Ibrutinib Combination Therapy Safely Treats DLBCL

SAN DIEGO-Ibrutinib can be safely combined with lenalidomide and rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to a new study (abstract 473) presented at the American Society of Hematology (ASH) 58th Annual Meeting and Exposition, held December 3–6.

In DLBCL, from 50% to 60% of patients are cured with standard rituximab plus CHOP (R-CHOP) therapy. But R-CHOP failures have very poor outcomes, with only 10% to 20% experiencing prolonged disease-free intervals with high-dose chemotherapy and autologous stem cell transplant, and frequent comorbidities and age prevent a high-dose therapy approach, said lead author Andre Goy, MD, of John Theurer Cancer Center, Hackensack University Medical Center in Hackensack, NJ.

“In patients with primary refractory disease and who are early failures less than 12 months from diagnosis, outcome is dismal, with overall response rate of 20% to 30% and median overall survival of 4 to 6 months,” said Goy. “This illustrates the need for novel options in relapsed/refractory DLBCL.”

Ibrutinib is a first-in-class, oral, once daily inhibitor of Bruton’s tyrosine kinase that has shown activity as a single agent in relapsed/refractory DLBCL, particularly in the nongerminal center B-cell-like (non-GCB) subtype. Lenalidomide is an immunomodulatory agent that has shown activity as monotherapy in non-GCB DLBCL and in combination with rituximab in phase II studies of relapsed/refractory DLBCL.

Goy and colleagues conducted a multicenter, open-label, phase Ib/II trial designed to evaluate the safety and efficacy of ibrutinib in combination with lenalidomide and rituximab in patients with relapsed/refractory DLBCL.

The study included 45 DLBCL patients, median age 64 years; 87% had stage III/IV disease. They had a median of three prior regimens, and two-thirds were refractory to the last therapy. One-quarter had primary refractory disease and 16% bulky disease.  

Patients received once daily ibrutinib 560 mg in combination with intravenous rituximab 375 mg/m² on day 1 of each 28-day cycle for 6 cycles and escalating doses of lenalidomide on day 1-21 of each 28-day cycle. The primary goal of the phase Ib portion of the study was to determine the maximum tolerated dose and/or recommended phase II dose of ibrutinib.  

Grade 3/4 adverse events were found among 80% of the patients. The most frequent were neutropenia (38%), thrombocytopenia (11%), and maculopapular rash (11%). Serious adverse events occurred in 44% of patients, including dehydration, pneumonia, cellulitis, and hypercalcemia.

A total of 71% of patients discontinued ibrutinib, including 63% of patients with progressive disease. Death occurred in 42% of patients, primarily due to progressive disease, Goy said.

“We saw modest activity in the non-GCB subtype and a trend toward needing higher doses of lenalidomide for response,” said Goy. With a 15 mg or higher dose of lenalidomide, 47% of non-GCB patients responded, and 21% had complete responses.

In conclusion, Goy said the phase II portion is being initiated at 20 mg of lenalidomide in combination with rituximab and ibrutinib. “The combination shows activity in heavily pretreated relapsed/refractory DLBCL, with a 56% overall response rate in non-GCB patients,” he said. The phase II portion of the study is ongoing in non-GCB patients only.