First complete remission favours haploidentical haematopoietic stem cell transplantation with post-transplant cyclophosphamide over cord blood transplantation in acute lymphoblastic leukaemia.

To assess the benefits of HLA-haploidentical haematopoietic stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) relative to those of umbilical cord blood (UCB) transplantation in acute lymphoblastic leukaemia (ALL), we analysed 1999 patients (PTCy-haplo, 330; UCB, 1669), using the nationwide Japanese registry. PTCy-haplo was associated with a significantly higher relapse rate, but lower non-relapse mortality, which results in overall survival and disease-free survival, comparable to those of UCB. Among patients in CR1, PTCy-haplo showed a significantly higher survival than UCB regardless of the CD34+ cell dose. Our findings provide valuable insights into the donor selection algorithm in allogeneic HSCT for adult patients with ALL.

[New era of GVHD prophylaxis using posttransplant cyclophosphamide].

Use of posttransplant cyclophosphamide (PTCy) for the prophylaxis of graft-versus-host disease (GVHD) has revolutionized the field of HLA-haploidentical stem cell transplantation, which was previously considered high-risk and only feasible in specialized centers. The rapid adoption of PTCy is attributed not only to its superior efficacy in suppressing GVHD but also to its affordability and the lack of need for specialized techniques or equipment to administer it. Recently, PTCy has gained attention for its potential effectiveness in GVHD prophylaxis beyond HLA-haploidentical stem cell transplantation. In a phase III trial (BMT CTN 1703 trial) in patients undergoing allogeneic HLA-matched stem cell transplantation with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly better among those who received PTCy-tacrolimus-mycophenolate mofetil than among those who received tacrolimus-methotrexate. In Japan, a phase II clinical trial that investigated PTCy for GVHD prophylaxis following HLA-matched or 1-2 allele mismatched peripheral blood stem cell transplantation confirmed the efficacy and safety of this approach. Effective suppression of GVHD using PTCy is expected to enhance the safety of allogeneic transplantation, potentially improving transplant outcomes and offering hope for better patient care in the field of transplantation.

[HLA-haploidentical stem cell transplantation].

HLA-haploidentical stem cell transplantations using posttransplant cyclophosphamide (PTCy-haplo) rapidly increased worldwide. In Japan, the number of HLA-haploidentical stem cell transplantation cases exceeded related HLA-matched transplants in 2020. Recent retrospective studies using Japanese registry data have reported comparable transplantation outcomes between PTCy-haplo and HLA-matched unrelated and cord blood transplantations. PTCy-haplo was initially developed in the bone marrow transplantation setting after non-myeloablative conditioning but has recently become widely used in peripheral blood stem cell transplantation and myeloablative conditioning. Peripheral blood stem cell transplantation increases the occurrence of graft-versus-host disease but may have more improved transplant outcomes compared with bone marrow transplantation. Other factors, such as the number of infused cluster of differentiation 34-positive cells, donor age, HLA class II mismatch, HLA-B leader, and reduced PTCy dosage, may also contribute to the outcome of PTCy-haplo transplantations. Furthermore, PTCy has been reportedly effective in related/unrelated HLA-matched transplantation and HLA-mismatched unrelated transplantations. A prospective phase II trial using PTCy in patients who underwent HLA-matched and 1-2 allele-mismatched transplantation is ongoing in Japan. Patient enrollment has already been completed, and the results will be revealed soon. Using PTCy to sufficiently reduce the occurrence of graft-versus-host disease will make performing allogeneic transplants with a higher safety level possible.

[HLA-haploidentical peripheral blood stem cell transplantation with post-transplantation cyclophosphamide for adult T-cell leukemia].

Recently, allogeneic peripheral blood stem cell transplantation from human leukocyte antigen (HLA)-haploidentical donors using post-transplantation cyclophosphamide (PTCY-haploPBSCT) has become available in clinical practice. However, the efficacy of PTCY in adult T-cell leukemia (ATL) is not fully established yet. In this study, we retrospectively examined data of seven patients who underwent PTCY-haploPBSCT. The overall survival rate at 100 days after transplantation was 85.7%, and the 1-year overall survival rate was 68.6%. The cumulative incidence of relapse at 1 year was 31.4%, whereas the 1-year nonrelapse mortality was 17.1%. The cumulative incidence of grade III-IV acute graft-versus-host disease (GVHD) on day 100 was 14.3%, and the incidence of chronic GVHD at 1 year was 33.3%. These results suggest that PTCY-haploPBSCT can be a viable option even in patients with ATL. Further accumulation of knowledge and improvement of transplantation outcomes are warranted in the future.

[Allogeneic hematopoietic stem cell transplantation for hematological malignancies: an algorithm for donor selection].

Allogeneic hematopoietic stem cell transplantation is a potentially curative treatment for patients with hematological malignancies with donor selection being one of the most important decisions for its success. Several possible donor options have been available, including matched related donor (MRD), matched unrelated donor (MUD), mismatched unrelated donor (MMUD), umbilical cord blood (UCB), and HLA-haploidentical donor. A MRD remains the preferred donor option for optimal transplant outcomes with approximately 30% of the patients having such a donor. Therefore, the remaining 70% of patients require an alternative donor source. Although a MUD is considered to be the next preferred donor option following a MRD, searching for a MUD may delay transplantation for patients unlikely to have a MUD. UCB or HLA-haploidentical donors allow for shorter time to transplant but are associated with increased risk. Recently, T-cell-replete haploidentical transplantation using posttransplantation cyclophosphamide (PTCY) has been developed. This strategy dramatically reduces the risk of graft versus host disease (GVHD), while transplant outcomes after PTCY-based HLA-haploidentical stem cell transplantation seem to be equivalent to those after HLA-matched stem cell transplantation. Recent advances in GVHD prophylaxis may change the algorithm for donor selection.

