Search

Refractoriness to platelet transfusion is a major problem in a small group of patients, and large-scale manufacturing of clinical grade functional platelets ex vivo has remained an elusive goal. Sugimoto et al report on the results of the first clinical trial of an autologous transfusion of induced pluripotent stem cell (iPSC)-derived platelets in a patient who had severe aplastic anemia but no compatible platelet donor. Using methodology described in a complementary article in Blood Advances, the results provide proof-of-principle and illustrate the challenges to be faced in taking this approach further.

The medium-dose etoposide (VP16) added on cyclophosphamide (CY)/total body irradiation (TBI) is one of the intensified myeloablative conditioning regimens used in allogenic hematopoietic stem cell transplantation (allo-HSCT) for acute lymphoblastic leukemia (ALL). However, the patient subgroups who can actually benefit from VP16/CY/TBI compared to CY/TBI have not been precisely defined. Therefore, we conducted a multi-center retrospective study using the Japanese nationwide registry database to elucidate the efficacy of VP16/CY/TBI on post-transplant prognosis. Biological and clinical distinct subtypes (i.e., Philadelphia chromosome-positive (Ph+) and -negative (Ph-) ALL) were evaluated separately, which included 820 Ph+ and 1463 patients with Ph- ALL, respectively. Compared with the CY/TBI group, the VP16/CY/TBI group showed superior progression-free survival (PFS) in patients with Ph+ ALL (65% vs. 57% at 3 years after HSCT; adjusted hazard ratio (HR), 0.73; 95% confidence interval (CI), 0.55-0.98; p = 0.03), along with significantly reduced incidence of relapse (adjusted HR, 0.58; 95% CI, 0.37-0.90; p = 0.02) without the increase of non-relapse mortality (NRM). By contrast, in patients with Ph- ALL, VP16/CY/TBI did not improve PFS nor incidence of relapse; addition of VP16 reduced relapse (HR, 0.65; p = 0.06) in patients with Ph- ALL transplanted at CR1, while improved PFS was not observed (HR, 0.90; p = 0.52) due to increased NRM. This study demonstrated that VP16/CY/TBI is a more effective and well-tolerated regimen in comparison with CY/TBI in patients with myeloablative allo-HSCT for adult Ph+ ALL. Our findings can provide a novel algorithm for conditioning regimen selection in patients with adult ALL.

It is challenging to preserve the fertility of female patients with B-cell acute lymphoblastic leukemia (B-ALL) before allogeneic hematopoietic stem cell transplantation (allo-HSCT) while maintaining treatment intensity. We report two cases of female patients with Philadelphia chromosome-negative (Ph -) B-ALL whose oocytes were retrieved after controlled ovarian stimulation during and after blinatumomab treatment. The first patient was a 30-year-old woman with relapsed Ph-B-ALL who received prednisolone (PSL) and cytoreductive chemotherapy with cyclophosphamide, vincristine, doxorubicin, and dexamethasone, followed by three courses of blinatumomab bridging to allo-HSCT. Ovarian stimulation was performed twice during blinatumomab administration, and two oocytes were retrieved during each course. The second patient was a 26-year-old woman with newly diagnosed Ph-B-ALL who received PSL, one course of conventional chemotherapy, and one course of high-dose methotrexate and cytarabine followed by two courses of blinatumomab bridging to allo-HSCT. Immediately after completion of the first course of blinatumomab, ovarian stimulation was performed, and three oocytes were retrieved. Use of a 2-week rest period enabled ovarian stimulation and oocyte retrieval to be performed without delaying treatment. Blinatumomab may be an option for preserving fertility while maintaining treatment intensity.

