1 drives immunological evasion in patients with RT. We hypothesized if combining nivolumab, a PD-1 blocking antibody, with the BTK inhibitor (BTKi) ibrutinib could potentiate tumor-cell killing. We conducted an investigator-initiated phase 2 clinical trial to assess the efficacy of combined nivolumab and ibrutinib in patients with diffuse large B-cell lymphoma (DLBCL) RT and CLL. Patients included were ≥18 years of age with adequate hepatic and renal function. Patients received nivolumab every 2 weeks of a 4-week cycle for a maximum of 24 cycles. Standard dose ibrutinib was initiated from cycle 2 onwards and continued daily until progression. A total of 24 patients with RT with a median age 64.5 years (range, 47-88) were enrolled. Ten patients (42%) had received prior treatment for RT and thirteen patients (54%) had received a prior BTKi. A total of 10 patients (42%) responded with a median duration of response of 15 months. The median overall survival was 13 months. Four of 24 (17%) patients had checkpoint inhibition-related immunological toxicities. In the CLL cohort, 10 patients were enrolled, of whom 3 patients converted from partial remission to complete remission; 1 patient had a grade 2 immunological toxicity. Combined nivolumab and ibrutinib is an active regimen for patients with DLBCL RT with an overall response rate of 42%. Given the limited treatment options for patients with RT, checkpoint inhibition provides a potential therapeutic option. This trial is registered at www.clinicaltrials.gov as NCT02420912.

Treatment of Richter Transformation of Chronic Lymphocytic Leukemia in the Modern Era

“…To improve upon single agent responses, investigations of checkpoint blockade in combination with other drugs are ongoing. A recently reported clinical trial evaluating the combination of nivolumab with ibrutinib demonstrated a 42% ORR with a median OS of 13 months (n = 24) and very few toxicities [ 66 ]. Another investigational strategy involving the combination of pembrolizumab, umbralisib (a PI3Ki) and ublituximab (a type I CD20 antibody) has shown promising initial results with an ORR of 50% in 4 relapsed/refractory RT patients with ongoing remissions of greater than 7 months [ 67 ].…”

A novel patient-derived 3D model recapitulates mantle cell lymphoma lymph node signaling, immune profile and in vivo ibrutinib responses

“…Therefore, effective therapeutic alternatives represent an unmet clinical need for MCL. In this scenario, the combination of ibrutinib with the anti-PD1 nivolumab has been studied in clinical trials [37] in several types of NHL but not in MCL, showing good results in CLL Richter transformation [38]. Thus, we analyzed the efficacy of this combination compared to ibrutinib in the PDLS system.…”

A novel Patient-Derived 3D Model Recapitulates Mantle Cell Lymphoma Lymph Node Signaling, Immune Profile and in vivo Ibrutinib Responses

“…In this scenario, the combination of ibrutinib with the anti-PD1 nivolumab has been studied in clinical trials 38 in several types of NHL but not in MCL, showing good results in CLL Richter transformation. 39 Thus, we analyzed the e cacy of this combination compared to ibrutinib in the PDLS system. As shown in Fig.…”