Imbruvica (Ibrutinib) Receives Expanded Indication, in Combination with Rituximab, as First-Line Treatment for Chronic Lymphocytic Leukemia

August 2020 Vol 13, Eleventh Annual Payers' Guide - FDA Approvals
Lisa A. Raedler, PhD, RPh
Medical Writer

The most common type of leukemia in adults, chronic lymphocytic leukemia (CLL) or its variant small lymphocytic lymphoma (SLL), is a cancer of B-cell lymphocytes.1 More than 21,000 Americans are estimated to be diagnosed with CLL in 2020.1 At the time of diagnosis, many patients are asymptomatic.2 As this cancer evolves, CLL can cause signs and symptoms such as severe fatigue, shortness of breath, spleen and lymph node enlargement, and infections.2

For patients with CLL or SLL who warrant active therapy based on symptoms and disease stage, initial regimens have traditionally contained 1 or more cytotoxic agents, such as fludarabine plus cyclophosphamide, combined with a monoclonal antibody that targets CD20, such as rituximab (Rituxan).3 Today, based on enhanced knowledge of the biology of CLL, combinations of monoclonal antibodies and targeted agents are important alternatives to chemotherapy-containing regimens.4

Novel agents for CLL or SLL include small-molecule drugs that lead to inhibition of Bruton tyrosine kinase (BTK), PI3 kinase, and BCL-2 protein, which are involved in CLL and SLL.5

FDA Approval for First-Line Treatment of CLL or SLL

On April 21, 2020, the US Food and Drug Administration (FDA) expanded the approval of ibrutinib (Imbruvica; Pharmacyclics/Janssen Biotech), an oral small-molecule drug that inhibits BTK, to include combination use with rituximab, a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre–B- and mature B-lymphocytes, for the first-line treatment of adults with CLL or SLL.6-9 The combination of ibrutinib plus rituximab was approved using the FDA’s Real-Time Oncology Review and Assessment Aid pilot programs, and was granted priority review for this indication.

According to Brian Koffman, MDCM, DCFP, FCFP, DABFP, MSEd, Chief Medical Officer and Executive Vice President, CLL Society, a national nonprofit organization that is focused on patient education, support, and research related to CLL, “The gold-standard first-line treatment option for many patients with chronic lymphocytic leukemia who were fit enough to tolerate an aggressive treatment course had been…FCR [fludarabine, cyclophosphamide, and rituximab]—that is, until today.”10

With this eleventh FDA-approved indication, ibrutinib can be administered as a single agent or in combination with rituximab or with obinutuzumab (Gazyva), or in combination with bendamustine (Bendeka) and ri­tuximab in patients with CLL or SLL.6,7

Ibrutinib is also indicated as monotherapy for the treatment of adults with mantle-cell lymphoma who have received at least 1 previous therapy, for patients with marginal-zone lymphoma who have received at least 1 previous anti-­CD20–based therapy, and for patients with chronic graft-versus-host disease who have not responded to 1 or more lines of systemic therapy.6,7

The use of ibrutinib with anti-CD20–based therapy has been approved in the past, including ibrutinib in combination with obinutuzumab for the first-line treatment of adults with CLL or SLL in January 2019, and ibrutinib in combination with rituximab for patients with Waldenström macroglobulinemia in August 2018.6

Mechanism of Action

Ibrutinib, a small-molecule drug that targets BTK, leads to the inhibition of BTK-specific enzymatic activity. BTK signaling occurs through the B-cell antigen receptor and the cytokine receptor pathways and affects B-cell trafficking, chemotaxis, and adhesion.7

Dosing and Administration

The recommended dose of ibrutinib for CLL or SLL, either as a single agent or in combination with rituximab, is 420 mg orally once daily until disease progression or unacceptable toxicity. When ibrutinib is used with rituximab on the same day, the dose of ibrutinib should be administered before the rituximab infusion.7

Ibrutinib should be taken at approximately the same time each day with a glass of water. The tablets should not be cut, crushed, or chewed.7

E1912 Pivotal Clinical Trial

The efficacy of ibrutinib in combination with rituximab in CLL or SLL was evaluated in the phase 3 E1912 clinical trial.7,11 In this study, 529 treatment-naïve patients aged ≥70 years with CLL or SLL who required systemic therapy were randomized to ibrutinib 420 mg daily until disease progression or unacceptable toxicity or to fludarabine plus cyclophosphamide and rituximab for 6 cycles.7,11

Rituximab was initiated in cycle 2 in the ibrutinib plus rituximab arm and in cycle 1 for the 3-drug arm. Treatment with rituximab was administered at 50 mg/m2 on day 1 of cycle 1, 325 mg/m2 on day 2 of cycle 1, and 500 mg/m2 on day 1 of the 5 subsequent cycles, for a total of 6 cycles. Each cycle was 28 days.7,11 The primary efficacy end point was progression-free survival, which was assessed by an independent review committee.7,11

Most patients who enrolled in the E1912 study were male (67%), white (90%), and had a baseline Eastern Cooperative Oncology Group performance status of 0 or 1 (98%).7,11 Their median age was 58 years (range, 28-70 years).7 At the time of study enrollment, 43% of patients had Rai stage 3 or 4 disease.7,11 More than half (59%) of the patients had high-risk factors (TP53 mutation [6%], deletion 11q [22%], or mutation-negative IGHV [53%]).7

