Blinatumomab

1. Cytokine release syndrome (reported in 7-15% cases in CT)

Cytokine Release Syndrome (CRS), potentially detrimental and lethal, is seen in patients receiving Blincyto treatment. CRS onset usually happens 2 days (median time) after starting blinatumomab infusion and takes 5 days (median time) to resolve, in cases that it actually got resolved.  CRS manifests as fever, nausea, headache, athenia, hypotension, increased levels of  of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin, as well as disseminated intravascular coagulation (DIC). After treatment, the manifestation may overlap with those of infusion reactions, capillary leak syndrome (CLS), and hemophagocytic histiocytosis/macrophage activation syndrome (MAS).

2. Neurological Toxicities (reported in 65% cases in CT, ICANS in 7.5% cases in CT)

BLINCYTO can cause serious or life-threatening neurologic toxicity, including ICANS or Immune Effector Cell-Associated Neurotoxicity Syndrome. Neurologic toxicities observed within the first 2 weeks of receiving treatment.

Common manifestations :

• headache
• tremor
• neurological toxicity profile varied by age group

Approximately 13% patients showed grade 3 or higher grades of neurological toxicities like

• encephalopathy
• convulsions
• speech disorders
• disturbances in consciousness
• confusion
• disorientation
• coordination and balance disorders

Most showed resolution post discontinuation or interruption of treatment.

Patients with a history or presence of clinically relevant CNS pathology were not included in clinical trials.

Patients with Down Syndrome may have a higher risk of seizures with this therapy; and are advised to consider seizure prophylaxis prior to initiation of  treatment.

3. Infections (observed in approx. 25% of the patients)

Infections (some of which were life threatening or fatal) such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections were observed in patients with ALL under blinatumomab treatment.

4. Tumor lysis syndrome (TLS),

• Life-threatening or fatal, has been observed in patients receiving blinatumomab.
• Pretreatment cytoreduction and on treatment hydration advised as prophylactic measures.

5. Neutropenia and febrile neutropenia

• Life threatening, has been observed in some patients receiving this treatment.
• Strict monitoring of laboratory parameters some of which may be white blood cell count, and absolute neutrophil count during blinatumomab infusion.
• Interrupt treatment in case of prolonged neutropenia.

6. Effects on ability to drive and use machines

• Patients undergoing blinatumomab therapy may be at risk for loss of consciousness due to neurological toxicities.
• Patients are advised to avoid driving, engaging in hazardous occupations or activities, handling heavy and dangerous machinery while undergoing treatment with blinatumomab.

7. Elevated liver enzymes

• Transient elevations in liver enzymes associated with this therapy.
• In patients with ALL receiving this treatment in clinical trials, the median time to onset of elevated liver enzymes was 3 days, most of them being observed in the setting of CRS.
• For the events observed outside a background of  CRS, the median time to onset was 19 days.
• Grade 3 or greater elevations in liver enzymes occurred in approximately 7% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients.

8. Pancreatitis

• Fatal pancreatitis has been reported in patients receiving blinatumomab in combination with dexamethasone in clinical trials and the postmarketing setting.
• Evaluate patients with signs and symptoms of pancreatitis.
• Management of pancreatitis may require either temporary interruption or discontinuation of both therapies – blinatumomab and dexamethasone.

9. Leukoencephalopathy

• Patients receiving blinatumomab therapy, especially those with background of cranial irradiation and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine) showed cranial magnetic resonance imaging (MRI) changes  indicating leukoencephalopathy. Clinical significance unknown.

10. Immunization

• Safety of administering live viral vaccines ( attenuated vaccines) during blinatumomab therapy not studied. Hence, to avoid risk, live viral vaccines are recommended against for at least 2 weeks before starting of this treatment, during treatment and until complete recovery of the immune system after the last dose of blinatumomab.

11. Benzyl alcohol toxicity in neonates

• Serious/fatal reactions, including “gasping syndrome” seen in some high risk groups.
• High-risk groups include very low birth weight neonates born <1500 g and infants <34 weeks gestation who have already received the intravenous =s drugs that benzyl alcohol as preservative.

Important symptoms include:

1. CNS depression
2. Metabolic acidosis
3. Gasping
4. Neurologic deterioration
   

• Other symptoms include seizures, hemorrhage, hematologic issues, skin breakdown, hepatic/renal failure, hypotension, bradycardia, cardiovascular collapse.
• Recommended to use formulations devoid of preservatives. Monitoring for metabolic acidosis. 72-, 96-hour, or 7-day infusions in patients <5.4 kg are advised against.

12. Embryo fetal toxicity

• Blinatumomab may cause fetal harm when administered to a pregnant woman.
• Advise pregnant women of the potential risk to the fetus and to use effective contraception during treatment and for 48 hours after the last dose of blinatumomab.

Monitoring and management –

• Monitor patients receiving blinatumomab treatment for signs and symptoms and in case such signs are visible, contact healthcare professionals.
• Management of such syndromes and toxicities may require interruption or permanent discontinuation of treatment as recommended and/or treatment with corticosteroids.
• As appropriate, administer prophylactic antibiotics and employ surveillance testing during treatment with blinatumomab, for TLS and infections.
• Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and total blood bilirubin prior to the start of and during treatment.
• Interrupt therapy if the levels of transaminases rise to greater than 5 times the upper limit of normal or if total bilirubin rises to more than 3 times the upper limit of normal.
• Errors in preparation and administration of infusion reported previously with this therapy. Hence, instructions for admixing and administration are to be strictly followed to minimise errors that may affect efficacy of medication, and avoid overdose or underdose