神田 善伸

BACKGROUND: The advent of novel therapeutic agents has improved the prognosis of multiple myeloma (MM). However, autologous stem cell transplantation (ASCT) remains a key treatment option for eligible patients. While stem cell mobilization using cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) has long been the standard approach, the introduction of plerixafor (PLER) has led to broader adoption of G-CSF±PLER-based mobilization, offering improved scheduling flexibility. Nevertheless, real-world data on current mobilization practices and their effects on post-ASCT outcomes remain limited. METHODS: We evaluated mobilization strategies and their associations with clinical outcomes in MM patients who underwent ASCT between 2019 and 2022. A total of 3,319 patients were analyzed, including 743 patients mobilized with cyclophosphamide and 2,576 mobilized with G-CSF±PLER. The primary endpoint was 2-year overall survival (OS). Multivariate analysis and propensity score matching were performed to identify factors associated with superior OS. RESULTS: The 2-year OS rates were 89.7% (95% CI: 87.0-91.8) and 93.2% (95% CI: 91.8-94.3) in the cyclophosphamide and G-CSF groups, respectively. Multivariate analysis showed that age <65 years (P < 0.001), lower ISS stage (P < 0.001), good performance status (P < 0.001), G-CSF mobilization (P = 0.005), and deep response pre-ASCT (P < 0.001) were independent predictors of superior OS. Propensity score matching analysis demonstrated significantly better OS in the G-CSF group than in the cyclophosphamide group (P = 0.041). Among patients achieving complete or very good partial response (CR/VGPR) pre-ASCT, OS did not differ between the groups; however, among patients who did not reach CR or VGPR pre-ASCT, the G-CSF group showed significantly better OS than the cyclophosphamide group. CONCLUSIONS: G-CSF‒based mobilization may offer prognostic advantages after ASCT, particularly in patients with suboptimal pre-ASCT response.

BACKGROUND: Previous reports have suggested an association between cytomegalovirus (CMV) infection and bacterial or fungal infections after allogeneic hematopoietic cell transplantation (HCT). This study aimed to examine the relationship between letermovir (LTV) prophylaxis and the incidence of bacteremia and invasive fungal infections. METHODS: Using a Japanese transplant registry database, we analyzed 19,531 patients who underwent their first allogeneic HCT from 2011 to 2022. Patients who initiated LTV prophylaxis within the first week post-transplantation were classified as the LTV group. RESULTS: A total of 4915 patients in the LTV group and 14,616 in the No LTV group were analyzed. The incidence of bacteremia by day 100 was significantly lower in the LTV group compared to the No LTV group (17.4 % vs. 21.7 %, P < 0.001). In the multivariate analysis, LTV prophylaxis (HR 0.75, 95 %CI: 0.69-0.81) was found to be significantly associated with a reduced risk of bacteremia, along with neutrophil engraftment. Age >50 years, male, non-remission status, alternative donors, higher values of the hematopoietic cell transplantation-comorbidity index, poor performance status, and grade II-IV acute graft-versus-host disease were associated with an increased risk of bacteremia. LTV was associated with a reduced risk of bacteremia both within 30 days (HR 0.74, 95 %CI: 0.68-0.81) and beyond 30 days (HR 0.76, 95 %CI: 0.66-0.89) after HCT. Conversely, it was not associated with the risk of invasive aspergillosis or candidemia. CONCLUSIONS: LTV prophylaxis significantly reduced the risk of bacteremia. However, it was not associated with the risk of invasive fungal infections.

Despite the increasing number of cancer survivors, the impact of prior solid tumors and their treatment modality on outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. This multi-center retrospective study compared transplant outcomes in allo-HSCT recipients with and without a history of solid tumors. Of 5,850 adult patients who underwent first allo-HSCT, 303 (5.2%) had a prior solid tumor. After propensity score matching, overall survival (OS) and cumulative incidences of relapse, non-relapse mortality (NRM), and acute and chronic graft-versus-host diseases were almost comparable between the two groups. Progression or recurrence of solid tumors after allo-HSCT occurred in only eight cases (2.8%). Importantly, patients who received both chemotherapy and radiation therapy (Chemo + RT) for prior solid tumors had significantly worse OS (35.3% vs. 54.1% [P < 0.001] vs. 56.8% [P < 0.001] at 2 years) and higher NRM (36.2% vs. 18.7% [P = 0.002] vs. 19.3% [P = 0.001] at 2 years) compared to patients who received other treatment modalities for prior solid tumors or patients without prior solid tumors. These findings highlight the feasibility of allo-HSCT in selected patients with prior solid tumors, while demonstrating the negative impact of Chemo + RT on outcomes after allo-HSCT.

HLA class I allele loss in acquired aplastic anemia (AA) represents an immune escape from the T cell-mediated pathogenesis. We investigated the impact of loss-prone HLA alleles on the hematopoietic cell transplantation (HCT) outcomes using registry data of 875 Japanese patients with acquired AA. HLA associations were evident exclusively among 399 patients who received HCT within 1 year of the diagnosis, consistent with the predominance of HLA loss in this group. A set of five HLA alleles with the highest propensity for loss (HLA-A*02:01, HLA-A*02:06, HLA-A*31:01, HLA-B*40:02, and HLA-B*54:01) was the strongest predictor of post-transplant survival among all possible allele combinations (5-year survival, 80.3% vs. 54.4%; p < 0.0001), partly due to improved engraftment and pre-transplant conditions. Another set (HLA-A*33:03, HLA-B*07:02, HLA-B*44:03, HLA-B*52:01, and HLA-B*54:01)-less frequently lost in AA and underrepresented in Epstein-Barr virus (EBV)-related diseases outside AA-was associated with an increased risk of post-transplant lymphoproliferative disorders (5-year incidence, 10.2% vs. 1.8%; p = 0.00019), suggesting that the loss of protective alleles against EBV during AA pathogenesis may predispose to EBV-driven lymphoproliferations. These associations were determined by recipient, not donor, HLA. Therefore, specific HLA class I alleles and their potential loss significantly influence the HCT outcomes in acquired AA.

