Cytokine Release Syndrome Associated with Treatment for Acute Lymphoblastic Leukemia

Web Exclusives - Acute Lymphoblastic Leukemia

Cytokine release syndrome (CRS) is a systemic inflammatory response that may occur with the use of T-cell–engaging therapies, wherein antigen–antibody interactions cause T-cell activation and release of inflammatory cytokines.1,2 In patients with CRS, interleukin-6 is the predominantly elevated cytokine, but interleukin-10, interferon-γ, and TNF-α may also be involved.3

In the setting of acute lymphoblastic leukemia (ALL), use of bispecific antibodies and chimeric antigen receptor T-cell (CAR-T) therapy has been associated with the development of CRS.1 In patients with ALL, CD19-directed immunotherapies have been associated with the development of CRS.4 Bispecific antibodies, such as the bispecific CD19-directed CD3 T-cell engager, blinatumomab,5 and the CD19-directed genetically modified autologous T-cell immunotherapy, tisagenlecleucel, promote T-cell expansion but are unarmed, so they produce rapid but short-lived CRS.1 In contrast, CAR-T therapy introduces armed T-cells that expand in vivo to cause delayed-onset but prolonged CRS.1

CRS risk varies by disease factors as well as specific therapy. High disease burden is the most important risk factor for CRS development,6 but the first dose, circulating disease, preexisting inflammation with active infection, high ferritin, or high C-reactive protein levels also increase risk.3 CRS is both more common and more severe with CAR-T than with bispecific antibody therapy.2 In clinical trials of pediatric and adult patients with ALL receiving CAR-T, the incidence of CRS ranged from 59% to 90%, and the incidence of serious CRS ranged from 12% to 29%.7 In contrast, clinical trials of bispecific antibodies show CRS incidence rates ranging from 3% to 14% and grade ≥3 CRS incidence rates ranging from 0% to 6%.6

The clinical presentation of CRS can vary from mild to severe, life-threatening disease. In mild CRS, patients may experience fever, malaise, headache, nausea, fatigue, rash, arthralgia, or myalgia.2,3 More severe disease may be characterized by hypoxia, hypotension, renal impairment, or acute liver injury.2 Life-threatening complications of pulmonary edema, capillary leak syndrome, disseminated intravascular coagulation, or hemophagocytic lymphohistiocytosis may also occur.2

Strategies to prevent CRS and minimize potential CRS severity include prephase treatment, premedication, and modification of therapeutic dose or infusion rate.8 Prephase cytoreduction should be considered for those with >50% blasts in the bone marrow, peripheral blast cell counts of ≥15,000 cells/µL, high extramedullary tumor load, or rapidly increasing lactate dehydrogenase levels.9,10 Premedication with dexamethasone is also recommended.6 For patients receiving blinatumomab, progressive dose escalation can also minimize CRS risk.9 Nurses involved in the care of patients being treated for ALL can help minimize CRS risk by (1) recognizing which patients are at highest risk; (2) recognizing when CRS is most likely to occur; (3) closely monitoring vital signs; and (4) anticipating the need for care-level escalation and treatment needs.8

Prompt recognition and treatment of CRS are crucially important. The National Comprehensive Cancer Network recommends that, for patients receiving blinatumomab who develop CRS, the infusion should be held, and corticosteroids and vasopressors should be considered for those with severe symptoms.10 Tocilizumab can also be considered for those with severe CRS following receipt of blinatumomab.10 For those receiving tisagenlecleucel, severe CRS should be managed with tocilizumab or steroids in cases of tocilizumab-refractory CRS.10 Signs and symptoms of serious infection may mimic those of CRS, so evaluation for underlying infection should be performed, and empiric antimicrobial therapy should be considered.10


  1. Longhitano AP, Slavin MA, Harrison SJ, Teh BW. Bispecific antibody therapy, its use and risks for infection: bridging the knowledge gap. Blood Rev. 2021;49:100810.
  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. Salvaris R, Ong J, Gregory GP. Bispecific antibodies: a review of development, clinical efficacy and toxicity in B-cell lymphomas. J Pers Med. 2021;11:355.
  4. Novartis Pharmaceuticals Corporation. Kymriah prescribing information. 2021. Accessed November 11, 2021.
  5. Amgen Inc. Blincyto prescribing information. 2021. Accessed November 11, 2021.
  6. Jain T, Litzow MR. Management of toxicities associated with novel immunotherapy agents in acute lymphoblastic leukemia. Ther Adv Hematol. 2020;11:2040620719899897.
  7. 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.
  8. Browne EK, Daut E, Hente M, et al. Evidence-based recommendations for nurse monitoring and management of immunotherapy-induced cytokine release syndrome: a systematic review from the Children’s Oncology Group. J Pediatr Oncol Nurs. 2021;38:399-409.
  9. 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.
  10. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: acute lymphoblastic leukemia. Version 2.2021. July 19, 2021. Accessed November 10, 2021.
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