Obinutuzumab
Regulatory sources consulted
Approved indications
- Previously untreated chronic lymphocytic leukemia in combination with chlorambucil.
- Follicular lymphoma relapsed after or refractory to a rituximab-containing regimen, with bendamustine followed by obinutuzumab monotherapy; and untreated adult bulky Stage II, III, or IV follicular lymphoma, with chemotherapy followed by monotherapy after at least a partial response.
- Active lupus nephritis in adults receiving standard therapy.
Contraindications
Absolute
- Known hypersensitivity, including anaphylaxis, to obinutuzumab or its excipients, or prior serum sickness with obinutuzumab.
Clinical warnings
- Boxed warning · It can reactivate hepatitis B virus and cause fulminant hepatitis, liver failure, and death. Screen with HBsAg and anti-HBc before treatment; monitor current or prior infection and discontinue obinutuzumab and concomitant chemotherapy if reactivation occurs. — DailyMed, GAZYVA set_id df12ceb2-5b4b-4ab5-a317-2a36bf2a3cda
- Boxed warning · It can cause fatal progressive multifocal leukoencephalopathy. Evaluate any new or changing neurologic manifestation and discontinue if PML is diagnosed. — DailyMed, GAZYVA set_id df12ceb2-5b4b-4ab5-a317-2a36bf2a3cda
- Major warning · It can cause serious or fatal infusion reactions, hypersensitivity or serum sickness, tumor lysis syndrome, serious infections, neutropenia, thrombocytopenia, and disseminated intravascular coagulation. Premedicate, monitor, and modify or discontinue according to severity. — DailyMed, GAZYVA set_id df12ceb2-5b4b-4ab5-a317-2a36bf2a3cda
- Major warning · Avoid live-virus vaccines during treatment and until B-cell recovery. — DailyMed, GAZYVA set_id df12ceb2-5b4b-4ab5-a317-2a36bf2a3cda
Adverse events
Common (≥1%)
infusion-related reaction · neutropenia · fatigue · cough · upper respiratory tract infection · musculoskeletal pain · constipation · diarrhea · COVID-19 · urinary tract infection · bronchitis · pneumonia
Rare but serious
fatal HBV reactivation · fatal progressive multifocal leukoencephalopathy · fatal infusion reaction · disseminated intravascular coagulation
Pregnancy and lactation
It can cause fetal B-cell depletion. Use contraception during treatment and for 6 months afterward. Do not breastfeed during treatment or for 6 months afterward. In infants exposed in utero, avoid live vaccines until B-cell recovery is confirmed.
Recent literature (PubMed)
Obinutuzumab, a humanized type II anti-CD20 monoclonal antibody, provided significantly better renal responses than placebo in a phase 2 trial involving patients with lupus nephritis receiving standard therapy. In a phase 3, randomized, controlled trial, we assigned adults with biopsy-proven active lupus nephritis in a 1:1 ratio to receive obinutuzumab in one of two dose schedules (1000 mg on day 1 and at weeks 2, 24, 26, and 52, with or without a dose at week 50) or placebo. All patients received standard therapy with mycophenolate mofetil, along with oral prednisone at a target dose of 7.5 mg per day by week 12 and 5 mg per day by week 24. The primary end point was a complete renal response at week 76, defined by a urinary protein-to-creatinine ratio of less than 0.5 (with protein and creatinine both measured in milligrams), an estimated glomerular filtration rate of at least 85% of the baseline value, and no intercurrent event (i.e., rescue therapy, treatment failure, death, or early trial withdrawal). Key secondary end points at week 76 included a complete renal response with a prednisone dose of 7.5 mg per day or lower between weeks 64 and 76 and a urinary protein-to-creatinine ratio lower than 0.8 without an intercurrent event. A total of 271 patients underwent randomization; 135 were assigned to the obinutuzumab group (combined dose schedules) and 136 to the placebo group. A complete renal response at week 76 was observed in 46.4% of the patients in the obinutuzumab group and 33.1% of those in the placebo group (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 2.0 to 24.8; P = 0.02). A complete renal response at week 76 with a prednisone dose of 7.5 mg per day or lower between weeks 64 and 76 was observed in more patients in the obinutuzumab group than in the placebo group (42.7% vs. 30.9%; adjusted difference, 11.9 percentage points; 95% CI, 0.6 to 23.2; P = 0.04), and a urinary protein-to-creatinine ratio lower than 0.8 without an
Whether fixed-duration acalabrutinib-venetoclax (with or without obinutuzumab) would result in better progression-free survival than chemoimmunotherapy in patients with untreated chronic lymphocytic leukemia (CLL) is unknown. In this phase 3, open-label trial, we included patients 18 years of age or older who had an Eastern Cooperative Oncology Group performance-status score of 0 to 2 (range, 0 to 5, with higher numbers indicating greater disability) and who did not have a 17p deletion or TP53 mutation. Patients were randomly assigned, in a 1:1:1 ratio, to receive acalabrutinib-venetoclax (acalabrutinib, cycles 1 to 14; venetoclax, cycles 3 to 14), acalabrutinib-venetoclax-obinutuzumab (as above, plus obinutuzumab, cycles 2 to 7), or chemoimmunotherapy with the investigator's choice of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab (cycles 1 to 6). The primary end point was progression-free survival (acalabrutinib-venetoclax vs. chemoimmunotherapy) in the intention-to-treat population, assessed by blinded independent central review. A total of 867 patients underwent randomization: 291 were assigned to receive acalabrutinib-venetoclax, 286 acalabrutinib-venetoclax-obinutuzumab, and 290 chemoimmunotherapy (of whom 143 received fludarabine-cyclophosphamide-rituximab and 147 bendamustine-rituximab). The median age of the patients was 61 years (range, 26 to 86), 64.5% were men, and 58.6% had unmutated IGHV. Estimated 36-month progression-free survival at a median follow-up of 40.8 months was 76.5% with acalabrutinib-venetoclax, 83.1% with acalabrutinib-venetoclax-obinutuzumab, and 66.5% with chemoimmunotherapy (hazard ratio for disease progression or death with acalabrutinib-venetoclax vs. chemoimmunotherapy, 0.65 [95% confidence interval {CI}, 0.49 to 0.87], P = 0.004; for the comparison of acalabrutinib-venetoclax-obinutuzumab with chemoimmunotherapy, P<0.001). Estimated 36-month overall survival was 94.1% with acalabrutinib-venetoclax, 87.7% with aca
- Chronic Lymphocytic Leukemia: 2025 Update on the Epidemiology, Pathogenesis, Diagnosis, and Therapy.
