Allogeneic chimeric antigen receptor T-cell therapy for recurrent chronic myeloid leukemia in lymphoid blast crisis after allogeneic hematopoietic stem cell transplantation: a two-case report and literature review

doi:10.3969/j.issn.2095-4344.1827

Abstract

Abstract:

BACKGROUND: In recent years, tumor immunotherapy has developed rapidly. Most scholars have focused on the single antibody treatment with autologous chimeric antigen receptor T-cell (CAR-T), but poor quality and small number of cultured cells are encountered. Therefore, allogeneic CAR-T cells have a better developmental potential.
OBJECTIVE: To investigate the efficacy and safety of allogeneic CAR-T cells in the treatment of recurrent leukemia after allogeneic hematopoietic stem cell transplantation.
METHODS: Two patients with relapsed refractory chronic myeloid leukemia in lymphoid blast crisis after allogeneic hematopoietic stem cell transplantation were treated with allogeneic CAR-T cells. Their clinical data were analyzed and relevant literature was reviewed.
RESULTS AND CONCLUSION: Case 1 was hospitalized because of fever and fatigue for 5 days, and was diagnosed as chronic myeloid leukemia in lymphoid blast crisis by bone marrow cell morphology, flow cytometry, chromosome analysis, fusion gene and other related examinations. After oral imatinib combined with low dose chemotherapy, HLA10/10 matched haploid transplantation from daughter to mother proceeded smoothly. Three months after transplantation, BCR-ABL (p210) was positive, and chimera: donor cells accounted for 67.4%. After treatment with fludarabine+cyclophosphamide regimen, anti-CD19 CAR-T cells were infused at a dose of 5 ×10⁶ cells/kg. Two weeks later, BCR-ABL (p210) turned negative and chimera: donor cells accounted for 99.62%. During the period, cytokine release syndrome level 1 appeared and symptomatic treatment was performed. The follow-up lasted for 6 months. Case 2 was treated in the local hospital in April 2011 because of left upper abdomen fullness for 1 year and night sweat for 15 days. One year later, it progressed to chronic myeloid leukemia in lymphoid blast crisis with T315I mutation. HLA 7/10 matched haploid stem cell transplantation from little brother to brother was performed after remission by chemotherapy. Anti-CD19 CAR-T cells were transfused at 2×10⁵/kg in the second relapse in 2018. During this period, cytokine release syndrome level 4 appeared. Chronic myeloid leukemia continued to alleviate for over 2 months and then relapsed resulting in death. Thus, the donor-derived CAR-T cells can be considered for the treatment of recurrent chronic myeloid leukemia in lymphoid blast crisis after allogeneic hematopoietic stem cell transplantation. It can be transfused repeatedly. It is safe and effective, and the incidence of Graft-versus-host disease is low. Sequential treatment with anti-CD22 CAR-T cells is safe and effective.

Key words: allogeneic, chimeric antigen receptor T-cell therapy, chronic myeloid leukemia, acute lymphoblastic leukemia, post-transplantation recurrence, National Natural Science Foundation of China

CLC Number:

Wang Zhen, Zhang Xuejun, Chen Yuqing, Zhang Lei, Zhu Zunmin, Li Yulong, Huang Zhoufeng, Lian Cheng, Shi Mingyue, Zhang Hongsheng, Wang Fuxu, Wen Shupeng, Yang Jing, Zheng Meiqiong, Sun Kai. Allogeneic chimeric antigen receptor T-cell therapy for recurrent chronic myeloid leukemia in lymphoid blast crisis after allogeneic hematopoietic stem cell transplantation: a two-case report and literature review[J]. Chinese Journal of Tissue Engineering Research, 2019, 23(33): 5263-5268.

References

[1]Wassmann B, Pfeifer H, Goekbuget N, et al. Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood. 2006;108(5): 1469-1477.

[2]Gross G, Eshhar Z. Therapeutic Potential of T Cell Chimeric Antigen Receptors (CARs) in Cancer Treatment: Counteracting Off-Tumor Toxicities for Safe CAR T Cell Therapy. Annu Rev Pharmacol Toxicol. 2016;56:59-83.

[3]Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725-733.

