Management of T-Cell Engaging Immunotherapy Complications

Abstract

The advent of T-cell–mediated immunotherapy has led to a new era in the treatment of relapsed, refractory B-cell lymphomas and leukemias. Chimeric antigen receptor T-cell and engineered T-cell receptor therapies have demonstrated impressive efficacy in treating refractory disease. The principal toxicities of these therapies include cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome (ICANS), but others exist as well. Cytokine release syndrome and ICANS are typically acute events occurring within 30 days of therapy, but other on-target/off-tissue toxicities may persist for years. There is no currently accepted single approach to managing all aspects of cytokine release syndrome and ICANS. However, there are clear trends in many areas and a clear need for further consensus surrounding others. This article will discuss T-cell–mediated immunotherapy complications and their suggested management. It is not intended to be comprehensive or applicable to every patient, so practitioners should exercise sound clinical judgment. Rather, this may serve as a starting point for further management discussions in the community.

Side-effect management of chimeric antigen receptor (CAR) T-cell therapy

“…51 ICANS can occur concomitantly with CRS, after resolution of CRS or independently of CRS. 31,74,88 In the latter case, neurological symptoms tend to be mild. 100 Usually, ICANS presents 4-5 days after CAR T-cell administration, 101 but delayed ICANS occurring 3-4 weeks after CAR T-cell treatment has also been reported.…”

“…40 For patients with clinical deterioration despite at least two doses of tocilizumab as well as for patients with increased risk of severe CRS and neurotoxicity, additional treatment with corticosteroids should be considered. 47,53,74 In contrast to tocilizumab, corticosteroids exert non-specific anti-inflammatory effects that abrogate inflammation by inhibiting CAR T cells as well as bystander immune cells. 75 Although initial studies reported reduced expansion and lacking persistence of CAR T cells in patients who received corticosteroids, 3 early steroid use in subsequent studies has not been associated with detrimental effects on clinical remission rates or CAR T cell persistence.…”

“…dexamethasone 10-20 mg or its equivalent of methylprednisolone. 51,53,74 To prevent further deterioration and end-organ damage, vasopressors and/or high-flow oxygen (via nasal cannula, face mask, or Venturi mask) 51,53,74 are advised. Regarding vasopressors, norepinephrine has been most widely used as first-line adrenergic agonist for hemodynamic support in CRS patients.…”

“…Here, management as in grade 3 should be continued, with methylprednisolone 1000 mg/day being used as corticosteroid of choice. 51,53,74,87 With early and aggressive management, even high-grade CRS is reversible. 74 As experience with CAR T cells and their related toxicities is growing, the rate of ICU admissions after CAR T-cell treatment compared with early CAR T-cell trials, in which approximately 45%-50% of patients required intensive care treatment, 14,88 has significantly decreased.…”

“…51,53,74,87 With early and aggressive management, even high-grade CRS is reversible. 74 As experience with CAR T cells and their related toxicities is growing, the rate of ICU admissions after CAR T-cell treatment compared with early CAR T-cell trials, in which approximately 45%-50% of patients required intensive care treatment, 14,88 has significantly decreased. 89 Of note, resolution of CRS can result in an anti-CRS syndrome with patients experiencing hypothermia and bradycardia 74 that has been associated with shifts in cytokine levels.…”