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This 3+3 dose-escalation phase I multicenter study investigated the optimal dose of azacitidine (AZA) for post-hematopoietic stem cell transplantation (HSCT) maintenance, which remains unknown in Japan. Recipients of a first HSCT for high-risk myelodysplastic syndromes (MDS, n = 12) or acute myeloid leukemia (AML) with antecedent MDS (n = 3) received post-HSCT AZA maintenance in 2015-2019. The optimal AZA dose was defined as the dose at which 50-70% of patients can complete four cycles without dose-limiting toxicity (DLT). The initial dose level 1 was set as 30 mg/m

Outcomes in patients with acute lymphoblastic leukemia (ALL) who experience relapse after allogeneic hematopoietic cell transplantation (HCT) are unsatisfactory. This study aimed to evaluate the outcomes of patients with ALL who underwent second HCT (HCT2) for relapse after first HCT. It was a single-center retrospective study including adult patients with ALL who underwent HCT2 between 1991 and 2020. The cohort was stratified according to the transplant year, and included 39 patients with a median age of 29 years. A more recent transplant year was associated with achievement of complete remission (CR) and use of reduced-intensity conditioning (RIC), compared with an earlier transplant year. The overall survival (OS) rate and 2-year cumulative incidence of non-relapse mortality (recent vs. earlier) were 55% vs. 8% (P 0.001) and 26% vs. 75% (P 0.001), respectively. In multivariate analysis, non-CR (vs. CR; HR 3.6, 95% CI 1.2-11.3, P = 0.025) and myeloablative conditioning (vs. RIC; HR 3.5, 95% CI 1.3-9.4, P = 0.011) were negative prognostic factors for OS. Outcomes of the recent cohort from real-world data are promising, and achieving CR and using the RIC regimen at HCT2 may be an important therapeutic strategy.

The introduction of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) treatment has dramatically improved the prognosis of CML patients and reduced the number of patients receiving allogeneic stem cell transplantation (allo-SCT). However, the impact of the newest-generation TKIs on the overall survival (OS) after allo-SCT has not been well described. To investigate the beneficial effects of TKIs on the prognosis after allo-SCT, we conducted a retrospective observational study using the Transplant Registry Unified Management Program database in Japan. We analyzed 1188 patients (male/female: 738/450; median age: 44 years; range: 16-75) who underwent their first allo-SCT between January 2001 and December 2018. We divided the patients into two groups according to the TKI treatment used before allo-SCT: group 1 was treated with the first generation TKI imatinib; group 2 was treated with the second generation TKIs nilotinib, dasatinib, or bosutinib and/or the third generation TKI ponatinib. We compared the post allo-SCT OS between the two groups. The 3-year OS rates (95%CI) of groups 1 and 2 were 59.3% (54.8%-63.5%) and 65.8% (61.6%-69.6%), respectively (p = 0.017). Multivariate analysis confirmed that group 2 had superior OS after allo-SCT compared to group 1 (p = 0.002). Other factors associated with superior prognosis were age ≤65, performance status (PS) 0/1, a 6/6 HLA-matched donor and chronic-phase (CP) disease status at allo-SCT. A subgroup analysis showed poor prognoses for patients who could not obtain a molecular response before allo-SCT and patients with positive T315I mutation in the BCR/ABL gene. In group 2, early allo-SCT was correlated with superior OS in patients with a blast-crisis disease status at allo-SCT (p = 0.001). The cumulative incidence of non-relapse mortality rate significantly decreased in group 2 (p = 0.0005). The post allo-SCT OS was improved both by pre- and post-management of allo-SCT and by the introduction of newer TKIs.

