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Ibrutinib in Combination With Obinutuzumab in Treatment-Naive CLL/SLL


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In the Clinic provides overviews of novel hematology and oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Early in 2019, ibrutinib was approved for use in combination with obinutuzumab in treatment-naive patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).1 This is the first approval of a nonchemotherapy combination regimen for treatment-naive patients with CLL/SLL.

The U.S. Food and Drug Administration also updated ibrutinib labeling to reflect long-term efficacy data supporting use of the agent as monotherapy in CLL/SLL, including approximately 5 years of follow-up from the phase III RESONATE and RESONATE-2 trials.

Supporting Efficacy Data

The current approval is based on findings in the open-label phase III iLLUMINATE trial,2 in which 229 patients were randomly assigned to receive ibrutinib at 420 mg daily (n = 113) or chlorambucil at 0.5 mg/kg on days 1 and 15 of each 28-day cycle for 6 cycles (n = 116), with both groups receiving obinutuzumab at 1,000 mg on days 1, 8, and 15 of the first cycle followed by treatment on the first day of 5 subsequent 28-day cycles. Patients were aged 65 years or older or younger than 65 years with coexisting medical conditions, reduced renal function (creatinine clearance < 70 mL/min), or the presence of a 17p deletion (del[17p]) or TP53 mutation. Patients with creatinine clearance ≤ 30 mL/min, aspartate transaminase or alanine transaminase ≥ 2.5 × upper limit of normal (ULN), or total bilirubin ≥ 1.5 × ULN (unless of nonhepatic origin) were excluded from the trial.

OF NOTE

Ibrutinib carries warnings/precautions for hemorrhage, infections, cytopenias, cardiac arrhythmia, hypertension, second primary malignancies, tumor-lysis syndrome, and embryofetal toxicity.

Patients had a median age of 71 years (range = 40–87 years), 64% were male, 96% were white, Eastern Cooperative Group Performance status was 0 in 48% and 1 or 2 in 52%, 214 had CLL and 15 had SLL, and 65% had high-risk factors (del[17p]/TP53 mutation in 18%, del[11q] in 15%, or unmutated immunoglobulin heavy-chain variable region in 54%). The most common reasons for initiating CLL therapy included lymphadenopathy (38%), night sweats (34%), progressive marrow failure (31%), fatigue (29%), splenomegaly (25%), and progressive lymphocytosis (21%).

Median follow-up was 31 months. On independent review committee assessment, median progression-free survival was not reached in the ibrutinib-plus-obinutuzumab group vs 19 months in the chlorambucil/obinutuzumab group (hazard ratio = 0.23, P < .0001). Among patients with high-risk disease, the hazard ratio for progression-free survival was 0.15 (95% confidence interval = 0.09–0.27). Overall response rates were 88.5%% vs 73.3%, with complete response in 19.5% vs 7.8%.

How It Works

Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK). The agent forms a covalent bond with a cysteine residue in the active site of BTK, leading to inhibition of BTK enzymatic activity.

BTK is a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways. BTK signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Preclinical studies have shown that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.

How It Is Used

The recommended dosage of ibrutinib in combination with obinutuzumab for CLL/SLL is 420 mg orally once daily until disease progression or unacceptable toxicity. The recommended dosage is 140 mg daily for patients with mild hepatic impairment and 70 mg daily for patients with moderate hepatic impairment. Use of the drug should be avoided in patients with severe hepatic impairment.

Product labeling provides information on stepwise dose reductions for recurrent adverse reactions and instructions on dose modification when ibrutinib is used with CYP3A inhibitors (eg, ketoconazole, clarithromycin, ciprofloxacin). Ibrutinib therapy should be interrupted for grade ≥ 3 nonhematologic toxicities, grade ≥ 3 neutropenia with infection or fever, and grade 4 hematologic toxicities.

Once toxicity has resolved to grade 1 or baseline, treatment may be reinitiated at the starting dose. If the toxicity reoccurs, the dose should be reduced by 140 mg/d, with a second reduction by 140 mg considered as needed. Treatment should be discontinued for toxicities that persist or recur after two dose reductions.

Safety Profile

The most common adverse events (≥ 20%) observed with ibrutinib in clinical trials in patients with B-cell malignancies have been thrombocytopenia, diarrhea, anemia, neutropenia, musculoskeletal pain, rash, bruising, nausea, fatigue, hemorrhage, and pyrexia.

The most common adverse events of any grade in the ibrutinib/obinutuzumab group in the iLLUMINATE trial were neutropenia (48% vs 64% in the chlorambucil/obinutuzumab group), thrombocytopenia (36% vs 28%), rash (36% vs 11%),

IBRUTINIB IN CLL/SLL

  • Ibrutinib was approved for use in combination with obinutuzumab in treatment-naive patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
  • The recommended dosage of ibrutinib in combination with obinutuzumab for CLL/SLL is 420 mg orally once daily until disease progression or unacceptable toxicity, with dosage modifications advised for hepatic impairment.

diarrhea (34% vs 10%), musculoskeletal pain (33% vs 23%), bruising (32% vs 3%), cough (27% vs 12%), infusion-related reaction (25% vs 58%), hemorrhage (25% vs 9%), and arthralgia (22% vs 10%). The most common grade ≥ 3 adverse events were neutropenia (39% vs 48%), thrombocytopenia (19% vs 11%), and pneumonia (9% vs 4%).

Among 781 patients receiving ibrutinib in 5 clinical trials in CLL/SLL (including iLLUMINATE), adverse events (including pneumonia, hemorrhage, atrial fibrillation, rash, and neutropenia) led to the discontinuation of treatment in 4% to 10% of patients and to dose reduction in approximately 7% of patients.

Ibrutinib carries 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. 

REFERENCES

1. Pharmacyclics, Janssen Biotech: Imbruvica (ibrutinib) capsules prescribing information, January 2019. Available at www.imbruvicahcp.com. Accessed May 7, 2019.

2. 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 20:43-56, 2019.


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