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

Jatiani, Shashidhar S.; Aleman, Adolfo; Madduri, Deepu; Chari, Ajai; Cho, Hearn Jay; Richard, Shambavi; Richter, Joshua; Brody, Joshua; Jagannath, Sundar; Parekh, Samir

doi:10.1016/j.clml.2020.04.020

Cited by 38 publications

(37 citation statements)

References 11 publications

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“…Among our cohort of hospitalized patients, those who died appeared to exhibit rather elevated pro-inflammatory cytokines, consistent in principle with what was seen in a large COVID-19 cohort analyzed at the Mount Sinai Health System 33 . It is possible that a CRS-like syndrome, similar though not identical to one seen in MM patients treated with CAR-T 14,34 and bispecific antibodies 35,36 , occurs in a significant portion of MM patients afflicted with COVID-19. Various agents including but not limited to anti-IL-6 39 monoclonal antibodies and JAK inhibitors 40 are presently under investigation to address potential components of immune dysregulation in COVID-19.…”

Section: Discussionmentioning

confidence: 99%

A tertiary center experience of multiple myeloma patients with COVID-19: lessons learned and the path forward

Wang

Oekelen

Mouhieddine

et al. 2020

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Background: The COVID-19 pandemic, caused by SARS-CoV-2 virus, has resulted in over 100,000 deaths in the United States. Our institution has treated over 2,000 COVID-19 patients during the pandemic in New York City. The pandemic directly impacted cancer patients and the organization of cancer care. Mount Sinai Hospital has a large and diverse multiple myeloma (MM) population. Herein, we report the characteristics of COVID-19 infection and serological response in MM patients in a large tertiary care institution in New York. Methods: We performed a retrospective study on a cohort of 58 patients with a plasma-cell disorder (54 MM, 4 smoldering MM) who developed COVID-19 between March 1, 2020 and April 30, 2020. We report epidemiological, clinical and laboratory characteristics including persistence of viral detection by polymerase chain reaction (PCR) and anti-SARS-CoV-2 antibody testing, treatments initiated, and outcomes. Results: Of the 58 patients diagnosed with COVID-19, 36 were hospitalized and 22 were managed at home. The median age was 67 years; 52% of patients were male and 63% were non-white. Hypertension (64%), hyperlipidemia (62%), obesity (37%), diabetes mellitus (28%), chronic kidney disease (24%) and lung disease (21%) were the most common comorbidities. In the total cohort, 14 patients (24%) died. Older age (>70 years), male sex, cardiovascular risk, and patients not in complete remission (CR) or stringent CR were significantly (p<0.05) associated with hospitalization. Among hospitalized patients, laboratory findings demonstrated elevation of traditional inflammatory markers (CRP, ferritin, D-dimer) and a significant (p<0.05) association between elevated inflammatory markers, severe hypogammaglobulinemia, non-white race, and mortality. Ninety-six percent (22/23) of patients developed antibodies to SARS-CoV-2 at a median of 32 days after initial diagnosis. Median time to PCR negativity was 43 (range 19-68) days from initial positive PCR. Conclusions: Drug exposure and MM disease status at the time of contracting COVID-19 had no bearing on mortality. Mounting a severe inflammatory response to SARS-CoV-2 and severe hypogammaglobulinemia were associated with higher mortality. The majority of patients mounted an antibody response to SARS-CoV-2. These findings pave a path to identification of vulnerable MM patients who need early intervention to improve outcome in future outbreaks of COVID-19.

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Section: Discussionmentioning

confidence: 99%

A tertiary center experience of multiple myeloma patients with COVID-19: lessons learned and the path forward

Wang

Oekelen

Mouhieddine

et al. 2020

Preprint

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“…Two animal model studies have reported that IL-1 blockade can prevent CRS, thereby reducing mortality [ 49 , 50 ]. A case report of two patients using tocilizumab and anakinra (200 mg subcutaneous three times daily) in a patient treated with anti-BCMA CAR T was published recently [ 51 ]. Only one dose of tocilizumab was given and a taper of anakinra over the following 10 days was done.…”

Section: Management and Treatmentmentioning

confidence: 99%

“…The authors noticed significant improvement of the patient’s symptoms shortly after anakinra was initiated. They theorize that IL-1 blockage decreased the duration and severity of the CRS as well as the need for further tocilizumab doses [ 51 ]. In addition, a phase II clinical trial to explore the role of anakinra further is underway (NCT04359784).…”

Section: Management and Treatmentmentioning

confidence: 99%

Cardiotoxicity Associated with Anti-CD19 Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: Recognition, Risk Factors, and Management

et al. 2021

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Chimeric antigen receptor T-cells (CAR-T) are improving outcomes in pediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukemias and subtypes of non-Hodgkin Lymphoma. As this treatment is being increasingly utilized, a better understanding of the unique toxicities associated with this therapy is warranted. While there is growing knowledge on the diagnosis and treatment of cytokine release syndrome (CRS), relatively little is known about the associated cardiac events that occur with CRS that may result in prolonged length of hospital stay, admission to the intensive care unit for pressor support, or cardiac death. This review focuses on the various manifestations of cardiotoxicity, potential risk factors, real world and clinical trial data on prevalence of reported cardiotoxicity events, and treatment recommendations.

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“…Other clinical trials in progress or completed have reported encouraging results of targeting the IL-1 pathway in various malignancies, which are reviewed elsewhere 146 . In summary, given the intimate involvement of the TME in both the progression of a multitude of cancers and the risks posed by CRS, it is of increased interest to combine CAR T cells with IL-1-inhibiting therapies 116 .…”

Section: Introductionmentioning

confidence: 99%

Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy

et al. 2021

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A paradigm shift has recently occurred in the field of cancer therapeutics. Traditional anticancer agents, such as chemotherapy, radiotherapy and small-molecule drugs targeting specific signalling pathways, have been joined by cellular immunotherapies based on T cell engineering. The rapid adoption of novel, patient-specific cellular therapies builds on scientific developments in tumour immunology, genetic engineering and cell manufacturing, best illustrated by the curative potential of chimeric antigen receptor (CAR) T cell therapy targeting CD19-expressing malignancies. However, the clinical benefit observed in many patients may come at a cost. In up to one-third of patients, significant toxicities occur that are directly associated with the induction of powerful immune effector responses. The most frequently observed immune-mediated toxicities are cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. This Review discusses our current understanding of their pathophysiology and clinical features, as well as the development of novel therapeutics for their prevention and/or management.

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

Cited by 38 publications

References 11 publications

A tertiary center experience of multiple myeloma patients with COVID-19: lessons learned and the path forward

A tertiary center experience of multiple myeloma patients with COVID-19: lessons learned and the path forward

Cardiotoxicity Associated with Anti-CD19 Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: Recognition, Risk Factors, and Management

Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy

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