The efficacy and clinical significance of pre-conditioning intervention (PCI) before allogeneic hematopoietic cell transplantation (HCT) in patients with acute lymphoblastic leukemia (ALL) not in remission remain inconclusive. The purpose of this multicenter retrospective study was to clarify the clinical significance of PCI before HCT in patients with non-remission ALL. Patients with non-remission ALL who received HCT between 2005 and 2015 at 16 institutions were included. PCI was objectively defined and classified to three groups according to the intensity of PCI (no, intensive, or moderate). The study cohort consisted of 104 patients with a median age of 38 (range 17–68). A significant decrease of blast percentage in the peripheral blood (PB) was confirmed in both PCI groups, suggesting that PCIs were effective to stabilize the disease activity. The group with moderate PCI had higher nucleated cell count in the BM compared to the group with intensive PCI or the group without PCI. The overall survival (OS) rates of groups with intensive and no PCI showed comparable and significantly better compared to the group with moderate PCI (P = 0.009). Multivariate analysis demonstrated that the OS of moderate PCI group was significantly worse compared to that of intensive PCI group (HR = 2.43, 95% CI: 1.32–4.14, P = 0.004), while the OS of intensive PCI group was comparable to that of the group without PCI. These results suggest that the intensity of PCI rather than the response to PCI may contribute to improve the transplant outcome in patients with ALL not in remission.

This study aimed to evaluate the impact of standard-dose dipeptidyl peptidase-4 inhibitors (DPP-4i) on the incidence of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). We retrospectively evaluated 207 diabetes mellitus patients undergoing allogeneic HCT between 2010 and 2019. The 100-day cumulative incidences (CI) of grade II–IV acute GVHD (aGVHD) in patients who took DPP-4i from day − 1 to 14, those who did not, and those who discontinued DPP-4i within 10 days after HCT because of difficulty taking the medicine were 33.9%, 32.8%, and 60.0% (P = 0.063), respectively. With regard to chronic GVHD (cGVHD), taking DPP-4i between days 21 and 60 was associated with a trend toward lower incidence of cGVHD (1-year CI: 25.4% vs. 35.6%, P = 0.094). In a multivariate analysis, the administration of DPP-4i between days 21 and 60 was significantly associated with lower incidence of cGVHD (hazard ratio 0.53, 95% confidence interval 0.30–0.96, P = 0.035). It was difficult to interpret the impact of standard-dose DPP-4i on the development of aGVHD since an inability to continue oral medication was significantly associated with higher incidence of aGVHD. On the other hand, taking DPP-4i over days 21–60 may suppress the development of cGVHD.

Chromosomal abnormalities in the role of prognostic factor for transplant patients with myelofibrosis (MF) are not fully investigated. Regarding complex karyotype (CK), we retrospectively analyzed 241 patients with primary and secondary MF who received a first allogeneic hematopoietic cell transplantation (HCT). Based on an unfavorable karyotype in the Dynamic International Prognostic Scoring System, we compared the outcomes in 3 groups: favorable karyotype, unfavorable karyotype including CK (unfavorable-CK(+)), and unfavorable karyotype not including CK (unfavorable-CK(-)). Overall survival was significantly shorter in the unfavorable-CK(+) group (hazard ratio (HR) 2.49, 95% CI: 1.46-4.24, P 0.001), whereas there was no difference between the unfavorable-CK(-) group and the favorable group (HR 0.57, 95% CI: 0.20-1.59, P = 0.28). In addition, a significantly higher proportion of patients in the unfavorable-CK(+) group did not achieve complete remission after HCT (P = 0.007). The cumulative incidence of disease progression was significantly higher in the unfavorable-CK(+) group (HR 2.5, 95% CI 1.6-3.92, P 0.001), whereas that in the unfavorable-CK(-) group was comparable to that in the favorable group (HR 0.49, 95% CI 0.12-1.94, P = 0.31). Further investigations will be needed to clarify the impact of CK on transplant outcomes in MF.

To date, there are no data focusing on outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U). This study aimed to evaluate outcomes and prognostic factors in patients with MDS/MPN-U after allo-HSCT using Japanese nationwide registry data. The primary endpoint was 3-year overall survival (OS); secondary endpoints included the cumulative incidence of relapse and nonrelapse mortality (NRM). We evaluated the prognostic factors for 3-year OS by univariate analysis using the log-rank test. In our cohort of 86 patients with MDS/MPN-U, we found a 3-year OS of 48.5%, cumulative incidence of relapse of 23.7%, and NRM of 26.3%. The 3-year OS was significantly worse in patients age ≥50 years compared with those age50 years (38.1% versus 65.0%; P = .049) and in patients with disease progression compared with those without disease progression (28.4% versus 57.2%; P = .042). Our results suggest that allo-HSCT may offer a curative option for patients with MDS/MPN-U, and that age and disease status could be important indicators in helping clinicians determine treatment options for these patients.

