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Treatment-Associated Neurotoxicity in Patients with Acute Lymphoblastic Leukemia

Web Exclusives - Acute Lymphoblastic Leukemia

Neurotoxicity, which encompasses a wide range of neurologic signs and symptoms, is an adverse event complicating acute lymphoblastic leukemia (ALL) treatment with bispecific antibody and chimeric antigen receptor T-cell (CAR-T) therapy.1 The mechanisms underlying neurotoxicity in patients with ALL are incompletely understood but may involve disruption to the blood–brain barrier by activated T-cells, with cytokine release upon binding to CD19+ B-cells in the central nervous system.1,2 It is believed that patients with ALL disease involving the central nervous system may be at increased risk for developing neurotoxicity.2

The clinical presentation of neurotoxicity associated with ALL treatment varies greatly. Patients may experience mild symptoms of headache, malaise, confusion, somnolence, or disorientation, to more severe signs of ataxia, seizure, aphasia, or stupor.2 Signs and symptoms of neurotoxicity generally develop within 7 days of blinatumomab infusion.2 Rates of neurotoxicity in clinical trials range from 20% to 53% with the bispecific T-cell engager, blinatumomab, and from 29% to 49% with CD19 CAR-T therapies, such as tisagenlecleucel.3,4

Successful management of neurotoxicity comprises risk minimization, prompt recognition, and rapid treatment.2 To minimize neurotoxicity risk associated with blinatumomab treatment for ALL, clinicians are advised to use progressive dose escalation over the course of the first week of therapy.1 Prophylactic antiseizure medicine can be considered during the first month after infusion of tisagenlecleucel,5 but some experts do not advocate for primary seizure prophylaxis because of its low incidence rate.1

Clinical practice guidelines stress the importance of monitoring patients for signs of neurotoxicity, including word-finding difficulty, somnolence, ataxia, tremor, seizure, and syncope, while receiving treatment for ALL.5 For patients receiving tisagenlecleucel who do experience neurotoxicity, corticosteroids are the mainstays of therapy.5 In patients receiving blinatumomab who experience grade 1 or 2 neurotoxicity, supportive care consisting of intravenous fluids, respiratory support, and anti-inflammatory therapy should be provided.1 Blinatumomab infusion may be continued in the case of grade 1 or 2 neurotoxicity, and corticosteroid therapy may also be considered to help prevent progression.1 For patients who experience severe neurotoxicity while receiving blinatumomab, guidelines recommend holding the infusion, considering corticosteroids in the case of severe symptoms, and re-starting therapy with dose adjustments following sufficient symptom improvement and a therapeutic break of at least 3 days.1,5 Blinatumomab should be permanently discontinued if >1 seizure occurs or if any grade 4 neurotoxicity occurs.6 Further evaluations may be indicated to assess for contributions of other neurologic diseases.1

References

  1. Conde-Royo D, Juárez-Salcedo LM, Dalia S. Management of adverse effects of new monoclonal antibody treatments in acute lymphoblastic leukemia. Drugs Context. 2020;9:2020-7-2.
  2. Jain T, Litzow MR. No free rides: management of toxicities of novel immunotherapies in ALL, including financial. Blood Adv. 2018;2:3393-3403.
  3. Jain T, Litzow MR. Management of toxicities associated with novel immunotherapy agents in acute lymphoblastic leukemia. Ther Adv Hematol. 2020;11:2040620719899897.
  4. Greenbaum U, Mahadeo KM, Kebriaei P, et al. Chimeric antigen receptor T-cells in B-acute lymphoblastic leukemia: state of the art and future directions. Front Oncol. 2020;10:1594.
  5. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: acute lymphoblastic leukemia. Version 2.2021. July 19, 2021. www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed November 10, 2021.
  6. Amgen Inc. Blincyto prescribing information. 2021. www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/blincyto/blincyto_pi_hcp_english.pdf. Accessed November 11, 2021.
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