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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.)

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.)

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.)

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.)

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.)

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT), and stratification of the high-risk group before transplantation is significant. Serum autotaxin (ATX) levels have been reported to increase in patients with liver fibrosis caused by metabolic inhibition from liver sinusoidal endothelial cells. Considering that the pathophysiology of VOD/SOS begins with liver sinusoidal endothelial cell injury, an increase in serum ATX levels may precede the onset of VOD/SOS. A retrospective study with 252 patients, including 12 patients with VOD/SOS, who had received allo-HCT was performed. The cumulative incidence of VOD/SOS was higher in the group with serum ATX levels before conditioning (baseline ATX) above the upper reference limit (high ATX group, p < 0.001), and 1-year cumulative incidences were 22.7% (95% confidence interval [95%CI], 3.1-42.4%) and 3.5% (95%CI, 1.1-5.8%), respectively. In the multivariate analysis, elevated baseline ATX was identified as an independent risk factor for VOD/SOS development and showed an additive effect on the predictive ability of known risk factors. Furthermore, the incidence of VOD/SOS-related mortality was greater in the high ATX group (16.7% vs. 1.3%; p = 0.005). Serum ATX is a potential predictive marker for the development of VOD/SOS., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hepatomegaly is an extramedullary disease (EMD) manifestation of hematological malignancy. Although EMD before allogeneic hematopoietic stem cell transplantation (allo-HCT) is a risk factor for relapse in patients not in complete remission (NonCR) patients, the significance of hepatomegaly to allo-HCT is unclear. We conducted a single-center retrospective observational study of 140 patients with acute leukemia and myelodysplastic syndrome who underwent allo-HCT at our institution from 2014 to 2019. Hepatomegaly was assessed by ultrasonography using the liver index (LI). In the univariable analysis, the LI/height ratio was significantly associated with relapse (hazard ratio [HR] per standard deviation [sd]: 1.51, 95% confidence interval [CI] 1.18-1.93, p = 0.001, sd = 13.8) in NonCR patients (n = 62), but showed no significant association in CR patients (n = 78) (HR per sd: 0.95, 95% CI 0.64-1.39, p = 0.780, sd = 8.7). In multivariable analysis, the LI/height ratio was significantly associated with relapse (HR per sd: 1.34, 95% CI 1.02-1.78, p = 0.037) after adjusting for the refined disease risk index and conditioning intensity. Interaction analysis showed a noteworthy but not statistically significant association between the LI/height ratio and CR status (p = 0.110). In conclusion, our findings suggest that the LI may be a risk factor for relapse in NonCR patients after allo-HCT., (© 2024. Japanese Society of Hematology.)

Background: No comparative data have shown significant survival differences between HLA-mismatched unrelated donor (MMUD) transplantation and cord blood (CB) transplantation, each with reduced-intensity/reduced-toxicity conditioning (RIC/RTC). However, advances in graft-versus-host disease (GVHD) prophylaxis might help update current strategies., Methods: We retrospectively compared the outcomes of first allogeneic hematopoietic cell transplantation from MMUDs (n = 15) or single unrelated CB (n = 35) after RIC/RTC., Results: The median age was 60 years. The MMUD group had a numerically lower 100-day incidence of grade III-IV acute GVHD (7% vs. 29%, P = 0.079) and non-relapse mortality (0% vs. 40%, P = 0.12). Eight MMUD recipients received anti-thymocyte globulin, bortezomib, or posttransplant cyclophosphamide for GVHD prophylaxis. They did not develop grade III-IV acute GVHD. The MMUD group had significantly better 5-year overall survival than the CB group (62% vs. 31%, P = 0.021), although relapse rates were similar. A multivariable analysis and sensitivity analysis also showed trends toward higher overall survival in the MMUD group., Conclusion: MMUD with better GVHD prophylaxis might be preferred over CB in patients with older age and comorbidities., Competing Interests: Declaration of competing interest HK reports receiving an honorarium from Novartis. TT reports receiving research funding from Pfizer and honoraria from Chugai, Janssen, Novartis, and Sanofi. MNi reports receiving research funding from Janssen and Pfizer and honoraria from Janssen and Otsuka. YN reports receiving research funding from Chugai and Novartis and honoraria from Chugai, Janssen, and Novartis. MH reports receiving scholarship grants from Chugai and Otsuka and honoraria from Chugai, Janssen, Novartis, Otsuka, Pfizer, and Sanofi. HN reports receiving research funding from Novartis and honoraria from Janssen, Novartis, and Otsuka. This report was not funded by any of these companies. The other authors declare no conflicts of interest associated with this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We herein report a case of idiopathic refractory ascites following allogeneic hematopoietic cell transplantation that was successfully treated with ibrutinib. A 39-year-old man presented with massive transudative ascites. Despite a high portal venous pressure, the liver histology showed traces of alloreactivity inconsistent with veno-occlusive disease/sinusoidal obstructive syndrome. Ibrutinib was administered for ascites possibly secondary to portal hypertension associated with the alloreactivity. The ascites dramatically improved, and the portal venous pressure was reduced. This case may help clarify the mechanism through which refractory ascites develops after allogeneic hematopoietic cell transplantation and establish appropriate treatment protocols.

