Efficacy and Safety of Chimeric Antigen Receptor T Cell Therapy in Chronic Lymphocytic Leukemia: A Systematic Review
Authors: Habib Rooma , Aiman Wajeeha , Garg Ishan , Niaz Rabiya , Butt Sigmone Khalid , Saeed Memoona , Zubair Hina , Kashif Tooba , Khan Huda , Farrukh Mahwish , Naveed Madiha , Tahir Nayha , Fatima Aqsa , Ali Muhammad Ashar 
Published: November 2021

Abstract
Background:
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults. Despite the advancements in drug therapies, CLL is largely incurable, and relapsed/refractory (R/R) patients have a very poor prognosis. Chimeric antigen receptor T (CART) cell therapy has shown promising results in B-cell malignancies. We conducted a systematic review to assess the efficacy and safety of CART cell therapy in patients with CLL.
Methods:
PRISMA guidelines were followed to perform the literature search and selection of articles for this systematic review. A search was performed using databases including PubMed, Cochrane, Web of Science, Embase, and clinicaltrials.gov. We used the following Mesh and Emtree terms, "Chronic lymphocytic leukemia" AND "Adoptive immunotherapy" from the inception of literature till 06/11/2021. Out of 1319 articles, we screened and included nine clinical studies (N=208) measuring the efficacy (i.e., complete response, partial response, etc.) and safety (adverse events ≥grade 3) in clinical terms. We excluded case reports, pre-clinical studies, review articles, and meta-analyses.
Results:
In 9 clinical studies, 158 patients with CLL were treated with anti-CD19 CART cell therapy. The range of age of the patients was 38-75 years. A high dose was used in 38 patients, and ibrutinib was added in 19 patients with CLL. The therapy was well tolerated with ≥grade 3 cytokine release syndrome (CRS) and neurological toxicity reported in 23/151 (15%) and 20/151 (13%) of the patients, respectively. Table 1. Complete response (CR), partial response (PR), and overall response (OR) were seen in 40% (54/134), 17% (22/126), and 56% (103/183). In the clinical study by Frey et al. (N=51)., progression-free survival (PFS) and ORR were significantly higher in the high dose (5x10 8 cells/kg) group as compared to the low dose (5x10 7 cells/kg) group (1.8 months vs. one month and 53% vs. 29%, respectively) without significantly increasing treatment-related adverse events (TRAE). In the clinical study by Gauthier et al. (N=38)., ORR was significantly high in the anti-CD19 CART cell therapy + ibrutinib group compared to the no ibrutinib group (83% vs. 56%). Neutropenia, infection, thrombocytopenia, leukemia, hypocalcemia, elevated ALT, and tumor lysis syndrome were common ≥grade 3 TRAEs reported in these patients (Table 1). More clinical trials are targeting CD-20, CD-137, CD-7, CD-28, ROR1, etc (Table 2).
Conclusion:
Anti-CD19 CART cell therapy was safe and effective in the treatment of CLL patients. A high dose of 5x10 8/kg CART cell therapy was well tolerated and had superior efficacy. Adding ibrutinib to CART cell therapy was safe and more effective than anti-CD19 CART cell therapy alone. More placebo-controlled randomized multicenter studies are needed to confirm these results.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.