Pre-emptive Anakinra for Cytokine Event Reduction

Summary

Objectives: The primary objective of this study will be to evaluate the impact of pre-emptive use of anakinra on the rate of severe cytokine release syndrome (CRS) following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for B-acute lymphoblastic leukemia (B-ALL) in children and young adults. Patient Population: Children and young adults \<25 years of age undergoing CAR T-cell therapy for B-ALL with bone marrow disease burden of ≥5% involvement or detectable peripheral blasts within 2 weeks of the initiation of lymphodepleting chemotherapy. Study Design: This is a pilot single arm study. The investigators will inquire into the efficacy and safety of using anakinra pre-emptively to reduce the rate of severe CRS in patients with \>/=5% bone marrow blasts or lymphoblasts in the peripheral blood. Treatment Plan: This is a single arm unblinded study in which patients will receive anakinra, 2.5 mg/kg (max 100mg), IV every 12 hours starting at the onset of persistent fever (fever \>38.5⁰ C x 2 occurrences separated by at least 4 hours in a 24 hour period). If there is persistence or progression of CRS, anakinra frequency will be increased to 2.5mg/kg IV (max 100mg), every 6 hours. Anakinra will be continued until 48 hours after resolution of CRS and ICANS, and at least 7 days post-CAR T infusion. If dose and frequency of anakinra is increased, the increased dose of anakinra will be continued until 48 hours after resolution of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) and at least 7 days post-CAR T infusion. For CRS worsening beyond dose escalation of anakinra, CRS will be managed as per standard of care management. Participants will be followed for 12 months following enrollment in the study and disease evaluations will be performed as per routine clinical care following CAR T-cell therapy.

