By: Daniel B. Rubin, MD, PhD (left); Henrikas Vaitkevicius, MD (right)
As the field of neurocritical care becomes increasingly recognized as essential to the care of patients with serious neurologic injury, we are necessarily encountering a more complex and diverse patient population. As a consequence, neurointensivists must learn how to use new treatment modalities and understand the risks associated with them. Effective collaboration with other specialists has become increasingly necessary to provide comprehensive and effective care, to keep up with clinical and scientific advances and to successfully expand the scope of practice within neurocritical units.
Traditionally, our colleagues in oncology have preferentially triaged their general oncology patients with critical care needs to the medical ICU. However, in recent years we have begun encountering severe neurologic toxicities in patients that have received novel oncological therapies, making the neuroICU a more suitable destination for many of these complex patients. The neuroscience ICU at Brigham and Women’s Hospital (BWH) has an exceptionally fruitful collaboration with the medical oncology division of the Dana Farber Cancer Institute (DFCI) that has led to an improvement in patient care and an advancement in our understanding of the unique toxicities associated with immunological therapies against neoplastic disorders.
For example, chimeric antigen receptor (CAR) T cell therapy is one of the most powerful new immunologic tools in the fight against cancer. Multiple clinical trials have demonstrated impressive and durable remission rates for relapsed and refractory leukemia and lymphoma, changing the way oncologists approach the treatment of these cancers and giving new hope to patients previously thought to have a poor prognosis. However, patients receiving CAR T cell therapy frequently experience a wide spectrum of neurologic side effects that can range from mild to severe encephalopathy and aphasia to fulminant cerebral edema and death. Symptoms are generally subacute in onset, but can at times appear as an acute neurologic syndrome mimicking acute stroke. Moreover, routine diagnostic studies, even in patients with severe and sudden toxicity, are generally unrevealing. Furthermore, the underlying pathophysiology of CAR T cell-associated neurotoxicity is poorly understood, and as neurologists, we are still learning how to manage and treat these patients. For this reason, we started to collaborate with the DFCI Cellular Therapy Group and began following all patients receiving CAR T therapy prospectively to better understand the nature of this novel neurologic syndrome and more effectively manage it. In doing so it quickly became clear to us, as well as the oncologists with which we collaborate, that the critical care of patients receiving CAR T cell therapy can better be provided within the neurocritical care unit.
Given this unique opportunity, we undertook a study to rigorously characterize the neurological complications of CAR T therapy so that other groups may benefit and learn from our experience. The early success of this program is demonstrated by the recently published manuscript in Brain by Rubin et al. The manuscript reports the clinical features, laboratory studies, imaging findings and results from neurodiagnostic studies in 100 patients treated with CAR T cell therapy at BWH/DFCI in Boston, Mass. This study is the largest and most comprehensive investigation to date focused on the neurologic side effects of CAR T cell therapy. The results provide significant new insight into our understanding of the neurologic toxicity associated with CAR T cell therapy and highlight the importance of neurocritical care in the multidisciplinary management of this burgeoning patient population.
One of the most salient features of this work is that it identifies biomarkers that may help predict which patients are likely to suffer neurotoxicity, and which of these patients are likely to suffer severe neurologic symptoms requiring ICU level care. In this study, patients with early symptoms of cytokine release syndrome (a multi-system disorder triggered by the CAR T-cells characterized by fever, tachycardia, hypotension and hypoxia) and patients with elevated and rapidly rising levels of serum C-reactive protein were more likely to develop neurotoxicity and severe symptoms. Such patients will undoubtedly benefit from early involvement of neurologic consultation for close monitoring and aggressive treatment. At BWH/DFCI, neurointensivists are now part of the multidisciplinary team caring for these patients and follow all the patients prospectively after CAR T cell infusion. In addition, the neuroICU has become the intensive unit of choice for any critical care needs that these complex patients may develop.
This collaboration is continuing to expand as additional immunologic therapeutics are being explored as part of clinical trials and routine practice. We have also observed that as our familiarity with an ever expanding armamentarium of immunological tools is growing, we are becoming more comfortable applying these tools to neurological patients with disorders outside of traditional oncological indications. This comfort and experience has led to significant improvement in the care we are able to provide to patients with a wide range of autoimmune and inflammatory neurologic disorders classically associated with dismal prognoses. By continuing to foster this and other multi-disciplinary collaborations, our hope is that we may continue to improve the care we are able to provide to all patients with complex neurologic symptoms.