[Congenital leukemia showing lineage switch following induction chemotherapy and attaining long-term remission after HLA-haploidentical stem cell transplantation].

Congenital leukemia is a rare subgroup of childhood leukemia. Lineage switches in leukemic cells are relatively rare events, which have been occasionally reported in congenital leukemia. To the best of our knowledge, the survival of congenital leukemia patients with lineage switch has not been previously documented. This lack of documentation may be attributable to extremely poor prognosis of these patients. We describe a case of a newborn female with initial diagnosis of MLL-AF4 positive B-precursor acute lymphoblastic leukemia, who developed lineage switch to acute monocytic leukemia following the induction therapy. Although morphological remission was temporary, she received an HLA-haploidentical bone marrow transplant from her father with non-remission status because of an early relapse at the age of 4 months. Despite many difficulties such as graft-versus-host disease, growth impairment, and psychomotor retardation, she remained in remission for 3 years and 7 months after the transplant. This successful outcome suggests that the graft-versus-leukemia effect was potentially accomplished in the patient. Taken together, early HLA-haploidentical stem cell transplant following remission is required for congenital leukemia patients with lineage switch, and it may be an effective alternative for refractory patients.

HLA-haploidentical transplantation with post-transplant cyclophosphamide.

Recently, post-transplant cyclophosphamide (PTCy) -based HLA-haploidentical stem cell transplantation (PTCy-haploSCT) has been increasingly performed. The mechanism of GVHD prevention by PTCy is selective depletion of proliferating alloreactive T cells, while preserving non-alloreactive T cells. Several studies have reported that the incidence of non-relapse mortality, relapse, disease-free survival, and overall survival after PTCy-haploSCT are equivalent to those after HLA-matched SCT. Furthermore, the incidence of GVHD, especially chronic GVHD, after PTCy-haploSCT was lower than that of HLA-matched SCT. In Japan, we have conducted several prospective, multicenter, phase II studies since 2013. To reduce relapse, several strategies have been developed. In the first study (Haplo13), we used peripheral blood stem cells and added busulfan (BU) to the original non-myeloablative regimen developed by a Johns Hopkins group. In the second study, we used a BU- or TBI-based myeloablative conditioning regimen (Haplo14 MAC). In the third study, we reduced the dose of PTCy (Haplo16 RIC). In the latest study (Haplo17), we reduced the dose and/or duration of MMF and tacrolimus. We hope that these studies improve the outcome of PTCy-haploSCT.

T-cell-replete haploidentical stem cell transplantation is highly efficacious for relapsed and refractory childhood acute leukaemia.

BACKGROUND: Despite improvements in first-line therapies, the outcomes of relapsed or refractory childhood acute leukaemia that has not achieved complete remission after relapse, has relapsed after stem cell transplantation (SCT), has primary induction failure and has relapsed with a very unfavourable cytogenetic risk profile, are dismal. OBJECTIVES AND METHODS: We evaluated the feasibility and efficacy of T-cell-replete haploidentical peripheral blood stem cell transplantation (haplo-SCT) with low-dose anti-human thymocyte immunoglobulin (ATG), tacrolimus, methotrexate and prednisolone (PSL) in 14 paediatric patients with high-risk childhood acute leukaemia. RESULTS: All patients achieved complete engraftment. The median time to reaching an absolute neutrophil count of more than 0.5 × 10(9) L(-1) was 14 days. Acute graft-vs-host disease (aGVHD) of grades II-IV and III-IV developed in 10 (71%) and 2 (14%) patients, respectively. Treatment-related mortality and relapse occurred in one (7%) patient and six (43%) patients, respectively. Eleven patients were alive and seven of them were disease-free with a median follow-up of 36 months (range: 30-159 months). The probability of event-free survival after 2 years was 50%. CONCLUSION: These findings indicate that T-cell-replete haplo-SCT, with low-dose ATG and PSL, provides sustained remission with an acceptable risk of GVHD in paediatric patients with advanced haematologic malignancies.

Successful HLA-haploidentical stem cell transplantation with post-transplant cyclophosphamide in an older patient with chronic active Epstein-Barr virus infection.

Chronic active Epstein-Barr virus infection (CAEBV) is a subtype of EBV-associated T/NK cell lymphoproliferative disease and is only curable by allogeneic hematopoietic stem cell transplantation. However, finding a human leukocyte antigen (HLA)-matched donor at a suitable time can sometimes be difficult. We report the case of a 60-year-old woman who received prednisolone (PSL) after being diagnosed with autoimmune hepatitis 3 years earlier. She suddenly developed high fever and impaired liver function. Based on a high EBV DNA load in the peripheral blood, CAEBV was diagnosed. The patient was started on cooling therapy with PSL, cyclosporine, and etoposide, which reduced symptoms. Subsequently, she received HLA-haploidentical stem cell transplantation (haplo-SCT) with reduced-intensity conditioning (fludarabine 25 mg/m2 for 5 days, melphalan 50 mg/m2 for 2 days, and total body irradiation at 2 Gy) and post-transplant cyclophosphamide (PTCy) because she lacked an HLA-matched donor. Liver function was restored, and EBV DNA load in peripheral white blood cells became undetectable. The patient is alive without relapse or severe complications over 1 year after transplantation. To our knowledge, this is the first report of successful haplo-SCT with PTCy for CAEBV. This approach may be an alternative therapeutic option for CAEBV patients lacking an HLA-matched donor.