Mixed-phenotype acute leukemia (MPAL) is associated with poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) can achieve long-term survival, optimal transplantation strategies remain unclear. We analyzed a national registry of adult patients with MPAL who underwent allo-HSCT between 2008 and 2022 in Japan. Among 417 patients, median age at transplant was 44 years (interquartile range, 32-55); 61% were male, 20% were BCR::ABL1-positive, and 66% underwent transplant during the first complete remission (CR; CR1). At 5 years posttransplant, overall survival (OS) was 54%, disease-free survival was 49%, relapse was 28%, and nonrelapse mortality was 23%. Multivariate analysis identified older age (adjusted hazard ratio [aHR], 1.78 [95% confidence interval (CI), 1.11-2.84] for ages 50-59 years; aHR, 2.65 [95% CI, 1.54-4.55] for ≥60 years; both vs <40 years), male sex (aHR, 1.56; 95% CI, 1.07-2.27), Eastern Cooperative Oncology Group performance status scale ≥2 (aHR, 3.05; 95% CI, 1.72-5.40), BCR::ABL1 -negative status (aHR, 1.64; 95% CI, 1.02-2.64), advanced disease status (aHR, 1.642 [95% CI, 0.80-3.36] for second CR; aHR, 4.01 [95% CI, 2.61-6.15] for third or higher CR, or non-CR vs CR1), and low conditioning intensity (aHR, 2.49 [95% CI, 1.21-5.13] for low transplant conditioning intensity [TCI] vs high TCI) as adverse prognostic factors for OS. A propensity score-matched comparison with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) during the same period showed that MPAL did not have significantly worse prognosis than AML or ALL. These findings suggest that allo-HSCT offers long-term survival in MPAL, with outcomes not inferior to those of AML and ALL.

Abstract Leukemia cells are consistently subjected to higher oxidative stress than normal cells. To mitigate reactive oxygen species (ROS) overload, which can trigger various forms of cell death, leukemia cells employ a robust antioxidant defense system and maintain redox homeostasis. Recent evidence suggests that dimethyl fumarate (DMF), a derivative of fumarate, inactivates the antioxidant glutathione (GSH), thereby inducing oxidative stress and metabolic dysfunction, eventually leading to cell death in cancer cells. In this study, we observed that DMF decreases the GSH/oxidated GSH ratio and increases intracellular ROS levels, the extent of which is closely correlated with cell death, in acute myeloid leukemia (AML) cell lines. DMF reduced the mitochondrial membrane potential and oxidative phosphorylation (OXPHOS), effects that were almost fully restored by the antioxidant N-acetylcysteine, suggesting that these responses are ROS-dependent. Electron microscopy and inhibition assays revealed that apoptosis, rather than necroptosis or ferroptosis, is the predominant form of cell death of AML cells following DMF treatment. Notably, the combination of DMF and the BCL-2 selective BH3-mimetic venetoclax induced marked cell death in AML cells, including venetoclax-refractory BCL-2 low expressing U937 and acquired venetoclax-resistant MOLM-14 cells. This combination also caused greater mitochondrial depolarization and a more profound reduction in OXPHOS activity than either agent alone. Collectively, our findings indicate that DMF exerts potent anti-leukemia activity in AML cells and sensitizes cells to venetoclax treatment by synergistically disrupting mitochondrial integrity through ROS accumulation.

Summary Severe graft‐versus‐host disease (GVHD) remains a major complication of allogeneic haematopoietic stem cell transplantation (allo‐HSCT), necessitating optimal immunosuppressive strategies. This retrospective study used data from the Japanese Transplant Registry Unified Management Program to compare three methotrexate (MTX)‐dosing regimens for GVHD prophylaxis in patients undergoing human leucocyte antigen (HLA)‐matched allo‐HSCT: a low‐dose 3‐day regimen (Ld3:10 mg/m² on day 1, 7 mg/m² on days 3 and 6), a low‐dose 4‐day regimen (Ld4: Ld3 with an additional 7 mg/m² on day 11) and an original‐dose 3‐day regimen (Od3: 15 mg/m² on day 1, 10 mg/m² on days 3 and 6). Among 2537 analysed patients, Ld3 was the most commonly used regimen. Multivariate analyses showed no significant differences in the cumulative incidence of grade II–IV acute GVHD among regimens. However, Od3 was associated with an increased risk of grade III–IV acute GVHD, and Ld4 was linked to delayed neutrophil engraftment. This study is the first large‐scale retrospective analysis of the impact of different MTX‐dosing regimens on the outcomes of HLA‐matched allo‐HSCT, providing valuable insights into optimal MTX‐dosing strategies in clinical practice.