Allogeneic peripheral blood stem cell transplantation (PBSCT) is associated with an increased risk of severe acute and chronic graft-versus-host disease (GVHD) compared to bone marrow transplantation. Anti-thymocyte globulin (ATG) can reduce severe acute and chronic GVHD in PBSCT; however, an optimal dose of ATG remains undefined. We conducted a multicenter phase II study to investigate safety and efficacy of low-dose ATG (a total of 2 mg/kg Thymoglobulin) in patients undergoing HLA-matched PBSCT after myeloablative conditioning. The primary endpoint was grades III–IV GVHD at 100 days. Seventy-seven patients were enrolled and 72 patients with a median age of 46.5 years were eligible for analysis. The primary endpoint, cumulative incidence of grades III–IV acute GVHD at 100 days was 1.4% (95% CI, 0.1–6.7%), which was greatly less than our pre-defined statistical threshold value (18.0%). The incidence of chronic GVHD at 1 year was also low (all-grade; 15.3%, moderate to severe; 5.6%). Non-relapse mortality, relapse, overall survival, disease-free survival, and GVHD-free, relapse-free survival at 1 year were 4.2%, 20.8%, 84.7%, 75.0%, and 69.4%, respectively. Low dose thymoglobulin is promising to reduce severe acute and chronic GVHD in HLA-matched PBSCT following myeloablative conditioning.

A multicenter retrospective study was performed to evaluate the prognostic factors in 104 patients with relapsed or refractory acute lymphoblastic leukemia (ALL), who underwent allogeneic hematopoietic cell transplantation (HCT) between 2005 and 2015. The median age was 38 (range, 17 to 68), and the median blast fraction in peripheral blood and bone marrow was 1% (range, 0 to 99%) and 52% (range, 0 to 100%), respectively. With a median follow-up of 47 months (range, 8.3 to 105 months), overall survival (OS), nonrelapse mortality, and relapse mortality at 1 year were 25%, 44%, and 31%, respectively. Multivariate analysis demonstrated independent predictors for poor OS, including nuclear cell count in the bone marrow ≥10 × 104/μL (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.33 to 3.43; P = .002), elevated lactate dehydrogenase level (HR, 1.66; 95% CI, 1.05 to 2.62; P = .031), and no primary induction failure (HR, 2.05; 95% CI, 1.11 to 3.78; P = .022). A prognostic scoring index was designed based on these survival predictors. At 2 years, OS was 28%, 14%, and 0% for good (score 0 or 1; n = 47), intermediate (score 2; n = 40), and poor (score 3; n = 17), respectively (P

