Search

Background: De novo chronic myeloid leukemia in blastic phase (CML-BP) showing lymphoid immunophenotype mimics Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). Although upfront allogeneic hematopoietic cell transplantation (HCT) is considered in both diseases, it is not yet clear whether the transplant outcomes are also similar., Methods: Using a registry database, the transplant outcomes between de novo CML-BP and Ph-positive ALL in negative-minimal residual disease (MRD), positive MRD, and nonremission cohorts were compared, respectively. All of the included patients had received tyrosine kinase inhibitor therapy before HCT and underwent HCT between 2002 and 2021. Regarding Ph-positive ALL, patients with p210 transcripts were excluded because there was concern that this group might include patients with de novo CML-BP., Results: Although most of the outcomes were comparable, in patients with positive MRD at HCT, de novo CML-BP was significantly associated with superior disease-free survival (DFS) (hazard ratio [HR] 0.6, p = .0032), overall survival (HR 0.66, p = .027), and a lower risk of relapse (HR 0.48, p = .0051). In subgroup analyses, BCR::ABL1 mutation status had a significant interaction with the disease (p for interaction = .0027). De novo CML-BP seemed to be associated with superior disease-free survival in a BCR::ABL1 mutation-positive cohort, whereas this association was not observed in a mutation-negative cohort., Conclusions: Considering previous reports that showed inferior outcomes for de novo CML-BP compared to Ph-positive ALL, the data suggested that allogeneic HCT could overcome the poor prognosis of de novo CML-BP. These findings highlight the importance of distinguishing de novo CML-BP from Ph-positive ALL., (© 2024 American Cancer Society.)

Competing Interests: Ethics approval and consent to participate: This study was approved by the Japanese Data Center for Hematopoietic Cell Transplantation and the Institutional Review Board of Kobe City Medical Center General Hospital and conducted in accordance with the Declaration of Helsinki (approval number: zn240506). Written informed consent was obtained from each patient at each institution before Transplant Registry Unified Management Program 2 registration. Competing interests: Shohei Mizuno received research funding from Hayashikane Sangyo and lecture fees from Janssen Pharmaceutical. The other authors declare no conflicts of interest associated with this manuscript.

