Myeloma CAR-T CRS Management With IL-1R Antagonist Anakinra

Introduction

Chimeric antigen receptor T cell (CAR-T) therapy has demonstrated unprecedented clinical efficacy, leading to global approvals of anti-CD19 CAR-T cells for the treatment of relapsed B cell acute lymphoblastic leukemia and non-Hodgkin B cell lymphomas.^1–4 Engagement of CAR-T cells with tumor cells causes proliferation and release of cytokines, resulting in the death of tumor cells but also causes systemic inflammatory state characterized by high fever, tachycardia, hemodynamic instability, tachypnea, hypoxia, hemophagocytic lymphohistiocytosis, neurotoxicity, and otherorgan damage.^5–7 Managementofthese symptoms can be challenging and fatal in the worst cases.^7,8

Interleukin (IL)-6 was first identified as a key inflammatory cytokine that mediates CAR-T cell toxicity⁹ in the leukemia setting. Consequently, the anti-IL-6 biologic, tocilizumab, administered alone or with steroids remains the first line of therapy for cytokine release syndrome (CRS).¹⁰ However, tocilizumab has been ineffective in treating neurotoxicity and hemophagocytic lymphohistiocytosis,¹⁰ which may ensue after CAR-T therapy.

Recently, 2 independent preclinical studies in humanized B-cell acute lymphoblastic leukemia mouse models of CAR-T CRS and neurotoxicity have independently implicated IL-1, in addition to IL-6, as a key inflammatory cytokine responsible for these life-threatening side effects.^11,12 In both studies, the use of the IL-1R antagonist anakinra alone and in combination with tocilizumab counteracted CAR-T CRS, leading to increased overall survival more effectively than the anti-IL6 alone. Based on these preclinical studies, we have incorporated anakinra into the management of CRS at our institution and contrast a patient treated with tocilizumab alone with another patient where combination therapy with tocilizumab and anakinra resolved CRS following anti-B-cell maturation antigen (BCMA) CAR-T therapy for myeloma.

Case Reports

Case 1

A 71-year-old male with IgA kappa myeloma was admitted for anti-BCMA CAR-T therapy. He was initially diagnosed 15 years before and had received 12 lines of therapy, including 2 proteasome inhibitors (bortezomib and carfilzomib), 3 immunomodulatory drugs (IMiDs) (thalidomide, lenalidomide, and pomalidomide), daratumumab, and 2 autologous stem cell transplants. He had received DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin) bridging followed by fludarabine/cyclophosphamide conditioning in preparation for his CAR-T infusion (See patient characteristics in Supplemental Table 1 in the online version). The patient developed fever (100.4°F) and chills with normal blood pressure (BP), oxygen saturation, and mental status (Immune effector cell-associated neurotoxicity syndrome [IEC-associated neurotoxicity] [ICANS] 10/10) 6 hours after CAR-T infusion. He was started on broad spectrum antibiotics empirically (vancomycin and daptomycin) and monitored overnight. At 5 am the next morning, he spiked fever (102.6°F) and continued to be hemodynamically and neurologically stable but febrile (104.2°F) with increase in C-reactive protein (CRP) from 21.5 to 50 ng/mL (Figure 1A). On day 2, he developed tachycardia (pulse, 110/min) and hypotension (BP, 86/39 mm Hg), consistent with CRS grade 3, and the patient was transferred to the intensive care unit (ICU) for closer monitoring. His BP did not have a sustained response to intravenous fluids, and he was given tocilizumab 4 mg/kg and started on vasopressor support (norepinephrine 10 mcg/hr), and his antibiotics were switched to imipenam. His CRP had increased to 201 ng/mL, and ferritin was > 22,000 mg/L (Figure 1A). He had a mild headache but no other signs of neurotoxicity (ICANS 10/10). On day 4, he continued to have fever to 101.8°F but was titrated off vasopressor support. His CRP was trending down, whereas his ferritin kept rising (Figure 1A). The patient remained febrile (101.7°F) but hemodynamically stable, with no growth on blood cultures and was transferred out of the ICU on day 5. He continued to have fever and headache on day 6 and day 7; magnetic resonance imaging of the brain was done but did not show any abnormalities such as edema or bleeding. His fever resolved on day 8 and headache on day 9, the antibiotics were discontinued, and the patient was discharged home on day 16. Longitudinal cytokine profiling confirmed elevated levels of CRS cytokines IL-2, interferon (IFN)g, IL-6, IL-10, IL-18, and sIL-2RA mirroring the clinical course of CRS (Figures 1C and 2).

Figure 1. Clinical Data and Serum Biomarkers Levels for 2 anti-BCMA CAR-T CRS Patients. A, Patient #1 Treated With Tocilizumab Alone. B, Patient #2 Treated With Combination Tocilizumab and Anakinra. C and D, Heat Map of Cytokine Levels Over Time. Scale Indicates Serum Levels (pg/mL).

Abbreviations: A = anakinra; BCMA = B-cell maturation antigen; BID = two times daily; BPM = beats per minute; CAR-T = chimeric antigen receptor T-cell; CRP = C-reactive protein; CRS = cytokine release syndrome; IFN = interferon; IL = interleukin; QD = once daily; T = tocilizumab; TID = three times daily; TNF = tumor necrosis factor; V = vasopressor.