A soluble form of suppression of tumorigenicity 2 (sST2) has emerged as a biomarker for acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM). We prospectively monitored sST2 levels during the early phase of hematopoietic stem cell transplantation (HSCT) and evaluated the clinical association with transplant-related complications including acute GVHD.Thirty-two adult Japanese patients who received a first allogeneic HSCT were enrolled in this study. Levels of sST2 were measured at fixed time points (pre-conditioning, day 0, day 14, day 21, and day 28).The median age was 50.5 years (range=16-66). With a median follow-up of 21.5 months (range=0.9-35.4), 9 patients developed grade II-IV acute GVHD. Median sST2 levels on the day of HSCT were higher than baseline and reached the maximum value (92.7 ng/mL; range=0-419.7) on day 21 after HSCT. The optimal cut-off value of sST2 on day 14 for predicting grade II-IV acute GVHD was determined as 100 ng/mL by ROC analysis. The cumulative incidence of acute GVHD was 56.7% and 16.5% in the high- and low-sST2 groups, respectively (p0.01). Multivariate analyses showed that high sST2 levels at day 14 were associated with a higher incidence of acute GVHD (hazard ratio=9.35, 95% confidence interval=2.92-30.0, p0.01). The cumulative incidence of NRM was increased in the highs-ST2 group (33% vs 0%, p0.01), but all the patients died of non-GVHD complications. Among 6 patients in the high-sST2 group without grade II-IV GVHD, 5 patients developed veno-occlusive disease (VOD) and one also had thrombotic microangiopathy (TMA).The early assessment of sST2 after HSCT yielded predictive values for the onset of acute GVHD and other transplant-related complications including VOD and TMA.Akut graft-konakçı hastalığı (GVHD) ve relaps dışı mortalite (NRM) için bir biyobelirteç olarak, tümör oluşumu 2’nin baskılanmasının (sST2) çözünür bir formu ortaya konulmuştur. Hematopoietik kök hücre transplantasyonunun (HSCT) erken safhasında sST2 düzeylerini prospektif olarak izledik ve akut GVHD dahil transplantla ilişkili komplikasyonlarla klinik ilişkisini değerlendirdik.Bu çalışmaya ilk allojenik HSCT’si olan 32 yetişkin Japon hasta alındı. sST2 seviyeleri sabit zaman noktalarında (hazırlık rejimi öncesi, 0. gün, 14. gün, 21. gün ve 28. gün) ölçüldü.Ortanca yaş 50,5 idi (aralık=16-66). Ortalama 21,5 aylık takip süresi (aralık= 0,9-35,4) ile 9 hastada Grade II-IV akut GVHD gelişti. Nakil gününde ortanca sST2 seviyeleri bazal değerlerden daha yüksekti ve HSCT’den sonraki 21. günde maksimum değere (92,7 ng/mL; aralık=0-419,7) ulaştı. Grade II-IV akut GVHD’yi tahmin etmek için 14. günde sST2’nin optimal eşik değeri, ROC analizi ile 100 ng/mL olarak belirlenmiştir. Akut GVHD’nin kümülatif insidansı yüksek ve düşük sST2 gruplarında sırasıyla %56,7 ve %16,5 idi (p0,01). Çok değişkenli analizler 14. günde yüksek sST2 düzeylerinin daha yüksek akut GVHD insidansı ile ilişkili olduğunu göstermiştir (tehlike oranı=9, 35, %95 güven aralığı=2,92-30,0, p0,01). NRM’nin kümülatif insidansı yüksek sST2 grubunda artmıştır (%33’e karşı %0, p0,01), ancak tüm hastalar GVHD dışı komplikasyonlardan öldü. Yüksek sST2 grubunda grade II-IV GVHD olmayan 6 hastadan 5’inde veno-oklüzif hastalık (VOD) gelişti ve birinde trombotik mikroanjiyopati (TMA) vardı.HSCT sonrası sST2’nin erken değerlendirmesi, akut GVHD’nin başlangıcı ve VOD ve TMA dahil transplantla ilişkili diğer komplikasyonlar için prediktif değerler vermiştir.

We evaluated the kinetics of immune reconstitution (IR) after allogeneic hematopoietic cell transplantation (HSCT) and analyzed the clinical effect of IR on posttransplant outcomes. Absolute lymphocyte and its subset counts were measured using flow cytometry on days 28, 100, 180, 365, and 730 after transplantation in 358 adult patients who underwent HSCT between 2009 and 2017. On day 100 after HSCT, 310 surviving patients were analyzed. Bone marrow transplantation (BMT), peripheral blood stem cell transplantation (PBSCT), and cord blood transplantation (CBT) were performed in 119, 55, and 136 patients, respectively. Mature B-cell and differentiated natural killer (NK) cell subset counts significantly increased after CBT. The 2-year overall survival (OS), nonrelapse mortality (NRM), cumulative incidence of relapse, and chronic GVHD in BMT, PBSCT, and CBT were 62%, 67%, and 76% (P = .021); 17%, 17%, and 13% (P = .82); 33%, 40%, and 27% (P = .063); and 43%, 45%, and 28% (P = .025), respectively. Multivariate analysis showed that higher CD16+CD57− NK cell counts correlated with lower disease relapse, whereas higher CD20+ B-cell counts correlated with lower NRM. OS-favoring factors were higher CD16+CD57− NK cell count (hazard ratio, 0.36; 95% confidence interval, 0.22-0.60; P < .001) and CD20+ B-cell count (hazard ratio, 0.53; 95% confidence interval, 0.30-0.93; P < .001) and lower Disease Risk/HCT-Specific Comorbidity index score. Collective contribution of graft source-specific and event-related immune reconstitution might yield better posttransplant outcomes in CBT.

