FDA Approves Expanded Indication for Frontline Rituximab Plus Ibrutinib in CLL/SLL


The FDA granted approval to the combination of ibrutinib plus rituximab for the frontline treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic leukemia.

An expanded indication of ibrutinib (Imbruvica) in combination with rituximab (Rituxan) has been approved for the frontline treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to a press release from the FDA.1

This marks the 11th approval for ibrutinib across 6 disease types; this is the 6th approval for ibrutinib as treatment of CLL.2

"FCR, a chemoimmunotherapy-based regimen, has been the standard of care for many previously untreated younger patients with CLL. With the introduction of this ibrutinib-rituximab combination, patients now have a more effective, non-chemoimmunotherapy option," said Brian Koffman, MD, CM, co-founder and chief nedical officer/executive vice president, CLL Society, a nonprofit organization focused on CLL patient education, support and research.

This approval was based on data from the E1912 clinical trial (NCT02048813) which evaluated the efficacy of the combination compared with fludarabine, cyclophosphamide and rituximab (FCR).1

Efficacy was measured by progression-free survival (PFS), and there was a statistically significant improvement in PFS for patients who received the combination versus those in the control arm (HR, 0.34; 95% CI, 0.22-0.52; P <.0001). After a median follow-up of 37 months, the median PFS was not reached in either arm.

The PFS rate with the combination was 88% at 37 months compared with 75% in the FCR arm.2

The most common adverse events (AEs) that were observed in 15% of patients or more included, fatigue (80%), musculoskeletal pain (61%), diarrhea (53%), rash (49%), hypertension (42%), arthralgia (41%), nausea (40%), headache (40%), bruising (36%), cough (32%), hemorrhage (31%), upper respiratory tract infection (29%), peripheral edema (28%), pyrexia (27%), pain (23%), stomatitis (22%), and dyspnea (22%).1

In this multicenter, open-label, actively controlled phase III E1912 trial, patients were randomized 2:1 to receive either the combination of ibrutinib plus rituximab (n = 354) or FCR (n = 175). Ibrutinib was administered at 420 mg daily until disease progression or unacceptable toxicity. Overall, 529 patients with treatment-naïve CLL or SLL who were 70 years or younger and required systemic therapy enrolled to the study.

The co-primary end points of the study were PFS and change in quality of life. Secondary end points included overall survival (OS) and incidence of AEs.2

With a median follow-up of 49 months, OS was not reached, and there was a total of 23 deaths, 11 from the combination arm (3%), and 12 from the FCR arm (7%).

In this study, patients had to have no prior chemotherapy, Bruton’s tyrosine kinase (BTK) inhibition therapy, or monoclonal antibody therapy for the treatment of CLL or SLL. They also had to have an ECOG performance status of 0, 1, or 2 and a life expectancy of ≥ 12 months. They had to be able to tolerate FCR-based therapy as well.1

The FDA previously approved the combination of ibrutinib plus rituximab for the treatment of previously untreated patients with CLL or SLL in January 2019. This decision was based on data from the phase III ILLUMINATE trial, and this was the first chemotherapy-free regimen approved for the treatment of untreated patients with CLL.

The decision to expand this approval occurred under Project Orbis, an initiative of the FDA Oncology Center of Excellence which provides a framework for concurrent submission and review of oncology drugs among international partners. This application was undertaken by a modified Project Orbis due to the timing of the submission to other regulatory agencies. The FDA reviewed the application in collaboration with the Australian Therapeutic Goods Administration, Health Canada, and Swissmedic.

The once-daily, first-in-class BTK inhibitor ibrutinib is the most comprehensively studied BTK inhibitor and is under evaluation in more than 150 ongoing clinical trials, which includes 5 phase III studies supporting the FDA label. There are 6 additional pivotal phase III trials of ibrutinib in CLL that have more than 5 years of efficacy, safety, and tolerability data.2

Ibrutinib is the only BTK inhibitor with long-term data from large randomized trials in the FDA label demonstrating PFS. Ibrutinib is approved in more than 95 countries for at least 1 indication. It was first approved by the FDA in November 2013. To date, the agent has been approved in 6 disease areas, which include 5 hematologic malignancies, such as CLL with or without 17p deletion, SLL with or without 17p deletion, Waldenström's macroglobulinemia, previously treated mantle cell lymphoma, and previously treated marginal zone lymphoma requiring systemic therapy and having had at least 1 prior anti-CD20-based therapy. Ibrutinib also has an indication for chronic graft-versus-host-disease after failure of 1 or more prior lines of systemic therapy.


  1. FDA approves ibrutinib plus rituximab for chronic lymphocytic leukemia [news release]. Published April 21, 2020. https://bit.ly/2VRsWgu. Accessed April 21, 2020.
  2. U.S. FDA Approves IMBRUVICA® (ibrutinib) Plus Rituximab for the Treatment of Patients with Chronic Lymphocytic Leukemia (CLL) [new release] Horsham, PA: Janssen; April 21, 2020. https://bit.ly/3an499u. Accessed April 21, 2020.
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