With regard to the Review article by Stone and DeAngelis, published in the February 2016 issue of this journal (Cancer-treatment-induced neurotoxicity — focus on newer treatments. Nat. Rev. Clin. Oncol. 13, 92–105 (2016))1, we wish to address an erroneous statement made by the authors that blinatumomab treatment “causes seizures in 15–20% of treated patients” (Ref. 1). According to the reference cited to support this statement within the Review2, and the published clinical-trial literature on blinatumomab3,4,5, this range refers to the total frequencies of all grade ≥3 neurological adverse events combined, including not only seizures, but also encephalopathy, confusion, and cerebellar symptoms. Across several studies involving adults with relapsed and/or refractory B-cell acute lymphoblastic leukaemia (B-ALL) who received blinatumomab, seizures of any grade were reported in 2.1–8.3% of 246 patients in total: one of 21 patients with persistence or relapse of minimal residual disease (4.8%) had a grade 3 seizure in an early phase II trial3; three of 36 patients (8.3%) had epileptic seizures or convulsions leading to treatment interruption in the dose-finding phase II study4; and four of 189 patients (2.1%) had convulsions in the confirmatory multicentre phase II trial5.
Among the patients treated with blinatumomab in clinical trials, most of the neurological adverse events observed have been low-grade tremors and dizziness3,4,5. More-serious neurological events, such as seizures and encephalopathy, have been the most-common reasons for treatment interruptions (frequency of 15–17%) and discontinuations (frequency of 4.8%)3,4,5, but patients have generally responded well to interventional therapy for these toxicities. Indeed, these adverse events have predominantly been limited in duration and primarily resolved with treatment interruption and/or standard anticonvulsive therapies, and most of the patients were subsequently able to resume blinatumomab therapy3,4,5.
Given the few treatment options currently available for relapsed and/or refractory B-ALL, we feel that accurately reporting the blinatumomab-related seizure rate is pertinent, in order to better inform appropriate treatment decisions.
References
Stone, J. B. & DeAngelis, L. M. Cancer-treatment-induced neurotoxicity — focus on newer treatments. Nat. Rev. Clin. Oncol. 13, 92–105 (2016).
Magge, R. S. & DeAngelis, L. M. The double-edged sword: neurotoxicity of chemotherapy. Blood Rev. 29, 93–100 (2015).
Topp, M. S. et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J. Clin. Oncol. 29, 2493–2498 (2011).
Topp, M. S. et al. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J. Clin. Oncol. 32, 4134–4140 (2014).
Topp, M. S. et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 16, 57–66 (2015).
Acknowledgements
We thank Dr Geoffrey Smith and Dr Janice Y. Ahn of Amgen Inc. for their medical writing contributions to this article.
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M.S.T. declares the receipt of personal fees and nonfinancial support from Amgen Inc. for work performed outside of the blinatumomab trials. Z.Z. declares that he is employed by and holds stock in Amgen Inc. H.M.K. declares no competing interests.
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Topp, M., Zimmerman, Z. & Kantarjian, H. Correction regarding data on blinatumomab-associated seizures. Nat Rev Clin Oncol 13, 650 (2016). https://doi.org/10.1038/nrclinonc.2016.133
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DOI: https://doi.org/10.1038/nrclinonc.2016.133