Timeline

Start

2026-10

Primary completion

2029-08-31

Completion

2030-02-28

Publications

• Background Gazeau N, Liang EC, Wu QV, Voutsinas JM, Barba P, Iacoboni G, Kwon M, Ortega JLR, Lopez-Corral L, Hernani R, Ortiz-Maldonado V, Martinez-Cibrian N, Martinez AP, Maziarz RT, Williamson S, Nemecek ER, Shadman M, Cowan AJ, Green DJ, Kimble E, Hirayama AV, Maloney DG, Turtle CJ, Gauthier J. Anakinra for Refractory Cytokine Release Syndrome or Immune Effector Cell-Associated Neurotoxicity Syndrome after Chimeric Antigen Receptor T Cell Therapy. Transplant Cell Ther. 2023 Jul;29(7):430-437. doi: 10.1016/j.jtct.2023.04.001. Epub 2023 Apr 7.
• Background Hines MR, Knight TE, McNerney KO, Leick MB, Jain T, Ahmed S, Frigault MJ, Hill JA, Jain MD, Johnson WT, Lin Y, Mahadeo KM, Maron GM, Marsh RA, Neelapu SS, Nikiforow S, Ombrello AK, Shah NN, Talleur AC, Turicek D, Vatsayan A, Wong SW, Maus MV, Komanduri KV, Berliner N, Henter JI, Perales MA, Frey NV, Teachey DT, Frank MJ, Shah NN. Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome. Transplant Cell Ther. 2023 Jul;29(7):438.e1-438.e16. doi: 10.1016/j.jtct.2023.03.006. Epub 2023 Mar 9.
• Background Rejeski K, Subklewe M, Aljurf M, Bachy E, Balduzzi A, Barba P, Bruno B, Benjamin R, Carrabba MG, Chabannon C, Ciceri F, Corradini P, Delgado J, Di Blasi R, Greco R, Houot R, Iacoboni G, Jager U, Kersten MJ, Mielke S, Nagler A, Onida F, Peric Z, Roddie C, Ruggeri A, Sanchez-Guijo F, Sanchez-Ortega I, Schneidawind D, Schubert ML, Snowden JA, Thieblemont C, Topp M, Zinzani PL, Gribben JG, Bonini C, Sureda A, Yakoub-Agha I. Immune effector cell-associated hematotoxicity: EHA/EBMT consensus grading and best practice recommendations. Blood. 2023 Sep 7;142(10):865-877. doi: 10.1182/blood.2023020578.
• Background Kineret. Package Insert. Biovitrum AB. December 18th.
• Background Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY, Eldjerou L, Gardner RA, Frey N, Curran KJ, Peggs K, Pasquini M, DiPersio JF, van den Brink MRM, Komanduri KV, Grupp SA, Neelapu SS. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638. doi: 10.1016/j.bbmt.2018.12.758. Epub 2018 Dec 25.
• Background Strati P, Jallouk A, Deng Q, Li X, Feng L, Sun R, Adkins S, Johncy S, Cain T, Steiner RE, Ahmed S, Chihara D, Fayad LE, Iyer SP, Horowitz S, Nastoupil LJ, Nair R, Hassan A, Daoud TE, Hawkins M, Rodriguez MA, Shpall EJ, Ramdial JL, Kebriaei P, Hong DS, Westin JR, Neelapu SS, Green MR. A phase 1 study of prophylactic anakinra to mitigate ICANS in patients with large B-cell lymphoma. Blood Adv. 2023 Nov 14;7(21):6785-6789. doi: 10.1182/bloodadvances.2023010653. No abstract available.
• Background Liang EC, Albittar A, Portuguese AJ, Huang JJ, Wuliji N, Wu Q, De Los Reyes J, Pin N, Torkelson A, Kirchmeier DR. Planned Interim Analysis of a Phase 2 Investigator-Initiated Trial of Anakinra to Prevent CRS and Neurotoxicity after Treatment with Lisocabtagene Maraleucel. Transplantation and Cellular Therapy. 2024;30(2):S179-S80.
• Background Frigault MJ, Gallagher KM, Wehrli M, Valles B, Casey K, Lindell K, Trailor M, Cho H, Brown JL, Horick NK. A phase II trial of anakinra for the prevention of CAR-T cell mediated neurotoxicity. Blood. 2021;138:2814.
• Background Park JH, Nath K, Devlin SM, Sauter CS, Palomba ML, Shah G, Dahi P, Lin RJ, Scordo M, Perales MA, Shouval R, Tomas AA, Cathcart E, Mead E, Santomasso B, Holodny A, Brentjens RJ, Riviere I, Sadelain M. CD19 CAR T-cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: phase 2 trial interim results. Nat Med. 2023 Jul;29(7):1710-1717. doi: 10.1038/s41591-023-02404-6. Epub 2023 Jul 3.
• Background Hines MR, Keenan C, Maron Alfaro G, Cheng C, Zhou Y, Sharma A, Hurley C, Nichols KE, Gottschalk S, Triplett BM, Talleur AC. Hemophagocytic lymphohistiocytosis-like toxicity (carHLH) after CD19-specific CAR T-cell therapy. Br J Haematol. 2021 Aug;194(4):701-707. doi: 10.1111/bjh.17662. Epub 2021 Jul 15.
• Background Dreyzin A, Jacobsohn D, Angiolillo A, Wistinghausen B, Schore RJ, Perez E, Wells E, Terao J, Bonifant C, Rohatgi R, Dave H, Vatsayan A. Intravenous anakinra for tisagenlecleucel-related toxicities in children and young adults. Pediatr Hematol Oncol. 2022 May;39(4):370-378. doi: 10.1080/08880018.2021.1988012. Epub 2021 Oct 21. No abstract available.
