GLOFITAMAB-GXBM INJ,SOLN
Clinical Criteria Summary
Document 595
Indications
- Relapsed or Refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL)
Cytokine Release Syndrome (CRS) Management & Monitoring
- Time Course: Median time to CRS onset after most recent dose is 2 days; median duration is 5 days. Highest risk occurs minutes to hours after step-up or induction infusions, but may occur once patient is discharged.
- Grading & Management:
- Grade 1: Symptomatic/supportive care (acetaminophen 650mg PO Q6H PRN for fever ≥38.0°C; IV hydration). Hold therapy until CRS resolves, then resume (except Grade 4).
- Grade 2: Continue supportive care + IV bolus/supplemental O2 as needed. Tocilizumab 8mg/kg IV over 1 hour (max 800mg/dose), repeat q8h (limit 3 doses/24h, max 4 total). If hypotension refractory to fluids, add dexamethasone 10mg IV q8-12h.
- Grade 3: Admit to ICU. Continue supportive care + vasopressors if needed. Dexamethasone 10mg IV q6h for 3 days, then rapidly taper. Tocilizumab per Grade 2 if max dose not reached and no improvement on high-dose steroids.
- Grade 4: Admit to ICU. Discontinue BsAb. Continue supportive care + mechanical ventilation as needed. High-dose methylprednisolone (500mg q12h x3d, then taper). Tocilizumab per Grade 2 if indicated.
- General: Outpatient management for Grade >1 requires inpatient admission. Initial step-up therapy may require inpatient admission depending on the BsAb.
- Monitoring:
- Clinic/Outpatient: Daily vital signs and weights; daily CBC with differential and complete metabolic profile; coagulation parameters twice weekly; CRP and ferritin daily during step-up and first full dose, then PRN; assess and grade CRS at least daily or with status changes.
- Inpatient/ICU: Vital signs every 4 hours (while awake if stable); monitor oral/IV fluid I/O; daily weights; daily CBC/CMP; coagulation parameters twice weekly; CRP daily during step-up until CRS resolves; assess and grade CRS every 12 hours or with changes; cardiac/hemodynamic monitoring by telemetry.
ICANS/Neurotoxicity Management & Monitoring
- Presentation & Diagnosis: Typically manifests within 2-3 days of CRS onset. Symptoms range from subtle (loss of attentiveness, language dysfunction) to severe (delirium, dysphasia, lethargy, confusion, aphasia, depressed LOC, encephalopathy, seizures, tremor, ataxia, cerebral edema). Diagnosis is one of exclusion; rule out other causes (e.g., CNS-acting meds, infection via head CT/MRI or LP if indicated).
- Grading: Use ASTCT grading scale with ICE score (10-point encephalopathy assessment evaluating orientation, naming, following commands, writing, attention) and neurotoxicity domains (level of consciousness, seizure, motor findings, elevated ICP/cerebral edema).
- Management:
- Grade 1: Supportive care with IV hydration and aspiration precautions.
- Grade 2: Supportive care + dexamethasone 10mg IV x2 (or equivalent) q6-12h, reassess; repeat if no improvement; rapidly taper once symptoms improve to Grade 1.
- Grade 3/4: Transfer to ICU. High-dose methylprednisolone IV (1000mg q12h for 3 days, adjust frequency as needed) until Grade 1, then taper. Consider mechanical ventilation for airway protection. For concurrent CRS, add tocilizumab 8mg/kg IV over 1 hour, repeat q8h PRN (max 3 doses/24h).
- General: Hold, dose-reduce, or discontinue per prescribing information. Consider antiseizure prophylaxis for high-risk patients (prior seizure history, CNS disease, EEG findings, brain lesions). Multidisciplinary discussion and specialty consults (Neurology, Ophthalmology) as indicated.
- Monitoring: Physical exam and vital signs daily; neurologic exam every 8-12 hours or with status changes; grade neuro assessment with ICE score and ASTCT neurotoxicity domain; monitor for increased ICP (fundoscopy); monitor severe hyponatremia; reserve ICU for worsening condition, cerebral edema, status epilepticus, or Grade 3-4 ICANS.
