On April 21, 2020, ibrutinib was granted an expanded indication for use in combination with rituximab for the initial treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).^1,2

The recommended dosage of ibrutinib in CLL/SLL is 420 mg, once daily, until disease progression or unacceptable toxicity.

Supporting Efficacy Data

Approval was based on findings in the phase III E1912 trial (ClinicalTrials.gov identifier NCT02048813).^2,3 In the open-label trial, 529 patients aged ≤ 70 years were randomly assigned 2:1 to receive ibrutinib plus rituximab (n = 354) or fludarabine, cyclophosphamide, and rituximab (FCR; n = 175). Patients with 17p deletion were excluded from the trial.

Ibrutinib was administered at 420 mg daily until disease progression or unacceptable toxicity. Fludarabine, 25 mg/m², and cyclophosphamide, 250 mg/m², were both given on days 1, 2, and 3 of cycles 1 to 6. Rituximab was started in cycle 2 in the ibrutinib/rituximab group and in cycle 1 in the FCR group and was given at 50 mg/m² on day 1 of the first cycle, at 325 mg/m² on day 2 of the first cycle, and at 500 mg/m² on day 1 of 5 subsequent cycles for a total of 6 cycles. Each cycle lasted 28 days.

Median patient age was 58 years (range = 28–70 years), 67% were male, 90% were white, and 98% had an Eastern Cooperative Oncology Group performance status of 0 or 1. Additionally, 43% had Rai stage 3 or 4 disease, and 59% had high-risk factors, including TP53 mutation in 6%, del(11q) in 22%, and unmutated IGHV in 53%.

After a median follow-up of 37 months, progression-free survival events had occurred in 12% of the ibrutinib/rituximab group vs 25% of the FCR group (hazard ratio for progression-free survival = 0.34, P < .0001). Median progression-free survival was not reached in either group.

Safety Profile

The most common adverse events of any grade (≥ 30%) in patients with CLL/SLL receiving ibrutinib in clinical trials have been thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea.

In the E1912 trial, the most common adverse events of any grade in the ibrutinib/rituximab group were fatigue (80% vs 78% in the FCR group), musculoskeletal pain (61% vs 35%), diarrhea (53% vs 27%), rash (49% vs 29%), hypertension (42% vs 22%), arthralgia (41% vs 10%), nausea (40% vs 64%), headache (40% vs 27%), bruising (36% vs 4%), cough (32% vs 25%), and hemorrhage (31% vs 8%). The most common grade ≥ 3 adverse events were hypertension, musculoskeletal pain, and arthralgia. The most common grade 3 or 4 laboratory abnormalities were decreased neutrophils (30% vs 44%) and decreased platelets (7% vs 25%).

Ibrutinib has warnings/precautions for hemorrhage, infections, cytopenias, cardiac arrhythmia, hypertension, second primary malignancies (including skin cancers and other carcinomas), tumor-lysis syndrome, and embryofetal toxicity. Patients must be monitored for bleeding, fever and infection, blood pressure, and symptoms of arrhythmia. Complete blood cell counts should be monitored monthly. Baseline risk for tumor-lysis syndrome should be assessed and precautions taken. Patients should be advised not to breastfeed while taking ibrutinib.

REFERENCES

1. U.S. Food and Drug Administration: FDA approves ibrutinib plus rituximab for chronic lymphocytic leukemia. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-ibrutinib-plus-rituximab-chronic-lymphocytic-leukemia. Accessed May 6, 2020.

2. U.S. Food and Drug Administration: Highlights of prescribing information for Imbruvica (ibrutinib) capsules. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/205552s030,210563s006lbl.pdf. Accessed May 6, 2020.

3. Shanafelt TD, Wang XV, Kay NE, et al: Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med 381:432-443, 2019.