• Background Lichtenstein DA, Schischlik F, Shao L, Steinberg SM, Yates B, Wang HW, Wang Y, Inglefield J, Dulau-Florea A, Ceppi F, Hermida LC, Stringaris K, Dunham K, Homan P, Jailwala P, Mirazee J, Robinson W, Chisholm KM, Yuan C, Stetler-Stevenson M, Ombrello AK, Jin J, Fry TJ, Taylor N, Highfill SL, Jin P, Gardner RA, Shalabi H, Ruppin E, Stroncek DF, Shah NN. Characterization of HLH-like manifestations as a CRS variant in patients receiving CD22 CAR T cells. Blood. 2021 Dec 16;138(24):2469-2484. doi: 10.1182/blood.2021011898.
• Background Diorio C, Vatsayan A, Talleur AC, Annesley C, Jaroscak JJ, Shalabi H, Ombrello AK, Hudspeth M, Maude SL, Gardner RA, Shah NN. Anakinra utilization in refractory pediatric CAR T-cell associated toxicities. Blood Adv. 2022 Jun 14;6(11):3398-3403. doi: 10.1182/bloodadvances.2022006983. No abstract available.
• Background Summerlin J, Wells DA, Anderson MK, Halford Z. A Review of Current and Emerging Therapeutic Options for Hemophagocytic Lymphohistiocytosis. Ann Pharmacother. 2023 Jul;57(7):867-879. doi: 10.1177/10600280221134719. Epub 2022 Nov 9.
• Background Hines MR, von Bahr Greenwood T, Beutel G, Beutel K, Hays JA, Horne A, Janka G, Jordan MB, van Laar JAM, Lachmann G, Lehmberg K, Machowicz R, Miettunen P, La Rosee P, Shakoory B, Zinter MS, Henter JI. Consensus-Based Guidelines for the Recognition, Diagnosis, and Management of Hemophagocytic Lymphohistiocytosis in Critically Ill Children and Adults. Crit Care Med. 2022 May 1;50(5):860-872. doi: 10.1097/CCM.0000000000005361. Epub 2021 Oct 5.
• Background Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, Cron RQ, Opal SM. Interleukin-1 Receptor Blockade Is Associated With Reduced Mortality in Sepsis Patients With Features of Macrophage Activation Syndrome: Reanalysis of a Prior Phase III Trial. Crit Care Med. 2016 Feb;44(2):275-81. doi: 10.1097/CCM.0000000000001402.
• Background Sonmez HE, Demir S, Bilginer Y, Ozen S. Anakinra treatment in macrophage activation syndrome: a single center experience and systemic review of literature. Clin Rheumatol. 2018 Dec;37(12):3329-3335. doi: 10.1007/s10067-018-4095-1. Epub 2018 Apr 16.
• Background Mehta P, Cron RQ, Hartwell J, Manson JJ, Tattersall RS. Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome. Lancet Rheumatol. 2020 Jun;2(6):e358-e367. doi: 10.1016/S2665-9913(20)30096-5. Epub 2020 May 4.
• Background Charlesworth JEG, Kavirayani A. Intravenous anakinra for the treatment of haemophagocytic lymphohistiocytosis/macrophage activation syndrome: A systematic review. Eur J Haematol. 2023 Sep;111(3):458-476. doi: 10.1111/ejh.14029. Epub 2023 Jun 21.
• Background Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M, Sanvito F, Ponzoni M, Doglioni C, Cristofori P, Traversari C, Bordignon C, Ciceri F, Ostuni R, Bonini C, Casucci M, Bondanza A. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018 Jun;24(6):739-748. doi: 10.1038/s41591-018-0036-4. Epub 2018 May 28.
• Background Giavridis T, van der Stegen SJC, Eyquem J, Hamieh M, Piersigilli A, Sadelain M. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med. 2018 Jun;24(6):731-738. doi: 10.1038/s41591-018-0041-7. Epub 2018 May 28.
• Background McNerney KO LS, Ishikawa K, Dreyzin A, Vatsayan A, Chen JJ, Baggott C, Prabhu S, Pacenta H, Phillips CL, Rossoff J, Stefanski HE, Talano JA, Moskop A, Verneris M, Myers D, Karras NA, Brown P, Bonifant C, Qayed M, Hermiston M, Satwani P, Krupski C, Keating AK, Baumeister S, Fabrizio VA, Chinnabhandar V, Egeler E, Mavroukakis S, Curran KJ, Mackall CL, Laetsch TW, Schultz LM. . HLH-like toxicities predict poor survival following use of tisagenlecleucel in children and young adults with B-ALL. Blood Adv. 2023. doi: https://doi.org/10.1182/bloodadvances.2022008893.
• Background Kadauke S, Myers RM, Li Y, Aplenc R, Baniewicz D, Barrett DM, Barz Leahy A, Callahan C, Dolan JG, Fitzgerald JC, Gladney W, Lacey SF, Liu H, Maude SL, McGuire R, Motley LS, Teachey DT, Wertheim GB, Wray L, DiNofia AM, Grupp SA. Risk-Adapted Preemptive Tocilizumab to Prevent Severe Cytokine Release Syndrome After CTL019 for Pediatric B-Cell Acute Lymphoblastic Leukemia: A Prospective Clinical Trial. J Clin Oncol. 2021 Mar 10;39(8):920-930. doi: 10.1200/JCO.20.02477. Epub 2021 Jan 8.
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• Background Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018 Feb 1;378(5):439-448. doi: 10.1056/NEJMoa1709866.

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Indications