HLA-haploidentical haematopoietic cell transplantation with post-transplant cyclophosphamide (PTCy-haplo) is emerging as an effective alternative due to donor availability and safety. We conducted a nationwide retrospective study comparing the outcomes of PTCy-haplo with both anti-thymocyte globulin (ATG)-free and ATG-administered matched unrelated donors (MUD) transplantation, using peripheral blood stem cells as the first transplantation for acute myeloid leukaemia (AML). Our study showed a lower and slower haematopoietic recovery and a higher incidence of infection-related deaths after PTCy-haplo than after MUD transplantation. In addition, we revealed an increased risk of acute and chronic graft-versus-host disease (GVHD) in ATG-free MUD transplantation in comparison to PTCy-haplo. For grades III-IV acute GVHD, the hazard ratio (HR) was 2.71 (95% CI, 1.46-5.01), and for extensive chronic GVHD, the HR was 3.11 (95% CI, 2.07-4.68). There was no significant difference regarding overall survival amongst the groups. In addition, GVHD-free relapse-free survival (GRFS) was lower in ATG-free MUD transplantation than in PTCy-haplo (HR, 1.46; 95% CI, 1.17-1.82). Notably, ATG-administered MUD transplantation showed no significant difference in GRFS from PTCy-haplo, negating the advantage of PTCy. Our results suggest that PTCy-haplo could be viable for AML patients without an HLA-matched related donor., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Ruxolitinib, a Janus kinase (JAK1-JAK2) inhibitor, has demonstrated safety and efficacy in patients with graft-versus-host disease (GvHD). This phase 3 randomized trial (REACH3) evaluated the efficacy and the safety of ruxolitinib 10 mg twice daily compared with investigator-selected best available therapy (BAT) in a subgroup of Japanese patients (n = 37) with steroid-refractory or dependent (SR/D) chronic GvHD. At data cut-off, treatment was ongoing in 17 patients and discontinued in 20. The overall response rate (complete or partial) at week 24 was greater with ruxolitinib than BAT (50% vs. 20%; odds ratio, 4.13 [95% CI, 0.90-18.9]). The best overall response rate (complete or partial response at any time point up to week 24) was higher with ruxolitinib than BAT (68.2% vs. 46.7%; odds ratio, 2.69 [95% CI, 0.66-10.9]). Ruxolitinib led to longer median failure-free survival than BAT (18.6 months vs. 3.7 months; hazard ratio, 0.34; [95% CI, 0.14-0.85]). The most common grade ≥ 3 adverse events up to week 24 were anemia (ruxolitinib: 22.7%; BAT: 6.7%) and pneumonia (22.7% and 20.0%, respectively). Ruxolitinib showed a higher response rate and improvement in failure-free survival in Japanese patients with SR/D chronic GvHD, with a safety profile consistent with the overall study population., Competing Interests: Declarations. Conflict of interest: SS, ND, MO, TK, TIshikawa and TIkeda have nothing to disclose. KF and MT received honoraria from Janssen. YO received honoraria from Novartis, Pfizer, Janssen, AsahiKasei, Abbvie, Astellas, Amgen, Chugai, Bristol-Myers Squibb, Symbio, MSD, Meiji Seika, Sumitomo Dainippon, Daiichi Sankyo, Nippon Shinyaku, IQVIA, KISSEI and Kyowa Kirin; research funding from Novartis, Pfizer, Janssen, Meiji Seika, Incyte, and Takara Bio. TG received honoraria from Novartis and Mallinckrodt. HN received honoraria from Novartis, Janssen, Chugai, Astellas, Bristol-Myers Squibb and Takeda; research funding from Novartis, Astellas, Bristol-Myers Squibb and Takeda. YM received research funding from from Asahi Kasei, Eisai, Otsuka, Kyowa Kirin, Taiho, Takeda, Chugai, Japan blood products, Nippon Kayaku, Nippon Shinyaku, Mallinckrodt, and Regimmune; and honoraria from Asahi Kasei, AstraZeneca, Astellas, Amgen, AbbVie, Viatris, Eisai, MSD, Otsuka, ONO, Gilead, Kyorin, Kyowa, Kissei, Konica, Sanofi, Celgene, Bristol-Myers Squibb, Bayer, CSL Behring, Daiichi Sankyo, Sumitomo Dainippon, Takeda, Terumo, Chugai, Nippon Shinyaku, Novartis, Pfizer, Mundipharma, Human Life CORD, Meiji Seika, Janssen and Yakult Honsha. KK received consulting fees from AbbVie, AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Janssen, and Novartis; honoraria from Bristol-Myers Squibb, Chugai, Sumitomo Pharma Co., Ltd., Janssen, Kyowa Kirin, MSD, Novartis and ONO; and research funding from AbbVie, MSD, Bristol-Myers Squibb, Janssen, Novartis, Chugai, Daiichi Sankyo, Eisai, Kyowa Kirin, and ONO. NU received honoraria from Novartis and Otsuka. AM, FS and TT are employees of Novartis Pharma K.K., Tokyo, Japan. TS is an employee of Novartis Pharma AG, Basel, Switzerland. TTeshima received honoraria from Novartis, Abbvie, Astellas, NIPPON SHINYAKU, Kyowa Kirin, Bristol-Myers Squibb, Sumitomo Pharma, Merck Sharp & Dohme, Celgene, Chugai, and Janssen; research funding from Astellas, Chugai, Fuji Pharma, Kyowa Kirin, Nippon Shinyaku, Asahi Kasei Pharma, Eisai, Sumitomo Pharma, ONO, Shionogi, Priothera SA, LUCA science and Otsuka; advisory board fees from Meiji Seika Pharma, Daiichi Sankyo, Asahi Kasei Pharma, Astellas, AstraZeneca, Takeda, Janssen, Toche Diagnostics, Sumitomo Pharma, Celgene, and Sanofi., (© 2024. The Author(s).)

