The most drastic progress in recent cancer therapy is the success of immunotherapy against conventional treatment-refractory cancers, which is demonstrated by CD19 specific chimeric antigen receptor gene-modified T cells (CD19 CAR-T) against refractory B-lymphoid blood cancers and immune check point inhibitors against various kinds of refractory solid cancers. Realistically speaking, CD19 CAR-T itself is facing not a few clinically important hurdles, such as cytokine release syndrome, neural toxicity, disease relapse after CAR-T therapy and so on. Within this context, global actions in CAR-T development are now aiming at brushing up the proven clinical efficacy of CD19 CAR-T and the extended applicability mainly focusing on solid cancers. To this end, modification of CAR gene construct has solely been centered hitherto. Currently, novel strategies dealing with immune cells to which CAR-gene transduced has opened a door to manufacturing “Off-the-shelf CAR-T drug”, which will have to be an ideal form of CAR-T drug. Viewing from these points, here in this article, we would like to overview the current global situation of CAR-T development.
Antithymocyte globulin (ATG) reduces chronic GVHD; however, effect of ATG on prognosis of allogeneic hematopoietic stem cell transplantation (HSCT) differs depending on characteristics of HSCT. In myeloablative conditioning (MAC), ATG has been shown to inhibit chronic GVHD without increase in relapse or decrease in survival, whereas in reduce intensity conditioning, ATG was also shown to inhibit chronic GVHD as in MAC; however, effect of ATG on relapse or survival after HSCT is still unclear. Prophylactic use of ATG is recommended in peripheral blood stem cell transplantation (PBSCT) or HLA 1-locus mismatched HSCT, while not recommended in cord blood transplantation. Although an optimal dose of ATG remains undefined, lower doses of ATG has been used in recent studies. In a nationwide retrospective study for ATG in unrelated PBSCT, low dose ATG significantly reduced the incidence of chronic GVHD. Recently, an association between absolute lymphocyte counts (ALC) before the administration of ATG and transplant outcomes has been reported, suggesting a strategy to individualize ATG dosing according to ALC before ATG.
Looking back over the past 15 years, allogeneic hematopoietic cell transplantation for myeloid malignancies in their 60s is rapidly expanding. In particular, the number of transplants aged 65-69 is increasing rapidly. Furthermore, reflecting the elderly society, the number of transplant cases in their 70s is gradually increasing both in foreign countries and Japan. According to TRUMP data obtained from the Japan Hematopoietic Cell Transplantation Data Center (JDCHCT) of Japanese Society for Transplantation and cell Therapy (JSTCT), it is reported that the presence or absence of remission is more important than age in the results of allogeneic transplantation for AML in the 60s and there was no difference in overall survival (OS) between the 60-64 year old group, the 65-69 year old group, and older in MDS. Analyzing allogeneic transplantation results for myeloid tumors in their 70s using TRUMP data, the median transplantation age for both AML and MDS was about 72 years. As the elderly get older, not only complete cure but also QOL is important, and if it becomes possible to extract factors as to whether or not transplantation can be expected to improve the prognosis of life, transplantation in the 70s has the potential to expand further.
The purpose of pre-transplant conditioning in allogeneic hematopoietic stem cell transplantation for patients with aplastic anemia is to avoid graft failure and prevent graft-versus-host disease (GVHD). Although the combination of high-dose cyclophosphamide (CY) and anti-thymocyte globulin (ATG) was developed as an effective conditioning regimen, cardiac toxicity due to high-dose CY has been a major problem. Reduction of the CY dose with the addition of fludarabine (Flu) has recently been considered to decrease toxicity. In the Kanto Study Group for Cell Therapy (KSGCT), a prospective study using Flu, reduced-dose CY and low-dose thymoglobulin as a conditioning regimen for aplastic anemia was performed to determine the appropriate regimen for Japanese patients. This study showed an excellent overall survival rate of 96.3% at 1 year. However, the use of Flu may affect the occurrence of secondary graft failure. Recently, outcomes in cord blood transplantation and transplantation from a haploidentical donor are improving with the appropriate preconditioning regimens. In addition, alemtuzumab may be a promising drug for pre-transplant conditioning for aplastic anemia.