After a median duration of 37 months of follow-up, a significant improvement in progression-free survival was demonstrated for ibrutinib plus rituximab compared with the 3-drug combination.7 With a median follow-up time of 49 months, the median overall survival was not reached.7 There were 11 deaths in the ibrutinib plus ri­tuximab cohort and 12 deaths in the 3-drug cohort.7 The efficacy data are shown in the Table.7,11


Adverse Events

The safety profile of ibrutinib plus rituximab is based on data from 352 patients with CLL or SLL who participated in the E1912 study.7 The median duration of treatment with ibrutinib plus rituximab was 34.3 months.7

In order of decreasing frequency, the most common (≥20%) adverse reactions of any grade observed among patients receiving ibrutinib plus rituximab were fatigue, musculoskeletal pain, diarrhea, rash, hypertension, arthralgia, headache, nausea, bruising, cough, hemorrhage, upper-respiratory infection, peripheral edema, pyrexia, pain, dyspnea, stomatitis, and dizziness.7

Grade 3 or higher adverse events that occurred more frequently with ibrutinib plus rituximab compared with fludarabine plus cyclophosphamide and rituximab included hypertension (19% vs 6%, respectively), musculoskeletal pain (5% vs 2%), arthralgia (5% vs 1%), diarrhea (4% vs 1%), abdominal pain (2% vs 1%), dyspnea (2% vs 1%), hemorrhage (2% vs 1%), pain (2% vs 0%), and vomiting (2% vs 0%).7

Drug Interactions

The coadministration of ibrutinib with a strong or moderate cytochrome (CY) P3A inhibitor increases ibrutinib’s plasma concentrations and the patient’s risk for drug-related toxicity.7 Concomitant use of strong CYP3A inhibitors with ibrutinib should be avoided.7

Coadministration of ibrutinib with strong CYP3A inducers should be avoided, because it can decrease ibrutinib’s concentrations.7

Ibrutinib has no contraindications.7

Use in Specific Populations

Ibrutinib can cause fetal harm. Female patients of reproductive potential should use effective contraception during treatment and for at least 1 month after the last dose of ibrutinib. Males should avoid fathering a child for at least 1 month after receiving the last dose of ibrutinib.7

Women should not breastfeed during treatment and for 1 week after receiving the final dose of ibrutinib.7

The safety and efficacy of ibrutinib have not been established in children.7

There were no differences observed in the effectiveness of ibrutinib compared with older (aged ≥65 years) and younger patients who participated in clinical trials. Among older patients who received treatment with ibrutinib, anemia (all grades), pneumonia (grade ≥3), thrombocytopenia, hypertension, and atrial fibrillation were observed more frequently than in younger patients.7

In patients with mild or moderate hepatic impairment (Child-Pugh class A and B), the modification of ibrutinib dosing is recommended. Treatment with ibrutinib should be avoided in patients with severe hepatic impairment (Child-Pugh class C). The drug’s safety has not been evaluated in patients with mild-to-severe hepatic impairment.7

Warnings and Precautions

Bleeding events have occurred in patients who received treatment with ibrutinib, with fatalities occurring in 0.4% of 2838 patients who have received ibrutinib in clinical trials.7

Fatal and serious cardiac arrhythmias have occurred with ibrutinib therapy. Higher rates of these complications have been observed in patients with cardiac risk factors, hypertension, acute infections, and a history of cardiac arrhythmias.7

Patients receiving ibrutinib should be monitored for hypertension and for cytopenias.7

Because fatal and nonfatal infections (bacterial, viral, or fungal) can occur, patients receiving ibrutinib who are at increased risk for opportunistic infections should be considered for prophylaxis according to standard of care.7

Tumor lysis syndrome has been reported with ibrutinib therapy. High tumor burden at baseline increases the risk for this syndrome.7

Second primary malignancies have also been documented in patients who received ibrutinib in clinical trials, most often nonmelanoma skin cancer (6%).7


The approval of ibrutinib plus rituximab as first-line treatment gives patients with CLL or SLL another chemotherapy-free induction regimen option and represents the eleventh indication for ibrutinib since its initial approval in 2012. This combination regimen demonstrated superior progression-free survival compared with fludarabine plus cyclophosphamide and rituximab in treatment-naïve patients with CLL or SLL.


  1. Cancer.Net. Leukemia - chronic lymphocytic - CLL: statistics. January 2020. Accessed June 22, 2020.
  2. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia: signs and symptoms. Accessed June 22, 2020.
  3. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia: chemotherapy and drug therapy. Accessed June 22, 2020.
  4. Cafasso J. Current and breakthrough treatments for CLL. Healthline. February 6, 2020. Accessed June 22, 2020.
  5. Pettijohn EM, Ma S. Targeted therapy in chronic lymphocytic leukemia (CLL). Curr Hematol Malig Rep. 2017;12:20-28.
  6. Imbruvica approval history. Accessed June 21, 2020.
  7. Imbruvica (ibrutinib) capsules/tablets, for oral use [prescribing information]. Sunnyvale, CA: Pharmacyclics; Horsham, PA: Janssen Biotech; April 2020.
  8. US Food & Drug Administration. FDA approves ibrutinib plus rituximab for chronic lymphocytic leukemia. April 21, 2020.­leukemia#:~:text=On%20April%2021%2C%202020%2C%20the,small%20lymphocytic%20lymphoma%20(SLL). Accessed June 21, 2020.
  9. Rituxan (rituximab) injection, for intravenous use [prescribing information]. South San Francisco, CA: Genentech; March 2020.
  10. PR Newswire. Imbruvica (ibrutinib) receives 11th FDA approval. April 21, 2020.­approval-301044668.html. Accessed June 21, 2020.
  11. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib–rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381:432-443.
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