Systemic corticosteroid therapy is a well-established first-line treatment for grades II-IV acute graft-versus-host disease (aGVHD). Recently, several developments have occurred, including the introduction of transplantation from human leukocyte antigen (HLA) haploidentical donors using post-transplant cyclophosphamide (PTCY-Haplo), and improvements in prognosis after cord blood transplantation (CBT) in Japan. This study aimed to analyze the association between donor sources and outcomes in patients with aGVHD. Our study included 2732 patients who developed grades II-IV aGVHD, and were treated with systemic corticosteroids. We compared HLA-matched related donors (MRD), HLA-matched unrelated donors (MUD), PTCY-Haplo, and CBT. We set endpoint as response rate, 1-year cumulative incidence of non-relapse mortality (NRM), and overall survival (OS). The adjusted odds ratios for a complete response (CR) were 0.99 (95% confidence interval [CI]: 0.74-1.31, P = 0.925) for MUD, 2.08 (95% CI: 1.35-3.25, P = 0.001) for PTCY-Haplo, and 1.08 (95% CI: 0.83-1.41, P = 0.550) for CBT compared with MRD. A significant increase in response rates for PTCY were only found in a single-organ involvement. No significant association was observed between the donor source and NRM or OS. In conclusion, PTCY-Haplo is associated with a high response rate in patients with a single-organ aGVHD; however, MUD and CBT were not associated with treatment response., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate statement: This study was approved by the Data Management Committee of the Japanese Data Center for Hematopoietic Cell Transplantation and the Ethics Committee of the Kobe City Hospital Organization, Kobe City Medical Center General Hospital. All methods were performed in accordance with the relevant guidelines and regulations. Patient consent was obtained prior to registration in the Transplant Registry Unified Management Program 2., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Unrelated cord blood transplantation (UCBT) and haploidentical transplantation using posttransplant cyclophosphamide (PTCy-haplo) are alternatives for patients lacking a human leukocyte antigen-matched donor. CD34 + cell counts in cord blood affect transplantation outcomes, particularly nonrelapse mortality (NRM). The primary objective of this study was to compare the transplantation outcomes after UCBT and PTCy-haplo focusing on CD34 + cell counts in cord blood. This retrospective study used data from 2014 to 2020 from a Japanese nationwide database. UCBT cases were divided into those with UCBT with higher (UCB-H; ≥.84 × 10 5 /kg) and lower (UCB-L; <.84 × 10 5 /kg) CD34 + cell counts, depending on the median CD34 + cell count. The study cohort comprised cases of PTCy-haplo (n = 1142), UCB-H (n = 3185), and UCB-L (n = 3172). In the multivariate analysis, neutrophil engraftment was significantly better in the PTCy-haplo than in the UCB-H (hazard ratio [HR], .64; 95% confidence interval [CI], .57 to .70; P < .001) and UCB-L groups (HR, .45; 95% CI, .41 to .50; P < .001). The UCB-H group showed similar NRM (HR, 1.19, 95% CI, 1.00 to 1.43, P = .051) and OS (HR, 1.05, 95% CI, .94 to 1.18, P = .38) compared with PTCy-haplo, whereas UCB-L was significantly associated with poor NRM (HR, 1.35, 95% CI, 1.13 to 1.61, P = .001) and OS (HR, 1.13, 95% CI, 1.01 to 1.26, P = .038). In contrast, the UCB-H (HR, .86; 95% CI, .75 to .98; P = .027) and UCB-L groups (HR, .80; 95% CI, .70 to .92; P = .001) were associated with lower relapse rate. Regarding the graft-versus-host disease (GVHD), the UCB-H and UCB-L groups were identified as significant risk factors for the development of grade II-IV acute GVHD (UCB-H: HR, 1.73; 95% CI, 1.51 to 1.99; P < .001; UCB-L: HR, 1.55; 95% CI, 1.35 to 1.78; P < .001) and grade III-IV acute GVHD (UCB-H: HR, 2.28; 95% CI, 1.78 to 2.91; P < .001; UCB-L: HR, 1.85; 95% CI, 1.44 to 2.37; P < .001), but neither were associated with the incidence of all-grade GVHD (UCB-H: HR, 1.12; 95% CI, .95 to 1.32; P = .16; UCB-L: HR, 1.08; 95% CI, .91 to 1.27; P = .37) or extensive chronic GVHD (UCB-H: HR, .86; 95% CI, .68 to 1.09; P = .21; UCB-L: HR, .88; 95% CI, .69 to 1.12; P = .31). Furthermore, higher NRM in UCB-L was attributed to higher infection-related mortality (HR, 1.50; 95% CI, 1.15 to 1.95; P = .003) but not GVHD-related mortality (HR, 1.15; 95% CI, .82 to 1.62; P = .43), whereas UCB-H was not a significant risk factor for both infection-related mortality (HR, 1.29; 95% CI, .99 to 1.69; P = .06) and GVHD-related mortality (HR, 1.28; 95% CI, .90 to 1.80; P = .16). UCB-H offered similar NRM and OS to PTCy-haplo, whereas UCB-L had worse outcomes. Our results can provide useful information for optimal donor selection., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

This study aimed to investigate the prognostic relevance of cytogenetic risk in 9826 adults with acute myeloid leukemia (AML) who underwent allogeneic hematopoietic cell transplantation (HCT) during the first or second complete remission. The 5-year probabilities of overall survival (OS) were 66%, 61%, and 47% (P < 0.001), the cumulative incidences of relapse were 14%, 19%, and 32% (P < 0.001), and the cumulative incidences of non-relapse mortality (NRM) were 23%, 23%, and 25% (P = 0.208) in patients with favorable (n = 1418), intermediate (n = 6747), and poor cytogenetic risk (n = 1661), respectively. The significant effect of cytogenetic risk on OS was strong in all subgroups stratified by age, sex, performance status, disease status, donor type, conditioning intensity, graft-versus-host disease prophylaxis, and transplantation period (P < 0.001 for all). The evaluation of trends in posttransplant outcomes for patients in each cytogenetic risk category indicated that the risk of relapse declined in patients with favorable and intermediate cytogenetics and that the risk of NRM decreased in those with intermediate and poor cytogenetics. Therefore, patients with intermediate cytogenetics experienced the best OS improvement. These results confirm cytogenetic risk as a universal prognostic factor in patients with AML undergoing allogeneic HCT while highlighting the requirement for further improvements in posttransplant OS by reducing NRM in patients with favorable cytogenetics and by reducing relapse in patients with poor cytogenetics., Competing Interests: Declarations Ethical approval This study was approved by the institutional review board of the Aichi Medical University and was conducted in accordance with the Declaration of Helsinki. All patients provided informed consent for the use of their clinical information for research. Competing interests SM received research funding from Hayashikane Sangyo, and AT received research funding from Air Water, lecture fees from Novartis Pharmaceutical, and donated funds from Chugai Pharmaceutical, Kyowa Kirin, and Zenyaku Kogyo., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment option for patients with refractory and relapsed acute myeloid leukemia (R/R AML) not in complete remission. Many studies investigating the prognosis of patients with R/R AML not in remission focused on patients who received myeloablative conditioning regimen (MAC). Conversely, reduced intensity conditioning regimen (RIC) could be a considerable conditioning regimen for some patients because of the high frequency of R/R AML in older patients who are not candidates for MAC., Objective: This study aimed to evaluate the prognosis and identify factors associated with outcomes in patients with R/R AML who underwent allogeneic HSCT with RIC., Study Design: This study included 707 adult patients with AML not in complete remission who had received RIC. The primary endpoint was progression-free survival (PFS), which was estimated using the Kaplan-Meier method. Prognostic factors were identified using a Cox proportional hazards model with multiple imputations using a chained equation approach., Results: The 5-year PFS, overall survival, relapse, and nonrelapse mortality were 18.8% (95% confidence interval [CI]: 15.6-22.2), 22.0% (95% CI: 8.5-25.7), 53.6% (95% CI 49.7-57.4%) and 27.5% (95% CI: 24.0-31.2), respectively. Multivariable analysis revealed that male sex, poor performance status, karyotype risk, and blasts in the peripheral blood were significantly associated with PFS., Conclusions: This study identified prognostic factors in patients with R/R AML not in complete remission. These results can help to develop a transplant strategy for the treatment of R/R AML., Competing Interests: Declaration of competing interest The authors declare no competing financial interests in this study., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