Allogeneic stem cell transplantation (allo-SCT) is a therapeutic option for myelodysplastic syndromes (MDS); however, a number of issues is need to be resolved to improve its outcomes. Multiple factors, including age, the risk of disease progression, the severity of comorbidities, the physical and mental status of patients, and socioeconomic issues, should be considered before allo-SCT. Although pre-transplant treatments improve the outcomes of allo-SCT in selected patients, optimal treatment regimens and durations have yet to be clarified. Relapse after allo-SCT affects the outcomes of patients. Patients with hematological relapse after allo-SCT have poor clinical outcomes. Early preemptive treatments based on the confirmation of minimal residual disease by standardized procedures or prophylactic treatments after allo-SCT need to be established for selected high-risk cases. Advances in transplantation procedures, including the development of novel drugs based on the molecular pathology of MDS, are required to further improve the outcomes of allo-SCT for MDS.
Recently, novel agents (e.g., molecularly-targeted drug, bispecific antibody, antibody-drug conjugate, and immunotherapy) have successively emerged in clinical practice. Expected role of these drugs included tumor reduction prior to allogeneic hematopoietic cell transplantation (allo-HCT), decreased risk of relapse with maintenance therapy after allo-HCT, and consequent improvement of transplant outcomes. Some of molecularly-targeted drugs could also be adapted for steroid-refractory acute and/or chronic graft-versus-host-disease (GVHD), that still remained leading cause of non-relapse mortality after allo-HCT. On the other hand, immune-modulating agents possibly develop excessive immune reaction including GVHD; thus, transplant physicians should pay attention to their “off-target” effects as well as opportunistic infections caused by substantial myelosuppression or immunosuppressive activity, and drug-drug interactions between agents used in supportive care. In this review, we would like to summarize the risk assessment and management of GVHD following pretransplant molecularly-targeted therapy. Moreover, recent advances in prophylaxis and treatment of GVHD using novel agents are also discussed.
Background: Cord blood is an alternative donor source for patients without HLA-matched donors. Calcineurin inhibitors (CNIs) alone, as prophylaxis for graft-versus-host disease (GVHD) in cord blood transplantation (CBT) patients, reportedly increase the incidence of severe pre-engraftment immune reaction (PIR), leading to transplant-related mortality (TRM) with primary engraft failure and multiple organ dysfunctions. Therefore, additional immunosuppressive agents are needed. Reportedly, short-term methotrexate (sMTX) plus CNIs improved outcomes in patients receiving CBT with full-intensity conditioning (FIC) regimens; however, safety and efficacy of sMTX plus cyclosporine have not been assessed in patients receiving CBT with reduced-intensity conditioning (RIC) regimens. Methods: We retrospectively analyzed 43 patients who received single-unit CBT and were treated with sMTX plus cyclosporine (RIC group, 15; FIC group, 28). Results: Neutrophil engraftment rate was significantly lower in RIC group (53.3%) than in FIC group (78.6%, P=0.04). Cumulative incidence of TRM tended to be higher in the RIC group than in the FIC group (P=0.12); the leading cause of death in the RIC group was bacterial infections. Conclusions: sMTX plus cyclosporine does not seem feasible for treating patients receiving single-unit CBT following RIC. MTX dose optimization or alternative immunosuppressive agent application should be considered in such patients.
[Purpose] In Japan, there is not enough research on delirium in allogeneic hematopoietic cell transplantation (HSCT) patients. This study aims to evaluate delirium among allogeneic HSCT patients at our hospital. We compared the risk factors, such as hypoxia, opioid use, and renal and hepatic dysfunction, of the delirium and non-delirium groups. [Results] The incidence of delirium within 30 days of transplantation was 30.3% (of which onset within 14 days was observed in 70%). Oxygen administration, opioid use, abnormal BUN, CRE, and Bil were more frequent in the delirium group: 70% and 19.6%, 70% and 60.9%, 85% and 39.1%, 65% and 26.1%, and 80% and 39.1% in the delirium and non-delirium groups, respectively. [Discussion] The incidence of delirium tended to be higher within 14 days after transplantation, which is the standard period for engraftment. Because of the intensive physical invasion of patients during this period, it is difficult to differentiate between decreased patient activity and hypoactive delirium. It is crucial to be aware of the risk factors of delirium specific to allogeneic transplant patients and the timing of care.