Use of long-term corticosteroids in patients treated with CAR T-cell therapy

Introduction

Chimeric antigen receptor (CAR) T-cell therapy has emerged as an effective treatment for patients with relapsed refractory B-cell lymphomas. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are common toxicities that are manageable. In ZUMA-2, the pivotal trial for brexucabtagene autoleucel in relapsed and refractory mantle cell lymphoma (MCL), CRS and ICANS occurred in 91% and 63% of patients, respectively. Severe grade 3 or higher ICANS was less common, occurring in 31% of patients in the ZUMA-2 trial, and required the use of corticosteroids with or without an Interleukin (IL)-6 receptor antagonist. ¹

Case report

We present the unique case of a 65-year-old male who received CAR T-cell therapy with brexucabtagene autoleucel for stage I/II MCL of the tonsils (blastoid variant, Tp53 wild-type, Ki67 95%, SOX11 positive) and achieved a complete remission despite receiving a prolonged course of corticosteroids for severe ICANS. With heavily pretreated relapsed refractory disease (six prior lines of therapy), the patient was slated to undergo CAR T-cell therapy with brexucabtagene autoleucel. He completed three days of fludarabine and cyclophosphamide lymphodepleting therapy then one day prior to CAR T infusion, the patient started experiencing intractable frontal headaches. Imaging studies including CT head and MRI brain showed new leptomeningeal enhancement in the supratentorial region of the brain with subsequent lumbar puncture and flow cytometry confirming new involvement of his cerebrospinal fluid (CSF) by MCL. Due to the development of new central nervous system (CNS) disease, CAR T-cell therapy was delayed and the patient received treatment with ibrutinib and twice-weekly intrathecal chemotherapy, leading to clearance of CSF by flow cytometry seven days after the diagnosis of CNS involvement. Three weeks after diagnosis of CNS involvement and two weeks after clearance of CSF, he was restarted on lymphodepletion, but was only given one day of chemotherapy due to significant pancytopenia (white blood count 0.08 k/mm³, absolute neutrophil count 0.02 k/mm³, hemoglobin 7.8 gm/dL, platelets 27 k/mm³). On day 0, brexucabtagene autoleucel was infused in the outpatient setting with subsequent admission for post-infusion monitoring per institutional protocol. On day + 1, the patient developed fever with grade 1 CRS, and tocilizumab was administered the next day due to fever persisting more than 24 h per institutional policy. Tocilizumab was repeated on two subsequent days for persistent fevers for a total of three doses with a maximum CRS of grade 2 due to hypotension. On day + 4, the patient's neurologic status declined with a CT head showing a new left frontoparietal subdural hematoma (SDH) (6 mm) without significant mass effect.

Continuous electroencephalogram (EEG) showed no epileptiform abnormalities. Patient received dexamethasone 10 mg every 8 h with some neurologic improvement. On day + 6, the patient developed status epilepticus requiring lorazepam, levetiracetam, and dexamethasone, transfer to the intensive care unit, as well as chemical sedation and mechanical intubation for airway protection. A repeat CT head showed no interval change in the SDH. He received methylprednisolone 1 g for ICANS grade 4 followed by methylprednisolone 500 mg every 12 h in addition to multiple antiepileptic therapies. Both steroids and sedation were weaned off, and the patient was extubated on day + 14, able to follow simple commands (immune effector cell-associated encephalopathy [ICE] score 4, ICANS grade 2). On day + 17, he had subclinical seizures noted on continuous EEG requiring a seven-day course of anakinra, an IL-1 receptor antagonist His ICE score and ICANS continued to fluctuate (ICE score 4-6, ICANS grade 2) with a possible contribution from hospital-associated delirium. As dexamethasone was tapered to 6 mg daily, the patient developed acute mental status changes on day + 38 (ICE score 2, ICANS grade 3) and dexamethasone was increased to 10 mg every 8 h with significant improvement in symptoms. An extensive work-up including an MRI brain, CSF analysis, and EEG were all negative and his altered mental status was attributed to a relapse of ICANS. Over the next month, he tolerated a slow steroid taper and was eventually discharged from the hospital on day + 52 with an ICE score of 6 and ICANS grade 2. He continued his slow steroid taper in the outpatient setting completing it on day + 97 post CAR T-cell infusion, with complete resolution of neurotoxicity and return to baseline mental status. His cumulative dexamethasone-equivalent exposure was 2019 mg over 93 days. Disease status assessment was deferred for clinical improvement and on his day + 100 disease restaging; bone marrow biopsy, CSF analysis, and whole-body positron emission tomography-computed tomography (PET/CT) scan were consistent with a complete response (Figure 1(a) and (b)). Figure 2 illustrates the relevant clinical course with changes in ICANS, ICE score and corticosteroid administration.

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Figure 1.

(a) PET/CT prior to CAR T therapy. (b) PET/CT day + 100 post CAR T therapy.

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Figure 2.

Time to event graph representing ICANS with grade, use of tocilizumab, dexamethasone (dex), and anakinra.