The typical optical pulse from a gain-switched semiconductor laser diode (LD) usually consists of a first-spike (FS) component and a quasi-steady-state (QSS) lasing component. For the stability and accuracy in some specific applications of sensing and detection, it is necessary to achieve a smooth QSS component without the FS component (regarded as spike noise). This Letter reports a technique to smooth the optical pulse shape from gain-switched LDs via stepped electric pulse, which can eliminate or suppress the FS component effectively, without any postprocessing. Rate-equation calculations well reproduced the major features of the experimental results and revealed that the pre-pump of the stepped electrical pulse plays a crucial role by adjusting the accumulated carrier density to be close to threshold before lasing in the LD, which suppresses the FS generation during the main pump injects and allows LD transit more rapidly into the QSS mode. The stepped electrical pulse pump provides a feasible and convenient method to smooth the optical pulse shape of gain-switched semiconductor LDs for various applications.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides durable remission for patients with adult T-cell leukemia/lymphoma (ATL); however, few studies have focused on post-transplant outcomes in ATL patients ≤49 years. To clarify prognostic factors in ATL among patients <40 years (adolescents and young adult [AYA]; n = 73) and 40-49 years (Young; n = 330), we conducted a nationwide retrospective study. Estimated 3-year overall survival (OS) rates were 61.8% and 43.1% in AYA and Young patients, respectively (p = 0.005). In the multivariate analysis, Young patients showed worse OS (Hazard ratio (HR) [95% confidential interval] 1.62 [1.10-2.39], p = 0.015), chronic graft-versus-host disease (GVHD)-free and relapse-free survival (CRFS) (HR 1.54 [1.10-2.14], p = 0.011), and GVHD-free and relapse-free survival (GRFS) (HR 1.40 [1.04-1.88], p = 0.026) than AYA patients. No significant differences were observed in OS, CRFS, or GRFS between the myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) regimens; however, non-relapse mortality was significantly lower in patients with the RIC regimen than those with the MAC regimen (HR 0.46 [0.24-0.86], p = 0.015). In summary, OS was worse in Young patients than in AYA patients in the allo-HSCT setting for ATL. Furthermore, the RIC regimen has potential as an alternative treatment option for ATL patients ≤49 years., (© 2024 John Wiley & Sons Ltd.)

Acute lymphoblastic leukemia (ALL) relapsed after allogeneic hematopoietic cell transplantation (allo-HCT) has a catastrophic prognosis. Blinatumomab, a CD3/CD19-directed bispecific T cell engager, is reportedly effective for advanced B-cell ALL (B-ALL), even after allo-HCT. However, the efficacy of blinatumomab in extramedullary relapse (EMR) is controversial. Donor lymphocyte infusion (DLI) is another immunological treatment worth considering for ALL relapsed after allo-HCT. We report the case of a 56-year-old woman with B-ALL. Allo-HCT was performed during the second complete remission (CR). Thirteen months after allo-HCT, isolated EMR (iEMR) of B-ALL developed without bone marrow lesions. A third CR was achieved with 2 cycles of blinatumomab. An additional four cycles each of blinatumomab and DLI were then administered. The patient did not develop graft-versus-host disease and has confirmed 2-year treatment-free remission without a second allo-HCT. Therefore, blinatumomab was considered an effective salvage therapy for iEMR of B-ALL after allo-HCT, because iEMR could have a lower tumor burden than that seen in systemic relapse, and low tumor burden was a prognostic factor for response to blinatumomab. Furthermore, immunological consolidation therapies could only provoke graft-versus-leukemia effects if the imbalanced effector/target ratio was restored and the tumor burden was lowered through immunosurveillance., (© 2024. Japanese Society of Hematology.)

