CLL occurs when the majority of cancer cells are located in the bloodstream and bone marrow, whereas SLL occurs when the cancer cells are concentrated in the lymph nodes.2 CLL and SLL are more frequently diagnosed in men than in women.3 CLL occurs most frequently in older patients, with a median onset age of 70 years.4
Based on Surveillance, Epidemiology, and End Results Program data from 2012 to 2016, the number of new cases of CLL or SLL was 4.5 per 100,000 men and women annually, and the number of deaths was 1 per 100,000 men and women annually.5 In addition, 20,720 people are estimated to be diagnosed with CLL in 2019, and an estimated 3930 people will die from the disease.3
CLL and SLL are considered slow-growing cancers; therefore, people can live a long time before requiring any treatment. However, with time, these cancers can grow aggressively.1 Typical pharmacologic therapies for CLL or SLL include targeted drugs, such as venetoclax (Venclexta); chemotherapy, such as chlorambucil or bendamustine (Treanda, Bendeka); monoclonal antibodies, such as rituximab (Rituxan); or a combination of these agents.6
Imbruvica plus Gazyva New First-Line Combination for CLL or SLL
On January 28, 2019, the US Food and Drug Administration (FDA) approved ibrutinib (Imbruvica; Pharmacyclics/Janssen Biotech) in combination with obinutuzumab (Gazyva; Genentech) for the treatment of adults with untreated CLL or SLL.7 This is the first approval of a nonchemotherapy combination regimen for the first-line treatment of patients with CLL or SLL.7
“This latest Imbruvica FDA approval gives the healthcare community the first chemotherapy-free, anti-CD20 combination to treat CLL and SLL patients who have not yet started therapy,” said Carol Moreno, MD, PhD, Consultant Hematologist, Hospital de la Santa Creu Sant Pau, Autonomous University of Barcelona, Spain, and lead investigator of the iLLUMINATE study. “This new treatment combination helps reduce the need for chemotherapy,” she noted.7
Ibrutinib was initially approved as a single agent for the treatment of other blood malignancies, including mantle-cell lymphoma, CLL or SLL with deletion 17p, Waldenström’s macroglobulinemia, and marginal-zone lymphoma. Ibrutinib is also approved for the treatment of patients with chronic graft-versus-host disease.8 Obinutuzumab is approved as a single agent for the treatment of CLL or follicular lymphoma.9
Mechanism of Action
Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), which is a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways. Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to the inhibition of BTK enzymatic activity. Preclinical studies showed that ibrutinib inhibits malignant B-cell proliferation and survival, as well as cell migration and substrate adhesion.8
Obinutuzumab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of B lymphocytes. When binding to CD20, obinutuzumab facilitates B-cell lysis.9
Dosing and Administration
The recommended dosage of ibrutinib for CLL or SLL, in combination with obinutuzumab, is 420 mg orally once daily until disease progression or until unacceptable toxicity.8
Ibrutinib tablets or capsules should be administered orally with water once daily at approximately the same time each day.8
When administered in combination with obinutuzumab, ibrutinib should be used before obinutuzumab.8 Obinutuzumab should be administered intravenously as 100 mg on day 1 and 900 mg on day 2 of cycle 1, 1000 mg on days 8 and 15 of cycle 1, and 1000 mg on day 1 of cycles 2 to 6.9
Pivotal Clinical Trial: iLLUMINATE
The FDA based its approval of the combination of ibrutinib plus obinutuzumab on the results of the phase 3, randomized, open-label iLLUMINATE clinical trial, which included 214 patients with CLL and 15 patients with SLL.8,10 The median patient age was 71 years. The majority of patients were male (64%); were white (96%); had CLL or SLL with high-risk factors, such as del17p or TP53 mutation, del11q, or immunoglobulin heavy-chain variable region without mutation; and had an Eastern Cooperative Oncology Group performance score of 0 to 2 (100%).8,10
The patients were randomized in a 1:1 ratio to ibrutinib 420 mg daily or to chlorambucil 0.5 mg/kg on days 1 and 15 of each 28-day cycle for 6 cycles.8,10 In both arms, patients received 1000 mg of obinutuzumab on days 1, 8, and 15 of the first cycle and then on the first day of the next 5 subsequent cycles. The first dose of obinutuzumab was divided between day 1 (100 mg) and day 2 (900 mg).8
After a median follow-up of 31 months, the median progression-free survival was not estimable in the ibrutinib plus obinutuzumab group versus 19 months (95% confidence interval, 15.1-22.1) in the chlorambucil plus obinutuzumab group. Ibrutinib plus obinutuzumab reduced the risk for disease progression or death by 77% compared with chlorambucil plus obinutuzumab.10 In addition, the overall response rate was 88.5% in the ibrutinib plus obinutuzumab group versus 73.3% in the chlorambucil plus obinutuzumab group (Table).8
The most common (≥20%) all-grade adverse reactions in patients with CLL or SLL who received ibrutinib plus obinutuzumab were neutropenia (48%), rash (36%), thrombocytopenia (36%), diarrhea (34%), musculoskeletal pain (33%), bruising (32%), cough (27%), infusion-related reaction (25%), hemorrhage (25%), and arthralgia (22%).8