To prospectively validate the incidence, manifestations, and outcomes of graft-versus-host disease (GVHD) by National Institutes of Health criteria, we recruited 406 hematopoietic stem cell transplantation recipients at 16 transplant centers in Japan from May 2012 to June 2014. The 2-year cumulative incidence of late acute and chronic GVHD was 3.2% (n = 13) and 35.4% (n = 145), with a median onset of 3.6 and 4.7 months after transplant, respectively. The global severity at onset was mild in 30.3%, moderate in 43.5%, and severe in 26.2%. Eighty-two patients were followed up for 2 years, with 79.3% still manifesting GVHD symptoms, and 80.6% (n = 117) of the patients received systemic immunosuppressive treatment (IST), with a 2-year cumulative incidence of IST termination of 33.1%. Severe patients showed a significantly lower rate of IST termination than those with mild and moderate severities (mild, 38.5%; moderate, 40.9%; and severe, 17.2%). The 2-year incidence of nonrelapse mortality (NRM) and relapse was not significantly different according to the severity at onset (NRM: mild [16.6%] versus moderate [8.7%] versus severe [16.1%]; relapse: mild [14.9%] versus moderate [14.7%] versus severe [5.3%]). As a result, 2-year overall survival (OS) and GVHD-specific survival (GSS) were equivalent according to the severity at onset (mild: OS = 81.0%, GSS = 85.7%; moderate: OS = 84.2%, GSS = 92.5%; severe: OS = 83.9%, GSS = 89.2%). Our study helped identify the characteristics of late acute and chronic GVHD in Japanese patients. Further investigation is needed to identify an optimal endpoint for survival prediction.

Cytomegalovirus (CMV) reactivation and natural killer (NK) cell reconstitution are well-recognized immunologic events occurring after allogeneic stem cell transplantation (allo-SCT). We aimed to study the outcome of CMV reactivation (CMVR) and NK cell reconstitution in patients with hematologic malignancies after allo-SCT. We retrospectively studied 246 adult patients (152 men, 94 women; median age, 51 years [range, 18 to 69]) who underwent allo-SCT for hematologic malignancies at the Kanagawa Cancer Center. CMVR was defined as initiation of preemptive CMV therapy after pp65 antigenemia surveillance. All patients' lymphocyte subsets were monitored by flow cytometry at 180, 365, and 730 days post-transplant. The median follow-up period was 3.2 years (range, .8 to 9.6 years). CMVR occurred in 141 patients (57%) at a median of 45 days (range, 15 to 93). In patients without CMVR (CMVR-) versus those with CMVR (CMVR+), 5-year overall survival (OS), nonrelapse mortality (NRM), and cumulative incidence of relapse (CIR) were 79% versus 55% (P.001), 3% versus 16% (P = .012), and 28% versus 38% (P = .09), respectively. CD8

The global standard therapy for chronic myeloid leukemia (CML) is tyrosine kinase inhibitors (TKIs). One of the causes of therapeutic resistance to some TKIs corresponds to point mutations in the BCR-ABL1 fusion gene. Allogeneic hematopoietic cell transplantation (HCT) is a treatment option for high-risk CML, including TKI resistance. Although BCR-ABL1 point mutations comprise a major factor in the assessment of the indications for HCT, there is limited evidence for their significance in relation to transplant outcomes. This study aimed to evaluate the profiles and transplant outcomes of BCR-ABL1 mutations in allografted patients with CML. The retrospective study used a nationwide registry data including adult patients with CML who underwent their first HCT between 2006 and 2016. The inclusion criterion was the evaluation of the status of the BCR-ABL1 mutation before HCT. The cohort included 315 patients with a median age of 44 years (range 16-70 years). Point mutations were detected in 152 patients, of which 101 (66%) harbored T315I mutations and 51 harbored mutations other than T315I (non-T315I). With a median follow-up period of 38 months (range 2-114 months), overall survival (OS) at 3 years was worse in the mutation group than in the no-mutation group (53% versus 71%; P = .002), which was validated by multivariate analysis (hazard ratio [HR] = 1.50; 95% confidence interval [CI], 1.0-2.2; P = .038); this difference was remarkable in the chronic phase of CML. OS in the non-T315I group was significantly worse than that in the no-mutation group (HR = 1.69; 95% CI, 1.0-2.8; P = .035). The nationwide study has successfully evaluated the BCR-ABL1 mutational profile and its outcomes in patients with CML who received HCT. The mortality risk was significantly higher in patients with the BCR-ABL1 mutation than in patients without the mutation. These findings would be useful to understand the clinical significance of various BCR-ABL1 mutations in CML and provide insight into the on mid need for treatment strategies for cases of CML with BCR-ABL1 mutations.

