Abstract
Introduction: Despite standard prevention strategies, obinutuzumab carries a significant risk of infusion-related reactions (IRRs) for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Reported rates of IRRs vary in phase III clinical trials evaluating obinutuzumab-containing regimens. Although obinutuzumab has a higher rate of severe (grade 3 and higher) IRRs than rituximab, clinical risk factors predicting IRR have not been identified, and therefore strata informing patient-specific risk of IRR have not been applied in practice. Methods: This multicenter, retrospective evaluation of patients with CLL/SLL estimated the incidence of obinutuzumab-related IRRs and evaluated risk factors for the development of IRR in a real-world population. Results: 68 patients with untreated or previously treated CLL/SLL were included in the analysis, with the majority being older adult (median age = 70) males (61.8%) with Rai stage III and IV CLL. All-grade IRRs occurred in 25% of patients, and severe IRRs occurred in 1.5% of patients. Of the variables evaluated, absolute lymphocyte count was a significant predictor (p ≤ .05) of the odds of experiencing an IRR in patients receiving obinutuzumab. Conclusion: Obinutuzumab IRR rates in a real-world population were comparable to most phase III clinical trial results succeeding implementation of split dosing and standard premedication. Absolute lymphocyte count is a statistically significant predictor for increased odds of experiencing an IRR. Future research evaluating risk-adapted obinutuzumab administration strategies is needed to recommend a specific approach.
References
Bourrier, N., Landego, I., Bucher, O., Squires, M., Streu, E., Hibbert, I.,…Banerji, V. (2022). Real world risk of infusion reactions and effectiveness of front-line obinutuzumab plus chlorambucil compared with other frontline treatments for chronic lymphocytic leukemia. BMC Cancer, 22(1), 148. https://doi.org/10.1186/s12885-022-09256-2
Byrd, J. C., Waselenko, J. K., Maneatis, T. J., Murphy, T., Ward, F. T., Monahan, B. P.,…White, C. A. (1999). Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: Association with increased infusion-related side effects and rapid blood tumor clearance. Journal of Clinical Oncology, 17(3), 791–791. https://doi.org/10.1200/JCO.1999.17.3.791
Fischer, K., Al-Sawaf, O., Bahlo, J., Fink, A.-M., Tandon, M., Dixon, M.,…Hallek, M. (2019). Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. New England Journal of Medicine, 380(23), 2225–2236. https://doi.org/10.1056/NEJMoa1815281
Freeman, C. L., Dixon, M., Houghton, R., Kreuzer, K.-A., Fingerle-Rowson, G., Herling, M.,…Goede, V. (2016). Role of CD20 expression and other pre-treatment risk factors in the development of infusion-related reactions in patients with CLL treated with obinutuzumab. Leukemia, 30(8), 1763–1766. https://doi.org/10.1038/leu.2016.41
Freeman, C. L., Morschhauser, F., Sehn, L., Dixon, M., Houghton, R., Lamy, T.,…Cartron, G. (2015). Cytokine release in patients with CLL treated with obinutuzumab and possible relationship with infusion-related reactions. Blood, 126(24), 2646–2649. https://doi.org/10.1182/blood-2015-09-670802
Genentech, Inc. (2017). Gazyva (obinutuzumab) package insert. https://www.gene.com/download/pdf/gazyva_prescribing.pdf
Goede, V., Fischer, K., Busch, R., Engelke, A., Eichhorst, B., Wendtner, C. M.,…Hallek, M. (2014). Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. New England Journal of Medicine, 370(12), 1101–1110. https://doi.org/10.1056/NEJMoa1313984
Leblond, V., Aktan, M., Ferra Coll, C. M., Dartigeas, C., Kisro, J., Montillo, M.,…Foà, R. (2018). Safety of obinutuzumab alone or combined with chemotherapy for previously untreated or relapsed/refractory chronic lymphocytic leukemia in the phase IIIb GREEN study. Haematologica, 103(11), 1889–1898. https://doi.org/10.3324/haematol.2017.186387
Moore, D. C., Gebru, T., & Plesca, D. (2021). Evaluation of a pharmacist-driven rapid infusion rituximab conversion protocol at a multisite cancer center. Journal of Oncology Pharmacy Practice, 27(8), 1914–1918. https://doi.org/10.1177/1078155220977898
Moreno, C., Greil, R., Demirkan, F., Tedeschi, A., Anz, B., Larratt, L.,…Flinn, I. W. (2019). Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): A multicentre, randomised, open-label, phase 3 trial. The Lancet Oncology, 20(1), 43–56. https://doi.org/10.1016/S1470-2045(18)30788-5
Plante, M., Garneau, L., Laprise-Lachance, M., Lemieux, P., & Dorval, M. (2021). Impact of split dosing the first rituximab infusion in patients with high lymphocyte count. Current Oncology, 28(5), 4118–4128. https://doi.org/10.3390/curroncol28050349
Roselló, S., Blasco, I., García Fabregat, L., Cervantes, A., & Jordan, K. (2017). Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines. Annals of Oncology, 28, iv100–iv118. https://doi.org/10.1093/annonc/mdx216
Sharman, J. P., Egyed, M., Jurczak, W., Skarbnik, A., Pagel, J. M., Flinn, I. W.,…Byrd, J. C. (2020). Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE-TN): A randomised, controlled, phase 3 trial. The Lancet, 395(10232), 1278–1291. https://doi.org/10.1016/S0140-6736(20)30262-2
Swan, J. T., Zaghloul, H. A., Cox, J. E., & Murillo, J. R. (2014). Use of a pharmacy protocol to convert standard rituximab infusions to rapid infusion shortens outpatient infusion clinic visits. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 34(7), 686–694. https://doi.org/10.1002/phar.1420
U.S. Department of Health and Human Services. (2017). Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm
Wierda, W. G., & Tambaro, F. P. (2020). How I manage CLL with venetoclax-based treatments. Blood, 135(17), 1421–1427. https://doi.org/10.1182/blood.2019002841
Winkler, U., Jensen, M., Manzke, O., Schulz, H., Diehl, V., & Engert, A. (1999). Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (Rituximab, IDEC-C2B8). Blood, 94(7), 2217–2224. https://doi.org/10.1182/blood.V94.7.2217.419k02_2217_2224
