• Drug Name: Glofitamab-gxbm
• Brand Name: Columvi
• Date of FDA Approval: 15th June 2023 [Ref]
• Manufacturer's Name: Genentech, Inc.
• Primary Indications: Diffuse Large B-Cell Lymphoma

Glofitamab-gxbm is a chemotherapeutic drug, a humanized IgG1 monoclonal antibody that targets CD20 and CD3ɛ receptors. It is also known as a bispecific CD20-directed CD3 T-cell engager.

Primary Indications of COLUMVI:

Relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS)

Large B-cell lymphoma (LBCL) developed from follicular lymphoma after two or more lines of systemic therapy.

COLUMVI should be used only in patients who have failed to respond to or are intolerant to two or more lines of systemic therapy.

Columvi (Glofitamab-gxbm) Dose:

Important dosing information for better tolerability and greater efficacy:

Administer COLUMVI only via a dedicated line (separate infusion line)through a sterile 0.2-micron in-line filter.

It should be administered in a healthcare setting where facilities are available to manage all kinds of emergencies including CRS (cytokine release syndrome), preferably in a hospital. In addition, the patient should remain admitted in the hospital for 24 hours following the infusion of step-up dose 1 that is administered on day 8 (cycle 1, dose 2.5 mg).

If the patient develops CRS after step-up dose 1 on day 8 of cycle 1, hospital admission will be necessary during the subsequent dose escalation (step-up dose 2 (10 mg on Cycle 1, Day 15). Also, keep in mind that patients who do not develop CRS after the first step-up dose are not immune to developing CRS during subsequent dose escalation.

Pretreatment with Obinutuzumab:

Before the treatment is initiated, all patients receive a single 1,000 mg dose of obinutuzumab intravenously as an infusion on Day 1 of Cycle 1 which is basically 7 days before the start of Columvi treatment. Obinutuzumab is administered to deplete all circulating lymphoid B cells.

COLUMVI Step-up Dose Schedule:

This is a 21-day dosing schedule.

• Cycle 1:
  • Day 1: Administer Obinutuzumab intravenously as an IV infusion over 4 hours. Premedicate the patient before the infusion.
  • Day 8: 2.5 mg (step-up dose 1) intravenously administered over 4 hours
  • Day 15: 10 mg (step-up dose 2) IV administered over 4 hours. However, if the patient developed CRS during the first infusion, this dose should be administered over 8 hours.
• Cycle 2: Cycle 2 is initiated after a total of 21 days. The dose is given only on Day 1 of Cycle 2 as a 30 mg intravenous infusion over 4 hours. However, the infusion time may be extended to 8 hours in patients who have had CRS due to prior therapy.
• Cycle 3: Day 1 of Cycle 3 starts after 21 days of Cycle 2. The dose is 30 mg over 2 hours but may be extended to 4 hours if there is a history of prior CRS.

A total of 12 cycles are administered or unit the disease progresses despite the therapy or the patient is unable to tolerate further doses whichever comes first.

Delayed or Missed Doses:

If Obinutuzumab has been administered and Columvi dose has not been given on Day 8 or delayed, then follow the schedule given below:

• After Obinutuzumab, the delay has been less than 14 days, administer Columvi in a dose of 2.5 mg and continue the schedule from that day onwards as usual.
• If, however, there has been a delay of more than 14 days, then restart the whole cycle. Administer Obinutuzumab 1000 mg followed by Columvi on Day 8, and so on. 

If the patient receives Obinutuzumab and the first dose of Columvi on Day 8 but then misses the second dose, follow the schedule given below:

• If the delay has been less than 2 weeks, administer the second dose (10 mg) and continue the schedule from that day onwards.
• If the delay has been more than 2 weeks but less than 4 weeks, restart the cycle from Day 8 of Cycle 1, that is repeat the 2.5 mg dose and then continue the schedule as usual.
• If the delay has been more than 4 weeks, then restart from Obinutuzumab, followed by 2.5 mg Columvi on day 8, and then the second dose.