Discussion

Brexucabtagene autoleucel is an anti-CD19 CAR T-cell therapy that can lead to durable remission in patients with relapsed refractory MCL after the failure of Bruton tyrosine kinase inhibitors. ¹ Common toxicities associated with this CAR T-cell therapy include CRS, ICANS, cytopenias and infections. In the pivotal trial evaluating the safety and efficacy of brexucabtagene autoleucel for relapsed refractory MCL, ZUMA-2, ICANS was seen in 63% of the patients with grade 3 or higher ICANS seen in 31% of the patients. Approximately 38% of the patients received corticosteroids for CRS and/or ICANS. This may be related to the disease burden/distribution where patients with MCL tend to have an extranodal disease and leukemic phase, accounting for CAR T-cell expansion and toxicity with a CD28 costimulatory domain. Although corticosteroids mitigate toxicities by inhibiting the proliferation and inflammatory cytokine production from CAR T-cells, ² their impact on CAR T-cell expansion and durability of response remains unknown. Hence, dose, duration and timing of corticosteroid use after CAR T-cell therapy remain clinically relevant unanswered questions. In the pivotal cohorts (cohort 1 and 2) of the ZUMA-1 trial evaluating the safety and efficacy of axicabtagene ciloleucel for aggressive large B-cell lymphoma, corticosteroids were reserved for grade 3 or higher CRS and ICANS and did not impact clinical response or durability. ³ Similarly, real-world experience with axicabtagene ciloleucel where corticosteroids were used for lower grade and early-onset toxicities did not reveal any concerns for compromised efficacy and durability of CAR T-cell therapy. ⁴ However, there is a single-center report involving axicabtagene ciloleucel raising concerns that early-onset and long-term use of corticosteroids is associated with inferior progression-free and overall survival, regardless of baseline tumor burden and CAR-T product characteristics. ⁵ This case highlights that grade 3 or higher ICANS can have a long-protracted course with a remitting relapsing pattern of neurotoxicity requiring a prolonged course of corticosteroids, multiple antiepileptic drugs, with the eventual recovery of neurological function without compromising efficacy and durability of CAR T-cell therapy. This case also raises questions about the intensity of lymphodepleting chemotherapy. Despite the inadequate duration of lymphodepleting chemotherapy (for only one day) due to significant cytopenias from full lymphodepletion completed 25 days prior, the patient developed severe ICANS, indicative of CAR T-cell expansion and penetration of blood–brain barrier, and achieved durable disease control. Lymphodepleting chemotherapy prior to CAR T-cell therapy plays a vital role in tumor debulking, alteration of tumor phenotype, modification of tumor microenvironment and suppression of host immune system. ⁶ Although preclinical studies have established that B-cell lymphomas treated with CAR T-cell therapy without pre-infusion lymphodepletion have poor cell expansion, ⁷ ideal combinations including doses and duration of lymphodepleting chemotherapeutic agents need further exploration to optimize the persistence and efficacy of the infused CAR T-cells. Whether fludarabine and cyclophosphamide can be dose reduced or eliminated for patients at risk of excessive toxicities with underlying comorbidities such as renal dysfunction and/or poor bone marrow reserve remains an unanswered question. Another novel aspect of this case was the presence of CNS disease prior to CAR T-cell therapy requiring systemic and intrathecal chemotherapy. Because of concerns for ICANS, patients with active CNS involvement have historically been excluded from pivotal studies evaluating CAR T-cell therapy for non-Hodgkin lymphomas. Per the U.S. Food and Drug Administration label, CD19-directed CAR T-cell therapies are approved for aggressive B-cell lymphomas with a specific exclusion for primary, but not secondary CNS lymphoma. A case report has previously demonstrated the efficacy of CD19-directed CAR T-cell therapy in a patient with simultaneous CNS and systemic involvement. ⁸ Similarly, Frigault et al. reported a cohort of eight patients treated with tisagenlecleucel for active secondary CNS lymphoma without excessive neurotoxicity. ⁹ Wang et al. reported the use of antithymocyte globulin (ATG) for grade 4 ICANS related to cerebral edema in a patient receiving brexucabtagene autoleucel for relapsed refractory MCL, where the use of ATG was associated with a rapid decline in CAR T-cells and pro-inflammatory cytokine levels leading to clinical resolution of severe ICANS. ¹⁰ An ongoing clinical trial is evaluating the safety and efficacy of CD19-directed CAR T-cell therapy in patients with CNS lymphoma including the history of or active disease at time of enrollment. ¹¹ With limited options for curative treatment after first relapse, CNS lymphomas continue to remain an area of unmet need. Future directions that need further exploration include more effective CNS-directed bridging chemotherapy, prophylactic use of corticosteroids and IL-6/IL-1 antagonists to mitigate excessive toxicity, and intraventricular route of CAR T-cells delivery for improved antitumor effects. Retrospective analysis of the safety and efficacy data in this patient population with CAR T consortiums and Center for International Blood and Marrow Transplant Research (CIBMTR) will add valuable information to the existing literature. Although limitations of this single case report include the lack of ability to generalize and extrapolate to other scenarios, this case describes the successful use of corticosteroids for the management of ICANS in a patient treated with CAR T-cell therapy for MCL.