Chimeric antigen receptor T-cell (CAR-T) therapy has exhibited astonishing efficacy against CD19＋ B-cell malignancies, and is currently the subject of intensive clinical studies as well as others types of research. Autologous CD19CAR-T therapy has demonstrated much greater clinical efficacy against acute lymphocytic leukemia than was expected, whereas its effects against chronic lymphocytic leukemia and malignant lymphoma were weaker than expected. To strengthen the clinical efficacy of CD19CAR-T therapy, its combination with allogeneic hematopoietic stem cell transplantation (allo-HSCT) and CD19CAR-T therapy has started to be examined in clinical trials. The potential advantages of the use of allogeneic T-cells for the generation of CD19CAR-T are as follows: it is easier to produce CD19CAR-T cells with healthy, chemo-naïve T-cells from an allo-HSCT donor and it might have a graft versus leukemia effect that reduces the risk of a relapse. In this review, the possible use of CAR-T therapy in combination with allo-HSCT and current research into CAR-T therapy will be reviewed by giving examples, such as CD19CAR-T and CD123CAR-T therapy.
The execution of a prospective trial involving the random assignment of adult patients with acute lymphoblastic leukemia (ALL) in first remission who have a human leukocyte antigen (HLA) -matched related donor into 1 of the 2 groups, those undergoing hematopoietic stem cell transplantation (HSCT) or those treated with chemotherapy alone, is difficult in terms of practicality. Therefore, we performed a decision analysis to establish the optimal post-remission treatment in such patients. Transition probabilities after continuing chemotherapy in the first remission period, and after treatment with HSCT in patients with various disease statuses, were established according to the results of Japan Adult Leukemia Study Group (JALSG) prospective studies, and data from the Transplant Registry Unified Management Program (TRUMP) of Japan Society for Hematopoietic cell transplantation (JSHCT), respectively. As a result, the decision to perform HSCT in the first remission period, as opposed to continuing treatment with chemotherapy in this period, is recommended for adult patients with ALL who have an HLA-matched related donor. In addition, we were able to demonstrate efficacy when combining the large amount of clinical data regarding chemotherapy and HSCT. Further improvement in two large nationwide data obtained from results of JALSG studies regarding chemotherapy and from TRUMP of JSHCT regarding HSCT is anticipated, and the direct association between these 2 large data will generate important results with respect to treatment strategies for hematological diseases in Japan.
Hematopoietic stem cell transplantation (HSCT) involves the potential for certain serious transplant-related complications such as graft-versus-host disease (GVHD), and recovery from such complications is vital for a successful HSCT outcome. Acute GVHD (aGVHD) occurs in the early period after transplantation and is initiated by alloreactive donor T cells. The mechanisms whereby immune responses trigger this post-transplantation condition remain unclear, but endothelial cell function might play a role in this. Authors investigated the expression of endothelial cell activation markers such as sE-selectin, sVCAM-1, PAI-1 and microparticle (MP) in patients undergoing allogeneic HSCT. Additionally, authors studied the effects of recombinant soluble thrombomodulin (rTM) on the expression of these markers. This study cohort included 312 patients who underwent allo HSCT at 25 institutions in Japan. In the 143 patients who developed aGVHD, levels of endothelial cell activation markers were significantly higher compared to patients who did not develop aGVHD. Moreover, patients who received rTM exhibited a significantly lower frequency of aGVHD and reduced levels of endothelial cell activation markers. These findings suggest that endothelial cell activation might be linked to aGVHD, and that rTM might at least in part act to prevent aGVHD by its effect on endothelial cells.
A process of hematopoietic stem cell harvesting, processing, preservation, and infusion is basically important for hematopoietic stem cell transplantation. Appropriate these procedures lead to a high quality of hematopoietic stem cell products, resulting in good clinical outcomes. These procedures should be done strictly according to several guidelines published by The Japan Society for Hematopoietic Cell Transplantation, The Japan Society for Transfusion Medicine and Cell Therapy, and Japan Marrow Donor Program. In this review, the current status of these procedures in Japan as well as in other countries is described.
Investigation of the factors that impair health-related quality of life (QOL) is important for designing nursing intervention. Forty patients who underwent either allogeneic hematopoietic cell transplantation (allo-HCT) (n=14) or autologous-HCT (auto-HCT) (n=26) participated in this QOL study using the SF-36. The survey was administered once a year for three years after HCT. To define parameters specific to allo-HCT, we interviewed the patients with a questionnaire (PN sheet) using the Patient Needs Assessment Tool and chronic graft-versus-host disease (cGVHD) severity defined by NIH in the final survey. The median age was 63 years, and the median follow-up was 50 months, ranging from 2-90 months. The scores of Physical Functioning (PF), Role-Physical, Vitality, and Physical Component Summary of allo-HCT patients were significantly lower than auto-HCT patients 4 years after HCT. When we examined the items reducing QOL score using the PN sheet, we found that an item for cGVHD reduced QOL scores of PF and Mental Health (MH), and difficulty of reinstatement reduced QOL scores of MH. These findings suggested that intervention in the symptoms of cGVHD and not quitting work would lead to improvement of the QOL. The PN sheet was useful to extract factors for QOL improvement.