Supplementary Data

Graft-versus-host-disease-free, relapse-free survival (GRFS) is a useful composite endpoint that measures survival without relapse or significant morbidity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aimed to develop a novel analytical method that appropriately handles right-censored data and competing risks to understand the risk for GRFS and each component of GRFS. This study was a retrospective data-mining study on a cohort of 2207 adult patients who underwent their first allo-HSCT at the Kyoto Stem Cell Transplantation Group (KSCTG), a multi-institutional joint research group of 17 transplantation centers in Japan. The primary endpoint was GRFS. A stacked ensemble of Cox proportional hazard regression and seven machine learning algorithms was applied to develop a prediction model. The median age of patients was 48 years. For GRFS, the stacked ensemble model achieved better predictive accuracy evaluated by C-index than other top-of-the-art competing risk models (ensemble model: 0.670, Cox-PH: 0.668, Random Survival Forest: 0.660, Dynamic DeepHit: 0.646). The probability of GRFS after 2 years was 30.54% for the high-risk and 40.69% for the low-risk group, respectively (hazard ratio [HR] compared to the low-risk group: 2.127; 95% CI: 1.19-3.80). We developed a novel predictive model for survival analysis that showed superior risk stratification to existing methods using a stacked ensemble of multiple machine learning algorithms., アンサンブル学習を用いた造血幹細胞移植予後予測モデルの開発 --機械学習を用いた新規生存時間解析手法の実装--. 京都大学プレスリリース. 2021-12-28.

Ceramide is a bioactive sphingolipid that mediates ionizing radiation- and chemotherapy-induced apoptosis. Neocarzinostatin (NCS) is a genotoxic anti-cancer drug that induces apoptosis in response to DNA double-strand breaks (DSBs) through ataxia telangiectasia mutated (ATM) activation. However, the involvement of ceramide in NCS-evoked nuclear events such as DSB-activated ATM has not been clarified. Here, we found that nuclear ceramide increased by NCS-mediated apoptosis through the enhanced assembly of ATM and the meiotic recombination 11/double-strand break repair/Nijmengen breakage syndrome 1 (MRN) complex proteins in human lymphoblastoid L-39 cells. NCS induced an increase of ceramide production through activation of neutral sphingomyelinase (nSMase) and suppression of sphingomyelin synthase (SMS) upstream of DSB-mediated ATM activation. In ATM-deficient lymphoblastoid AT-59 cells compared with L-39 cells, NCS treatment showed a decrease of apoptosis even though ceramide increase and DSBs were observed. Expression of wild-type ATM, but not the kinase-dead mutant ATM, in AT-59 cells increased NCS-induced apoptosis despite similar ceramide accumulation. Interestingly, NCS increased ceramide content in the nucleus through nSMase activation and SMS suppression and promoted colocalization of ceramide with phosphorylated ATM and foci of MRN complex. Inhibition of ceramide generation by the overexpression of SMS suppressed NCS-induced apoptosis through the inhibition of ATM activation and assembly of the MRN complex. In addition, inhibition of ceramide increased by the nSMase inhibitor GW4869 prevented NCS-mediated activation of the ATM. Therefore, our findings suggest the involvement of the nuclear ceramide with ATM activation in NCS-mediated apoptosis. SIGNIFICANCE STATEMENT: This study demonstrates that regulation of ceramide with neutral sphingomyelinase and sphingomyelin synthase in the nucleus in double-strand break-mimetic agent neocarzinostatin (NCS)-induced apoptosis. This study also showed that ceramide increase in the nucleus plays a role in NCS-induced apoptosis through activation of the ataxia telangiectasia mutated/meiotic recombination 11/double-strand break repair/Nijmengen breakage syndrome 1 complex in human lymphoblastoid cells.

Purpose: The purpose of this study was to clarify the independent factors related to patient-reported physical functioning (PF) scores at discharge of patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: A total of 103 patients who underwent allo-HSCT were included in this cross-sectional study. As a screening method, a single regression analysis was conducted with the PF domain in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 at discharge as the dependent variable, and body mass index, adverse events related to HSCT, and objective physical functions as independent variables. Multiple regression analysis was performed with PF as the dependent variable and variables that passed the screening by single regression analysis and confounders as independent variables. Results: The mean PF score at discharge of the patients was 76.5 (standard deviation: 15.2). Based on the results of screening by the single regression analysis, length of stay, infections (+/−), acute graft-versus-host disease grade, brief fatigue inventory score (BFI), knee extensor strength, and 6-min walk distance (6MWD) were included in the multiple regression analysis. BFI (B = − 11.94, p < 0.001) and 6MWD (per 10m) (B = 0.56, p = 0.001) were extracted as significant independent variables governing the PF at discharge in the multiple regression model (adjusted R2 = 0.59). Conclusion: Higher exercise tolerance and lower fatigue in patients who underwent allo-HSCT were associated independently with patient-reported better PF scores at discharge.