Overall response (OR) that combines complete (CR) and partial responses (PR) is the conventional end point for acute graft-versus-host disease (GVHD) trials. Because PR includes heterogeneous clinical presentations, reclassifying PR could produce a better end point. Patients in the primary treatment cohort from the Japanese Society for Transplantation and Cellular Therapy (JSTCT) were randomly divided into training and validation sets. In the training set, a classification and regression tree algorithm generated day 28 refined response (RR) criteria based on symptoms at treatment and day 28. We then evaluated RR for primary and second-line treatments, using the area under the receiver operating characteristic curve (AUC) and negative predictive value (NPV) for 6-month nonrelapse mortality as performance measures. RR considered patients with grade 0/1 at day 28 without additional treatment as responders. RR for primary treatment produced higher AUCs than OR with small improvement of NPVs in both validation sets: JSTCT (AUC, 0.73 vs 0.69 [P < .001]; NPV, 92.0% vs 89.6% [P < .001]) and the Mount Sinai Acute GVHD International Consortium (MAGIC; AUC, 0.71 vs 0.68 [P = .032]; NPV, 90.9% vs 89.8% [P = .009]). RR for second-line treatment produced similar AUCs but much higher NPVs than OR in both validation sets of JSTCT (AUC, 0.64 vs 0.63 [P = .775]; NPV, 74.5% vs 66.0% [P < .001]) and MAGIC (AUC, 0.67 vs 0.64 [P = .105]; NPV, 86.8% vs 76.1% [P = .004]). Classifying persistent but mild skin symptoms as responses and residual lower gastrointestinal GVHD as nonresponses were major drivers in improving the prognostic performance of RR. Our externally validated day 28 RR would serve as a better end point than conventional criteria in future first- and second-line treatment trials.

Patient age might influence donor selection priorities in allogeneic hematopoietic stem cell transplantation (allo-HCT), due to the differences in donor age, organ function, and resistance to graft-versus-host disease between younger and older patients. We compared the transplant outcomes among human leukocyte antigen (HLA)-matched related donors (M-RDs, n=4,106), HLA 1-antigen-mismatched related donors (1MM-RDs, n=592), HLA 2-3-antigen-mismatched related donors (23MM-RDs, n=882), HLA-matched unrelated donors (M-UDs, n=3,927), HLA 1-locus-mismatched unrelated donors (1MM-UDs, n=2,474), and unrelated cord blood units (U-CBs, n=5,867) between patients aged.

Primary plasma cell leukemia (pPCL) is a rare and aggressive subtype of plasma cell malignancy. Although hematopoietic stem cell transplantation (HCT), including autologous HCT (auto-HCT) and allogeneic HCT (allo-HCT), is widely used, an optimal treatment strategy is undetermined. We retrospectively analyzed patients with pPCL who underwent HCT between 2006 and 2022 in Japan using Japanese registry data. Overall, 182 patients (117 and 65 who underwent auto-HCT and allo-HCT, respectively) were included. Patients in the allo-HCT group were younger, had more advanced disease, and underwent tandem HCT more frequently than did those in the auto-HCT group. There was no statistically significant difference in overall survival (OS) between the groups (P=0.46), with a median OS of 3.2 years (95% CI 2.1-4.3 years) in the auto-HCT group and 1.4 years (95% CI 0.8-3.9 years) in the allo-HCT group. Comparing the four different transplantation strategies (single auto-HCT, single allo-HCT, tandem autologous-autologous HCT, and tandem autologous-allogeneic HCT), the single allo-HCT group had the poorest OS because of early mortality. Tandem autologous-allogeneic HCT appeared to provide better long-term survival. In the multivariate analysis, disease status, Eastern Cooperative Oncology Group Performance Status, and tandem transplantation were significant factors influencing OS. A matched-pair analysis using propensity scores revealed no significant differences in OS between the auto-HCT and allo-HCT groups. However, the allo-HCT group appeared to have better long-term survival than the auto-HCT group. Allogeneic transplantation, including tandem autologous-allogeneic-HCT, may offer long-term survival benefits with appropriate patient selection. Further studies are warranted to optimize the transplantation strategies and pre- and post-transplantation treatments for pPCL.

The optimal alternative donor type for patients lacking human leucocyte antigen (HLA)-matched related or unrelated donors remains unclear. In comparative studies evaluating donor types, graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) represents a well-established end-point but has limitations. The win ratio approach addresses these limitations by analysing multiple end-points with varying severities to account for the relative component priorities. We compared HLA-mismatched unrelated donors, haploidentical donors and cord blood using both the hazard ratio (HR) of GRFS and the win ratio related to GRFS. The haploidentical donor group had a similar HR of GRFS (HR: 1.01, 95% confidence interval [CI]: 0.85-1.19, p = 0.916) and win ratio (win ratio: 0.86, 95% CI: 0.72-1.02, p = 0.081) to HLA-mismatched unrelated donors. Cord blood transplantation showed similar GRFS compared to HLA-mismatched unrelated donors in the Cox proportional model (HR: 1.14, 95% CI: 0.98-1.32, p = 0.085), significantly lower win ratio (win ratio: 0.80, 95% CI: 0.68-0.93, p = 0.004) and similar outcomes to haploidentical donors. HLA-mismatched unrelated donor transplantation showed comparable to superior outcomes among alternative donor types. Our results indicate the need to present the win ratio alongside conventional methods to assess the end-point robustly.

Previous studies have shown that the pre-transplant C-reactive protein (CRP)/platelet ratio (CP ratio) is a predictor of survival. The aim of this multicenter retrospective study was to evaluate the clinical significance of CP ratio in patients with malignant lymphoma (ML) who underwent allogeneic hematopoietic stem cell transplantation (alloHCT). The cohort included patients with ML who underwent first alloHCT from 2007 to 2021. CP ratio was defined as CRP [mg/dL]/platelet [104/μL] and evaluated prior to alloHCT. The cutoff value for CP ratio was set at 0.05 based on previous studies. A total of 311 cases were analyzed, of which 134 were mature B cell lymphoma, 177 were T/NK cell lymphoma (including 70 cases of adult T-cell leukemia/lymphoma), and 17 were Hodgkin's lymphoma. The median age was 53 years (range: 17-69 years). High CP ratio was associated with status of disease, presence of infections, poor performance status at alloHCT, and high transfusion volume received prior to alloHCT. Overall survival (OS) at 2 years according to CP ratio (low vs. high) was 61.1% versus 30.1% (p < 0.001), non-relapse mortality (NRM) was 21.4% versus 40.7% (p = 0.001), and the relapse rate was 23.7% versus 32.6% (p = 0.061), respectively. In multivariate analysis, the high CP ratio group was associated with poor OS (HR = 2.20, 95% CI: 1.61-3.02, p < 0.001) and higher NRM (HR = 1.90, 95% CI: 1.28-2.81, p = 0.0014). High CP ratio was found to be associated with poor post-transplant OS and NRM, and was a suitable prognostic biomarker for stratifying the risk of patients with ML who are candidates for alloHCT.