Donor lymphocyte infusion (DLI) is a curable treatment option, inducing a graft-versus-tumor effect in patients with relapsed hematological malignancies after allogeneic hematopoietic cell transplantation (allo-HCT). However, not only graft-versus-host disease but also pulmonary complications are problematic adverse events after DLI. Although viral infections can be associated with pulmonary complications after DLI, the mechanism underlying these complications remains unclear. Detecting the causative virus infections after pulmonary complications following DLI is challenging, as invasive examinations, such as bronchoalveolar lavage and lung biopsies, are necessary. Family Picornaviridae, including Human-Rhinovirus (HRV) and Enterovirus (EnV), can induce fatal lower respiratory tract infection (LRTI) in recipients who undergo allo-HCT, which can be underdiagnosed. We encountered a 62-year-old man with relapsed myelodysplastic syndrome 20 days after a second HLA-haplo-identical allo-HCT and 4 DLI procedures who was later found to have HRV and EnV LRTI by postmortem electron microscopy. Despite high-dose immunosuppression, severe hypoxemia did not improve, and he succumbed to respiratory failure. Immunosuppressive therapy for idiopathic pneumonia syndrome after allo-HCT may be effective, but its efficacy for acute respiratory failure after DLI is controversial. Our case indicated that the control of viral replication should be prioritized over that of inflammation in HRV and EnV LRTI after DLI., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Eosinophilic gastrointestinal disorders (EGIDs) are infrequent complications after allogeneic hematopoietic cell transplantation (allo-HCT). Furthermore, it is well-known that allergic diseases are transferable after allo-HCT from allergic donors to non-allergic recipients. However, the type of graft-versus host disease (GVHD) prophylaxis that leads to allergic disease transfer is unclear. Furthermore, no study has reported a case of acquired food allergy resulting in EGID that was detected based on the clinical course and the detection of antigen-specific immunoglobulin E after allo-HCT. We encountered two patients with acute leukemia accompanied by eosinophilic esophagitis (EoE) and eosinophilic gastroenteritis (EGE) due to newly appearing food allergy after cord blood transplantation (CBT) with T-cell non-depletion GVHD prophylaxis. Despite having no history of allergic disease, the patients experienced allergic symptoms due to dairy products (Case 1) and eggs (Case 2) after CBT. They subsequently experienced severe nausea, heartburn, and anorexia (Case 1) and diarrhea (Case 2). Cases 1 and 2 were diagnosed with EoE and EGE, respectively, based on endoscopic and histological examinations. Dietary treatment without steroids improved the symptoms in both cases. These cases highlight that the unexpected transfer of food allergy after CBT can lead to EGIDs, especially in patients receiving T-cell non-depletion GVHD prophylaxis., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest in association with the present study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is being increasingly recognized as a severe complication that contributes to poor prognoses among patients with COVID-19. However, little is known regarding the clinical course of CAPA with hematological malignancies, especially after allogeneic hematopoietic stem cell transplantation (HSCT). A 29-year-old woman was diagnosed with proven CAPA with an Aspergillus fumigatus identified by cultures of bronchoalveolar lavage and lung biopsy four years after haploidentical HSCT for acute myelogenous leukemia. She had been taking oral prednisolone for bronchiolitis obliterans syndrome that developed after HSCT. Although prolonged RT-PCR positivity for SARS-CoV-2 (133 days after the onset of COVID-19) without shedding of viable virus was observed, the COVID-19 was treated with favipiravir, remdesivir, dexamethasone, and enoxaparin. However, the CAPA did not respond to combination therapy, which included triazole (voriconazole, itraconazole, posaconazole) and echinocandin (caspofungin, micafungin), even though the Aspergillus fumigatus isolate was found to be susceptible to these agents in vitro. Nevertheless, a total of 16 weeks of liposomal amphotericin B (L-AMB) therapy led to a favorable response, and the patient was discharged from the hospital on day 213. This case provided essential experience of CAPA treated with L-AMB in a recipient with chronic respiratory disease after HSCT., Competing Interests: Declaration of competing interest Hideo Koh, Hirohisa Nakamae, Hiroshi Kakeya, and Masayuki Hino received honorarium from Sumitomo Dainippon Pharma Co., Ltd. Masayuki Hino received research funding from Sumitomo Dainippon Pharma Co., Ltd. The other authors declare that there is no conflict of interests., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