Cord blood transplantation (CBT) is an alternative donor transplantation method and has the advantages of rapid availability and the possibility of inducing a more potent graft-versus-leukemia effect, leading to a lower relapse rate for patients with non-remission relapse and refractory acute myeloid leukemia (R/R AML). This study aimed to investigate the impact of CBT, compared to human leukocyte antigen-matched related donor transplantation (MRDT). This study included 2451 adult patients with non-remission R/R AML who received CBT (1738 patients) or MRDT (713 patients) between January 2009 and December 2018. Five-year progression-free survival (PFS) and the prognostic impact of CBT were evaluated using a propensity score (PS) matching analysis. After PS matching, the patient characteristics were well balanced between the groups. The five-year PFS was 25.2% (95% confidence interval [CI]: 21.2-29.5%) in the CBT group and 18.1% (95% CI: 14.5-22.0%) in the MRDT group (P = 0.009). The adjusted hazard ratio (HR) was 0.83 (95% CI: 0.69-1.00, P = 0.045); this was due to a more pronounced decrease in the relapse rate (HR: 0.78, 95% CI: 0.69-0.89, P < 0.001) than an increase in the NRM (1.42, 1.15-1.76, P = 0.001). In this population, CBT was associated with a better 5-year PFS than MRDT after allogeneic HSCT.

Late-onset non-infectious pulmonary complications (LONIPCs) after allogeneic hematopoietic stem cell transplantation are fatal; however, lung transplantation might achieve good survival. Nevertheless, improving the health-related quality of life (HRQoL) is still a major concern. This study aimed to investigate, in detail, the recovery in HRQoL and social reintegration status after lung transplantation in patients with LONIPC after allo-HSCT. This prospective cohort study involving 18 patients examined changes in the health and social reintegration status after lung transplantation following LONIPC. Physical function and HRQoL were lowest before lung transplantation. Two years after lung transplantation, the dyspnea scores and performance status improved. Most patients had made a successful return to society, and patients who achieved social reintegration were significantly younger and had a good performance status. However, their Physical Functioning score and Physical Component Summary did not show significant improvement after lung transplantation. Moreover, recipients who were unemployed before lung transplantation were likely to remain unemployed and continued to show poor HRQoL. These results showed poor recovery of HRQoL, especially in terms of physical function, and the likelihood of failure to reintegrate into society within 2 years after lung transplantation. It is necessary to consider long-term follow-up and physical training to improve social reintegration and HRQoL.

Thus far, there have been no large cohort studies on total body irradiation (TBI)-containing conditioning regimens without antithymocyte globulin (ATG) in adults with aplastic anemia (AA) undergoing umbilical cord blood (UCB) transplantation (UCBT). We retrospectively analyzed 115 adults with idiopathic AA undergoing UCBT using TBI-containing reduced-intensity conditioning (RIC) regimens without ATG between 2000 and 2018 on behalf of the Adult Aplastic Anemia Working Group of the Japanese Society for Hematopoietic Cell Transplantation. We then compared transplantation outcomes between a fludarabine (Flu)- and melphalan (Mel)-based regimen (FM) and a Flu- and cyclophosphamide (Cy)-based regimen (FC). The median patient age at UCBT was 41 years. The median total nucleated cell and total CD34+ cell doses in a UCB unit at cryopreservation were 2.5 × 107/kg and 0.7 × 105/kg, respectively. The median follow-up period for survivors was 47 months. The cumulative incidence rate of neutrophil engraftment was 76.5%, and the 4-year overall survival (OS) rate was 64.3%. In multivariate analysis, the covariates that were significantly associated with a higher neutrophil engraftment were total CD34+ cell dose in an UCB unit (≥ 0.7 × 105/kg; hazard ratio, 0.57, P = 0.01) and total dose of TBI (4 Gy of TBI; hazard ratio, 0.32, P = 0.01). There was no significant difference in the cumulative incidence of neutrophil engraftment and the 4-year OS between the FM and FC groups. In conclusion, TBI-containing RIC regimens without ATG are suitable for adults with AA undergoing UCBT. There were no significant differences in transplantation outcomes between the FM and FC groups.

Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Stem cell source or HLA disparity may exert a significant impact on the overall survival (OS) after the development of aGVHD. In order to clarify this point, we performed a retrospective analysis using a database of the Japan Society for HCT. We analyzed the clinical outcomes of 10,035 patients who developed grade II-IV aGVHD. The median age of the patients was 48 years. The probability of 2-year OS after the onset of grade II-IV aGVHD in the study cohort was 54.1%. The multivariate analysis showed that the HLA ≥2-loci mismatched related donor and HLA 1-locus mismatched unrelated donor were significantly associated with an inferior OS after grade II-IV aGVHD. In a subgroup analysis, peripheral blood stem cells and HLA disparity were associated with an inferior OS in patients who received related or unrelated HCT. Thus, the clinical outcome after grade II-IV aGVHD significantly varied as per the combination of the presence of HLA disparity and stem cell source. Further research using other databases is necessary to confirm our findings.

To characterize the issues regarding work and employment specific to allogeneic hematopoietic cell transplantation (allo-HCT) survivors, we conducted a nationwide cross-sectional questionnaire survey. We targeted allo-HCT survivors employed at diagnosis, aged 20–64 at survey, and survived ≥2 years without relapse. The questionnaire included the timing of and reasons for resignation (termination of employment contract), and patient-related, HCT-related, work-related, and HCT center-related factors. A total of 1048 eligible participants were included in the analysis (response rate, 60%). The median time after allo-HCT was 5 years (range, 2–30) at the time of survey. After diagnosis, 41% of participants resigned from work throughout the course of treatment. The most frequent timing of the first resignation was “after discharge post-HCT” (46%), followed by “from diagnosis to initial treatment” (27%). Factors significantly associated with resignation included female gender, older age, and part-time employment. Favorable factors included the presence of occupational health staff at the workplace, employment of ≥10 years, and self-employed/freelance. After resignation, the overall incidence of return to work with some accommodations was 76% at 5 years after HCT, but it was 52% without any accommodation. Overall, the rate of resignation was 41%, and the most frequent timing of resignation was after discharge post-HCT, accounting for approximately half of the resignations (46%). Workplace accommodations increased the rate of return to work from 52% to 76%. Early detection of employment-related concerns and support throughout the treatment process are necessary for patients receiving allo-HCT.

Pretransplant measurable residual disease (MRD) has been shown to be associated with relapse incidence following allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). However, it remains less clear whether pretransplant MRD status affects transplant outcomes in core binding factor AML (CBF-AML). We retrospectively evaluated the effect of pretransplant MRD, which was measured by a polymerase chain reaction of RUNX1-RUNX1T1 or CBFB-MYH11 fusion transcripts, on transplant outcomes for a cohort of 959 adult patients with t(8;21) or inv(16) AML treated by allogeneic HCT during complete remission (CR), between 2000 and 2018. Multivariate analysis showed the absence of pretransplant MRD was significantly associated with lower relapse (hazard ratio [HR], 0.46; P