Although allogeneic hematopoietic stem cell transplantation (allo-HCT) is considered a potentially curative therapy for multiple myeloma, disease progression after allo-HCT remains a major limitation. Post-transplant maintenance therapy may help reduce the risk of relapse. Lenalidomide, an immunomodulatory agent, has demonstrated efficacy in multiple myeloma, but its use after allo-HCT is limited due to concerns regarding graft-versus-host disease (GVHD). To evaluate the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of lenalidomide when used as maintenance therapy after allo-HCT for multiple myeloma. This was a prospective, multicenter, phase I/II clinical trial conducted from 2014 to 2019. Lenalidomide maintenance therapy was initiated 100-365 days post-allo-HCT. Eligible patients received lenalidomide on days 1-21 of a 28-day cycle for at least four cycles, beginning at 5 mg/day. A standard 3 + 3 dose-escalation design (Fibonacci method) was used to determine DLT and MTD. The study included 10 patients; one was excluded due to early disease progression, leaving nine patients evaluable for toxicity. The phase II portion was not conducted due to expiration of the trial period. The median interval from allo-HCT to initiation of lenalidomide was 244 days (range, 169-330 days). At the 10 mg/day dose level, one patient experienced moderate chronic GVHD meeting the predefined criteria for DLT. No other DLTs occurred, establishing the MTD at 10 mg/day. No acute GVHD was observed. Two additional patients developed mild chronic GVHD, which resolved spontaneously without treatment. The 2-year progression-free survival (PFS) and overall survival (OS) rates from the start of maintenance therapy were 53% and 78%, respectively. Late initiation of lenalidomide maintenance therapy after allo-HCT for multiple myeloma was feasible at a dose of 10 mg/day and was associated with a low incidence of GVHD-related complications. However, further studies are required to confirm treatment efficacy.

Primary refractory acute myeloid leukaemia (AML) remains a major clinical challenge, with poor outcomes despite salvage chemotherapy. Allogeneic haematopoietic cell transplantation (HCT) continues to be a potentially curative option for these patients. However, recent data on outcomes and prognostic factors specific to primary refractory AML remain limited. We conducted a retrospective analysis of 2600 adult patients with primary refractory AML who underwent their first allogeneic HCT between 2013 and 2022, using data from the Japanese national registry. The 3-year overall survival (OS) and leukaemia-free survival (LFS) rates were 28.5% and 24.4% respectively. The multivariate analysis identified older age (≥50 years), poor performance status (≥2), adverse cytogenetics, extramedullary disease at diagnosis and higher peripheral blood blast count at HCT (≥10%) as significant risk factors for worse OS and LFS. The cumulative incidences of relapse and non-relapse mortality at 3 years were 49.8% and 25.8% respectively. Based on the five significant risk factors, we developed a scoring system that effectively stratified patients into distinct prognostic groups for OS and LFS. This nationwide analysis demonstrated that allogeneic HCT offers the potential for long-term survival in adult patients with primary refractory AML. The proposed risk-scoring system may support clinical decision-making and patient counselling.

High-dose chemotherapy with autologous stem cell transplantation (ASCT) is an option for patients aged ≥ 65 years with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Few data are available to select patients suitable for chimeric antigen receptor T-cell (CAR-T) therapy or bispecific antibodies. We retrospectively analyzed the risk factors for poor outcomes for 451 Japanese patients aged ≥ 65 years with R/R DLBCL who received ASCT at either second complete remission or first partial remission (n = 336 and 115, respectively) between 2011 and 2022. CAR-T became commercially available in Japan in March 2019, and the annual number of ASCTs for older patients with R/R DLBCL increased significantly until 2018. However, the number of ASCT cases plateaued in 2018. Multivariate Cox regression analysis identified ≤ 24 months from diagnosis to ASCT (hazard ratio [HR], 1.497) and performance status > 0 at ASCT (HR, 1.460) as independent predictors of overall survival (OS) and an association with late recurrence. The 3-year OS rates were 73.4% (95% confidence interval [CI], 65.8%-79.6%) in patients with > 24 months from diagnosis to ASCT and 58.6% (95% CI, 51.2%-65.2%) in those with ≤ 24 months from diagnosis to ASCT. The 3-year OS rates were 69.4% (95% CI, 62.5%-75.2%) in patients with performance status (PS) = 0 and 60.6% (95% CI, 62.5%-70.4%) in those with PS > 0. CAR-T therapy or bispecific antibodies may be used initially instead of ASCT for early relapsed and refractory patients. However, ASCT remains beneficial for older chemo-sensitive patients with late recurrence and good performance status.

