I remember being in complete awe of the effects of CAR T-cell therapy, when I witnessed the complete resolution of a refractory, life threatening, aggressive B-cell lymphoma in one of the first CAR T-cell patients in my outpatient clinic. When we first met, she was at the beginning of her fifties, living together with her husband and three adolescent children. She had been disappointed for many times when only experiencing toxic side effects to chemotherapy while being left with a non-responsive tumor. However, she was well determined to undergo CAR T-cell therapy as she was ‘’not ready to die and leave my family’’. It was an intensive treatment trajectory; first she developed severe cytokine release syndrome and then she became confused, unable to talk and recognize her family with a declining level of consciousness, all part of the severe immune effector cell associated neurotoxicity syndrome for which she had to be admitted briefly to the intensive care unit. But, after several doses of high-dose methylprednisolone these symptoms resolved and after three weeks of hospital admission she could return home. When, one month after CAR T-cell infusion, the PET-CT scan showed complete remission of the lymphoma she and her family burst into tears. Now, twelve months later her lymphoma is still in complete remission.
It was at the beginning of 2020 and the COVID-19 pandemic already dominated our world. I got a phone call from my patient and she told me her husband was diagnosed with COVID-19. She had a negative PCR test and no symptoms and promised me to avoid any contact with her husband. I advised her to redo the PCR test in a couple of days and immediately call the hospital in case she would develop any symptoms. A week later her PCR test became positive and soon after, she developed fever and severe dyspnea. Hospital admission followed, she needed oxygen support and her condition deteriorated rapidly. I was wondering how this would end, and what we should do to treat her best. I searched in the literature for answers but could not find any cohort studies describing the outcome of patients with COVID-19 after CAR T-cell therapy. I turned to my supervisor Marie José Kersten for answers and in no time she contacted several hematologists from the European Hematology Association (EHA) Lymphoma Group to seek for any former experiences. Based on clinical rationale, we gave our patient convalescent plasma. It was a nerve-racking period but in the end her clinical condition improved. Now I know even more, how lucky she has been.
Marie José Kersten and I joined forces with our colleagues, Nicolaus Kroger, Per Ljungman and Stephan Mielke from the European Society for Blood and Marrow Transplantation (EBMT) Infectious Diseases Working Party, who had already developed a special COVID-19 report form, to conduct a multicenter survey study on patients with COVID-19 after CAR-T-cell therapy for hematologic malignancies. This collaboration made it possible to rapidly inform the medical field on the impact of COVID-19 on CAR-T-cell therapy recipients. In our cohort of 56 patients, the COVID-19 attributable mortality rate was 41.1%. Older age, not being in complete remission at the time of the COVID-19 diagnosis and having metabolic comorbidities such as hypertension, diabetes and cardiovascular disease were all associated with a higher mortality risk while a better performance status was associated with a lower mortality risk. The number of patients in our cohort study was probably too small to observe any effect of treatment on outcome. There is also currently no other data available to support the effect of treatment with convalescent plasma, COVID-19 hyperimmune globulin or SARS-CoV2 monoclonal antibodies specifically in CAR-T-cell recipients. But in our opinion, based on hopeful results in large randomized trials testing cocktails of monoclonal antibodies in patients with COVID-19 in the general population, there is also a clinical rationale to use these monoclonal antibodies in CAR T-cell recipients, who have been shown to have a very low capability of mounting an antibody response upon SARS-CoV2 infection or vaccination.
Our study also demonstrated that patients can have severe symptoms and need prolonged hospital admissions; the median hospital admission duration was 25 days with a maximum up to 171 days and almost half of the admitted patients had to be admitted to the ICU for a median duration of 14 days. The median resolution of COVID-19 based on longitudinal PCR tests was 48 days. Long duration of disease is problematic. Not only for COVID-19 patients themselves, but as concerning evidence is arising that immunocompromised patients with long lasting COVID-19 might enable the evolution of more transmissible and pathogenic multimutational SARS CoV-2 variants, it is also problematic for other vulnerable patients in the general population.
It is clear that preventing SARS CoV-2 transmission and disease development in CAR-T-cell recipients is very important. As long as it remains uncertain whether currently applied vaccination strategies are effective in CAR T-cell therapy recipients, vaccination of health-care personnel and family members in combination with protective measures against viral exposure are crucial in protecting this vulnerable group of patients. But we urgently need to focus on better prevention and treatment strategies as we cannot underestimate the negative impact of social isolation on quality of life.
We are grateful to all physicians, nurses, and other staff treating these patients under very challenging circumstances. We hope, that with the unprecedented pace of scientific developments, the pandemic will come under control and prevent the patients we are trying to cure from hematologic malignancies to die from COVID-19.