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Immunotherapy-Related Adverse Events
How I Manage Immunotherapy-Related Adverse Events in My Patients Receiving Blinatumomab

Released: November 17, 2015

Expiration: November 15, 2016

Elias Jabbour
Elias Jabbour, MD
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Case Presentation
I recently used blinatumomab to treat a 37-year-old woman with relapsed acute lymphocytic leukemia (ALL). She was started on blinatumomab 9 µg/day for 7 days, with planned dose escalation to 28 µg on Day 8. Thirty-six hours after starting blinatumomab, she developed a high fever of 39.3°C (102.7°F) with slight tachycardia, headache, tremors, and fatigue. We immediately started dexamethasone 8 mg IV every 8 hours for 3 days and then tapered off over 4 days. The patient was also started on broad-spectrum antibiotics, but a blood culture later came back negative for infection.

This patient was showing signs of grade 2 cytokine release syndrome (CRS), which is highly manageable and can be limited by early detection and premedication with steroids. Of note, our patient developed grade 2 headache, grade 1 tremors, and grade 2 fatigue, which did not impede treatment.

After 1 week of treatment, her fever subsided and she seemed to be improving, so on Day 8, we escalated the blinatumomab dose up to 28 µg/day. She also received additional steroids and had a fever of 38.0°C (100.4°F) but no other symptoms.

On Day 15, a biopsy showed blast‑free marrow and she was negative for minimal residual disease. By Day 29 when she finished her first cycle of blinatumomab treatment, her bone marrow was only 1% blasts, and blood work showed absolute neutrophil count (ANC) of 800 cells/mm3 and platelets were 53,000 cells/mm3—in short, she had a marrow CR with partial hematologic recovery.

On Day 42, 6 weeks after starting blinatumomab, her bone marrow was free of blasts, and the second course of blinatumomab was started with 28 µg/day. However, 7 days later, she developed grade 2 confusion, grade 2 dizziness, grade 2 tremor, and grade 2 ALT/AST increase, and the drug was held until these adverse events declined to less than grade 1, which took 6 days. Treatment was then resumed for a total of 28 days of infusion.

Blinatumomab is known to cause CNS problems, typically grade 1/2, and as in this case is typically not problematic. Although the CRS at the beginning of this patient case was resolved, we usually hold the drug with any significant safety concerns. If the hold is less than 7 days, treatment can be resumed for a total of 28 days of treatment. A hold for more than 1 week means a new course is needed. This patient received her second course and achieved a remission, which allowed her to receive the transplant. Today, she’s still alive and in remission.

This case illustrates the most common safety concerns observed with blinatumomab: CRS and CNS problems. As discussed, we started with steroid premedication and held the drug as needed, which mitigated these safety concerns. Of importance, this woman, who was refractory to multiple treatments, went into remission and was able to receive a transplant and remains in remission more than 2 years later.

Additional Considerations for Promising Immunotherapies for ALL
Chimeric antigen receptor (CAR) T cells are another promising treatment approach for patients with ALL that is also associated with CRS. CRS is observed with nearly all patients who receive CAR T cells, and it can be much more severe than what is observed with blinatumomab. However, few patients will have grade 5 CRS. Studies are ongoing to determine how to best treat CRS related to CAR T cells; current data suggest that less disease at the time of the infusion correlates with a lower risk of CRS. Therefore, patients should receive an effective salvage regimen prior to receiving CAR T cells in order to minimize CRS. For patients who do develop CRS after receiving CAR T cells, they will require a heavier intervention, such as intensive care unit–level care and anti‒IL-6.

Inotuzumab ozogamicin has shown exciting results in recent clinical trials for patients with ALL. This antibody–drug conjugate that combines an anti‑CD22 monoclonal antibody with calicheamicin can limit the toxic effects of systemic chemotherapy. However, there have been safety concerns with the occurrence of hepatic sinusoidal obstruction syndrome (SOS), especially in patients who received a transplant and are receiving a hepatotoxic drug. Due to the risk of SOS, clinicians should be very careful to only select patients with no heavy previous history of liver damage. Lower-dose schedules are being explored to minimize the safety concern.

Are you using these immunotherapies to treat your patients with acute leukemias? How have these related adverse events challenged you in the clinic? Share your experience in the comments below.

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What treatment-related symptom has been a major challenge in your practice with the use of blinatumomab to treat patients with acute leukemias?
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