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a lethal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). According to the 2016 European Society for Blood and Marrow Transplantation criteria, SOS/VOD is classified into classical SOS/VOD and late-onset SOS/VOD, but their similarities and differences remain unclear. Here we retrospectively investigated the incidence, risk factors, and impact on transplant outcomes of classical and late-onset SOS/VOD in 16 518 allo-HSCT recipients using the Japanese nationwide registry data. The cumulative incidences of classical and late-onset SOS/VOD were 2.5% and 2.2%, with a median onset of 13 and 42 days after transplantation, respectively. Both patients with classical (hazard ratio [HR], 3.45; 95% CI, 3.07-3.87) and late-onset (HR, 3.98; 95% CI, 3.51-4.51) SOS/VOD had a significantly worse overall survival compared with those without. The risk factors for classical and late-onset SOS/VOD are different. Hepatic comorbidities, high-risk diseases, use of melphalan (MEL), and myeloablative conditioning are associated with both types of SOS/VOD. Whereas poor performance status, a prior history of transplantation, and positive hepatitis C virus are associated with only classical SOS/VOD, allo-HSCT from cord blood or related human leukocyte antigen-haploidentical donors, use of total body irradiation and busulfan (BU), and tacrolimus-based graft-versus-host disease prophylaxis are associated with only late-onset SOS/VOD. In particular, the incidence of late-onset SOS/VOD is much higher in patients receiving both BU- and MEL-containing conditioning regimens. These findings suggest that different monitoring and treatment approaches are necessary for allo-HSCT recipients at high risk for classical and late-onset SOS/VOD.

Allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-matched donors is the gold standard. However, haploidentical stem cell transplantation using posttransplant cyclophosphamide (PTCY-haplo) and cord blood transplants (CBTs) are alternatives when HLA-matched donors are not available. Using Japanese registry data, we evaluated the impact of haploidentical donor age on posttransplant outcomes by comparing PTCY-haplo and CBT. We analyzed data for 5161 patients aged 16 to 70 years who received their first HSCT for acute leukemia, myelodysplastic syndrome, or chronic myeloid leukemia. Haploidentical donors were categorized as "younger" (aged <40 years) or "older" (aged ≥40 years), and the patients were divided into younger (aged <50 years) and older (aged ≥50 years) cohorts. In the older cohort, PTCY-haplo from younger donors had better overall survival (OS; 55.5% vs 50.8%, P = .006), lower nonrelapse mortality (NRM; 17.3% vs 28.6%, P < .001), and higher relapse rates (33.0% vs 24.9%, P = .017) than with CBT. PTCY-haplo from older donors had comparable OS (44.1% vs 50.8%, P = 1.00), NRM (27.3% vs 28.6%, P = 1.00), and relapse (29.2% vs 24.9%, P = .90) to that with CBT. In the younger cohort, PTCY-haplo from younger and older donors showed OS, NRM, and relapse comparable with CBT. In the older cohort, cumulative incidence of acute graft-versus-host disease (GVHD) was higher with CBT than with PTCY-haplo, regardless of donor age. However, in the younger cohort, acute GVHD was lower in PTCY-haplo from younger donors than with CBT. PTCY-haplo from younger donors to older patients offers better clinical outcomes than CBT.

It is uncertain whether FLU/BU4 regimens, classified as myeloablative conditioning (MAC), improve prognosis compared to conventional MAC regimens (conv-MAC) such as CY/TBI and BU/CY. We compared FLU/BU4 with conv-MAC among 6551 patients (FLU/BU4 905, conv-MAC 5646), including acute myeloid leukemia (AML) patients aged 16-59 who received a first allogeneic transplantation from the Japanese nationwide registry. The primary endpoint was overall survival (OS), while secondary endpoints were treatment-related mortality (TRM) and relapse at 3 years. Results indicated comparable OS for conv-MAC regimens among the entire cohort (3-year OS: FLU/BU4 50.4% vs. conv-MAC 55.4%, p < 0.001). Subgroup analysis focusing on elderly patients (aged 50-59) indicated that FLU/BU4 showed a statistically significant improvement in OS (47.0% vs. 42.8%, p = 0.036). Notably, for patients in this cohort transplanted at complete remission (CR), FLU/BU4 demonstrated a substantial advantage over conv-MAC with superior OS (HR 0.75, p = 0.046), lower TRM (HR 0.66, p = 0.035), and comparable relapse (HR 0.84, p = 0.390). These benefits were not observed in elderly patients transplanted at non-CR or in other age groups. In summary, our findings suggest that FLU/BU4 regimen, rather than conv-MAC, may be preferable in MAC-tolerant AML patients, aged 50-59 at CR status. This treatment improves survival by reducing TRM without increasing relapse risk.

