Despite unprecedented efficacy, 1 the use of axicabtagene ciloleucel (axi-cel) for the treatment of patients with relapsed or refractory large B-cell lymphoma (LBCL) remains associated with acute toxicity, such as grade $3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), occurring in 11% and 32% of patients, respectively. 2 Analysis of 44 different analytes in the serum of patients with relapsed or refractory LBCL treated with axi-cel showed that an increase in IL-6 or IL-1 may be associated with such toxicity. 3 However, in 2 murine models, whereas IL-6 blockade (typically achieved in clinical practice with the use of tocilizumab) prevented CRS only, only IL-1 blockade prevented both CRS and/or ICANS. 4,5 IL-1 blockade can be clinically achieved with the use of anakinra, an IL-1 receptor antagonist, currently approved by the US Food and Drug Administration for the treatment of patients with rheumatoid arthritis and neonatal-onset multisystem inflammatory disease. 6,7 Anakinra is also used off label for the treatment of secondary hemophagocytic lymphohistiocytosis (HLH), a condition in the spectrum of CRS potentially associated with chimeric antigen receptor (CAR) T-cell therapy. 8,9 Data regarding the clinical use of anakinra for the mitigation of axi-cel-associated toxicity have not been published.Patients with relapsed or refractory LBCL treated with standard axi-cel therapy, who received anakinra for mitigation of CAR T-cell therapy-associated toxicity at The University of Texas MD Anderson Cancer Center from September 2018 through September 2019, were eligible for this study. During this time, 100 patients with relapsed or refractory LBCL were treated with standard-of-care axi-cel, 41 developed grade $3 ICANS, 9 had grade $3 CRS, and 5 had HLH. Among these, 8 patients with LBCL (6 with diffuse LBCL and 2 with transformed follicular lymphoma) were treated with anakinra. CRS and ICANS were prospectively graded according to the CAR toxicity (CARTOX) grading system. 10 An unpaired Student t test was used for area-under-the-curve comparisons.
With anthracycline-based regimens such as R-CHOP and R-EPOCH, very elderly patients with DLBCL had superior outcomes similar to those achieved for younger patients with DLBCL. Cancer 2016;122:3145-51. © 2016 American Cancer Society.
Summary Primary and secondary central nervous system lymphomas (PCNSL/SCNSL) are aggressive rare malignancies with dismal outcomes. Encouraging data have emerged from Phase I/II clinical trials treating relapsed/refractory PCNSL/SCNSL with ibrutinib. We analysed 33 patients who received ibrutinib, alone or with other therapies, for PCNSL (n = 9) or SCNSL (n = 24). The objective response rate was 58% (complete response 55%). The median progression‐free survival and overall survival for patients with PCNSL were both 3·1 months; for SCNSL, 10·2 and 11·5 months respectively. Only one invasive fungal infection was observed, despite concurrent or recent use of dexamethasone 8–16 mg daily in 14 patients (42%). Ibrutinib has encouraging activity in these aggressive malignancies.
Patients with B-cell hematologic malignancies who progress through first- or second-line chemotherapy have a poor prognosis. Early clinical trials with autologous anti-CD19 chimeric antigen receptor (CAR) T cells have demonstrated promising results for patients who have relapsed or refractory disease. Lymphodepleting conditioning regimens, including cyclophosphamide, fludarabine, pentostatin, bendamustine, interleukin-2, and total body irradiation, are often administered before the infusion of CAR T cells, allowing for greater T-cell expansion. The major toxicity associated with CAR T-cell infusions is cytokine release syndrome (CRS), a potentially life-threatening systemic inflammatory disorder. The quick onset and progression of CRS require rapid detection and intervention to reduce treatment-related mortality. Management with tocilizumab can help ameliorate the symptoms of severe CRS, allowing steroids, which diminish the expansion and persistence of CAR T cells, to be reserved for tocilizumab-refractory patients. Other toxicities of CAR T-cell therapy include neutropenia and/or febrile neutropenia, infection, tumor lysis syndrome, neurotoxicity and nausea/vomiting. A review of patients' medications is imperative to eliminate medications that may contribute to treatment-related toxicities. Studies are ongoing to help optimize patient selection, preparation, safety, and management of individuals receiving CAR T cells. Long-term follow-up will help establish the place of CAR T cells in therapy.
Idelalisib is a well-tolerated and effective treatment for patients with relapsed or refractory CLL or indolent NHL, providing a novel targeted therapeutic option for the management of these hematologic malignancies.
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