Pseudoprogression As Adverse Event of Chimeric Antigen Receptor T Cell Therapy
Authors: Schroeder Torsten , Martens Tjark , Chitadze Guranda , Yalcin Fatih , Trautmann Heiko , Brüggemann Monika , Heinen Christine , Nakov Philipp , Albici Anca Maria , Spath Nicolas , Sprenger Lukas , Kramp Laura Jane , Ritgen Matthias , Wellnitz Dominique , Simon Maciej , Lippross Sebastian , Iaccarino Ingram , Klapper Wolfram , Fransecky Lars , Valerius Thomas , Schub Natalie , Pott Christiane , Baldus Claudia D , Stoelzel Friedrich 
Published: December 2023

CAR-T-cell therapy (CARTCT) expands the range of therapeutic options for patients with hematologic malignancies. While complications such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are well known, pseudoprogression (PP) is until now mainly described after checkpoint inhibition. Some reports on CARTCT induced PP (CARTiPP) exist distinguishing it from progressive disease, while only few reports focus on acute local complications. Considering the paucity of data about CARTiPP, we aimed to assess patients treated in our center. We defined CARTiPP as initial volume increase of malignant manifestations within ten days of CARTCT followed by tumor regression without another genesis being more probable. Distinction from true progression of malignancy can be achieved either retrospectively or by histopathological findings.

Here, we characterize a retrospective monocentric patient cohort with the occurrence of CARTiPP. Evaluation of clinical, laboratory, radiological, and/or histopathological data was carried out. A total of n=8 patients were identified with CARTiPP throughout a treatment period of 46 months with n=78 patients receiving CARTCT resulting in a frequency of 10%. These eight patients had different B cell Non-Hodgkin lymphoma (B-NHL) subtypes (n=7) or multiple myeloma (n=1, extramedullary involvement) and were treated with anti-CD19 or anti-BCMA CAR-T-cells after standard lymphodepletion (once fludarabine monotherapy). The median age of patients was 61 years (range 39-76 years). Routine staging before CARTCT assessed n=4 patients as in partial remission (PR), n=1 with stable disease (SD) and n=3 with progressive disease (PD). CARTiPP occurred at a median of 5 days (range 4-7 days) after CARTCT. CAR T-cell expansion measured via droplet digital polymerase chain reaction (ddPCR) peaked earlier than expected from literature data after an average of 8 days post-infusion (range 7-11 days) in patients experiencing PP with a median peak of 182 CAR T copies/µL (range 39-2812 copies/µL) at this time.

We observed variable complications, e.g. superior vena cava syndrome, postrenal kidney injury and compartment syndrome. The analogy in clinical CARTiPP presentation with previous symptoms in stages of further advanced disease was striking in most patients (n=6). All events were rated as adverse events ≥ CTCAE II (Common Terminology Criteria of Adverse Events). CRS occurred parallely with PP in n=7, ICANS in n=3 patients. Complication management ranged accordingly from intensified monitoring to treatment with glucocorticoids/tocilizumab to limb amputation in one patient.There was no CARTiPP-associated mortality. In one of the affected cases intensive care treatment was required due to complications other than CARTiPP.

CARTiPP may be still underreported. Frequency and in some cases severity underline the need for raising awareness of treating physicians. Laboratory analyses and imaging may supplement clinical assessment and should be further examined. The establishment of risk assessment, preventive measures and early detection to reduce therapy-induced morbidity as well as a systematic documentation analogous to CRS and ICANS might be required for CARTiPP. The increasing availability of corresponding CAR-T-cell therapies for a steadily expanding number of disease entities with variable manifestations and different disease stages makes an increasing frequency of CARTiPP plausible.