August 28, 2019
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Triplet therapy active in diffuse large B-cell lymphoma

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The combination of ibrutinib, lenalidomide and rituximab demonstrated robust, ongoing activity among patients with relapsed or refractory diffuse large B-cell lymphoma, especially those with nongerminal center B-cell DLBCL, according to results of the dose-escalation portion of a phase 1b/phase 2 study published in Blood.

“Diffuse large B-cell lymphoma is the most common form of non-Hodgkin lymphoma and is increasing in incidence, particularly for elderly patients. The R-CHOP regimen is curative for over half of patients with DLBCL,” Andre Goy, MD, MS, chairman and director of the John Theurer Cancer Center and chief of the division of lymphoma at Hackensack University Medical Center, and colleagues wrote. “Though the standard of care in patients who fail first-line chemoimmunotherapy is salvage therapy followed by high-dose therapy and stem cell transplantation, only 10% to 20% of patients have long-term DFS. Patients with primary refractory disease or who relapse within 12 months have a dismal outcome with the current standard of care; median OS is about 5 to 6 months.”

In the phase 1b portion of the open-label, multicenter study, Goy and colleagues sought to determine the maximum tolerated dose of ibrutinib (Imbruvica; Pharmacyclics, Janssen), lenalidomide (Revlimid, Celgene) and rituximab (Rituxan; Genentech, Biogen) and review safety and tolerability of the combination among 45 transplant-ineligible patients (median age, 64 years; 56% men) with relapsed or refractory DLBCL.

Participants underwent treatment with once-daily 560 mg ibrutinib; 375 mg/m2 IV rituximab on day 1 of cycles 1 to 6; and 10 mg, 15 mg, 20 mg or 25 mg lenalidomide on days 1 to 21 of each 28-day cycle. Median time since diagnosis was 14.1 months. Fifty-one percent of patients had nongerminal center B-cell (nonGCB) DLBCL, 33% had transformed DLBCL, 60% were refractory and 27% were primary refractory.

Dose-limiting toxicities among patients receiving 15 mg lenalidomide (n = 12) led to the formation of a de-escalation cohort (10 mg lenalidomide). No dose-limiting toxicities occurred with subsequent re-escalation to 25 mg lenalidomide, so researchers could not establish a maximum tolerated dose.

Median follow-up was 25.6 months (range, 0.4-44.8).

Results showed an overall response rate among response-evaluable patients (n = 39) of 44% (95% CI, 28-60), including a 28% rate of complete response (CR). Reponses were more prevalent among patients with nonGCB DLBCL (n =17; 65% ORR, 41% CR) than those with GCB DLBCL (n =17; 29% ORR, 18% CR).

Response-evaluable patients with refractory disease (n = 23) attained an ORR of 26%, those with primary refractory disease (n = 12) had an ORR of 17% and those with secondary refractory disease (n =27) had an ORR of 56%. Patients with relapsed disease (n = 16) attained an ORR of 69%.

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The most prevalent treatment-emergent adverse events included gastrointestinal events, myelosuppression, fatigue, hypokalemia, peripheral edema and maculopapular rash. New-onset atrial fibrillation occurred in five patients, and two patients had pre-existing atrial fibrillation , which did not worsen during treatment.

Most of the patients (93%; n = 42) experienced a grade 3 or worse adverse event, including 34 (76%) whose event was deemed related to study medication.

Median duration of response among all patients was 15.9 months, with two patients remaining on treatment beyond 3 years.

Researchers initiated the phase 2 portion of the study with 20 mg lenalidomide among patients with relapsed or refractory nonGCB DLBCL, and 25-mg cohort in phase 2 is currently under evaluation.

“The triplet of ibrutinib, lenalidomide and rituximab demonstrated promising activity and a manageable safety profile in patients with relapsed/refractory DLBCL, particularly nonGCB DLBCL, and warrants further evaluation in this patient population with a significant unmet medical need,” the researchers wrote. “The ongoing phase 2 portion of this study further evaluates the efficacy and safety of this combination regimen in transplant-ineligible patients with relapsed/refractory nonGCB and activated B-cell DLBCL, including a cohort with 25 mg lenalidomide.” – by Jennifer Byrne

Disclosures: Goy reports research funding, consulting fees, speaker fees and honoraria from Acerta, Genentech, Gilead, Janssen, Kite Pharma, Pharmacyclics LLC and Takeda, and a leadership role with or stock ownership in COTA. Please see the study for all other authors’ relevant financial disclosures.