Acute basophilic leukaemia (ABL) is a rare subtype of acute myeloid leukaemia (AML); therefore, few data are available about its biology. Herein, we analysed two ABL patients using flow cytometry and next-generation sequencing (NGS). Two cell populations were detected by flow cytometry in both patients. In Case no. 1, blasts (CD34+ , CD203c- , CD117+ , CD123dim+ ) and basophils (CD34- , CD203c+ , CD117± , CD123+ ) were identified, both of which were found by NGS to harbour the 17p deletion and have loss of heterozygosity of TP53. In Case no. 2, blasts (CD33+ , CD34+ , CD123- ) and basophils (CD33+ , CD34+ , CD123+ ) were identified. NGS detected NPM1 mutations in either blasts or basophils, and TET2 in both. These data suggest an overlap of the mutational landscape of ABL and AML, including TP53 and TET2 mutations. Moreover, additional mutations or epigenetic factors may contribute for the differentiation into basophilic blasts.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is one of the curative treatment options for acute lymphoblastic leukaemia (ALL). However, the outcomes in patients transplanted without complete remission (non-CR) have not yet been fully reported, and detailed analyses are required to identify subgroups in which optimal prognosis is expected and to optimize pre-transplant therapeutic strategies. Hence, we performed a multicentred retrospective cohort study including a total of 663 adult ALL patients transplanted at non-CR status; the median bone marrow (BM) blast counts at HSCT was 13·2%, and 203 patients (30·6%) were treated at primary induction failure status. The overall survival (OS) was 31·1% at two years, and the multivariate analyses identified five prognostic risk factors, including older age (≥50 years), increased BM blasts (≥10%), poor performance status, high haematopoietic cell transplantation (HCT)-comorbidity index, and relapsed disease status, among which BM blast was the most significantly related. A predictive scoring system composed of these risk factors clearly stratified OS (15·6-59·5% at two years). In conclusion, this is the first large-scale study to analyze the correlation of patient characteristics with post-transplant prognosis in ALL transplanted at non-CR status. The importance of blast control before HSCT should be focused on for better patient prognosis.

Allogenic hematopoietic stem cell transplantation (allo‐HCT) is the standard treatment for acute myeloid leukemia (AML) in non‐complete remission (non‐CR); however, the prognosis is inconsistent. This study aimed to develop and validate nomograms and a web application to predict the overall survival (OS) of patients with non‐CR AML undergoing allo‐HCT (cord blood transplantation [CBT], bone marrow transplantation [BMT], and peripheral blood stem cell transplantation [PBSCT]). Data from 3052 patients were analyzed to construct and validate the prognostic models. The common significant prognostic factors among patients undergoing allo‐HCT were age, performance status, percentage of peripheral blasts, cytogenetic risk, chemotherapy response, and number of transplantations. The conditioning regimen was a significant prognostic factor only in patients undergoing CBT. Compared with cyclophosphamide/total body irradiation, a conditioning regimen of ≥3 drugs, including fludarabine, with CBT exhibited the lowest hazard ratio for mortality (0.384; 95% CI, 0.266–0.554; p, Allogenic hematopoietic stem cell transplantation (allo‐HCT) is the standard treatment for acute myeloid leukemia (AML) in non‐complete remission (non‐CR); however, the prognosis is inconsistent. We developed and validated prognostic models (nomograms and web application) to predict the overall survival of patients with non‐CR AML undergoing allo‐HCT (cord blood transplantation, bone marrow transplantation and peripheral blood stem cell transplantation) using a large cohort. The web application is available at https://JSHCT‐AMLWG.shinyapps.io/Predict‐OS‐nonCR‐AML‐post‐HCT/.

A decline in physical functions at the early stage of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a serious issue. Belt electrode-skeletal muscle electrical stimulation (B-SES) can induce significant muscle contractions with electrical stimulation and reduce muscle weakness. However, this approach has not been used in allo-HSCT patients. This study aimed to examine the effect of B-SES on physical function, and safety in patients during the early post-transplantation period. Forty-three adult patients who underwent B-SES after allo-HSCT were stratified into 2 groups based on the intensity of electrical stimulation (high versus low). B-SES was performed in combination with exercise therapy for 4 post-transplantation weeks. Knee extensor strength (KES) in the low B-SES group decreased significantly, whereas no change was observed in the high-intervention group. A significant positive correlation was observed between total intensity and ΔKES. A reduction in the 6-minute walking distance in the high B-SES group patients was lower than that of historical data. Two patients had B-SES-related complications including muscle pain. This study is the first to propose a new rehabilitation intervention strategy for allo-HSCT. Combined use of B-SES may be a new approach to reducing the decline of physical function in the early post-transplantation period.

Impact of donor age considering HLA disparity on hematopoietic cell transplantation (HCT) outcomes has not been fully evaluated. We evaluated 8486 patients who received unrelated bone marrow transplantation (UR-BMT) from 8/8 or 7/8 HLA-matched donors. Compared to 8/8 HLA-matched younger donors (