Even in the era of high-intensity chemotherapy, disease recurrence remains a major cause of treatment failure in adult patients with Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (Ph-negative B-ALL). For patients who achieved second complete remission (CR2) with salvage chemotherapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be the best curative treatment. However, limited data are available on the outcomes of allo-HSCT for adult Ph-negative B-ALL in CR2 in the high-intensity chemotherapy era. We evaluated the transplantation outcomes of adult patients with Ph-negative B-ALL in CR2 compared with those in CR1. We also clarified the prognostic factors among adult allo-HSCT recipients with Ph-negative B-ALL in CR2. We conducted a nationwide retrospective study using the data form Japanese transplant registry database. Patients aged ≥16 years and underwent their first allo-HSCT between 2003 and 2017 were included. The 3-year overall survival (OS) rate of the patients in CR2 (n = 382) was significantly lower than that in first complete remission (n = 1375) (51.8% versus 68.1%; P.001), accompanied by a higher relapse rate (34.2% versus 17.6% at 3 years; P.001). In a multivariate analysis among CR2 patients, time from diagnosis to allo-HSCT (≤2 years) was a significant factor for OS (hazard ratio [HR] 1.87; P.001) and relapse (HR = 1.88; P.001), whereas age at allo-HSCT (≥30 years) was a significant factor for OS (HR = 2.10, P.001) and nonrelapse mortality (HR = 2.68; P.001). By assigning a score of 1 to each factor, the 3-year OS rate of CR2 patients significantly stratified: 70.7% in patients with score 0, 56.4% with score 1, and 28.4% with score 2 (P.001). The survival outcomes of allo-HSCT in adult Ph-negative B-ALL patients in CR2 were inferior to those in CR1 in the high-intensity chemotherapy era, mainly because of the higher relapse rate. Among the CR2 patients, the short time between diagnosis and allo-HSCT was a significant risk factor for disease recurrence and overall mortality. Better disease control with novel treatment strategies may be needed for early relapse. In addition, the nonrelapse mortality rate in patients over 30 years of age was particularly high among CR2 patients, suggesting the need for improved supportive care for these patients. Further studies are warranted on the outcomes of allo-HSCT after achieving CR2 with novel drugs, such as inotuzumab ozogamicin and blinatumomab.

Smoking is associated with a high risk for different diseases including respiratory tract infections in immunocompetent patients. However, data about the effects of cigarette smoking on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are limited. Therefore, we retrospectively investigated 608 patients aged ≥20 years with hematological disorders who received their first allo-HSCT at our group of hospitals between 2000 and 2015, and evaluated the impact of cigarette smoking before allo-HSCT on clinical outcomes by dividing patients into two groups according to the Brinkman index (BI) (nonsmokers or light smokers [BI: 0-500] and heavy smokers [BI: ≥ 500]). Multivariate analyses showed that heavy smoking was associated with a high 5-year cumulative incidence of chronic graft-versus-host disease (cGVHD) (hazard ratio [HR]: 1.73, 95% confidence interval [CI]: 1.15-2.61, p 0.01). The 5-year overall survival (HR: 1.16, 95% CI: 0.86-1.58, p = 0.33) and disease-free survival (HR: 1.12, 95% CI: 0.83-1.52, p = 0.45) were similar between the two groups. Hence, cigarette smoking is correlated with cGVHD, although prospective studies must be conducted to further verify this result.

The most significant prognostic factor in allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) is the remission status at HCT. Although HCT is recommended to be performed after complete remission, there are cases in which HCT is performed in non-remission status. Although the outcomes of HCT for non-remission AML have been very poor, the subjects in these studies had heterogeneous backgrounds in terms of relapsed, refractory, and untreated AML. In this review article, non-remission AML is classified into the following two categories: refractory/relapsed AML and untreated AML. Recent advances in HCT for non-remission AML, such as prognostic factors and pre and postHCT interventions, have been summarized. In the preHCT setting, preHCT tumor burden was confirmed to be the primary prognostic factor. Preconditioning intervention that successfully eliminated blasts in the peripheral blood was associated with better outcomes after HCT. PostHCT maintenance therapy may be one of the treatment options after HCT. Even in untreated AML, lower tumor burden at HCT was associated with superior outcomes after HCT. With the primary significance of tumor control before and after HCT, it is crucial to establish a comprehensive strategy for HCT in the non-remission stage, including preHCT and postHCT interventions.