Chronic lymphocytic leukemia (CLL) is the most frequent type of leukemia. It typically occurs in older patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that interfere with the regulation of proliferation and apoptosis in clonal B-cells. The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B-lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen as well as typical B-cell markers. Two clinical staging systems, Rai and Binet, provide prognostic information by using the results of physical examination and blood counts. Various biological and genetic markers provide additional prognostic information. Deletions of the short arm of chromosome 17 (del(17p)) and/or mutations of the TP53 gene predict a shorter time to progression with most targeted therapies. The CLL international prognostic index (CLL-IPI) integrates genetic, biological, and clinical variables to identify distinct risk groups of patients with CLL. The CLL-IPI retains its significance in the era of targeted agents, but the overall prognosis of CLL patients with high-risk stages has improved. Only patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. When treatment is indicated, several therapeutic options exist: combinations of the BCL2 inhibitor venetoclax with obinutuzumab, or venetoclax with ibrutinib, or monotherapy with one of the inhibitors of Bruton tyrosine kinase (BTK). At relapse, the initial treatment may be repeated if the treatment-free interval exceeds 3 years. If the leukemia relapses earlier, therapy should be changed using an alternative regimen. Combinations of targeted agents now provide efficient therapies with a fixed duration that generate deep and durable remissions. These fixed-duration therapies have gained territory in the management of CLL, as they are cost-effective, avoid the emergence of resistance
In the CLL14 study, patients with previously untreated chronic lymphocytic leukemia (CLL) and coexisting conditions were randomized to 12 cycles of venetoclax-obinutuzumab (Ven-Obi, n = 216) or chlorambucil-obinutuzumab (Clb-Obi, n = 216). Progression-free survival (PFS) was the primary end point. Key secondary end points included time-to-next-treatment (TTNT), rates of undetectable minimal residual disease (uMRD), overall survival (OS), and rates of adverse events. Patient reported outcomes of time until definitive deterioration (TUDD) in quality of life (QoL) were analyzed. At a median observation time of 76.4 months, PFS remained superior for Ven-Obi compared with Clb-Obi (median, 76.2 vs 36.4 months; hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.31-0.52; P < .0001). Likewise, TTNT was longer after Ven-Obi (6-year TTNT, 65.2% vs 37.1%; HR, 0.44; 95% CI, 0.33-0.58; P < .0001). In the Ven-Obi arm, presence of del(17p), unmutated immunoglobulin heavy-chain variable region, and lymph node size of ≥5 cm were independent prognostic factors for shorter PFS. The 6-year OS rate was 78.7% in the Ven-Obi and 69.2% in the Clb-Obi arm (HR, 0.69; 95% CI, 0.48-1.01; P = .052). A significantly longer TUDD in global health status/QoL was observed in the Ven-Obi than in the Clb-Obi arm (median, 82.1 vs 65.1 months; HR, 0.70; 95% CI, 0.51-0.97). Follow-up-adjusted second primary malignancies incidence rates were 2.3 and 1.4 per 1000 patient-months in the Ven-Obi and Clb-Obi arm, respectively. The sustained long-term survival and QoL benefits support the use of 1-year fixed-duration Ven-Obi in CLL. This trial was registered at www.ClinicalTrials.gov as #NCT02242942.
TP53-mutant mantle cell lymphoma (MCL) is associated with poor survival outcomes with standard chemoimmunotherapy. We conducted a multicenter, phase 2 study of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in untreated patients with MCL with a TP53 mutation. Patients initially received 160 mg zanubrutinib twice daily and obinutuzumab. Obinutuzumab at a dose of 1000 mg was given on cycle 1 day 1, 8, and 15, and on day 1 of cycles 2 to 8. After 2 cycles, venetoclax was added with weekly dose ramp-up to 400 mg daily. After 24 cycles, if patients were in complete remission with undetectable minimal residual disease (uMRD) using an immunosequencing assay, treatment was discontinued. The primary end point was met if ≥11 patients were progression free at 2 years. The study included 25 patients with untreated MCL with a TP53 mutation. The best overall response rate was 96% (24/25) and the complete response rate was 88% (22/25). Frequency of uMRD at a sensitivity level of 1 × 10-5 and uMRD at a sensitivity level of 1 × 10-6 at cycle 13 was 95% (18/19) and 84% (16/19), respectively. With a median follow-up of 28.2 months, the 2-year progression-free, disease-specific, and overall survival were 72%, 91%, and 76%, respectively. Common side effects were generally low grade and included diarrhea (64%), neutropenia (32%), and infusion-related reactions (24%). BOVen was well tolerated and met its primary efficacy end point in TP53-mutant MCL. These data support its use and ongoing evaluation. This trial was registered at www.ClinicalTrials.gov as #NCT03824483.