A hematopoietic cell transplantation (HCT) registry serves as a database for grasping HCT activity in Japan. Registry data contributes to retrospective observational research activity. In January 2020, TRUMP® version 2.4, a Web database developed for the purpose of centralized online management of HCT outcome data, was released after a major revision of survey items. After the launch of a genetically modified T cell (CAR-T) therapy product, three HCT registries (CIBMTR, EBMT, and JSHCT/JDCHCT) harmonized survey items for cellular therapy. Thus, these HCT registries developed into HCT and cellular therapy registries. In March 2020, JSHCT/JDCHCT launched the Japanese version of FormsNet3 for their cellular therapy outcome registry based on the revised JSHCT/JDCHCT HCT and Cellular Therapy registry protocol. This cellular therapy registry enables the collection of outcome data for cellular therapy, including multiple CAR-T products, on the same platform with compatibility across registries. The activity will lead to a better outcome research platform for HCT and cellular therapy.
Mutations in the TP53 gene occur in 10-15% of AML and 10-30% of MDS and are more frequent in treatment-related neoplasms. Although TP53-mutated myeloid neoplasms usually have a very poor prognosis, TP53 mutations are also found in clonal hematopoiesis in healthy individuals, and in this case, they usually take a one-allele pattern. These mutations are assumed to develop into bi-allelic pattern after getting the second hits or accompanied by loss of heterozygosity (LOH) in the TP53 locus when they are observed in tumors. Mutations in one allele pattern can also be found in tumors, where the clinical picture, including genetic characteristics and prognosis, is like that of TP53 mutation-negative cases. TP53-mutated myeloid tumors are refractory to most treatments but respond to DNA methylation inhibitors. However, the duration of remission period is usually short, precluding prolonged survival. This has led to the development of new agents to improve remission rates and attempts to combine short remission periods with HSCT.
Several chromosomal abnormalities and gene mutations that are involved in the onset and recurrence of acute myeloid leukemia (AML) have been discovered owing to the recent progress in genome analysis. This technology can be used not only for the identification of prognostic factors and minimal residual disease markers but also for the development of novel molecular-targeted drugs. Several new drugs such as first-generation FLT3 inhibitors, IDH1/2 inhibitors, and BCL-2 inhibitors have been developed in Europe and the United States. In addition, second-generation FLT3 inhibitors such as gilteritinib and quizartinib were developed in Japan. These drugs have significantly improved treatment outcomes in AML patients. However, there is still a disparity in drug availability among Europe, the United States, and Japan. Consequently, treatment guidelines in Europe and United States cannot be utilized in Japan. This paper provides guidelines for use of gene diagnosis for prognostic stratification and indication of allogeneic hematopoietic cell transplantation in AML, applicable to Japan.
Alemtuzumab is a monoclonal antibody against CD52, which is expressed on pan-lymphocytes. It has a long terminal half-life after it has been added to conditioning regimens. Therefore, it can prevent graft rejection and graft-versus-host disease (GVHD) by depleting host and donor T-cells, respectively. Previous clinical trials have shown that human leukocyte antigen (HLA)-mismatched haploidentical transplantation using alemtuzumab could be performed safely, although prophylaxis against viral infection should be considered carefully. On the other hand, a high relapse/progression rate was still observed in non-remission patients, even in the present trials, which included lower doses of alemtuzumab and methotrexate and rapid tapering of cyclosporine. We are now planning to perform prophylactic donor lymphocyte infusion after haploidentical transplantation to augment the graft-versus-tumor effect.
Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is known to be one of lethal complications after hematopoietic stem cell transplantation (HSCT). In Japan, 462 of 4,290 patients who underwent allogeneic HSCT between 1999 and 2010 were diagnosed with SOS/VOD according to the Seattle criteria (cumulative incidence 10.8%). The 100 day overall survival rate was 32%. Multivariate analyses showed that the statistically significant independent risk factors for SOS/VOD were the number of HSCTs, age, performance status, hepatitis C virus-seropositivity, advanced disease status, and myeloablative regimen. SOS/VOD was highly associated with overall mortality. Defibrotide (DF) has been approved and become available in Japan. Recombinant human soluble thrombomodulin (rhTM) is approved for the treatment of disseminated intravascular coagulation, which pathologically resembles SOS/VOD in the etiology associated with endothelial damage. Data of 65 patients who underwent allogeneic HSCT and received DF (n=24) or rhTM (n=41) for SOS/VOD treatment were collected. Complete response rates for SOS/VOD on day 100 were 50% and 54% in the DF and rhTM groups, respectively. The 100 day overall survival rates were 50% in the DF group and 48% in the rhTM group, respectively. Although we can use defibrotide for SOS/VOD treatment globally, SOS/VOD remains one of the critical problems.