We compared characteristics of myeloid neoplasms (MNs) following allogeneic hematopoietic cell transplantation (HCT) versus autologous HCT using a Japanese HCT registry database. Among 43 788 patients who underwent allogeneic (n = 18 874) or autologous HCT (n = 24 914) for non-myeloid malignancies or non-malignant diseases, 352 developed MNs. The cumulative incidence of MNs was lower after allogeneic HCT than after autologous HCT (0.3% vs. 1.8% at 10 years, respectively, p < .001). Compared with autologous HCT, MNs following allogeneic HCT developed in younger patients (median, 42 vs. 57 years old, respectively) and sooner after HCT (median, 16 vs. 33 months, respectively). Approximately half of MNs following allogeneic HCT were donor-derived and occurred later than recipient-derived MNs (median, 26 vs. 6 months, respectively, p = .003). In multivariate analysis, reduced-intensity conditioning and cord blood transplantation were associated with MN development after allogeneic HCT. Overall survival was similar in patients who developed MNs following allogeneic versus autologous HCT (18% vs. 22% at 5 years, respectively, p = .48). Patient age ≥ 55 years, the presence of previous HCT, AML subtype, and chromosome 5 or 7 abnormalities were adverse factors for overall survival after MN diagnosis. Further research is warranted to elucidate the mechanisms of MN development following allogeneic HCT., (© 2021 Wiley Periodicals LLC.)

NKG2D-mediated cytotoxicity is regulated by the single nucleotide polymorphism rs1049174, and its antitumor effect has been observed in various clinical settings. There are no previously published data on the influence of donor rs1049174 polymorphism on HLA-haploidentical allogeneic hematopoietic cell transplantation using post-transplantation cyclophosphamide (PTCy-haplo). We aimed to investigate the effect of donor NKG2D gene polymorphism on PTCy-haplo recipients. We retrospectively reviewed 91 consecutive PTCy-haplo recipients at our institution, and genotyped rs1049174 of the NKG2D gene in both donors and patients. In the patients who received PTCy without antithymocyte globulin (ATG) as graft-versus-host disease prophylaxis, the 2-year cumulative incidence of relapse/progression (RI) of PTCy-haplo from rs1049174 CC donors was lower than that from rs1049174 CG/GG donors (25.0% versus 52.4%; P = .041), and rs1049174 CC donors were associated with a decreased risk of relapse/progression (adjusted hazard ratio, 0.2; 95% confidence interval, 0.0 to 0.6; P = .007). Furthermore, a beneficial effect of rs1049174 CC donor on OS and RI was observed in non-acute myelogenous leukemia patients. This study demonstrates that receipt of PTCy-haplo from rs1049174 CC donors was associated with a decreased risk of relapse/progression in the patients who underwent PTCy-haplo without ATG. Future large-scale validation studies are needed to test the significance of donor NKG2D polymorphism in the development of a new donor selection algorithm for PTCy-haplo., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

A combination of three post-transplant drugs, cyclophosphamide (PTCy), a calcineurin inhibitor, and mycophenolate mofetil, has long been used for prophylaxis of graft-versus-host-disease (GVHD) after HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT). Recently, this combination has been used following HLA-matched allo-HCT as well, but the optimal combination of drugs for GVHD prophylaxis in an HLA-matched setting remains unclear. This prospective phase II study evaluated the safety and efficacy of PTCy plus tacrolimus (TAC) for GVHD prophylaxis after allo-HCT from HLA-matched related donors (MRD) or HLA-matched unrelated donors (MUD). The cumulative incidences of grades II-IV and III-IV acute GVHD at 100 days post-transplantation were 18% and 5.9%, respectively, in the MRD group, and 18% and 9.1%, respectively, in the MUD group. The cumulative incidences of moderate to severe chronic GVHD at 1 year were 12% and 9.1% in the MRD and MUD groups, respectively. The 1-year overall survival rates in the MRD and MUD groups were 88% and 64%, respectively, and the 1-year GVHD-free, relapse free survival rates were 59% and 50%, respectively. These results suggest that GVHD prophylaxis with a less intensive double drug combination (PT/Cy and TAC) might be feasible after HLA-matched allo-HCT.Clinical Trial Notation This trial was a prospective single-center trial registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; identification number: UMIN000023890) and the Japan Registry of Clinical Trials (jRCTs051180143)., (© 2021. Japanese Society of Hematology.)

