Severe Breakthrough COVID-19 in CAR T-cell treated patient

A 51-year-old woman, with anemia and rib fractures, diagnosed with IgG-kappa multiple myeloma (MM) in 2012, initially achieved complete remission. However, in 2020, she experienced a clinical relapse followed by a biochemical relapse. In 2021, she received two doses of the mRNA vaccine BNT162b2 against SARS-CoV-2, yielding no serological response. Subsequently, before undergoing CAR T-cell therapy, she received a third vaccine boost in March. Two months later, in July 2022, she contracted a SARS-CoV-2 infection, presenting with a dry cough and low-grade fever.

Due to relapsed/refractory multiple myeloma (R/R MM), the patient underwent various treatments, including CAR T-cell therapy. Despite achieving minimal residual disease negativity post-infusion, she developed severe COVID-19 pneumonia, posing challenges to her clinical management.  Her prolonged hospitalization was marked by a complex interplay of factors: pulmonary embolism, immune deficiencies including B-cell aplasia and lymphocyte subpopulation deficits, and secondary infections like pulmonary aspergillosis. 

Despite antiviral therapy with molnupiravir, her cough worsened, and a CT scan on admission revealed bilateral interstitial pneumonia. Blood tests indicated lymphopenia (800 cells/µl), hypogammaglobulinemia (200 mg/dl), and elevated inflammatory markers (CRP 38,000 µgr/l and IL-6 38 pg/ml). Standard treatments like remdesivir and tixagevimab-cilgavimab failed to improve her clinical condition, exacerbated by pulmonary embolism, necessitating high-flow oxygen therapy. Viral genotyping identified a non-BA.2 omicron variant with positive viremia, and antinucleocapsid antibodies were not detected. Hyperimmune plasma infusion gradually resolved opacities, improving respiratory failure. Subsequently, pulmonary aspergillosis emerged and was successfully treated with a two-month course of isavuconazole. Intravenous immunoglobulin G therapy (IVIG) at 400 mg/kg weekly, during antifungal treatment, aimed to reach normal IgG levels (≥ 700 mg/dl). SARS-CoV-2 clearance was achieved in December 2022, leading to the patient's discharge after a five-month hospitalization.

Optimal therapeutic strategies against COVID-19 in immunocompromised patients remain poorly understood. Combined treatments, such as passive immunotherapy (convalescent plasma and/or monoclonal antibodies) and antivirals, show promise in B-cell-depleted patients. Careful monitoring of immune reconstitution post-CAR T-cell therapy is crucial in the hematological population, necessitating further investigations to identify tailored therapeutic strategies against COVID-19.


REFERENCE

Ielo C, Fazio F, Rocchi S, Rizzello I, Mancuso K, Zamagni E, Cavo M, Petrucci MT. Severe SARS-CoV-2 and subsequent fungal infections after CAR T-cell therapy for relapsed/refractory multiple myeloma: a challenging and happy ending fight. Leuk Res Rep. 2023 Nov 27;21:100399. doi: 10.1016/j.lrr.2023.100399. PMID: 38078287; PMCID: PMC10698652.


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