Although various relapse prediction models based on pretransplant information have been reported, they cannot update the predictive probability considering post-transplant patient status. Therefore, these models are not appropriate for deciding on treatment adjustment and preemptive intervention during post-transplant follow-up. A dynamic prediction model can update the predictive probability by considering the information obtained during follow-up. This study aimed to develop and assess a dynamic relapse prediction model after allogeneic hematopoietic cell transplantation (allo-HCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) using peripheral blood Wilms' tumor 1 messenger RNA (WT1mRNA). We retrospectively analyzed patients with AML or MDS who underwent allo-HCT at our institution. To develop dynamic models, we employed the landmarking supermodel approach, using age, refined disease risk index, conditioning intensity, and number of transplantations as pretransplant covariates and both pre- and post-transplant peripheral blood WT1mRNA levels as time-dependent covariates. Finally, we compared the predictive performances of the conventional and dynamic models by area under the time-dependent receiver operating characteristic curves. A total of 238 allo-HCT cases were included in this study. The dynamic model that considered all pretransplant WT1mRNA levels and their kinetics showed superior predictive performance compared to models that considered only pretransplant covariates or factored in both pretransplant covariates and post-transplant WT1mRNA levels without their kinetics; their time-dependent areas under the curve were 0.89, 0.73, and 0.87, respectively. The predictive probability of relapse increased gradually from approximately 90 days before relapse. Furthermore, we developed a web application to make our model user-friendly. This model facilitates real-time, highly accurate, and personalized relapse prediction at any time point after allo-HCT. This will aid decision-making during post-transplant follow-up by offering objective relapse forecasts for physicians., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Objectives: Impaired B-cell reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT) contributes to the pathogenesis of chronic graft-versus-host disease (cGVHD). Therefore, methods to consistently achieve effective B cell lymphogenesis are required. We assessed the long-term effects of posttransplantation cyclophosphamide (PTCy) use on immune reconstitution in clinical settings, an emerging strategy to suppress allogeneic immunological inflammation early after allo-HCT and prevent subsequent GVHD., Methods: We comprehensively analyzed peripheral immune cell subsets and measured serum immunoglobulin G (IgG) or cytokine levels in 39 patients who survived for >1 year after allo-HCT., Results: The absolute counts of B1 and IgM memory B cells were significantly lower in patients with severe cGVHD than in those without. The absolute count and percentage (among total CD19+ B cells) of switched memory B cells and serum IgG levels were significantly higher in patients transplanted with PTCy than in those transplanted with conventional GVHD prophylaxis. Interestingly, increased percentages of switched memory B cells and serum IgG levels were observed only in patients transplanted with PTCy and not in those transplanted with umbilical cord blood., Conclusions: PTCy administration can mediate favorable memory B-cell reconstitution long after allo-HCT and may therefore suppress cGVHD., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Allogeneic hematopoietic stem cell transplantation from a female donor to a male recipient (female-to-male allo-HCT) is a well-established risk factor for chronic graft-versus-host disease (GVHD) and non-relapse mortality (NRM). The inferior outcomes of female-to-male allo-HCT are considered to be due to allo-immunity against H-Y antigens. However, the influence of minor histocompatibility antigens in haplo-identical allo-HCT remains to be elucidated. We investigated the impact of female-to-male allo-HCT according to the haplo-HCT subtype. In the post-transplant cyclophosphamide (PTCY) cohort (n = 660), a female-to-male sex-mismatch was significantly associated with a decreased risk of relapse (HR: 0.70 [95% CI: 0.49-0.99], P = 0.045), but not with overall survival (OS) or NRM (HR: OS 0.89 [95% CI: 0.68-1.16], P = 0.40; NRM 0.98 [95% CI: 0.68-1.41], P = 0.90). On the other hand, in the non-PTCY cohort (n = 219), a female-to-male sex-mismatch was associated with inferior risks of OS and NRM, but was not associated with relapse. These results suggested that the survival impact of the haplo-HCT subtype differed according to the presence of a sex-mismatch. PTCY might be feasible for overcoming the inferiority of female-to-male allo-HCT and might preserve a GVL effect against H-Y antigens., Competing Interests: Declaration of competing interest M.Tamaki received honoraria from Astella Pharma. H.Nakasone. received subsidies from JCR Pharmaceuticals, Kyowa Kirin, Terumo, Santen Pharmaceutical, Taiho Pharma, and honoraria from Takeda Pharmaceutical, Otsuka Pharmaceutical, Bristol-Myers Squibb, Pfizer, Novartis, Janssen Pharmaceutical, Eisai, Chugai Pharmaceutical, Meiji Seika Pharma, and Nippon Shinyaku., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