The optimal dose of posttransplant cyclophosphamide (PTCy) for use in patients undergoing HLA-haploidentical hematopoietic cell transplantation with posttransplant cyclophosphamide (PTCy-haplo) has not been sufficiently examined. This study evaluates the safety and efficacy of HLA-haploidentical hematopoietic cell transplantation with a reduced dose of PTCy for patients with a poor prognosis or those with refractory hematological malignancies. We conducted a prospective clinical study of PTCy-haplo with peripheral blood stem cells (PBSCs) using a modified PTCy dosage regimen consisting of 50 mg/kg on day 3 posttransplantation and a reduced dose of 25 mg/kg on day 4. The cumulative incidences of grades II to III and IV acute graft-versus-host disease (GVHD) at day 100 posttransplantation were 30% and 0%, respectively. The cumulative incidence of moderate-to-severe chronic GVHD after transplantation was 7.0%. The cumulative incidence of nonrelapse mortality at 1 year posttransplantation was 6.1%. Overall survival (OS) at 1 year was 66%. In addition, the restricted cubic-spline Cox regression analysis showed nonlinear relationship between the number of infused CD34 + cells and CD3 + cells, and OS. A graft composition of >4.54 × 10 6 /kg CD34 + cells and >1.85 × 10 8 /kg but ≤3.70 × 10 8 /kg CD3 + cells was significantly associated with better survival, irrespective of the disease status (hazard ratio, 0.13; 95% confidence interval, 0.04-0.41; P < 0.001). These results suggest that PTCy-haplo with PBSCs using a de-escalated dose of 50 mg/kg on day 3 and 25 mg/kg on day 4 posttransplantation is a feasible option.

This study characterized the outcomes of patients who underwent hematopoietic cell transplantation (HCT) for transformed follicular lymphoma (tFL), and clarified the association of low-dose anti-thymocyte globulin use with outcomes after allogeneic HCT. The retrospective study cohort included 74 consecutive patients who underwent autologous (n = 23) or allogeneic (n = 51) HCT at our center from 2000 to 2017. Compared with the allogeneic HCT group, the autologous HCT group underwent fewer systemic regimens before HCT (median 2 vs. 5, p < 0.001) and were more likely to have chemosensitive disease at HCT (100% vs. 82%, p = 0.05), while age, sex and HCT-specific comorbidity index were similar between the two groups. With a median follow-up of 5.8 years among survivors, the 5-year probability of progression-free survival was 64% after autologous HCT and 55% after allogeneic HCT (p = 0.21). The 5-year cumulative incidence of non-relapse mortality was 0% after autologous HCT and 9.5% after allogeneic HCT (p = 0.062). The 5-year cumulative incidence of disease progression was similar between autologous and allogeneic HCT (36% vs. 36%, respectively, p = 0.88). In the allogeneic HCT group, the use of low-dose anti-thymocyte globulin was associated with a lower incidence of severe acute GVHD but not with an increased risk of mortality or disease progression. More than half of patients with early phase chemosensitive tFL and approximately half of those with advanced-phase tFL achieved long-term progression-free survival with autologous and allogeneic HCT, respectively. Disease progression was the major cause of treatment failure after both types of HCT. Further strategies are needed to reduce the risk of disease progression., (© 2021 John Wiley & Sons Ltd.)

Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous reports suggest that TA-TMA is caused by complement activation by complement-related genetic variants; however, this needs to be verified, especially in adults. Here, we performed a nested case-control study of allo-HSCT-treated adults at a single center. Fifteen TA-TMA patients and 15 non-TA-TMA patients, matched according to the propensity score, were enrolled. Based on a previous report showing an association between complement-related genes and development of TA-TMA, we first sequenced these 17 genes. Both cohorts harbored several genetic variants with rare allele frequencies; however, there was no difference in the percentage of patients in the TA-TMA and non-TA-TMA groups with the rare variants, or in the average number of rare variants per patient. Second, we measured plasma concentrations of complement proteins. Notably, levels of Ba protein on Day 7 following allo-HSCT were abnormally and significantly higher in TA-TMA than in non-TA-TMA cases, suggesting that complement activation via the alternative pathway contributes to TA-TMA. All other parameters, including soluble C5b-9, on Day 7 were similar between the groups. The levels of C3, C4, CH50, and complement factors H and I in the TA-TMA group after Day 28 were significantly lower than those in the non-TA-TMA group. Complement-related genetic variants did not predict TA-TMA development. By contrast, abnormally high levels of Ba on Day 7 did predict development of TA-TMA and non-relapse mortality. Thus, Ba levels on Day 7 after allo-HSCT are a sensitive and prognostic biomarker of TA-TMA., Competing Interests: KO, NW, and NI are councilors of the Japanese Association for Complement Research (JACR). HN received research funds from Alexion GK. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Okamura, Nakamae, Shindo, Ohtani, Hidaka, Ohtsuka, Makuuchi, Kuno, Takakuwa, Harada, Nishimoto, Nakashima, Koh, Hirose, Nakamae, Wakamiya, Hino and Inoue.)

To elucidate the incidence, causes, and risk factors associated with readmission due to transplant-related complications, we studied 213 consecutive patients who were discharged without progression of primary disease after their first allogeneic hematopoietic cell transplantation at our center between 2013 and 2016. The median patient age was 50 years (range, 18-71 years). Eighty-three patients had AML or MDS, 66 had lymphoma, 28 had ALL, 23 had ATL, and 13 had other diseases. The median duration of hospitalization for transplantation was 56 days (range 27-325 days). The cumulative incidences of readmission due to transplant-related complications were 8% at 30 days, 16% at 100 days, and 25% at 1 year after discharge. The most frequent cause of readmission was infection, followed by graft-versus-host disease throughout the first year. In multivariate analysis, steroid use at discharge was the only risk factor associated with readmission within 30 days, and steroid use at discharge, absolute lymphocyte count < 500/µl at discharge, and documented bacterial infection during admission were risk factors associated with readmission within 1 year. Our results indicated that factors during hospitalization or discharge, but not at transplantation, were associated with readmission. Patients with these risk factors should be monitored carefully after discharge.

Post-transplantation acute limbic encephalitis (PALE) is a rare, severe inflammatory disorder in the bilateral limbic system, including the hippocampus. To date, only a few studies have reported details, including risk factors for PALE; however, further clinical evidence of PALE, especially in cerebrospinal fluid human herpesvirus 6-negative cases, is warranted. In addition, data are sparse regarding the risk factors for calcineurin inhibitor (CNI)-induced encephalopathy (CNIE) following allogeneic hematopoietic cell transplantation (allo-HCT) in adults. Therefore, we examined the risk factors for and clinical details of PALE and CNIE. We retrospectively analyzed consecutive patients who underwent allo-HCT between January 2005 and November 2017. A total of 485 patients age 46 years (median) were eligible. In total, 14 PALE cases and 11 CNIE cases were identified. Multivariable analyses identified older age, use of an HLA-mismatched unrelated donor (URD), graft-versus-host disease (GVHD) prophylaxis with CNI and mycophenolate mofetil, and grade II-IV acute GVHD as significantly associated with an increased risk of PALE. In 13 patients who received high-dose methylprednisolone (mPSL) therapy, 6 (46%) responded to mPSL therapy, and 3 (23%) achieved complete remission at day 90 after mPSL administration. Furthermore, myelodysplastic syndrome (MDS), HLA-mismatched URD, and grade II-IV acute GVHD were significantly associated with an increased risk of CNIE. The 5-year nonrelapse mortality rate was 50% in PALE and 63% in CNIE, suggesting a very poor prognosis. In conclusion, this study provides evidence that HLA-mismatched URD and acute GVHD may independently contribute to the development of PALE, possibly in part through HLA-mismatch-derived alloimmune responses. Other than acute GVHD, we have identified MDS and HLA-mismatched URD as novel predictors of CNIE after allo-HCT., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Posttransplant lymphoproliferative disorder (PTLD) after allogeneic hematopoietic cell transplantation (HCT) is usually donor derived, associated with Epstein-Barr virus (EBV), and of B-cell origin. T-cell PTLD (T-PTLD) after allogeneic HCT is extremely rare. Four of 1015 (0.39%) allogeneic HCT patients were diagnosed with T-PTLD; peripheral T-cell lymphoma-not otherwise specified, anaplastic large cell lymphoma, monomorphic T-cell PTLD and polymorphic PTLD with chronic active EBV infection-like symptoms. Three of the four patients developed T-PTLD within 6 months after HCT from HLA-mismatched unrelated donor. Three (75%) and 4 (100%) cases were positive for EBV-encoded small RNA in situ hybridization and EBV-DNA load in peripheral blood, respectively. Chimerism analysis showed that 75% of T-PTLD tissues (3/4) were recipient derived. T-PTLD was refractory to salvage chemotherapy and fatal in all four patients. Including the 10 patients in the literature, the median interval from HCT to diagnosis of T-PTLD was 5 months (range 1-72 months), 55% were negative for EBV, and 56% were recipient-derived. T-PTLD, which often occurred early after allogeneic HCT, was more likely to be EBV negative and recipient derived than B-cell PTLD after allogeneic HCT. Like T-PTLD after solid organ transplant, T-PTLD after allogeneic HCT demonstrated morphological heterogeneity and poor prognosis.