The utility of allogeneic hematopoietic stem cell transplantation (allo-HSCT) from sources other than matched related donors (alternative donors) in the management of elderly acute myeloid leukemia (AML) patients in first complete remission (CR1) has not been clarified. To investigate the benefit of allo-HCST in the management of elderly AML patients in CR1, we retrospectively collected data from consecutive AML patients aged 60-66 years, who had been diagnosed between 2000 and 2014 and achieved CR. A total of 43 patients were included in this study, and 12 patients received allo-HSCT in CR1 only from alternative donors. Compared to chemotherapy alone, allo-HSCT improved overall survival (OS) (P=0.050) and cumulative incidence of relapse (CIR) (P=0.0059) in univariate analysis. OS and CIR at 3 years from CR1 were 82.5% vs 34.2%, and 17.5% vs 74.6%, respectively. In multivariate analysis, allo-HSCT also improved OS (hazard ratio (HR), 0.18; 95% confidence interval (CI), 0.039-0.80) and CIR (HR, 0.090; 95% CI, 0.029-0.28). Allo-HSCT from an alternative donor is a credible option in the treatment of elderly AML patients in CR1.
Although anaerobic bloodstream infections (ABI) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are rare, the mortality rate is high. In this retrospective study, we examined ABI episodes in 981 consecutive patients who underwent allo-HSCT at the National Cancer Center Hospital from January 2001 to October 2013. We identified 23 strains of anaerobes from 23 ABI episodes. Of these, 14 ABI episodes occurred before engraftment and 9 episodes occurred after engraftment. Fusobacterium sp. and Porphyromonas sp. were predominantly detected during the pre-engraftment period and were assumed to be derived from the oral cavity or upper intestinal tract. In contrast, Bacteroides sp. and Clostridium sp. were the frequently isolated anaerobes in the post-engraftment and were assumed to be derived from the lower intestinal tract. The presence of polymicrobial bacteremia was significantly associated with ABI episodes and was assumed to be derived from the lower intestinal tract. These results indicate the differences in clinical features of ABI between the pre- and post-engraftment periods and provide valuable information for the selection of appropriate antibiotics as an empirical treatment.
This case describes a 38-year-old woman who visited her previous physician because of fever and general malaise that she had experienced since March 2014. An increased leukocyte count was observed, and the patient was subsequently referred to our department. She was diagnosed with acute myeloid leukemia (AML) and achieved complete remission with remission induction therapy given in accordance with the JALSG AML201 protocol. However, AML relapsed after remission therapy. FLAGM therapy was performed for the re-induction of remission but was ineffective. The patient was consequently pre-treated with gemtuzumab ozogamicin, and subsequently underwent peripheral blood stem cell transplantation from a related donor in October. Although a bone marrow aspiration performed on day 33 revealed that complete remission had been achieved, peripheral hemoblasts were detected on day 47. Immediately after transplantation the patient presented with heart failure which was resistant to drug treatment, indicating a refractory condition. Moreover, AML invasion was confirmed through pericardiocentesis. The patient did not wish to undergo aggressive therapy and eventually died in December. Here, we report a rare case of pericardial invasion that occurred after hematopoietic stem cell transplantation.
A 29-year-old male with myelodysplastic syndrome (RAEB-1) underwent allogeneic peripheral blood stem cell transplantation from his father whose HLA-DR was serologically mismatched at the DR locus. Neutrophils>500/μL and platelets>20,000/μL were achieved on day 17 and day 25 respectively, but two months after transplantation, pancytopenia was progressed associated with cytomegalovirus antigenemia. Chimerism analysis showed complete donor type, but six month later he was dependent on RBC transfusion. He was diagnosed as poor graft function. Booster transplantation of bone marrow from the same donor was performed without pre-conditioning therapy nine months after transplantation, hematopoietic recovery was rapid with no aggravation of graft versus host disease and then immunosuppressant was tapered. These observations suggest that booster transplantation of bone marrow including mesenchymal stem cells might contribute to be improvement of bone marrow microenviroment, which led to hematopoietic recovery in a patient with poor graft function.