Effective T-cell replete haploidentical stem cell transplantation for pediatric patients with high-risk hematologic disorders.

OBJECTIVES: Patients with high-risk hematologic diseases require intensive modalities, including high-dose chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Haploidentical T-cell-replete transplantation is a logical choice because of the limited availability of matched sibling donors and the prolonged time needed to identify matched unrelated donors in Thailand. METHODS: The clinical outcomes data of 43 patients undergoing allo-HSCT were reviewed. All patients had high-risk hematologic malignancies, were younger than 20 years, and were in complete cytological remission at the time of allo-HSCT. We used two different conditioning regimens: total body irradiation (TBI) combined with cyclophosphamide, fludarabine, and melphalan (n = 23) and thiotepa combined with fludarabine and busulfan (n = 20). All patients received a graft-versus-host disease prophylaxis regimen consisting of cyclophosphamide, mycophenolate mofetil, and a calcineurin inhibitor or sirolimus. RESULTS: There was no difference in engraftment between patients receiving either of the regimens. After a median follow-up of 35.8 (range, 0.6-106.2) months, the overall survival (OS) and event-free survival (EFS) rates were 62.4% and 54.7%, respectively. OS and EFS were comparable between the respective regimens. CONCLUSIONS: We conclude that thiotepa-based conditioning has similar efficacy and tolerability as TBI-based conditioning for haploidentical HSCT with post-transplant cyclophosphamide.

Production and characterization of haploidentical CD19 CAR T cells: Validated to induce a continuous complete remission in a patient with relapsed refractory B-cell ALL.

AIMS: The purpose of this study was to design and manufacture CD19 chimeric antigen receptor (CAR)-modified T cells for clinical use in Thailand, as a model for how this technology can be directly applied at individual institutions treating high-risk leukemia patients. METHODS: We constructed second-generation CAR T cells expressing CD19 scFV-CD28-CD3ζ with different lengths of the spacer region: full, intermediate, and short length, by using a lentiviral vector. We wanted to determine whether the difference in length of the spacer would affect the cytotoxic potential of the CD19 CAR T cells against the leukemic cells. RESULTS: We found that all constructs of CD19 CAR T cells exhibited a similar level of cytotoxicity against several human lymphoma and leukemia cell lines. For the clinical application, we chose the intermediate length spacer construct CD19 CAR T cells, hypothesizing that the highest transduction efficiency coupled with a slower initial proliferation in vitro might lead to effective leukemic cell kill, yet a lower probability for serious clinical side effects. We then tested the clinical efficacy of our CD19 CAR T cells in one patient with refractory/relapsed acute B-cell lymphoblastic leukemia. This patient indeed had minimal clinical side effects after the CAR T-cell infusion, and he remains in an unmaintained, ongoing complete remission 10+ months after his T-cell treatment. CONCLUSION: Our CD19 CAR T cells demonstrated efficacies in acute lymphoblastic B-cell leukemia, and will be used to establish an immunotherapeutic program for high-risk B-cell acute lymphoblastic leukemia in Thailand. We propose that this approach can be used as a model for how this new exciting technology can be applied directly at individual institutions that treat (a large number of) patients with high-risk leukemia.

Long-Term Outcomes of Modified St Jude Children's Research Hospital Total Therapy XIIIB and XV Protocols for Thai Children With Acute Lymphoblastic Leukemia.

BACKGROUND: We studied long-term outcomes and prognostic features of Thai children with acute lymphoblastic leukemia treated with modified St Jude Children's Research Hospital (SJCRH) protocols. PATIENTS AND METHODS: Pediatric patients newly diagnosed with acute lymphoblastic leukemia were included. From 1997 to 2003, the first group received modified Total Therapy XIIIB (previous protocol). From 2004 to 2014, the latter had modified Total Therapy XV (current protocol). RESULTS: In 250 patients, the event-free survival rates (± standard error) of the previous protocol (n = 95) were 82.8 ± 3.9%, 81.7 ± 4.0%, and 81.7 ± 4.0% at 5, 10, and 15 years, respectively; current protocol event-free survival rates (n = 155) were 84 ± 3.0%, 80.8 ± 3.4%, and 80.8 ± 3.4%, respectively. Previous protocol overall survival rates for the same years were 89.2 ± 3.2%, 84.8 ± 3.8%, and 84.8 ± 3.8%, and for the current protocol were 90 ± 2.5%, 86.9 ± 3.2%, and 83.7 ± 4.4%. Previous protocol relapses were 10.5% (10 patients), with 7 having isolated hematologic and 3 isolated/combined central nervous system relapses. Current protocol relapses were 9.7% (15 patients), with 7 having isolated hematologic, 6 isolated/combined central nervous system, and 2 extramedullary relapses. Patients with leukocyte counts over 100 × 109/L and who had disease classified as high risk had worse event-free survival using the previous protocol. However, only initial leukocyte counts of ≥ 100 × 109/L predicted adverse outcomes under the current protocol. Minimal residual disease positivity was a prognostic factor of worse overall survival only for previous protocol patients. CONCLUSION: Favorable outcomes of childhood acute lymphoblastic leukemia occurred using adapted SJCRH protocols, perhaps because of multidisciplinary care teams and improved parent advocacy. Inferior outcomes might be prevented by addressing predictive factors to ameliorate monitoring and care.