Study Finds Adding Ibrutinib to Rituximab and Lenalidomide Not Justified in Frontline Setting for Follicular Lymphoma

Treatment with the triplet combination of ibrutinib, rituximab, and lenalidomide led to a high overall response rate (ORR) of 95 percent in patients with follicular lymphoma (FL), as well as a high incidence of toxicities that required dose modifications, according to results from a multicenter, single-arm, phase I study published in Blood. Chaitra S. Ujjani, MD, of the Lombardi Comprehensive Cancer Center at Medstar Georgetown University Hospital in Washington, DC, and co-authors concluded that the risk outweighed the benefit, deeming the toxicity rate “unacceptable for a frontline FL regimen.”

This combination was explored based on previous research that had shown “promising activity” with rituximab and lenalidomide in treatment-naïve FL and with ibrutinib in relapsed FL. Because the use of chemoimmunotherapy also has been associated with high rates of acute and long-term toxicity, researchers are investigating therapies such as the tyrosine kinase inhibitor ibrutinib, as a potentially more effective and tolerable alternative.

As part of the Alliance Trials in Oncology, Dr. Ujjani and colleagues evaluated the safety and efficacy of a multitargeted biologic regimen of ibrutinib plus rituximab and lenalidomide in 22 adult patients with previously untreated, histologically confirmed FL.

Patients were included if they had:

  • a World Health Organization (WHO) classification grade of 1, 2, or 3a FL
  • Lugano Classification bulky stage II (mass ≥7 cm), III, or IV
  • an Eastern Cooperative Oncology Group performance status of 0-2
  • acceptable organ function and blood counts
  • low (0-1), intermediate (2), and high (>3) FL international prognostic index (FLIPI) risk scores

Patients were excluded if they:

  • received prior or concurrent chemotherapy, immunotherapy, radiation therapy, or investigational agents
  • received corticosteroids within two weeks prior to study entry unless as maintenance therapy for a non-malignant condition
  • had known central nervous system involvement

Patients were enrolled between June 2013 and August 2014 at seven Alliance trial centers. The median age was 53.5 years (range = 36-81 years). Most patients were male (68%), 27 percent had WHO classification grade 3a FL, and 77 percent had stage IV disease. Most patients had more than four nodal sites of disease involvement (64%) and bone marrow involvement (77%).

The study used a 3+3 dose escalation design to determine the maximum-tolerated dose (MTD; primary endpoint) of ibrutinib. Rituximab was administered intravenously at 375 mg/m2 on days one, eight, 15, and 22 of cycle one and on day one of cycles four, six, eight, and 10. Lenalidomide was administered orally on days one through 21 for eighteen 28-day cycles. Ibrutinib was administered orally per cohort dose daily until disease progression or unacceptable toxicity. See TABLE 1 for dose level cohorts of lenalidomide and ibrutinib. No dose-limiting toxicities were observed, so the MTD of ibrutinib was set at 560 mg (dose level 2).

Patients underwent positron emission tomography and computed tomography (CT) scans at enrollment and again at weeks 10, 24, and 52, after which patients underwent CT scans every four months for two years, followed by every six months until progression for 10 years. Bone marrow biopsies were also performed at enrollment and again in patients who achieved complete remission (CR) and had marrow involvement at baseline.

The most common grade 3 and 4 hematologic adverse event (AE) was neutropenia (18%), while the most common grade 3 non-hematologic AEs were rash (36%), diarrhea (5%), febrile neutropenia (5%), atrial flutter (5%), and arthralgia (5%). Almost all patients (n=18/22) developed a rash, with grade 1 or 2 rash occurring in 46 percent of patients, and grade 3 occurring in 36 percent. Two patients withdrew from the study due to persistent rashes that occurred after cycle one.

Half of the patients (50%; n=11) from all dose levels required dose reduction due to AEs, including rash (n=7; 36%), neutropenia (n=3; 14%), and thrombocytopenia (n=1; 5%). Six patients discontinued treatment due to AEs, including grade 3 rash (n=2; 9%), grade 3 atrial flutter (n=1; 5%), grade 3 diarrhea (n=1; 5%), hypertension (n=1; 5%), and depression (n=1; 5%).

In addition, five patients reported new malignancies.

Focusing on efficacy, the overall response rate was 95%, with 36% of patients achieving a complete response. The median time to first response was 2.3 months (range = 1.9-11.1 months), and the median time to best response was 5.5 months (range = 1.9-25.1 months). See TABLE 2 for dose responses. After a median follow-up of 19.2 months (range = 2.3-27.1 months), the 12-month progression-free survival was 80 percent (95% CI 57-92). None of the eight patients who discontinued therapy early experienced FL progression.

The authors noted that responses were independent of FLIPI score and bulky disease, “further supporting the consideration of biologic regimens for the treatment of FL,” they wrote.

The study is limited by its small patient cohort, short median follow-up, and lack of repeat bone marrow biopsies in some patients to confirm CR.

However, given the toxicity profile, the investigators did not recommend further studies of the ibrutinib, lenalidomide, and rituximab combination. “An improvement in clinical benefit with the additional third agent was not apparent,” the authors concluded. “While further investigation of the triplet seems unwarranted in this setting, the rituximab–lenalidomide combination remains a promising option. Ibrutinib may have a place in the relapsed setting as a single agent or in combination with another biologic.”


Reference

Ujjani CS, Jung SH, Pitcher B, et al. Phase I trial of rituximab, lenalidomide, and ibrutinib in previously untreated follicular lymphoma: Alliance A051103. Blood. 2016 October 3. [Epub ahead of print]

TABLE 1. Dose Level Cohorts
Dose Level Lenalidomide Ibrutinib
Level 0 (n=3) 15 mg 420 mg
Level 1 (n=3) 15 mg 560 mg
Level 2 (n=16) 20 mg 560 mg

TABLE 2. Response Rates According to Dose Level (DL)
Response All patients

(n=22)

DL 0

(n=3)

DL 1

(n=3)

DL 2

(n=16)

Overall response rate 95% 100% 100% 94%
Complete response 36% 33% 33% 38%
Partial response 59% 67% 67% 56%
Stable disease 5% 0% 0% 6%

SHARE