Abstract
Donor-derived CD19-directed chimeric antigen receptor-modified T (CAR-T) cell therapy seems be effective and safe for relapsed B-ALL after allogeneic haematopoietic stem cell transplantation (allo-HSCT). We report two cases of children who received Donor-derived CAR-T cell therapy. After transfusion, the children experienced different degrees of chronic graft-versus-host disease (cGVHD). Early intervention included strengthening immunosuppressant, FAM regimen, tyrosine kinase inhibitor, and auxiliary cell therapy. Their dyspnoea and lung function were significantly improved and recovered. They did not receive the second transplant. Timely and effective intervention is crucial to improve both prognosis and quality of life.
Key words: Donor-derived, CD19-directed chimeric antigen receptor modified T (CAR-T), chronic graft-versus-host disease
Introduction
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective method for the treatment of refractory and relapsed acute lymphoblastic leukaemia (R / R-ALL) in children, but relapse after transplantation is still the main reason for treatment failure. Chimeric antigen modified T (CAR-T) cell therapy has a strong ability to clear leukemic cells and is associated with a high remission rate in R/R B-ALL[1-2]. CAR‑T cell sources can be autogenous or donor. It can be difficult to collect enough T lymphocytes for children with a high leukaemia burden or relapse after transplantation. CAR-T cells from a donor can overcome this problem but carry the risk of graft-versus-host disease (GVHD) after infusion. We describe two cases of chronic GVHD (cGVHD) secondary to donor-derived CAR-T therapy.
Cases description
Patient 1: A 17-year-old boy was diagnosed with acute lymphocytic leukaemia (B cell). Chemotherapy was stopped per protocol in December 2016, and continuous complete remission (CR) of bone marrow was observed during the treatment. Unfortunately, minimal residual disease (MRD) increased to 0.18% at 3 months after discontinuation. Morphology suggested relapse with testicular leukaemia, and two courses each of consolidation and shelter treatment were completed. The infiltration of testis improved, and MRD continued to turn negative after treatment. On October 4, 2017, we completed a matched-sibling donor HSCT (sister donor, human leucocyte antigen (HLA) 10/10). There was no GVHD expression after transplantation, and cyclosporine was gradually reduced from 2 months after transplantation. MRD was 1.67% at 5 months after transplantation. Two weeks later, bone marrow morphology and MRD were 6% and 4.65%, respectively. A comprehensive evaluation and diagnostic workup showed R/R-ALL with an indication for CAR-T cell treatment. On May 1, 2018, donor-derived CAR-T cells were infused(Table.1).
A total of 12.6 × 106/kg CAR-T cells were infused and evaluated as cytokine release syndrome (CRS)grade II. At + 14 days, bone marrow was in CR, with MRD <0.01%; + 21 days, rashes of upper limbs, face, and back appeared, and acute GVHD (aGVHD) was considered. After methylprednisolone (0.5 mg/kg.d) for 2 weeks, and the rash gradually subsided. At +52 days, the rash appeared again, body-wide (Fig. 1A), and methylprednisolone (1 mg/kg.d) was added again. At the same time, basiliximab was given for symptomatic treatment, and the rash gradually subsided, but with pigmentation. At +76 days, liver damage was indicated (ALT 603 IU/L; R-GGT 305 IU/L), and in addition to continued methylprednisolone, sirolimus and ursodeoxycholic acid were added so that the liver damage would gradually recover. At +93 days, there was repeated persistent oral ulcer (Fig. 1B), a clinical diagnosis of cGVHD, so oral immunosuppressant treatment was continued, and oral care was strengthened. At +110 days, the patient developed signs of bronchiolitis obliterans syndrome[3-4] (BOS; Fig. 1C–E). We tried to use the FAM (fluticasone, azithromycin, and montelukast) regimen [5], mesenchymal stem cells (MSCs) (once every 2 weeks, four units each time, four times total), low-dose ruxolitinib (10 mg, once a day), and prednisone (0.25 mg/kg.d), which was gradually reduced to 5 mg prednisone for maintenance. At this writing, there was no significant wheezing attack or chest tightness during 20 months after CAR-T. Chest CT and lung function were improved, and the primary disease evaluation always showed CR.
Patient 2: A 5-year-old boy was diagnosed with B-ALL (pre-B) after intermittent lower extremity pain and left eyelid oedema for half a year. Genetics analysis was positive for E2A-PBX1 and chromosome 46, XY, t (1,19) (q21; p13). After induction of chemotherapy with the VPDL regimen (vincristine + prednisolone + daunorubicin + L-asparaginase), the bone marrow showed remission, immune residue turned negative, and E2A-PBX1 dropped to 0.02%. Regular chemotherapy was administered, and maintenance treatment began on February 6, 2017. In October 2017, the bone puncture was re-evaluated because of systemic bone pain. Results indicated that the tumour cells could not be controlled, and MRD continued to be positive. On December 7 and 8, 2017, auto CAR-T cells were retransmitted. The bone marrow showed CR, and MRD turned negative. On February 28, 2018, haploid HSCT (father donor, HLA 6/10) was performed. At 3 months after transplantation, bone puncture showed 8% immature lymphocytes and 1.02% MRD, indicating another relapse. The father gave peripheral blood for the preparation of CD19 CAR-T, and then Flu/CTX pretreatment was administered. On June 8 and June 13, 2018, donor-derived CAR-T cells were retransmitted (Table 1).
A total of 13.3 × 106/kg CAR-T cells were infused and evaluated as CRS grade I. There was no obvious GVHD manifestation. At +28 days, we evaluated the continuous remission state of the bone marrow. At +3 months, this patient also received a clinical diagnosis of BOS. Prednisone (2 mg/kg) was given combined with the FAM regimen. At +4 months, chest CT showed resolution of mediastinal emphysema, wheezing was improved, lung function still showed moderate obstruction of ventilation function, and prednisone was gradually reduced to small dose maintenance. At +6 months, wheezing was reported, while lung function was not improved, and imatinib treatment was increased. Finally, lung symptoms were controlled, and lung function was improved. At this writing, 18 months after CAR-T, the patient’s condition was stable and in complete remission from leukaemia (Table I).