Thomas Pabst1, Raphael Joncourt2, Evgenii Shumilov3, Alexander Heini4, Gertrud Wiedemann2, Myriam Legros5, Katja Seipel4, Christof Schild5, Katarzyna Jalowiec2, Behrouz Mansouri Taleghani2, Michaela Fux6, Urban Novak4, Naomi Porret2, Sacha Zeerleder2, Ulrike Bacher7. 1. Department of Medical Oncology, Inselspital Bern, Bern University Hospital, University of Bern, Bern, Switzerland. Electronic address: thomas.pabst@insel.ch. 2. Department of Hematology, Inselspital Bern, Bern University Hospital, University of Bern, Bern, Switzerland. 3. Department of Hematology, Inselspital Bern, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Hematology and Medical Oncology, University Medicine Göttingen, Göttingen, Germany. 4. Department of Medical Oncology, Inselspital Bern, Bern University Hospital, University of Bern, Bern, Switzerland. 5. Center of Laboratory Medicine, Inselspital Bern, Bern University Hospital, University of Bern, Bern, Switzerland. 6. Center of Laboratory Medicine, Inselspital Bern, Bern University Hospital, University of Bern, Bern, Switzerland; Institute of Clinical Chemistry, Inselspital Bern, Bern University Hospital, University of Bern, Bern, Switzerland. 7. Department of Hematology, Inselspital Bern, Bern University Hospital, University of Bern, Bern, Switzerland; Center of Laboratory Medicine, Inselspital Bern, Bern University Hospital, University of Bern, Bern, Switzerland. Electronic address: veraulrike.bacher@insel.ch.
Abstract
INTRODUCTION: Chimeric antigen receptor T-cell (CAR-T) therapies are increasingly used to treat relapsed B-cell lymphomas and acute lymphoblastic leukemia. Considering the frequency of cytokine release syndrome and CAR-T-related encephalopathy syndrome (CRS/CRES) after CAR-T administration, strategies enabling timely prediction of impending CRS/CRES are a clinical need. METHODS: We evaluated the dynamics of serum interleukin (IL)-6 levels and CAR-T transgene copy numbers by digital droplet polymerase chain reaction in the peripheral blood of 11 consecutive patients with aggressive B-cell malignancies. RESULTS: Four of 11 patients developed CRS, and 3 patients had CRES (33%), 2 of them had previous CRS. IL-6 levels increased on the day of clinical manifestation of CRS. All CRS patients had increased IL-6 peak levels (median IL-6 peak 606 pg/mL in CRS patients vs. 22 pg/mL in non-CRS patients, p = 0.0061). Different patterns emerged from the dynamics of CAR-T/µg genomic DNA: "rapid increase and rapid decrease with complete disappearance," "rapid increase and slow decrease with higher persistence," "rapid increase and rapid decrease with lower persistence," and "slow increase and rapid decrease with almost disappearance." Patients with the pattern "rapid increase and slow decrease with higher persistence" of CAR-T/µg genomic DNA concentration seemed to be at higher risk of developing CRS/CRES. CONCLUSION: Thus, the dynamics of CAR-T transgene copy numbers merits further evaluation for a possible association with manifestation of CRS. Increased IL-6 serum levels at CRS manifestation may contribute to the interpretation of symptoms.
INTRODUCTION: Chimeric antigen receptor T-cell (CAR-T) therapies are increasingly used to treat relapsed B-cell lymphomas and acute lymphoblastic leukemia. Considering the frequency of cytokine release syndrome and CAR-T-related encephalopathy syndrome (CRS/CRES) after CAR-T administration, strategies enabling timely prediction of impending CRS/CRES are a clinical need. METHODS: We evaluated the dynamics of serum interleukin (IL)-6 levels and CAR-T transgene copy numbers by digital droplet polymerase chain reaction in the peripheral blood of 11 consecutive patients with aggressive B-cell malignancies. RESULTS: Four of 11 patients developed CRS, and 3 patients had CRES (33%), 2 of them had previous CRS. IL-6 levels increased on the day of clinical manifestation of CRS. All CRSpatients had increased IL-6 peak levels (median IL-6 peak 606 pg/mL in CRSpatients vs. 22 pg/mL in non-CRSpatients, p = 0.0061). Different patterns emerged from the dynamics of CAR-T/µg genomic DNA: "rapid increase and rapid decrease with complete disappearance," "rapid increase and slow decrease with higher persistence," "rapid increase and rapid decrease with lower persistence," and "slow increase and rapid decrease with almost disappearance." Patients with the pattern "rapid increase and slow decrease with higher persistence" of CAR-T/µg genomic DNA concentration seemed to be at higher risk of developing CRS/CRES. CONCLUSION: Thus, the dynamics of CAR-T transgene copy numbers merits further evaluation for a possible association with manifestation of CRS. Increased IL-6 serum levels at CRS manifestation may contribute to the interpretation of symptoms.
Authors: Savannah E Butler; Rachel A Brog; Cheryl H Chang; Charles L Sentman; Yina H Huang; Margaret E Ackerman Journal: Cancer Immunol Immunother Date: 2021-05-27 Impact factor: 6.968