In recent years, there have been notable advancements in the treatment of malignant lymphoma. However, a certain percentage of patients are unlikely to achieve a cure through chemotherapy alone. Therefore, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a crucial curative treatment for malignant lymphoma. FluBu4, comprising fludarabine (Flu) combined with a myeloablative dose of intravenous busulfan (Bu; 12.8 mg/kg in total), is a widely used conditioning regimen for allo-HSCT, but its usefulness in malignant lymphoma (ML) has not been fully investigated. The objective of this study was to evaluate the efficacy and safety of FluBu4 in allo-HSCT for lymphoma by comparing the outcomes of two conditioning regimens: FluBu4 and FluMel140. We used a Japanese national database from the Transplant Registry Unified Management Program to retrospectively analyze the first allo-HSCT for ML in patients aged ≥16 years. Allo-HSCT cases treated with posttransplant cyclophosphamide were excluded. Two groups, namely FluBu4 and FluMel140 were selected by propensity score matching (PSM) with a case ratio of 1:2. From 921 cases, 113 were selected by PSM for the FluBu4 group and 226 for the FluMel140 group. The median age was 54 (19 to 68) years, the median observation period of survivors was 33.8 months, and 145 (42.7%) had a history of autologous HSCT. There were no significant differences in patients' backgrounds between the two groups after PSM. Three-year overall survival (OS) was significantly worse for FluBu4 than for FluMel140 (28.0% versus 48.6%; P < .01). The 3-year cumulative relapse rate was comparable for FluBu4 and FluMel140 (40.1% versus 38.5%; P = .65). However, 3-year nonrelapse mortality was significantly higher for FluBu4 than for FluMel140 (35.3% versus 22.5%; P = .02). There was no significant difference between the two treatment groups in the cumulative incidence of acute graft-versus-host disease (aGVHD) at day 100 after allo-HSCT and the 3-year cumulative incidence of chronic GVHD. While the common and major cause of death was the relapse of lymphoma, aGVHD, and noninfectious lung complications were observed more frequently with FluBu4 than with FluMel140. One-year cumulative incidence of interstitial pneumonia was significantly higher for FluBu4 than for FluMel140 (5.3% versus 0.4%; P = .03). FluBu4 use was associated with worse nonrelapse mortality (NRM) and OS in allo-HSCT for ML compared with FluBu4 and FluMel140 adjusted by PSM. Patients treated with FluBu4 had a higher incidence of noninfectious pulmonary complications and an increased number of associated deaths. A higher rate of NRM in the patients treated with FluBu4 was particularly evident in patients aged ≥60, and its use should be avoided in this patient population.

Fludarabine and myeloablative busulfan (FluBu4) in allogeneic hematopoietic stem cell transplantation (HSCT) for older people have not been adequately examined. This retrospective study analyzed data from a large-scale, nationwide database in Japan. Adult patients (> 15 years old, y/o) who received their first HSCT with FluBu4 for hematological malignancies were included. They were categorized into the younger (< 60 y/o, N = 1295) and the older group (≥ 60 y/o, N = 993). The 3-year overall survival (OS) rate after HSCT was significantly worse in the older group than in the other (p < 0.01, 39.9% vs. 48.5%). The 3-year non-relapse mortality (NRM) was significantly higher in the older group than in the other (p < 0.01, 30.9% vs. 23.0%), and the 3-year cumulative incidence of relapse was comparable between them. According to the multivariate analysis, age ≥ 60 years was significantly associated with poor OS and high NRM. In a subgroup analysis of the older group, the use of additional chemotherapeutic drugs to FluBu4 was significantly associated with poor OS and high NRM. Total body irradiation was significantly associated with high NRM and 1-year incidence of sinusoidal obstruction syndrome but not with OS. Thus, FluBu4 should be used with caution in older people.

Although the hematopoietic cell transplantation (HCT)-comorbidity index (HCT-CI) score is associated with an increased risk of mortality after allogeneic HCT, it remains unclear how pre-HCT liver dysfunction affects clinical outcomes. We retrospectively compared clinical HCT outcomes among four groups stratified according to the presence of HCT-CI liver and other organ scores, using a Japan transplant registry database between 2010 and 2020. Of the 14235 recipients, 1527 tested positive for an HCT-CI liver score including HBV or HCV hepatitis (n = 503). The 5-year overall survival (OS) was significantly lower in the HCT-CI liver(+) other(+) and HCT-CI liver(-) other(+) groups compared to the HCT-CI liver(+) other(-) and HCT-CI liver(-) other(-) groups [49.9% vs. 59% vs. 66.5% vs. 68.3%, p < 0.001]. A multivariate analysis showed that both the HCT-CI liver(+) other(+) [HR 1.62, p < 0.001] and HCT-CI liver(-) other(+) groups [HR 1.21, p < 0.001] were significantly associated with inferior OS. Similarly, both the HCT-CI liver(+) other(+) [HR 1.89, p < 0.001] and liver(-) other(+) groups [HR 1.26, p < 0.001] were significantly associated with an increased risk of NRM. On the other hand, the HCT-CI liver(+) other(-) group was not associated with either OS or NRM. Separately analyzing the subcohorts with or without HCT-CI other scores, the presence of an HCT-CI liver score alone did not affect survival, while the co-presence of pretransplant liver dysfunction seemed to synergistically increase the adverse impact on OS and NRM among recipients with other organ comorbidities. Further studies will be needed to identify optimal strategies for recipients with pretransplant liver dysfunction.

Influenza virus infections (IVIs) are an important cause of complications and death in immunocompromised patients, but the incidence and risk factors for IVIs in hematological diseases including benign diseases are not fully understood. We retrospectively investigated IVIs in patients with hematological diseases who visited our hematology outpatient department between 2012 and 2019. In 4,864 outpatients, 81(1.67%) IVIs were identified. The incidence of IVIs was 4.82 (95% confidence interval [CI], 3.85-5.96) per 1,000 person-years, with significantly higher rates in post-allogeneic transplant patients (21.0, 95% CI, 12.8-32.5). Progression to lower respiratory tract infection (LRTI) was observed in 7 (8.6%) of 81 patients with IVIs. In a univariate logistic regression analysis, LTRI was associated with age ≥60 years and moderate to severe chronic GVHD. Patients after hematopoietic stem cell transplantation may be at a higher risk for IVIs. Advanced age exacerbated the effects of IVIs on hematological diseases.