If the patient has received the complete one cycle (including Obinutuzumab and 2 doses of Columvi), but there has been a delay in starting the second cycle, then follow the schedule given below:

• If there is a delay of fewer than 2 weeks, then administer 30 mg Columvi (Day 1 Cycle 2) and resume the schedule from there.
• If there has been a delay in starting the second cycle of 2 - 6 weeks, then repeat the 10 mg dose (Cycle 1 Day 15) and resume the cycle thereafter
• If there has been a delay of more than 6 weeks in starting the second cycle, then start from the beginning. Administer Obinutuzumab, followed by 2.5 mg Columvi, and 10 mg Columvi on the recommended days, and then continue with the second cycle.

From Cycle 2 onwards, if there has been a delay of less than 6 weeks, then resume with the 30 mg dose and continue. However, if there has been a delay of more than 6 weeks, then restart all the medications from the beginning.

How to pre-medicate the patient?

All patients should receive the following premedications during the first three cycles before each dose of Columvi:

• Dexamethasone 20 mg intravenously administer at least one hour before starting Columvi infusion
• Acetaminophen 500 mg to 1,000 mg orally, at least 30 minutes before the infusion
• Antihistamine (diphenhydramine 50 mg orally or intravenously or equivalent), at least 30 minutes before the infusion

From Cycle 3 onwards, administer only acetaminophen and antihistamine. However, if there has been a prior episode of CRS, then also administer Dexamethasone 20 mg one hour before the infusion. 

Prophylaxis to Prevent Tumor Lysis Syndrome:

Hydrate and give uric-acid-lowering drugs to prevent TLS.

Antiviral Prophylaxis:

Prior to the initiation of COLUMVI, it is advisable to consider the initiation of antiviral prophylaxis to prevent the reactivation of the herpes virus and in high-risk patients, CMV infections.

Pneumocystis jirovecii Pneumonia (PJP) Prophylaxis:

Patients at an increased risk of developing Pneumocystis jirovecii pneumonia (PJP) should be given Co-Trimoxazole (Septran) or any other appropriate therapy as per the hospital policies and the patient's condition before starting COLUMVI therapy.

Dosage Modifications for Adverse Reactions:

There is no recommended dosage reduction for COLUMVI in response to adverse reactions. However, appropriate management strategies should be employed.

Cytokine Release Syndrome (CRS):

CRS should be identified early because it can be life-threatening. Consider CRS in any patients with fever, hypoxia, and hypotension.

If CRS is suspected, COLUMVI should be withheld, and management should follow the recommendations:

• Grade 1 (Temperature of 100.4F or more): 
  • Withhold the treatment.
  • Wait for the symptoms to resolve and then restart at a lower dose.
  • If the next dose is scheduled, wait for at least 72 hours after the resolution of CRS.
• Grade 2 (Temperature ≥ 100.4°F (38°C) + Hypotension not requiring vasopressors and/or - Hypoxia requiring low-flow oxygen:
  • Follow the recommendations as mentioned for Grade 1 CRS, however, the patient should be monitored in a hospital setting. In addition, if Grade 2 CRS is recurrent, then its should be managed as Grade 3 (see below)
• Grade 3 (Temperature ≥ 100.4°F (38°C) + Hypotension requiring vasopressors and/or - Hypoxia requiring high-flow oxygen:
  • Withhold the treatment and manage per the current practice guidelines. Hospital and intensive care observation may be required.
  • For recurrent Grade 3 CRS, the treatment may be permanently discontinued.
• Grade 4 (Temperature ≥ 100.4°F (38°C) + Hypotension requiring multiple vasopressors (excluding vasopressin) and/or - Hypoxia requiring oxygen by positive pressure (e.g., CPAP, BiPAP, intubation, and mechanical ventilation) :
  • Permanently discontinue the treatment. Manage per the current guidelines.

Dosage Modifications for Neurologic Toxicity, Including ICANS

When managing neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), the following actions should be considered based on the severity of the adverse reaction. It is important to evaluate and rule out other potential causes of neurologic symptoms.