Pre-medication & Supportive Care
- Pre-medication: Dexamethasone 16 mg IV (administered 60 minutes prior to BsAb).
- General supportive medications per FDA labeling include corticosteroids, antihistamines, and antipyretics. Antifungal prophylaxis should be considered in patients receiving corticosteroids.
Dosing & Administration
- Step-up dosing strategy is recommended to decrease CRS risk; package labels recommend step-up dosing in the inpatient setting due to long observation times for CRS/ICANS.
- Dose delays require review of prescribing information for restart recommendations.
Document 671
Exclusion Criteria
- Facility is not equipped to monitor and manage Cytokine Release Syndrome (CRS), if necessary
- Patient unable to be hospitalized for step-up dose on Cycle 1, Day 8 and/or Day 15 followed by 24 hours of monitoring, if any grade of CRS is experienced on either day
- Absolute Neutrophil Count < 1500/µL, Platelet count < 75,000/µL (if no bone marrow involvement)
- Total bilirubin > 1.5 times the upper limit of normal (unless Gilbert’s syndrome or liver involvement)
- Alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase > 3 times the upper limit of normal (unless liver involvement)
- Creatinine clearance < 50 ml/min
- Active or uncontrolled infection
- Unmanageable drug-drug interaction
- Pregnancy
- Lactating
Inclusion Criteria
- Relapsed or refractory, diffuse large B-cell lymphoma (DLBCL) or large B-cell lymphoma (LBCL) arising from follicular lymphoma (FL)
- Previously treated with > 2 prior lines of therapy (including 1 line with anti-CD20 monoclonal antibody)
- Care is provided by a VA/VA Community Care oncology or hematology provider
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Goals of care and role of Palliative Care consult have been discussed and documented
Additional Inclusion Criteria
- For patients who can become pregnant and patients with partners who can become pregnant: Counseling provided on potential risks vs benefits of treatment and the use of effective contraception during therapy and for 1 month after stopping treatment.
Document 672
Indication & Patient Population
- Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or large B-cell lymphoma (LBCL) arising from follicular lymphoma (FL) after > 2 lines of therapy (LOT)
- Heavily pretreated population with median prior LOT of 3; includes patients with primary refractory disease, prior CAR T-cell therapy, and prior autologous hematopoietic stem cell transplantation (HSCT)
Performance Status & Laboratory Criteria
- ECOG PS 0-1
- ANC > 1500 cells/mcL
- Platelets > 75,000 cells/mcL
- Transfusion-independent
- SCr < 1.5 x ULN (or CrCl > 50 ml/min)
- Transaminases < 3x ULN
Exclusion Criteria
- Active or prior CNS lymphoma
- CNS disease
- Acute infection
- Recent infection requiring IV antibiotics
- Prior allogeneic HSCT
Dosing & Administration Requirements
- Day 1: obinutuzumab 1000mg IV x1
- Day 8: Step up dose 1 glofitamab 2.5mg IV x1
- Day 15: Step up dose 2 glofitamab 10mg IV x1
- Cycles #2-12 (Day 1): glofitamab 30mg IV x1
- Repeat every 21 days for up to 12 cycles
Monitoring & Management Requirements
- Monitor for neurologic toxicity, including ICANS; hold or discontinue based on severity
- Monitor signs and symptoms of serious infections; treat appropriately
- Monitor patients at risk for tumor flare
- Advise patients of embryo-fetal toxicity and potential fetal harm; require use of effective contraception
- Hospitalization recommended 24 hours after step up dose #1 and step up dose #2, if CRS occurs in cycle 1
- If CRS > Grade 2 occurs with infusion, hospitalize during and for 24 hours after completion of subsequent infusion
VA Clinical Pathway & Guideline Recommendations
- Recommended per VA Oncology Clinical Pathway for multiply relapsed DLBCL if ASCT and CAR T-cell therapies are not an option and disease progression occurs following rituximab-bendamustine-polatuzumab
- Listed as a preferred regimen in NCCN guidelines for 3L and subsequent therapy for DLBCL