ABSTRACT Recent evidence indicates that the TCA cycle metabolite fumarate plays a specific role in modulating signaling pathways in immune cells. We have previously shown that dimethyl fumarate (DMF) reduces glutathione (GSH) activity and causes the accumulation of cellular reactive oxygen species (ROS), thereby compromising effector immune responses and metabolic activities in activated T‐cells. However, the precise mechanism by which DMF modulates T‐cell signaling pathways remains to be elucidated. This study demonstrates that DMF inhibits T‐cell proliferation, independent of T‐cell receptor (TCR) engagement, and this response is fully reversible by replenishing GSH. Immunoblot analysis showed that DMF had different impacts on TCR downstream signaling by decreasing MYC expression while promoting the phosphorylation of Akt and Erk1/2. Cell cycle analysis demonstrated that exposure to DMF led to negative regulation of cell cycle‐related proteins and induced T‐cells into G0/G1 arrest, which was also rescued by antioxidants. Several genes related to GSH synthesis were upregulated at the same time, suggesting that a potential compensatory response may occur to reduce oxidative burst following DMF treatment. Our results suggest that DMF‐mediated oxidative stress alters a range of cell signaling pathways, including MYC, leading to cell cycle arrest and a defective proliferative response of T‐cells during activation.

Although allogeneic hematopoietic cell transplantation (HCT) is an alternative treatment for relapsed or refractory (R/R) acute promyelocytic leukemia (APL), little is known regarding the utility of allogeneic HCT for R/R therapy-related APL (t-APL). We retrospectively analyzed data for 144 patients with APL (t-APL, n = 20 and de novo APL, n = 124) who received a first allogeneic HCT between 2008 and 2020. We found no significant differences in survival between the t-APL and de novo APL groups. The 3-year overall survival (OS) rates were 53.8% in the t-APL group and 52.4% in the de novo APL group. However, as previously reported, patients without complete remission (CR) at HCT had significantly worse OS than those with CR (P = 0.004). The 3-year OS rates were 61.1% in patients with CR and 36.5% in those without CR. These findings suggest that allogeneic HCT may be considered a viable treatment option for patients with t-APL and de novo APL, with an emphasis on achieving CR before transplantation to optimize outcomes. However, clinicians should be aware of the potential for worse outcomes in male patients and those with lower performance status, highlighting the need for personalized treatment approaches and careful patient selection.

Rapid tapering of cyclosporine (CsA) in the early phase after allogeneic transplantation may induce a potent graft-versus-leukemia/lymphoma (GVL) effect. We retrospectively reviewed the outcomes of patients with high-risk hematological malignancies who underwent their first transplantation at our institution. The blood CsA concentration was maintained at around 300 ng/ml. Our planned schedule for tapering CsA in patients without graft-versus-host disease (GVHD) or with limited GVHD was to reduce the dose by 10% per week starting from day 30 for related HSCT or from day 50 for unrelated HSCT. In total, we began tapering CsA in 36, and classified them into 2 an "On-schedule group" or "Delayed group" based on the timing of starting tapering. The cumulative incidences of grade II-IV acute GVHD overall were 33.8% and 39.4% (P = 0.746) in the On-schedule and Delayed groups. The On-schedule group showed no significant difference in non-relapse mortality, but showed a trend toward a higher relapse rate, resulting in significantly worse overall survival (55.6% vs 72.2% at 1y, P = 0.025) and worse disease-free survival (38.9% vs 66.7% at 1y, P = 0.059). These findings suggest that early CsA tapering after HSCT in high-risk patients was not effective.

BACKGROUND: Cytomegalovirus reactivation (CMV-react) is an indicator for the worse non-relapse mortality (NRM) and overall survival (OS) after allogeneic hematopoietic stem cell transplantation using HLA-matched related donor (MRD) and unrelated donor (URD) for adult T-cell leukemia/lymphoma (ATL). However, it remains unclear whether CMV-react correlates with outcomes after unrelated cord blood (U-CB) transplantation. METHODS: We conducted a retrospective nationwide study to evaluate the impact of CMV-react on the outcomes after posttransplant 100 days. Data were collected from 205, 461, and 268 patients who used MRD, URD, and U-CB, respectively, between 2001 and 2022 and survived without relapse for over 100 days after transplantation. RESULTS: In multivariate analyses, CMV-react correlated with worse OS in the MRD (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.02-2.39; p = 0.04) and URD groups (HR, 1.45; 95% CI, 1.00-2.09; p = 0.05), but not in the U-CB group (HR, 1.34; 95% CI, 0.88-2.03; p = 0.2). CMV-react correlated with higher NRM in the MRD (HR, 1.79; 95% CI, 1.01-3.16; p = 0.05) and URD groups (HR, 1.68; 95% CI, 1.01-2.82; p = 0.05), but not in the U-CB group (HR, 1.16; 95% CI, 0.62-2.19; p = 0.6). CMV-react did not correlate with the incidence of relapse in any group. CONCLUSION: CMV-react was not associated with the outcomes in the U-CB group, while CMV-react correlates with worse OS and NRM in the MRD and URD groups, indicating the need for a more intensive strategy for late-phase complications in U-CB transplantation for ATL with and without CMV-react.

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.

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.

BACKGROUND: The advantage of intensified myeloablative conditioning (MAC) over standard MAC has not been determined in haematopoietic stem cell transplantation (HSCT) for adult acute lymphoblastic leukemia (ALL) patients. METHODS: To evaluate heterogeneous effects of intensified MAC among individuals, we analyzed the registry database of adult ALL patients between 2000 and 2021. After propensity score matching, we applied a machine-learning Bayesian causal forest algorithm to develop a prediction model of individualized treatment effect (ITE) of intensified MAC on reduction in overall mortality at 1 year after HSCT. RESULTS: Among 2440 propensity score-matched patients, our model shows heterogeneity in the association between intensified MAC and 1-year overall mortality. Individuals in the high-benefit group (n = 1220), defined as those with ITEs greater than the median, are more likely to be younger, male, and to have higher refined Disease Risk Index (rDRI), T-cell phenotype, and grafts from related donors than those in the low-benefit group (n = 1220). The high-benefit approach (applying intensified MAC to individuals in the high-benefit group) shows the largest reduction in overall mortality at 1 year (risk difference [95% confidence interval], +5.94 percentage points [0.88 to 10.51], p = 0.011). In contrast, the high-risk approach (targeting patients with high or very high rDRI) does not achieve statistical significance (risk difference [95% confidence interval], +3.85 percentage points [-1.11 to 7.90], p = 0.063). CONCLUSIONS: These findings suggest that the high-benefit approach, targeting patients expected to benefit from intensified MAC, has the capacity to maximize HSCT effectiveness using intensified MAC.