Little is known about the prognostic significance of muscle loss for allogeneic hematopoietic stem cell transplantation (allo-HCT). We retrospectively analyzed consecutive patients who received allo-HCT from 2013 to 2015. All patients underwent computed tomography (CT) imaging and bioelectrical impedance analysis (BIA) within 30 days before allo-HCT. Skeletal muscle area (cm 2 ) at the third lumbar vertebra level on CT imaging and skeletal muscle mass (kg) measured by BIA were normalized by height in meters squared (m 2 ) to calculate the skeletal muscle area index (SMI) and skeletal muscle mass index (SMMI). SMI and SMMI were significantly correlated (r = 0.744; P < 0.001). The cumulative incidence of 1-year non-relapse mortality (NRM) was significantly higher in patients with low SMI than high SMI (17% versus 0%, respectively; P = 0.023). Overall survival was shorter in patients with low SMI than high SMI (56% versus 93%, respectively; P < 0.001). In univariate analysis, low SMI was associated with increased risk of NRM (HR 7.46; 95% CI 1.05-52.98; P = 0.044), and in multivariate analysis it was associated with higher overall mortality (HR 5.35; 95% CI 1.71-16.72; P = 0.004). These results suggest that low muscle mass is an independent predictor of mortality after allo-HCT.

Chronic graft versus host disease (cGVHD) of the central nervous system is a rare condition that could occur after allogeneic hematopoietic stem cell transplantation (SCT) but has been poorly documented. Here, we report a patient diagnosed with recurrent acute disseminated encephalomyelitis (ADEM) with longitudinal extensive transverse myelitis (LETM) as cGVHD after HLA haploidentical peripheral blood SCT using posttransplantation cyclophosphamide for mixed-phenotype acute leukemia. We observed clinical and radiological improvement after the rituximab treatment of the condition that had been refractory to steroids. To the best of our knowledge, no report of cGVHD presented recurrent ADEM with LETM after allogeneic SCT and successfully treated with rituximab. Hence, ADEM should be included in the differential diagnosis of neurological symptoms in posttransplant patients with cGVHD.

Aim: Small-scale clinical studies have reported on drug interactions between caspofungin (CPFG) and calcineurin inhibitors in healthy subjects; however, little is known about these interactions in allogeneic haematopoietic cell transplantation (allo-HCT) patients., Methods: We retrospectively assessed the drug interactions and safety profiles in allo-HCT recipients treated concomitantly with CPFG and calcineurin inhibitors., Results: Ninety-one consecutive cases were evaluated. There were no statistically significant differences in the plasma concentration/dose (C/D) ratios of tacrolimus (TAC) in 34 patients before and after co-administration with CPFG (median: 575.6-672.4, P = 0.200). In contrast, the median C/D ratio of cyclosporin A (CsA) in 16 patients was significantly elevated after co-administration with CPFG (median: 62.8-74.9, P = 0.016). There were no serious adverse effects on liver or renal function associated with the therapy., Conclusions: Our data show that CPFG did not affect the pharmacokinetics of TAC and that it could mildly increase CsA blood concentrations in allo-HCT patients., (© 2017 The British Pharmacological Society.)