• Grade 1:
  • Continue the treatment and monitor the symptoms
  • For patients who have developed ICANS, manage per the current guidelines.
• Grade 2:
  • ​​​​​​​Withhold the treatment and manage according to the current guidelines until the symptoms have resolved to the baseline or Grade 1.
  • Consider evaluation by a neurologist.
  • For patients who have developed ICANS, manage per the current guidelines.
• Grade 3:
  • ​​​​​​​Withhold the treatment and manage according to the current guidelines until the symptoms have resolved to the baseline or Grade 1 for at least 7 days.
  • If the neurological symptoms persist beyond 7 days, permanently discontinue the treatment.
  • Evaluate by a neurologist and provide supportive treatment.
  • For patients who have developed ICANS, manage per the current guidelines.
• Grade 4:
  • Permanently discontinue the treatment.
  • Provide supportive care including intensive care and evaluation by a neurologist.
  • For patients who have developed ICANS, manage per the current guidelines.

Dosage Modifications for Other Adverse Reactions

Active infection:

• Withhold the treatment if there is an active infection of any severity until the infection resolves.
• May permanently discontinue the treatment for infections of Grade 4 severity.

Tumor Flare:

• Grade 1:
  • Monitor for symptoms of obstruction due to rapid tumor growth.
• Grade 2 - 4:
  • Monitor for signs of obstruction due to rapid tumor growth.
  • Withhold the treatment until the Tumor Flare resolves.
  • Provide appropriate treatment such as antihistamines and corticosteroids.

Neutropenia:

• Withhold COLUMVI treatment until the absolute neutrophil count is at least 0.5 x 109/L or higher.

Thrombocytopenia:

• Withhold COLUMVI treatment until the platelet count is at least 50 x 109/L or higher.

Other Adverse Reactions:

• Withhold Glofitamab-gxbm treatment until the toxicity resolves to Grade 1 or baseline.​​​​​​​​​​​​​​

Preparation and Administration of COLUMVI:

Inspect the vial:

• Inspect the vial of COLUMVI. It should have clear and colorless contents. Discard if there is any particulate matter, discoloration is cloudy, or the vial contains particles.

Aseptic technique:

• Use an aseptic technique when preparing the solution.

Determine the dose and volume:

• Determine the appropriate dose.

Preparing the infusion:

• Dilute the COLUMVI solution to achieve a final concentration of 0.1 mg/mL to 0.6 mg/mL.
• Gently invert the infusion bag to mix the solution. Avoid shaking the bag excessively to prevent foaming.

Infusion and storage:

• Use the prepared COLUMVI solution immediately. If not used immediately, refrigerate at 2°C to 8°C (36°F to 46°F) for up to 64 hours, or at room temperature up to 25°C (77°F) for up to 4 hours.
• Avoid freezing the diluted solution.
• Discard the diluted solution if the storage time exceeds the specified limits.

 How to administer?

• COLUMVI should only be administered as an IV infusion using a dedicated infusion line that includes a sterile 0.2-micron in-line filter.
• Do not mix COLUMVI with other drugs or solutions.
• The maximum time for the administration of the diluted infusion solution can be extended up to 8 hours.

Select the appropriate COLUMVI vial based on the prescribed dose:

• 2.5 mg/2.5 mL (1 mg/mL) in a single-dose vial
• 10 mg/10 mL (1 mg/mL) in a single-dose vial

Contraindications to Glofitamab-gxbm (Columvi):

None mentioned by the manufacturer.

CRS (Cytokine release syndrome:

Cytokine Release Syndrome (CRS) is a serious side effect of Columvi. It may endanger the life of the patient if not identified and treated early. The following information provides details about CRS and its management:

Incidence:

• 70% of the patients in clinical trials who received Columvi.
• Grade 1 CRS: 52% of patients,
• Grade 2 in 14%,
• Grade 3 in 2.8%, and
• Grade 4 in 1.4%.

Common manifestations:

• Fever, tachycardia, hypotension, chills, and hypoxia.

Timing and recurrence:

• The median time to onset of CRS from the start of infusion was 14 hours,
• CRS resolved in 98% of cases with a median duration of 2 days.
• Recurrent CRS occurred in 34% of patients.