[4]Luskin MR, DeAngelo DJ. Chimeric Antigen Receptor Therapy in Acute Lymphoblastic Leukemia Clinical Practice. Curr Hematol Malig Rep. 2017;12(4):370-379.

[5]Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509-1518.

[6]Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013;342(6165):1432-1433.

[7]Cruz CR, Micklethwaite KP, Savoldo B, et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood. 2013;122(17):2965-2973.

[8]陈育红,徐兰平,陈欢,等.CAR-T细胞治疗allo-HSCT后急性B淋巴细胞白血病复发的安全性与疗效[J].中华器官移植杂志,2016, 37(7):421-426.

[9]Ruella M, Xu J, Barrett DM, et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med. 2018;24(10):1499-1503.

[10]Fraietta JA, Nobles CL, Sammons MA, et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature. 2018;558(7709):307-312.

[11]Kebriaei P, Ciurea SO, Huls MH, et al. Pre-Emptive Donor Lymphocyte Infusion with CD19-Directed, CAR-Modified T Cells Infused after Allogeneic Hematopoietic Cell Transplantation for Patients with Advanced CD19+ Malignancies. Blood.2015;126(23):862.

[12]Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-195.

[13]闫志凌,徐开林.异基因移植后复发的白血病患者-选择CAR-T治疗[J].临床血液学杂志,2018,31(5):672-675.

[14]Tasian SK, Gardner RA. CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL). Ther Adv Hematol. 2015;6(5):228-241.

[15]Sotillo E, Barrett DM, Black KL, et al. Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy. Cancer Discov. 2015; 5(12):1282-1295.

[16]Ruella M, Maus MV. Catch me if you can: Leukemia Escape after CD19-Directed T Cell Immunotherapies. Comput Struct Biotechnol J. 2016;14:357-362.

[17]Fischer J, Paret C, El Malki K, et al. CD19 Isoforms Enabling Resistance to CART-19 Immunotherapy Are Expressed in B-ALL Patients at Initial Diagnosis. J Immunother. 2017;40(5): 187-195.

[18]童春容.第二代CD19-CAR-T细胞治疗难治复发急性B淋巴细胞白血病的经验及问题[J].中国肿瘤生物治疗杂志, 2017,24(1): 18-21.

[19]Davila ML, Sadelain M. Biology and clinical application of CAR T cells for B cell malignancies. Int J Hematol. 2016; 104(1):6-17.

[20]Eyquem J, Mansilla-Soto J, Giavridis T, et al.Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543(7643):113-117.

[21]Cherkassky L, Morello A, Villena-Vargas J, et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016;126(8): 3130-3144.

[22]Haso W, Lee DW, Shah NN, et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood. 2013;121(7):1165-1174.

[23]Lussana F, Intermesoli T, Gianni F, et al. Achieving Molecular Remission before Allogeneic Stem Cell Transplantation in Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Impact on Relapse and Long-Term Outcome. Biol Blood Marrow Transplant. 2016;22(11): 1983-1987.

[24]Liu J, Zhong JF, Zhang X, et al. Allogeneic CD19-CAR-T cell infusion after allogeneic hematopoietic stem cell transplantation in B cell malignancies. J Hematol Oncol. 2017;10(1):35.

[25]Fousek K, Rouce R, Ahmed N,et al. Safety of multiple doses of car T cells. Cytotherapy. 2015;17(6):S12-S13.

[26]Kochenderfer JN, Dudley ME, Carpenter RO, et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood. 2013;122(25):4129-4139.

[27]Cruz CR, Micklethwaite KP, Savoldo B, et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood. 2013;122(17):2965-2973.

[28]Brudno JN, Somerville RP, Shi V, et al. Allogeneic T Cells That Express an Anti-CD19 Chimeric Antigen Receptor Induce Remissions of B-Cell Malignancies That Progress After Allogeneic Hematopoietic Stem-Cell Transplantation Without Causing Graft-Versus-Host Disease. J Clin Oncol. 2016;34(10):1112-1121.

[29]Chen Y, Cheng Y, Suo P, et al. Donor-derived CD19-targeted T cell infusion induces minimal residual disease-negative remission in relapsed B-cell acute lymphoblastic leukaemia with no response to donor lymphocyte infusions after haploidentical haematopoietic stem cell transplantation. Br J Haematol. 2017;179(4):598-605.