The reportedly poor outcome of late-onset idiopathic pneumonia syndrome (IPS) necessitates new approaches to its treatment. A 55-year-old man who had undergone allogeneic hematopoietic cell transplantation (allo-HCT) for myelodysplastic syndrome 1 year ago developed dyspnea with acute skin graft-versus-host disease (GVHD) flare-up while tapering immunosuppressive agents. He presented with acute respiratory distress syndrome with ground-glass opacities in the right upper and left lower lobes. All infectious tests, including multiplex polymerase chain reaction of nasal wash, were negative, and broad-spectrum antibiotic therapy was refractory. The patient was diagnosed with late-onset IPS and was refractory to methylprednisolone pulse therapy. He then showed a favorable response to mesenchymal stem cell (MSC) infusion. After eight infusions of MSCs, he had no IPS recurrence for over one year. Recently, preclinical studies have reported the potential therapeutic utility of MSC infusion for treating IPS, and our case supports its potential for treating late-onset IPS., Competing Interests: Declaration of competing interest M.H. received grants from JCR Pharmaceuticals Co., Ltd., The remaining authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Peptide-binding motif (PBM) model, a hierarchical clustering of HLA class I based on their binding specificity, was developed to predict immunopeptidome divergence. The effect of PBM mismatches on outcomes is unknown in HLA-haploidentical haematopoietic cell transplantation with post-transplant cyclophosphamide (PTCy-haplo). We therefore conducted a retrospective study using national registry data in PTCy-haplo. Overall, 1352 patients were included in the study. PBM-A bidirectional mismatch was associated with an increased risk of overall mortality in multivariable analysis (hazard ratio, 1.26; 95% confidence interval, 1.06 to 1.50; p = 0.010). None of relapse, non-relapse mortality (NRM) and graft-versus-host disease showed significant differences according to PBM-A bidirectional mismatch status in the entire cohort. The impact of PBM-A bidirectional mismatch on overall survival (OS) was preserved within the HLA-A genotype bidirectional mismatch population, and their lower OS stemmed from higher relapse rate in this population. The worse OS due to high NRM with PBM-A bidirectional mismatch was prominent in lymphoid malignancies receiving reduced-intensity conditioning. The PBM model may predict outcomes more accurately than HLA genotype mismatches. In conclusion, this study demonstrated that the presence of PBM-A bidirectional mismatch elevated the risk of mortality of PTCy-haplo. Avoiding PBM-A bidirectional mismatch might achieve better outcomes in PTCy-haplo., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Abstract: Chronic graft-versus-host disease (GVHD) is 1 of the major complications after allogeneic hematopoietic cell transplantation (allo-HCT). Although various risk factors for chronic GVHD have been reported, limited data are available regarding the impact of acute GVHD on chronic GVHD. We examined the association between acute and chronic GVHD using a Japanese registry data set. The landmark point was set at day 100 after allo-HCT, and patients who died or relapsed before the landmark point were excluded. In total, 14 618 and 6135 patients who underwent allo-HCT with bone marrow or peripheral blood (BM/PB) and with umbilical cord blood (UCB), respectively, were analyzed. In the BM/PB cohort, the risk for chronic GVHD that requires systemic steroids increased with each increase in acute GVHD grade from 0 to 2 (grade 0 vs 1 [hazard ratio (HR), 1.32; 95% confidence interval (CI), 1.19-1.46; P < .001]; grade 1 vs 2 [HR, 1.41; 95% CI, 1.28-1.56; P < .001]), but the risk was similar between acute GVHD grade 2 and grade 3 to 4 (HR, 1.02; 95% CI, 0.91-1.15; P = 1.0). These findings were confirmed in the UCB cohort. We further observed that the risk for severe chronic GVHD increased with each increment in the grade of acute GVHD, even between acute GVHD grade 2 and grade 3 to (grade 2 vs 3-4: HR, 1.70; 95% CI, 1.12-2.58; P = .025). In conclusion, the preceding profiles of acute GVHD should help to stratify the risk for chronic GVHD and its severity, which might be useful for the development of risk-adopted preemptive strategies for chronic GVHD., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

We present an erratum to our Letter [Opt. Lett.48, 6344 (2023)10.1364/OL.510237]. This erratum corrects the error of Figs. 3(b) and 4(b) made via incorrect scaling in the horizontal axes. The corrections have no influence on the main text and conclusions of the original Letter.

Changes in the gut microbiome have pivotal roles in the pathogenesis of acute graft-versus-host disease (aGVHD) after allogenic haematopoietic cell transplantation (allo-HCT) 1-6 . However, effective methods for safely resolving gut dysbiosis have not yet been established. An expansion of the pathogen Enterococcus faecalis in the intestine, associated with dysbiosis, has been shown to be a risk factor for aGVHD 7-10 . Here we analyse the intestinal microbiome of patients with allo-HCT, and find that E. faecalis escapes elimination and proliferates in the intestine by forming biofilms, rather than by acquiring drug-resistance genes. We isolated cytolysin-positive highly pathogenic E. faecalis from faecal samples and identified an anti-E. faecalis enzyme derived from E. faecalis-specific bacteriophages by analysing bacterial whole-genome sequencing data. The antibacterial enzyme had lytic activity against the biofilm of E. faecalis in vitro and in vivo. Furthermore, in aGVHD-induced gnotobiotic mice that were colonized with E. faecalis or with patient faecal samples characterized by the domination of Enterococcus, levels of intestinal cytolysin-positive E. faecalis were decreased and survival was significantly increased in the group that was treated with the E. faecalis-specific enzyme, compared with controls. Thus, administration of a phage-derived antibacterial enzyme that is specific to biofilm-forming pathogenic E. faecalis-which is difficult to eliminate with existing antibiotics-might provide an approach to protect against aGVHD., (© 2024. The Author(s).)

