Obinutuzumab: Effect in chronic lymphocytic leukemia

Obinutuzumab (trade name Gazyvaro) is a humanized monoclonal Anti CD20 antibody of the second generation, developed by Swiss company Roche. Compared to its predecessor Rituximab, the structure was optimized through glycoengineering, so that antibody dependent cellular cytotoxicity (ADCC) is significantly enhanced. In Germany, Obinutuzumab has been approved since 2014 and is used in hematooncology as an important therapy for chronic lymphocytic leukemia (CLL) and follicular lymphoma. The substance is part of modern therapy regimens in combination with chemotherapy or targeted therapies such as Venetoclax.

Obinutuzumab has demonstrated in clinical trials such as CLL11 and GALLIUM a significant prolongation of progression free survival compared to Rituximab based regimens. Today Obinutuzumab is an integral part of CLL standard therapy in combination with Venetoclax or with Chlorambucil in elderly patients with comorbidities. Administration occurs exclusively in specialized hematologic oncology centers due to therapy complexity and potentially severe infusion reactions.

Mechanism of action

Obinutuzumab is a humanized glycomodified monoclonal antibody of the IgG1 subclass that binds specifically to the CD20 antigen on the surface of mature B lymphocytes. CD20 is a membrane bound protein expressed on healthy B cells as well as on most malignant B cell clones, including CLL cells and lymphoma cells. The binding results in several cellular effects that contribute to death of CD20 positive B cells.

Obinutuzumab belongs to the type 2 Anti CD20 antibodies and primarily triggers direct cell death like effects through activation of intracellular signaling pathways. Furthermore, binding leads to antibody dependent cellular cytotoxicity (ADCC) by natural killer cells and macrophages and to antibody dependent phagocytosis. Complement dependent cytotoxicity (CDC) is less pronounced compared to Rituximab. The optimized glycosylation of the Fc region enhances binding to Fcγ III receptors on effector cells, resulting in stronger ADCC.

Pharmacokinetically, Obinutuzumab is released into the circulation after intravenous administration and distributes primarily extracellularly. The elimination half life is approximately 30 days, so that drug levels persist in the body for a long time even after therapy ends. B cell depletion remains effective for months, which clinically leads to sustained tumor control, but can also increase infection risk due to hypogammaglobulinemia.

Indications

• Chronic lymphocytic leukemia (CLL) first line therapy in combination with Chlorambucil in elderly patients and patients with comorbidities
• CLL first line therapy in combination with Venetoclax, a targeted therapy with fixed therapy duration (usually 12 months)
• Follicular lymphoma first line therapy in combination with chemotherapy such as CHOP, CVP or Bendamustine, followed by maintenance therapy
• Relapsed follicular lymphoma in combination with Bendamustine and subsequent maintenance therapy
• Other CD20 positive B cell lymphomas in specific indications, often in study context

Obinutuzumab is administered in specialized hematologic oncology centers with experience in treating B cell lymphomas. Indication is determined according to S3 guidelines and taking into account patient characteristics and genetic risk factors such as del(17p) status or TP53 mutation.

Dosage and administration

CLL in combination with Chlorambucil: Cycle 1 day 1, 100 mg intravenously, day 2, 900 mg, day 8, 1000 mg, day 15, 1000 mg. Subsequently cycles 2 through 6, each 1000 mg on day 1 every 28 days.

CLL in combination with Venetoclax: similar dosing schedule, followed by 12 months Venetoclax.

Follicular lymphoma induction therapy: 1000 mg on days 1, 8, 15 of cycle 1, then 1000 mg on day 1 in cycles 2 through 6 or 8.

Maintenance therapy follicular lymphoma: 1000 mg every 2 months for up to 2 years.

Administration: exclusively intravenously as infusion over several hours. Begin first infusion slowly, increase infusion rate according to tolerance. The split first dose (100 mg on day 1, 900 mg on day 2) reduces the risk of severe infusion reactions.

Premedication: Glucocorticoid, Paracetamol and antihistamine before each infusion to reduce infusion reactions. In case of tumor burden risk additionally tumor lysis syndrome prophylaxis with Allopurinol or Rasburicase.

Renal insufficiency: with mild and moderate impairment no specific adjustment. Hepatic insufficiency: limited data, individual assessment.

Side effects

Very common: Infusion reactions (especially at the first infusion), neutropenia, thrombocytopenia, anemia, infections (pneumonia, bronchitis, urinary tract infections, viral infections), cough, diarrhea, nausea, fever, fatigue, headache.

Common: Hepatitis B reactivation, elevated liver values, weight loss, sleep disturbance, skeletal muscle pain, pruritus, skin rash.

Occasional to rare: Tumor lysis syndrome especially with high tumor burden in CLL, severe infusion reactions with anaphylaxis, bronchospasm, hypotension, cardiovascular events, progressive multifocal leukoencephalopathy (PML, very rare), interstitial lung disease.

Important: Hepatitis B screening mandatory before therapy initiation. With positive serology antiviral prophylaxis or therapy. Reactivation can be fatal.

Long term consequences: Hypogammaglobulinemia with increased infection risk, possibly substitution therapy. Live vaccines contraindicated.

Drug interactions

• Other immunosuppressants and cytostatics: additive bone marrow depression and infection risk, physician monitoring.
• Live vaccines: contraindicated during therapy and some months thereafter due to increased infection risk.
• Inactivated vaccines: effectiveness significantly reduced. Vaccinations if possible before therapy initiation.
• Antihypertensives: caution during infusion due to hypotension risk, possibly pause.
• Antibiotics and antiviral prophylaxis: comedication against opportunistic infections reasonable, physician instructions.
• Bendamustine, Chlorambucil, Venetoclax: combined use according to therapy protocol.

Special precautions

Pregnancy: contraindicated in pregnancy because monoclonal antibodies cross the placenta and can trigger fetal B cell depletion. Effective contraception during and at least 18 months after therapy. Breast feeding: contraindicated.

Children: Safety and effectiveness in children and adolescents not established.

Contraindications: known hypersensitivity, active severe infection, severe Hepatitis B infection without adequate therapy.

Before therapy: Hepatitis B serology, HIV status, tuberculosis exclusion, echocardiogram, EKG, detailed blood count, estimate tumor lysis syndrome risk, check vaccination status, booster vaccinations before initiation.

During therapy: regular blood count monitoring, liver values, Hepatitis B serology, clinical progress monitoring. Inform patient about symptoms such as fever, shortness of breath, unusual fatigue.

Lifestyle: Infection protection with hygiene, update vaccination status before therapy, no live vaccine during therapy. With symptoms of infection early physician presentation.

Driving ability: Therapy itself does not directly impair, however fatigue, dizziness and infusion reactions can reduce reaction ability.

You might also be interested in

• Rituximab, Anti CD20 antibody of the first generation
• Venetoclax, BCL2 inhibitor in CLL therapy
• Ibrutinib, BTK inhibitor in CLL therapy
• Bendamustine, chemotherapeutic agent in B cell lymphomas
• Teclistamab, bispecific antibody in multiple myeloma

Frequently asked questions

Sources

• Gelbe Liste, Obinutuzumab drug profile
• BfArM, Federal Institute for Drugs and Medical Devices
• German Society for Hematology and Medical Oncology (DGHO)
• AWMF S3 Guidelines for CLL and follicular lymphoma
• European Medicines Agency, EPAR Gazyvaro