Safety and Efficacy of CD19-CAR T Cells in Richter's Transformation after Targeted Therapy for Chronic Lymphocytic Leukemia
Authors: Benjamini Ohad , Shimoni Avichai , Besser Michal , Shem-Tov Noga , Danylesko Ivetta , Yerushalmi Ronit , Merkel Drorit Grizim , Tadmor Tamar , Lavie David , Fineman Riva , Jacobi Elad , Nagler Arnon , Avigdor Abraham 
Published: February 2021

Background: Richter's transformation (RT) is a rare complication of Chronic Lymphocytic Leukemia (CLL), usually into clonally related diffuse large B cell lymphoma (DLBCL). Currently there is no effective therapy to RT and CLL relapse after targeted therapy. Chimeric antigen receptor-modified T (CART) cells directed to CD19+ B-cell malignancies have promising results in relapsed DLBCL. However, its effectiveness in CLL relapse after targeted therapy and RT is less clear and no systematic reports are available.
Methods: From July 2019 to May 2020 we enrolled eight CLL patients with disease transformation after chemoimmunotherapy and therapy with BTK and/or BCL2 inhibitors as part of single center phase 2 CAR T-cell therapy in B-cell malignancies (NCT02772198). Following lymphodepletion consisting of cyclophosphamide and fludarabine patients received an infusion of locally produced 1x106 CD19-CART- cells/kg, which were generated by modifying autologous T cells with retroviral vector encoding a CAR comprising FMC63 anti-CD19 ScFv linked to a CD28 costimulatory domain, and CD3-zeta intracellular signaling domain.
Results: All 8 patients (pts) were relatively young with median age at CLL diagnosis of 56y (47-62). Disease transformation developed after a median of 8 years (range 1-16) from CLL diagnosis. Patients treated with CD19-CAR T-cells at median age of 64 y (54-73) having median comorbidity G-CIRS score 2 (0-5), performance status ECOG 1 (0-2) and CCT 66ml/min (26-89). Pts had history of CLL with del17p/TP53 in 83%, 5/6 available, del11q 2/6 prior to transformation. Disease transformation included RT in 6 pts with DLBCL, 1 accelerated CLL and 1 prolymphocytic transformations. Among RT pts 67% (4/6) had advanced stage DLBCL, 50% (3/6) extarnodal and 33% (2/6) bulky disease. Patients received median of 3 (0-5) CLL therapies and 2 (1-3) large cell lymphoma directed therapy. CLL therapies included chemoimunotherpay: 5 Fludarabine, cyclophosphamide, rituximab/obinutuzumab (FCR/FCO), 1 bendamustin rituximab (BR); 5 dual targeted therapy (ibrutinib and Venetoclax), 2 ibrutinib only, 1 venetoclax only. Last CLL treatment was Venetoclax in 71% (5/7) and ibrutinib in 29% (2/7) with 32 (range 15-39) months duration on ibrutinib and 10 (2-17) months on venetoclax. The reason for ibrutinib discontinuation was CLL progression (PD) in 5, disease transformation in 2, and venetocalx discontinuation due to progressive disease (PD) - 4 and transformation - 2. Post transformation all RT pts were treated with R-CHOP, second line tx 2, one patient with prolymphocytic transformation was treated with alemtuzumab, allo-SCT, ibrutinib and venetoclax. All pts had PD before treatment with CAR T-cells, 63% (5/8) had elevated LDH and 5/8 evaluable PET CT before treatment had deauville score (DS) 5 with median SUVmax 8.7 (3.7-21). After infusion of CAR T-cells 7 patients had cytokine release syndrome (CRS), 4 grade 1 and 3 grade 3-4 that required tocilizumab. Three patients had CNS toxicity, two grade 3. Seventy five percent (6/8) developed neutropenia, (3/8) grade 3-4, all neutropenia resolved except in one patient that succumbed to PD, 2 pts had infections (campylobacter and H1N1 influenza, each). There were no fatalities due to CAR T-cell toxicity. There were two fatalities due to disease progression. All 71% (5/8) responders achieved complete response with DS1 in PET CT scan on day 28. After median follow up duration of 6 (4-10) months, 2 patients proceeded to allo-SCT.
Conclusion: CD19-CART-cell therapy in CLL patients with disease transformation is safe and has high complete remission rate with promising clinical response. Long term remission rate after CD19-CART-cell therapy for RT needs to be further evaluated in more patients.

Disclosures
Benjamini: Abbvie Inc: Consultancy, Research Funding. Tadmor:AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Medison: Consultancy, Speakers Bureau; Neopharm: Consultancy, Speakers Bureau; 6. Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Consultancy, Speakers Bureau. Fineman:Abbvie Inc: Consultancy, Research Funding. Jacobi:Novartis: Consultancy. Avigdor:Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding.