Co-infusion of haplo-identical CD19-chimeric antigen receptor T cells and stem cells achieved full donor engraftment in refractory acute lymphoblastic leukemia

Abstract

Background: Elderly patients with relapsed and refractory acute lymphoblastic leukemia (ALL) have poor prognosis. Autologous CD19 chimeric antigen receptor-modified T (CAR-T) cells have potentials to cure patients with B cell ALL; however, safety and efficacy of allogeneic CD19 CAR-T cells are still undetermined.

Case presentation: We treated a 71-year-old female with relapsed and refractory ALL who received co-infusion of haplo-identical donor-derived CD19-directed CAR-T cells and mobilized peripheral blood stem cells (PBSC) following induction chemotherapy. Undetectable minimal residual disease by flow cytometry was achieved, and full donor cell engraftment was established. The transient release of cytokines and mild fever were detected. Significantly elevated serum lactate dehydrogenase, alanine transaminase, bilirubin and glutamic-oxalacetic transaminase were observed from days 14 to 18, all of which were reversible after immunosuppressive therapy.

Conclusions: Our preliminary results suggest that co-infusion of haplo-identical donor-derived CAR-T cells and mobilized PBSCs may induce full donor engraftment in relapsed and refractory ALL including elderly patients, but complications related to donor cell infusions should still be cautioned.

Trial registration: Allogeneic CART-19 for Elderly Relapsed/Refractory CD19+ ALL. NCT02799550.

Keywords: Allogeneic anti-CD19 chimeric antigen receptor (CAR) T cells; B cell acute lymphoblastic leukemia (B-ALL); Case report; Haplo-identical mobilized peripheral blood stem cell infusion; Relapsed and refractory.

Fig. 1

Protocol of haplo-identical CAR-T cell and G-PBSC infusions following chemotherapy and treatment for “GVHD-like” reaction. a Protocol of CAR-T and G-PBSC infusion in combination with chemotherapy. Chemotherapy included vindesine, idarubicin, pegaspargase, and dexamethasone. CAR-T cells were infused at a total dose of 0.32 × 10⁸/kg CD3⁺ cells (0.15 × 10⁸/kg CAR-T cells), and the numbers of mononuclear, CD34⁺ and CD3⁺ cells infused in the G-PBSCs were 1.82 × 10⁸/kg, 1.93 × 10⁶/kg, and 0.46 × 10⁸/kg, respectively. b Flow chart of treatment after developing “GVHD-like” reaction. Methylprednisolone at a dose of 3 mg/kg per day was administered intravenously right after the finding of liver dysfunction from day 14, and tacrolimus at a dose of 0.03 mg/kg per day was started intravenously on day 15. Anti-CD25 antibody at a dose of 25 mg per day was given on days 14 and 16. Mesenchymal stem cells with a number of 5 × 10⁵/kg per day were injected to the bone marrow cavity on days 18, 21, and 25

Fig. 2

Clinical responses to infusions of haplo-identical CAR-T cells and G-PBSCs in the patient with ALL. a Leukemic cells in the bone marrow decreased and were finally undetected 15 days after the first CAR-T cell infusion. Meanwhile, the percentage of donor cells elevated to 100% 21 days after the first CAR-T cell infusion. b White blood cell count recovered slowly after the first CAR-T cell infusion, and the proportion of CD3⁺CD19⁻cells in nucleated cells in peripheral blood elevated to 90% and CD3⁻CD19⁺ cells decreased dramatically to 0.1% 21 days after the first CAR-T cell infusion. c Changes in the platelet count and hemoglobin level. d Elevated serum LDH, ALT, and GOT were detected on day 14. Levels of ALT and GOT achieved the peak on day 15. The level of LDH reached the peak on day 17. Elevations of TB and DB were also present following rises of LDH, ALT, and GOT and reached the peak on day 18. e Levels of the allogeneic CAR gene were monitored. The highest level in the peripheral blood was reached on day 7 with a copy number within twofold of the baseline. f Serum levels of cytokines were measured at the indicated time points before or after CAR-T cell and G-PBSC infusions. Levels of IL-6, IL-8, IL-10, and TNF-α elevated markedly on day 3 and then dropped quickly