Sinusoidal obstruction syndrome (SOS), also called veno-occlusive disease (VOD) of the liver, is one of the most relevant complications of hepatic sinusoidal endothelial origin that appears early after haematopoietic cell transplantation (HCT). Despite its relatively low incidence and the fact that most cases of SOS/VOD resolve spontaneously, in the severe SOS/VOD that evolve to multi-organ failure have a mortality rate>80% and represent one of the major clinical problems after HCT. In these patients, the sinusoidal endothelial cells and hepatocytes are damaged by toxic metabolites generated by the conditioning regimen. Several risk factors have been identified for the development of SOS/VOD. Although defibrotide is recommended for both prevention and treatment, there is no satisfactory therapy for managing severe SOS/VOD. This review describes the new definition for late onset SOS/VOD diagnosis and the severity grading of suspected SOS/VOD from the European Society for Blood and Marrow Transplantation, the results of current treatment including the Japanese therapeutic use program, defibrotide treatment protocol.
HLA-haploidentical transplantation with posttransplant high-dose cyclophosphamide (PTCy-haplo) is becoming a platform for HLA-haploidentical transplantation. However, a series of recent meta-analytical reports have shown that although the risk of chronic GVHD in the PTCy-haplo is significantly lower than that in the HLA-matched transplantation, more risk of relapse was found in the PTCy-haplo than that in the HLA-matched unrelated transplantation. To reduce the incidence of relapse, it is important to analyze the underlying mechanisms of the (graft-versus-leukemia, GVL) effects of PTCy-haplo. Some reports have suggested that alloreactivity of NK cells plays a crucial role in the GVL effects of PTCy-haplo. However, NK cell recovery affected by PTCy has also been reported. In order to further improve outcomes in the PTCy-haplo, an evaluation of donor selection methods, amounts of cells in infused graft, optimal doses and timings of PTCy administration, and administration methods of immunosuppressive drug is required.
It has already been more than 30 years since the first cord blood transplantation in France. During this period, the position of cord blood transplantation has been changing, given the decreased incidence of graft failure or identification of powerful GVL effect. Despite the decrease in the annual number of cord blood transplantation in both the US and the EU, mostly due to increased transplants from haploidentical donors, cord blood transplantations are still increasing in Japan. Better management of early complications, infections or alloimmune reactions in particular, and disease recurrence after cord blood transplant would be vital to improving the outcomes.
HLA-haploidentical stem cell transplantation using post-transplant cyclophosphamide (PTCy-haploSCT) is increasingly being performed in clinical practice. Although PTCy-haploSCT is associated with a low risk of severe graft-versus-host disease and non-relapse mortality, cytokine release syndrome (CRS) is a major complication after PTCy-haploSCT. CRS, caused by hypercytokinemia, presents with diverse symptoms, including fever, hypotension, and respiratory failure. Patients may develop a variety of symptoms; however, the major clinical manifestation of CRS is high-grade fever early after stem cell infusion. Although CRS is mild in most patients and resolves rapidly after PTCy administration, some patients may develop a severe form of this condition. Tocilizumab administration is recommended in patients with severe CRS; however, corticosteroids serve as first-line therapy because tocilizumab is not approved for PTCy-haploSCT-induced CRS in Japan. Prophylactic corticosteroid administration before PTCy should be avoided because corticosteroids inhibit proliferation of alloreactive T cells and can theoretically reduce the effectiveness of PTCy. Severe CRS is known to be associated with poor prognosis; however, the effects of mild CRS on transplantation outcomes remain unclear. Further investigations are warranted to confirm whether an acceptable level of CRS is associated with antitumor effects.