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545 Safety and Efficacy of CD19-CAR T Cells in Richter’s Transformation after Targeted Therapy for Chronic Lymphocytic Leukemia

Program: Oral and Poster Abstracts
Type: Oral
Session: 642. CLL: Therapy, excluding Transplantation II
Hematology Disease Topics & Pathways:
Leukemia, Diseases, CLL, Lymphoid Malignancies
Monday, December 7, 2020: 7:45 AM

Ohad Benjamini1,2*, Avichai Shimoni, MD1,2*, Michal Besser, PhD3,4*, Noga Shem-Tov, MD1,2*, Ivetta Danylesko, MD1,2*, Ronit Yerushalmi, MD1,2, Drorit Grizim Merkel, MD1,2, Tamar Tadmor, MD5*, David Lavie, MD6*, Riva Fineman, MD7*, Elad Jacobi, MD2,8*, Arnon Nagler, MD1,9 and Abraham Avigdor, MD1,2

1Hematology Division, Chaim Sheba Medical Center, Tel-Hashomer, Israel
2Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
3Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv, Israel
4Ella Lemelbaum Institute for Immuno Oncology, Sheba Medical Center, Ramat-Gan, Israel
5Hematology Unit, Bnai Zion Medical Center, Haifa, Israel
6Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
7Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
8Department of Pediatric Hematology-Oncology, Safra Children's Hospital, Chaim Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
9Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

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.

*signifies non-member of ASH