The most common (>5%) grade 3 or 4 adverse events with ibrutinib plus obinutuzumab were neutropenia (39%), thrombocytopenia (19%), pneumonia (9%), and atrial fibrillation (5%).8
Overall, 1 patient in the ibrutinib plus obinutuzumab group and 1 patient in the chlorambucil plus obinutuzumab group died as a result of treatment-related adverse events.10
Ibrutinib has no contraindications.8 Obinutuzumab is contraindicated in patients with known hypersensitivity reactions to obinutuzumab or to any of its excipients.9
The coadministration of ibrutinib with strong or moderate cytochrome (CY)P3A inhibitors may increase ibrutinib plasma concentrations, thereby increasing the risk for drug-related adverse events.8 The concomitant use of ibrutinib with other strong CYP3A inhibitors should be avoided. Grapefruit and Seville oranges contain strong or moderate inhibitors of CYP3A and should thus be avoided during treatment with ibrutinib.8
The coadministration of ibrutinib with strong CYP3A inducers can decrease ibrutinib concentrations and should be avoided.8
Obinutuzumab has no drug interactions.9
Use in Specific Patient Populations
Ibrutinib can cause fetal harm. Pregnant women should be informed about the potential hazards to the fetus and should have a pregnancy test before starting ibrutinib therapy.8 Women of reproductive potential should avoid pregnancy while taking ibrutinib and for up to 1 month after stopping treatment. Men should avoid fathering a child while receiving ibrutinib and for 1 month after the last dose.8
There are no data regarding the presence of ibrutinib in human milk, its effects on the breastfed child, or the effects on milk production.8
The safety and effectiveness of ibrutinib have not been established in pediatric patients.8
Anemia, pneumonia, thrombocytopenia, hypertension, and atrial fibrillation were more common among older patients than younger patients who received ibrutinib.8
Ibrutinib should not be used in patients with severe hepatic impairment. The dose of ibrutinib should be reduced in patients with mild or moderate hepatic impairment.8
Warnings and Precautions
Fatal bleeding events have occurred with ibrutinib. Ibrutinib may increase the risk for bleeding in patients who receive antiplatelet or anticoagulant therapies.8
Fatal and nonfatal infections have occurred with ibrutinib therapy.8
Treatment-emergent grade 3 or 4 cytopenia, including neutropenia, thrombocytopenia, and anemia, has occurred in patients who received ibrutinib.8
Fatal and serious cardiac arrhythmias have occurred with ibrutinib therapy; therefore, patients should be monitored for cardiac arrhythmias.8
Because hypertension has occurred with ibrutinib treatment, patients’ blood pressure should be monitored during treatment.8
Second primary malignancies have occurred after ibrutinib therapy, including nonmelanoma skin cancer.8
Tumor lysis syndrome has been reported with ibrutinib therapy.8
The FDA approval of the combination of ibrutinib plus obinutuzumab represents the first chemotherapy-free combination available for the first-line treatment of patients with newly diagnosed CLL or SLL, regardless of the presence of high-risk conditions.
In the iLLUMINATE clinical trial that led to the approval of the combination of ibrutinib plus obinutuzumab, this chemotherapy-free anti-CD20 combination regimen significantly improved progression-free survival and reduced mortality risk compared with the chemotherapy-containing combination of chlorambucil plus obinutuzumab.
- Lymphoma Research Foundation. About lymphoma: chronic lymphocytic leukemia/small lymphocytic lymphoma. www.lymphoma.org/aboutlymphoma/cll/. Accessed May 15, 2019.
- American Cancer Society. Types of B-cell lymphoma. Revised January 29, 2019. www.cancer.org/cancer/non-hodgkin-lymphoma/about/b-cell-lymphoma.html. Accessed May 15, 2019.
- National Cancer Institute. SEER cancer stat facts: leukemia-chronic lymphocytic leukemia (CLL). https://seer.cancer.gov/statfacts/html/clyl.html. Accessed May 22, 2019.
- Shanafelt T. Treatment of older adults with chronic lymphocytic leukemia: key questions and current answers. Hematology Am Soc Hematol Edu Program. 2013;2013:158-167.
- National Cancer Institute. SEER cancer stat facts: NHL-chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). https://seer.cancer.gov/statfacts/html/cllsll.html. Accessed May 22, 2019.
- National Cancer Institute. Drugs approved for non-Hodgkin lymphoma. www.cancer.gov/about-cancer/treatment/drugs/non-hodgkin. Accessed May 24, 2019.
- AbbVie. AbbVie announces U.S. FDA approval of Imbruvica (ibrutinib) plus obinutuzumab (Gazyva)-first chemotherapy-free, anti-CD20 combination regimen approved for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in previously untreated patients. January 28, 2019. https://news.abbvie.com/news/abbvie-announces-us-fda-approval-imbruvica-ibrutinib-plus-obinutuzumab-gazyva--first-chemotherapy-free-anti-cd20-combination-regimen-approved-for-chronic-lymphocytic-leukemiasmall-lymphocytic-lymphoma-cllsll-in-previously-untreated-pati.htm. Accessed May 17, 2019.
- Imbruvica (ibrutinib) capsules/tablets, for oral use [prescribing information]. Sunnyvale, CA: Pharmacyclics; Horsham, PA: Janssen Biotech; January 2019.
- Gazyva (obinutuzumab) injection, for intravenous use [prescribing information]. South San Francisco, CA: Genentech; November 2017.
- Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:43-56. Erratum in: Lancet Oncol. 2019;20:e10.