Figure 2. Longitudinal Analysis of Inflammatory Cytokines in 2 CAR-T CRS Patients. Patient #1 (Blue) Treated With Tocilizumab Alone and Patient #2 (Orange) Treated With Combination Tocilizumab-Anakinra.

Abbreviations: CAR-T = chimeric antigen receptor T-cell; CRS = cytokine release syndrome; IFN = interferon; IL = interleukin; TNF = tumor necrosis factor.

Case 2

A 61-year-old male with immunoglobulin (Ig)G lambda myeloma was diagnosed 2 years before when he presented with shoulder pain from a lytic lesion in his right humerus. He subsequently progressed through 2 proteasome inhibitors (bortezomib, carfilzomib), 2 IMiDs (lenalidomide, pomalidomide), high-dose melphalan-based stem cell transplant, and daratumumab (See patient characteristics in Supplemental Table 1 in the online version). Following T-cell apheresis, he was given daratumumab, pomalidomide, and dexamethasone as bridging therapy for 3 weeks, which was stopped owing to influenza pneumonitis. Upon recovery, he underwent lymphodepletion with fludarabine and cyclophosphamide, followed by anti-BCMA CAR-T infusion.

He developed fever the same evening after infusion (101.8°F) without hypotension or CNS symptoms (ICANS 10/10) consistent with American Society for Transplantation and Cellular Therapy grade 1 CRS (Figure 1B). He had no clear infectious source and, being neutropenic (0.5 k/μl), was empirically started on cefepime and vancomycin. His fever continued on day 2 after CAR-T (104.2°F), and the patient required intravenous fluids owing to hypotension (BP, 83/49 mm Hg). He therefore started on tocilizumab 8 mg/kg for American Society for Transplantation and Cellular Therapy grade 2 CRS. He continued to be neurologically intact (ICE 10/10). He continued to spike fevers on day 3 (102.0°F) and was started on anakinra 200 mg subcutaneously 3 times a day for persistent fevers. He remained febrile on day 4 (102.0°F), day 5 (101.7°F), and day 6 (101.8°F), despite Tylenol alternating with Motrin. A repeat computed tomography (CT) scan showed resolving pneumonia attributed to influenza infection. He defervesced after a single fever (101.3°F) on the morning of day 7. He continued anakinra but decreased frequency from 3 times a day to twice a day on day 9. He continued anakinra until discharge on day 14. Longitudinal cytokine profiling was performed for assaying IL-2, IFNγ, IL-6, IL-10, and IL-18 levels, which mirrored clinical CRS but were consistently lower than for Patient #1. Tumor necrosis factor (TNF)-alpha levels were comparable between the 2 patients (Figures 1D and 2).

Discussion

In both patients, we administered tocilizumab at the onset of CRS. A wait and watch approach in Patient #1 led to grade 3 CRS and required ICU monitoring. For Patient #2, when symptoms were not mitigated with routine supportive care and his ferritin level continued to rise, anakinra was administered 3 times daily for 6 days until discharge from hospital. Given the much longer half-life of tocilizumab¹³ versus anakinra,¹⁴ a combination effect as seen in the preclinical setting¹² cannot be ruled out. However, the rapid improvement of clinical signs and symptoms as well as biochemical parameters following anakinra administration strongly suggests that anti-IL-1R therapy may limit the extent and duration of CRS when given as an adjunct to tocilizumab and obviate the need for additional doses of tocilizumab or steroids, which may increase immunosuppression and infectious risk in CAR-T patients.¹⁵ Further, there are theoretical concerns around steroids dampening CAR-T efficacy.

Real-time cytokine monitoring and a personalized approach incorporating IL-1R inhibition into the management of CRS could improve the safety of CAR-T cell therapies, as highlighted by the clinical examples in this report. There is a growing body of literature on the use of anakinra in patients with lymphoma/acute lymphoblastic leukemia treated with CAR-T cells, and it is being proposed as an alternative to tocilizumab in the United Kingdom.¹⁰

Conclusions

Given the recent insights implicating IL-1 in the biology of CRS and our own clinical experience, we see merit in the use of anakinra as a valuable adjunct in the management of CRS following CAR-T therapy in myeloma.

Clinical Practice Points.

• Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T cell (CAR-T) cell therapy has demonstrated promising clinical efficacy in myeloma but is accompanied by cytokine release syndrome (CRS), wherein clinical management is challenging owing to lack of therapeutic options.

• Interleukin (IL)-6 inhibition with the monoclonal antibody tocilizumab, administered alone or with steroids is the most common approach for treating CRS currently. Anti-IL-1 therapy has a strong preclinical scientific rationale for CRS mitigation after CAR-T cell therapy and may complement current approaches.

• We contrast clinical features and laboratory parameters from 2 patients having CRS post anti-BCMA CAR-T infusion for myeloma, 1 treated with tocilizumab alone and the other illustrating the use of adjunctive anti-IL-1R therapy with anakinra.

• We therefore see merit in the use of IL-1 inhibition as a valuable adjunct in the management of CRS following CAR-T therapy in myeloma.