Dosing schedule and hospitalization:

• Administer COLUMVI in a hospital setting.
• The step-up dosing schedule is designed to reduce the risk of CRS. Patients should be hospitalized during and for 24 hours after completing the 2.5 mg step-up dose and for 24 hours after the 10 mg dose and after subsequent doses.

Management:

• Manage CRS according to the current guidelines.
• The decision to withhold the treatment or discontinue it should be based on the severity of CRS.

Neurological Toxicity:

COLUMVI has the potential to cause serious and even fatal neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity (ICANS). Here are important details about neurologic toxicity associated with COLUMVI:

Incidence:

• Headache (10%),
• peripheral neuropathy (8%),
• dizziness or vertigo (7%), and
• mental status changes (4.8%).
• Grade 3 or higher toxicity: 2.1%. It included somnolence, delirium, and myelitis.
• ICANS of any grade occurred in 4.8% of patients.

Monitoring and management:

• Closely monitor the patients and treat them immediately.
• May need to withhold or discontinue the treatment

Infections:

Serious infections may occur which can be life-threatening. Here are important details regarding infections associated with COLUMVI:

Incidence:

• Serious infections were reported in 16% of patients in clinical trials
• Grade 3 or 4 infections occurred in 10% of patients.
• Fatal infections were reported in 4.8% of patients.
• Grade 3 or higher infections include:
  • COVID-19 infection (6%),
  • Sepsis (4.1%).
  • Febrile neutropenia was reported in 3.4% of patients.

Precautions and monitoring:

• Avoid using COLUMVI in patients with sepsis or active infections. Provide appropriate prophylaxis and treat on a priority basis if an infection is suspected.
• In severe infections, withhold or permanently discontinue the treatment.

Tumor Flare:

COLUMVI can cause a flare-up of the tumor, especially in patients with bulky disease. It can be identified if the patient develops localized pain and swelling at the sites of lymphoma lesions and/or difficulty breathing due to new pleural effusions.

Here are important details regarding tumor flare associated with COLUMVI:

• Incidence: 12% in clinical trials.
• Grade 2 tumor flare: 4.8%
• Grade 3 tumor flare: 2.8% of patients.
• Recurrent tumor flares: 12%.
• The median time of onset: 2 days (ranging from 1 to 16 days).
• The median duration of tumor flare: 3.5 days (ranging from 1 to 35 days).

Manifestations:

• Tumor flare is characterized by localized pain and swelling at the sites of lymphoma lesions. It can also lead to dyspnea (difficulty breathing) resulting from pleural effusions.

Monitoring and treatment:

• Patients with bulky tumors or diseases located near the airways or vital organs should be closely monitored during the initial therapy with COLUMVI. It is important to watch for signs and symptoms of compression or obstruction caused by mass effect resulting from tumor flare.
• Appropriate treatment should be instituted promptly. COLUMVI should be withheld until the tumor flare resolves.

Fetal toxicity:

Glofitamab-gxbm can harm the fetus. Women of reproductive age are advised effective contraception and to avoid pregnancy. Women who get pregnant during the treatment or within one month after the last dose should inform their healthcare providers immediately.

 

Glofitamab-gxbm (COLUMVI) Side Effects

The most common adverse reactions (Side effects) that affected at least 10% of the patients included:

Immune system disorders:

• Cytokine release syndrome (All Grades: 70%; Grade 3 or 4 severity: 4.1%)

Musculoskeletal and connective tissue disorders:

• Musculoskeletal pain (All Grades: 21%; Grade 3 or 4 severity: 2.1%)

General disorders:

• Fatigue (All Grades: 20%; Grade 3 or 4 severity: 1.4%)
• Pyrexia (All Grades: 16%; Grade 3 or 4 severity: 0%)
• Edema (All Grades: 10%; Grade 3 or 4 severity: 0%)

Skin and subcutaneous tissue disorders:

• Rash (All Grades: 20%; Grade 3 or 4 severity: 1.4%)

Gastrointestinal disorders:

• Constipation (All Grades: 14%; Grade 3 or 4 severity: 0%)
• Diarrhea (All Grades: 14%; Grade 3 or 4 severity: 0%)
• Nausea (All Grades: 10%; Grade 3 or 4 severity: 0%)
• Abdominal pain (All Grades: 10%; Grade 3 or 4 severity: 0%)