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.

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.

Abstract 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 &lt;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.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for relapsed or refractory non-Hodgkin lymphoma (R/R NHL). Allo-HSCT using post-transplant cyclophosphamide (PTCY-haplo) and umbilical cord blood transplantation (uCBT) are important donor options in the absence of matched related siblings. However, the data comparing these two donor sources in R/R NHL are limited. Using the Japanese nationwide transplantation registry data, we identified 857 patients with R/R NHL, including 169 patients who received PTCY-haplo and 688 who received uCBT for their first allo-HSCT between January 2013 and December 2021; 514 patients (60%) had B-cell lymphoma. More PTCY-haplo recipients received allo-HSCT using a reduced-intensity conditioning regimen in recent years. The 3-year overall survival (OS), progression-free survival (PFS), and graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) rates in the PTCY-haplo and uCBT groups were 44% versus 39% (P = 0.326), 34% versus 33% (P = 0.660), and 19% versus 23% (P = 0.910), respectively; the adjusted hazard ratios for OS, PFS, and GRFS were 0.89 (95% confidence interval: 0.69-1.15, P = 0.373), 0.98 (0.78-1.22, P = 0.852), and 0.92 (0.83-1.21, P = 0.920), respectively. The PTCY-haplo group showed faster neutrophil and platelet engraftment and a lower incidence of grade III-IV acute GVHD. Thus, PTCY-haplo and uCBT could serve as alternative donor sources in patients with R/R NHL.

The tumor microenvironment's cells can promote or inhibit tumor formation, and there are no reports on the CD4/CD8 ratio's association with outcomes post allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively evaluated the pre-transplant peripheral blood CD4/CD8 ratio in 168 patients who underwent their first allo-HSCT for hematological malignancies at our institution. When patients were divided into two groups according to the median CD4/CD8 ratio 1.35 (range, 0.09-19.89), the high CD4/CD8 ratio group had a higher incidence of relapse, equivalent non-relapse mortality and worse overall survival (OS) than the low CD4/CD8 ratio group. In a multivariate analysis, the CD4/CD8 ratio was significantly associated with an increased risk of relapse, although there was a marginally significant difference in OS. The pre-transplant peripheral blood CD4/CD8 ratio could be a novel biomarker for predicting the prognosis of allo-HSCT.

A prospective multicenter observational study of organ response was conducted in patients with chronic GVHD diagnosed by the NIH criteria. When response was assessed at 12 months (12 M) in 118 patients, 74.6% were classified as responders and 25.4% as non-responders. The skin and oral cavity were the most frequent organs used as the basis for determining overall response. The lungs, liver, and eyes were also used in 20% of patients. Non-response decisions at 12 M were most frequent in the lungs. A significantly higher percentage of responders than non-responders completed systemic treatment (24.3% vs. 3.3%, P = 0.02). Global scoring showed significant changes, with improvement in responders and worsening in non-responders throughout the observation period. Two-year transplant-related mortality, using the 12 M assessment as the landmark, was significantly worse in non-responders (28.5% vs. 2,7%, P = 0.0001), while the 2-year recurrence rate was equivalent (5.4% vs. 4.8%, P = 0.78). Consequently, the 2-year overall survival rate from the 12 M assessment was significantly better in responders than non-responders (95% vs. 65.3%, P = 0.0001). Our data suggests that patients who do not achieve a response within the first year should be candidates for clinical studies on chronic GVHD.

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.

The impact of absolute neutrophil count (ANC) before allogenic hematopoietic stem cell transplantation (HSCT) on the outcomes for patients with aplastic anemia (AA) remains unclear. We retrospectively evaluated the relationship between ANC before transplantation and patient outcomes, involving 883 adult Japanese patients with AA who underwent allogeneic HSCT as their first transplantation between 2008 and 2020. Patients were divided into three groups based on ANC: 0/µL (n = 116); 1-199 (n = 210); and ≥ 200 (n = 557). In the low ANC groups (ANC < 200), patient age was higher, previous anti-thymocyte globulin (ATG) treatments were infrequent, duration from diagnosis to transplantation was shorter, hematopoietic cell transplantation-comorbidity index (HCT-CI) was higher, ATG-based conditioning was used infrequently, and peripheral blood stem cell from related donor and cord blood were used frequently. In multivariate analysis, patient age, previous ATG treatment, HCT-CI, stem cell source, and ANC before transplantation were significantly associated with 5-year overall survival (OS) ("ANC ≥ 200": 80.3% vs. "ANC 1-199": 71.7% vs. "ANC 0": 64.4%). The cumulative incidence of bacterial infection, invasive fungal disease, and early death before engraftment were significantly higher in the low ANC groups. Among patients with ANC of zero before transplantation, younger patient age, shorter duration from diagnosis to transplantation, HCT-CI of 0, and bone marrow from related donor as stem cell source were significantly associated with better OS. Consequently, ANC before allogeneic HSCT was found to be a significant prognostic factor in adult patients with AA. Physicians should pay attention to ANC before transplantation.