Kidney Disease after CD19-Targeted Chimeric Antigen Receptor T Cell Therapy for Pediatric Acute Lymphoblastic Leukemia
Background: Chimeric Antigen Receptor (CAR) T cell therapy has been a transformative treatment for children with acute lymphoblastic leukemia (ALL) whose disease has relapsed or not responded to other therapies. However, CAR T-cell therapy is also associated with toxicities, which may be severe. One common side effect is acute kidney injury, but the spectrum of kidney disease has not previously been well described. In addition, we do not know if CAR T- cell therapy has any long-term effects on the kidney.
Project Goal: We propose a study to evaluate acute and chronic kidney disease after CAR T cell therapy. Our first aim is to characterize acute kidney injury in the first 30 days after CAR T cell infusion, by assessing its incidence, severity, outcome and risk factors. Our second aim is to compare the changes in kidney function after CAR T cell infusion with the changes in other important laboratory tests that are related to cytokine release syndrome or tumor lysis syndrome. This will help us understand the mechanisms that lead to kidney injury and identify specific times after CAR T cell infusion that clinicians may be able to intervene to prevent or lessen kidney injury. Our third aim is to evaluate whether acute kidney injury in the first 30 days after infusion is associated with chronic kidney disease 3, 6, and 12 months later. This will help us understand what impact CAR T cell therapy may have on long-term kidney function. We will accomplish our aims by assessing a cohort of 160-200 children, who received CAR T cell therapy at Children's Hospital of Philadelphia between 2012 and 2018, either on or off a clinical trial. We will use a data extraction tool that queries the children's electronic medical records and automatically returns all their laboratory results, medications administered, and vital sign information to secure data files. We will also analyze cytokine values that were run as part of previous clinical trials. In order to evaluate long-term renal function, we will test the level of a biomarker called cystatin C on blood samples that were previously collected and stored.
The results of this study will provide important guidance to patients and their families, clinicians and other researchers. The study will help us understand the burden and impact of kidney injury as well as identify key strategies and timepoints for intervention to mitigate kidney disease. In addition, the results will help inform the development of multiple, future projects, including studies that collect and test blood and urine samples upfront to better understand the mechanisms of kidney injury and studies that investigate other, potentially severe toxicities of CAR T cells.
Project Update 2023: With support from the Young Investigator Award, I built the CHOP CAR Cohort, a cohort of >470 children and young adults treated with CART therapy at CHOP. We then developed a data pipeline to integrate data from clinical trials databases, multicenter registry databases, the electronic health record, and correlative studies. This cohort building and data integration process led to the creation of a powerful data resource. After building the data resource, the primary focus of the award was to study kidney disease after CART19, a toxicity that had not previously been well studied. We know that acute kidney injury (AKI) is an important toxicity in children receiving other leukemia-directed therapy and can have a significant impact on overall outcomes and survival. In this analysis that included 280 patients (a subset of the full CHOP CAR Cohort), we found that AKI is common, with more than 1 in 5 children developing AKI in the first month after CART19 treatment. Furthermore, approximately 1 in 8 children developed severe AKI in that first month. We found that children with a high percentage of bone marrow blasts at the time of CART infusion were at highest risk for developing AKI. In addition, children with multiply relapsed B-ALL were at higher risk for developing AKI than children with primary refractory B-ALL. We found that severe cytokine release syndrome (CRS, the most common toxicity after CART) was highly associated with AKI. Over half of patients with severe (grade 4) CRS also developed severe AKI. In examining time of AKI, we found that biomarkers of CRS (body temperature, specific laboratory values) rise prior to the creatinine (which defines AKI), suggesting that AKI occurs later in the CRS course and that there may be a window to intervene with kidney-protective measures before AKI occurs. We also found that electrolyte abnormalities occur later than the AKI, suggesting that the AKI causes electrolyte derangements after CART as opposed to tumor lysis syndrome. Fortunately, we also found that AKI resolves in the majority of children by 30 days after CART19. We plan to publish these findings in the next 6 months and then later steps include evaluation of long-term kidney function to better understand if AKI after CART19 is associated with longer-term kidney problems. In addition to studying kidney disease after CART19, the funding provided by this award allowed me to leverage the data resource built for this study to investigate interventions to reduce the risk of relapse or to treat post-CART19 relapse. This included: (1) a multicenter study to identify patients at highest risk for subsequent relapse so they could be targeted for relapse prevention interventions; (2) an analysis of a phase 1 trial of humanized CART19 to prevent or treat post-CART19 relapse; (3) an investigation of the effectiveness of CART19 reinfusions in reducing relapse risk or treating post-CART19 relapse; and (4) an analysis of a phase 1 clinical trial of CART22 to treat post-CART19 relapse.