Neoplasms:

• Tumor flare (All Grades: 12%; Grade 3 or 4 severity: 2.8%)

Neurologic Disorders

• Headache (All Grades: 10%; Grade 3 or 4 severity: 0 %)

Other less common side effects include:

• infusion-related reaction,
• peripheral neuropathy, tremors, and myelitis
• infections including pneumonia, upper respiratory tract infection, sepsis, herpes zoster infection, and febrile neutropenia
• mental status changes,
• vomiting and GI bleeding
• tumor lysis syndrome

Laboratory abnormalities that affected at least 20% of the patients include:

Hematology:

• Lymphocytopenia (All Grades: 90%; Grade 3 or 4 severity: 83%)
• Anemia (All Grades: 72%; Grade 3 or 4 severity: 8%)
• Neutropenia (All Grades: 56%; Grade 3 or 4 severity: 26%)
• Thrombocytopenia (All Grades: 56%; Grade 3 or 4 severity: 8%)

 Chemistry:

• Decreased Fibrinogen Levels (All Grades: 84%; Grade 3 or 4 severity: 21%)
• Hypophosphatemia (All Grades: 69%; Grade 3 or 4 severity: 28%)
• Hyponatremia (All Grades: 49%; Grade 3 or 4 severity: 7%)
• Hypocalcemia (All Grades: 48%; Grade 3 or 4 severity: 2.1%)
• Increased GGT (Gamma-glutamyl transferase) (All Grades: 33%; Grade 3 or 4 severity: 9%)
• Hypokalemia (All Grades: 32%; Grade 3 or 4 severity: 6%)
• Hyperuricemia (All Grades: 23%; Grade 3 or 4 severity: 23%)

Columvi Drug Interactions:

Columvi causes the release of cytokines which can temporarily suppress the activity of CYP hepatic enzymes. Thus, there is an increased risk of drug toxicity which is primarily metabolized by the CYP enzymes.

It is important to monitor the patient for toxicities and reduce the drug levels when given along with Glofitamab-gxbm. The risk is present for up to 14 days of Glofitamab-gxbm administration and is especially there in patients who develop CRS.​​​​​​​

Glofitamab-gxbm MOA (Mechanism of action):

Glofitamab-gxbm, the active component of COLUMVI, is a bispecific antibody that targets both B and T cells. It binds to CD20, which is expressed on the surface of B cells, and CD3 receptor, which is expressed on the surface of T cells. By binding to both CD20 and CD3, glofitamab-gxbm facilitates the activation and proliferation of T cells, leading to the secretion of cytokines and the destruction of CD20-expressing B cells.

The binding of glofitamab-gxbm to CD20 on B cells helps to target and eliminate these cancerous or abnormal B cells. The activation and proliferation of T cells enhance the immune response against B cells, resulting in their lysis and clearance. This mechanism of action enables glofitamab-gxbm to exhibit anti-tumor activity, particularly in the context of B-cell malignancies.

Circulating B Cell Count: 86.5% of the patients had undetectable circulating B lymphocytes on Day 8 (cycle 1) and 88.2% of the patients had undetectable levels of B lymphocytes on Day 10 (cycle 1), effectively depleting B cells.

Cytokine Concentrations: There is reversible cytokine release with Columvi treatment. This can be tracked from the cytokine levels as they reach a peak within 6 hours after the first dose (2.5 mg) on Cycle 1 Day 8 and return to baseline levels within 48 hours after the first dose of 30 mg on Cycle 2 Day 1. 

Terminal half-life elimination: 7.6 days.

Metabolism: It is metabolized into small peptides through a protein catabolic pathway.

In terms of specific populations, no clinically significant changes in the pharmacokinetics of glofitamab-gxbm were observed based on age (21 to 90 years), body weight (31 to 148 kg), sex, mild to moderate renal impairment (CLcr 30 to < 90 mL/min), and mild hepatic impairment (total bilirubin > ULN to ≤ 1.5 x ULN or AST > ULN). In severe hepatic and renal impairment, the effects of Columvi are not known.​​​​​​​