Cytomegalovirus (CMV) reactivation is a prominent complication associated with adverse outcomes in allogeneic hematopoietic stem cell transplantation (HSCT). However, CMV reactivation after allogeneic HSCT may be associated with a lower incidence of relapse in some hematological malignancies. This study analyzed the Japanese registry data from 1082 patients with myelodysplastic syndrome (MDS) who underwent their first allogeneic HSCT and survived for 100 days after transplantation without graft failure or disease relapse to investigate this association. Patients who received cord blood transplants, demonstrated in vivo T cell depletion, underwent prophylactic anti-CMV treatment, or diagnosed with secondary MDS were excluded. CMV reactivation measured by pp65 antigenemia within 100 days after allogeneic HSCT was observed in 57.5% of patients, with a median time of 46 days from transplant. The 5-yr overall survival and cumulative incidence of relapse (CIR) in the cohort were 60.5% and 15.6%, respectively. The 5-yr CIR showed no significant difference between patients with and without CMV reactivation (14.4% versus 17.2%; P = .185). Interestingly, CMV reactivation within 100 days was significantly associated with a lower 5-yr CIR (7.6% versus 16.4%; P = .002) in patients with <5% myeloblasts in the bone marrow (BM) just before HSCT. Furthermore, this relevancy confirmed even when excluding patients with Grade II to IV acute GVHD (Hazard ratio: 0.38; 95% confidential intervals: 0.18-0.801; P = .011). Our findings indicate a correlation between early CMV reactivation and MDS relapse, based on the proportion of myeloblasts in the BM. These results may contribute to the development of effective CMV prophylaxis post-HSCT., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Acute graft-versus-host disease (aGvHD) is a major complication after allogeneic hematopoietic stem cell transplantation in Japan and other countries. Nearly one-third of patients do not respond to standard systemic steroid therapy and no standard second-line treatment has been established in Japan. We report efficacy and safety findings of ruxolitinib versus best available therapy (BAT) from a subgroup analysis of the international, phase 3 REACH2 study in Japanese patients with steroid-refractory aGvHD. The primary endpoint was overall response rate (ORR) at day 28. Overall, 9 patients received ruxolitinib and 21 received BAT. The ORR at day 28 (88.9% vs 52.4%) and durable ORR at day 56 (66.7% vs 28.6%) were higher with ruxolitinib versus BAT. The estimated cumulative incidence of loss of response at 6 months was 12.5% with ruxolitinib and 18.2% with BAT. The median failure-free survival was longer with ruxolitinib versus BAT (2.73 vs 1.25 months). The most common adverse events up to day 28 in the ruxolitinib and BAT groups were anemia (55.6% vs 19.0%) and thrombocytopenia (44.4% vs 4.8%, respectively). Ruxolitinib showed better efficacy outcomes and a consistent safety profile compared with BAT in the Japanese subgroup, and the findings were consistent with overall study results., (© 2024. The Author(s).)

Post-transplant cyclophosphamide (PTCy) is becoming the standard prophylaxis for graft-versus-host disease (GVHD) in HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) and in HLA-matched allo-HCT. Immune reconstitution in the post-transplant setting may influence the graft-versus-tumor (GVT) effect because PTCy has a profound effect on T cell and natural killer cell functions and their reconstitution after allo-HCT. However, many recent studies have shown that the incidence of relapse after allo-HCT with PTCy is comparable to that after conventional allo-HCT. To further improve the outcomes, it is critical to establish a strategy to maintain or effectively induce the GVT effect when using PTCy as a platform for GVHD prophylaxis. However, there is a paucity of studies focusing on the GVT effect in allo-HCT with PTCy. Therefore, focusing on this issue may lead to the establishment of more appropriate strategies to improve transplantation outcomes without exacerbating GVHD, including novel therapies involving cell modification., Competing Interests: HN received research funding from Astellas Pharma Inc., Alexion Pharmaceuticals, Novartis Pharma K.K., Bristol-Myers Squibb, Takeda Pharmaceutical Co., Ltd., and Meiji Seika Pharma; and honoraria from Astellas Pharma Inc., Otsuka Pharmaceutical Co., Ltd., Novartis Pharma K.K., Bristol-Myers Squibb, Takeda Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Daiichi Sankyo, Chugai Pharmaceutical Co., Ltd., and Sanofi outside of this current work. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Nakamae.)

Background Aims: Haploidentical hematopoietic stem cell transplantation (haplo-HCT) is an appropriate option when an HLA-matched related or unrelated donor is not available. Haplo-HCT using post-transplant cyclophosphamide (PTCy) is being increasingly performed worldwide due to its effective suppression of GVHD and its safety., Methods: We conducted a large nationwide cohort study to retrospectively analyze 366 patients with acute myeloid leukemia undergoing haplo-HCT with PTCy between 2010 and 2019 and to identify prognostic factors., Results: A multivariate Cox analysis revealed that an older recipient age (≥60 years), a male donor to a male recipient, a cytomegalovirus IgG-negative donor to a cytomegalovirus IgG-positive recipient, a poor cytogenetic risk, a noncomplete remission status at the time of transplantation, and a history of HCT were independently associated with worse overall survival (OS). Based on each hazard ratio, these factors were scored (1-2 points) and stratified by their total score into three groups: favorable (0-1 points), intermediate (2-3 points), and poor (4 points or more) groups, and 2-year OS rates were 79.9%, 49.2%, and 25.1%, respectively (P < 0.001)., Conclusions: The present study revealed significant prognostic factors in haplo-HCT with PTCy, and a scoring system based on these factors may be used to predict outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: ABO blood group mismatch between the donor and the recipient can affect the success of the transplant as well as problems with the red blood cells during allogeneic haematopoietic cell transplantation (HCT). However, the impact of the Rhesus (Rh) D mismatch on transplant outcomes in allogeneic HCT has been poorly elucidated., Materials and Methods: We retrospectively evaluated the impact of the RhD mismatch on post-transplant outcomes in 64,923 patients who underwent allogeneic HCT between 2000 and 2021 using a Japanese registry database., Results: Out of the whole group, 64,293, 322, 270 and 38 HCTs were done when the recipient or donor was RhD-mismatched with (+/+), (-/+), (+/-) or (-/-) combinations. The difference in RhD between recipient/donor (-/+), (+/-) and (-/-) did not affect haematopoietic recovery, acute and chronic graft-versus-host disease (GVHD), overall survival (OS), non-relapse mortality (NRM) or relapse when RhD (+/+) was used as the reference group in multivariate analysis., Conclusion: Our registry-based study demonstrated that RhD mismatch between recipient and donor did not significantly impact haematopoietic recovery, GVHD, OS, NRM or relapse after allogeneic HCT. These data suggest that RhD mismatches may not need to be avoided for recipient and donor combinations in allogeneic HCT., (© 2024 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.)

Myelodysplastic syndrome (MDS) is well known to be complicated by systemic inflammatory autoimmune disease (SIADs). However, it remains unclear how the prognosis after allogenic hematopoietic stem cell transplantation (allo-HSCT) in patients with MDS is impacted by SIADs that occur before allo-HSCT. Therefore, we hypothesized that SIADs before allo-HSCT may be a risk factor for negative outcomes after allo-HSCT in patients with MDS. We conducted a single-center, retrospective, observational study of sixty-nine patients with MDS or chronic myelomonocytic leukemia who underwent their first allo-HCT. Fourteen of the patients had SIADs before allo-HSCT. In multivariate analysis, the presence of SIADs before allo-HSCT was an independent risk factor for overall survival (HR, 3.36, 95% confidence interval: 1.34-8.42, p = 0.009). Endothelial dysfunction syndrome was identified in five of 14 patients with SIADs who required immunosuppressive therapy or intensive chemotherapy, and notably, all patients with uncontrollable SIADs at allo-HSCT developed serious endothelial dysfunction syndrome and died in the early phase after allo-HSCT. The development of SIADs in the context of MDS is thought to reflect the degree of dysfunction of hematopoietic cells in MDS and suggests a higher risk of disease progression. In addition, MDS patients with SIADs before allo-HSCT are considered to be at higher risk of endothelial dysfunction syndrome because of preexisting vascular endothelial dysfunction due to SIADs. In conclusion, SIADs before allo-HSCT constitute an independent risk factor for death in MDS patients undergoing allo-HSCT., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Chronic myelomonocytic leukaemia (CMML) is a haematological malignancy with a poor prognosis. Allogeneic haematopoietic stem cell transplantation remains the only curative approach. Without human leucocyte antigen-matched related sibling donors, the optimal alternative donor has yet to be established. Although unrelated bone marrow transplantation (UBMT) has been extensively studied, cord blood transplantation (CBT) for CMML remains largely unexplored. This nationwide retrospective study compared the outcomes of UBMT and single-unit umbilical CBT in patients with CMML. This study included 118 patients who underwent their first allo-HSCT during 2013-2021. Of these, 50 received BMT (UBMT group), while 68 underwent CBT (CBT group). The primary endpoint was the 3-year overall survival (OS). There were comparable 3-year OS rates between the UBMT (51.0%, 95% confidence interval [CI]: 34.1-65.5%) and CBT (46.2%, 95% CI: 33.2-58.1%; P = 0.60) groups. In the inverse probability of treatment weighting analysis, CBT did not show significantly improved outcomes compared with UBMT regarding the 3-year OS rate (hazard ratio 0.97 [95% CI: 0.57-1.66], P = 0.91). Thus, CBT may serve as an alternative to UBMT for patients with CMML. Further research is necessary to optimise transplantation strategies and enhance outcomes in patients with CMML undergoing CBT., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)