To evaluate the prognostic impact of melphalan dose and total body irradiation (TBI) in acute lymphoblastic leukemia (ALL) patients undergoing reduced-intensity allogeneic transplantation, we retrospectively compared the outcomes between higher-dose melphalan (120-140 mg/m

The optimal dose, schedule, and other aspects of bendamustine plus rituximab treatment remain unclear for patients with relapsed or refractory follicular lymphoma (FL). Herein, we analyzed the efficacy of bendamustine combined with rituximab (RB-120) treatment for Japanese patients with relapsed or refractory FL. This phase II clinical trial included patients with relapsed or refractory FL who received 375 mg/m2 rituximab on day 1 and 120 mg/m2 bendamustine on days 2 and 3 every 28 days for up to 6 cycles. The primary endpoint was the overall response rate (ORR), and the secondary endpoints included the complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and safety. Thirty-seven patients were enrolled in the trial (median age 62 years, range 42–75 years). All patients were previously treated with rituximab-containing chemotherapy, and 83.8% were previously treated with the R-CHOP regimen. A median of 5 cycles (range 1–6) and 48.6% of patients completed 6 cycles. The ORR was 91.9% (95% confidence interval [CI] 78.1–98.3%), with a CR rate of 86.5% (95% CI 71.2–95.5%). The 3-year PFS and OS were 70.9% (95% CI 52.3–83.3%) and 88.9% (95% CI 73.1–95.7%), respectively, with the median 39.5 months follow-up duration. The most-frequently observed grade 3/4 adverse events were hematologic: lymphopenia (95%) and neutropenia (70%). No treatment-related deaths were observed. RB-120 showed a good efficacy with equivalent toxicities, compared with the bendamustine 120 mg/m2 monotherapy. However, the problem of high drop-out incidences cannot be ignored.

A multicenter retrospective study was performed to explore a prognostic scoring index in order to identify a population who are least likely to benefit from allogeneic hematopoietic cell transplantation (HCT) in patients with relapsed or refractory acute myeloid leukemia (AML). The cohort included 519 patients with AML, who received HCT between 2005 and 2015 at a status of relapse or primary induction failure. Multivariate analysis demonstrated five independent predictors for OS, including C-reactive protein ≥ 1 mg/dL, peripheral blood blast fraction ≥ 20%, poor-risk karyotype, performance status ≥ 2, and bone marrow unrelated donor as a stem cell source. A prognostic scoring index was explored based on these predictors, and successfully separated the cohort into four groups. At 2 years, OS was 47%, 24%, 8%, and 0% for Good (Score 0, 1: n = 118), Intermediate-1 (Score 2: n = 75), Intermediate-2 (Score 3: n = 39), and Poor (Score 4: n = 24), respectively (P

Though second allogenic haematopoietic stem cell transplantation (HSCT) is considered a curative treatment option after myelodysplastic syndrome (MDS) relapse, scant epidemiological data are available. We investigated the outcomes and prognostic factors of second allogenic HSCT in 99 patients with MDS who relapsed after the first HSCT. The median age was 53 years (interquartile; 45-59) and 57 patients (57·6%) were male. Five-year overall survival was 25·3%. Early relapse (adjusted hazard ratio: 2·78, 95% confidence interval: 1·08-7·21, P = 0·035) and poor performance (3·03, 1·71-5·37, P < 0·001) were associated with a significantly poor 5-year overall survival compared to the other groups (P < 0·001).

This single-center retrospective study was performed in consecutive patients with acute lymphoblastic leukemia who relapsed after allogeneic hematopoietic cell transplantation (HCT) and received salvage therapy using inotuzumab ozogamicin (InO). Ten patients (median age: 27 years) treated between June 2018 and July 2020 who met the eligibility criteria were included in this study. Nine patients received InO in one cycle and seven of these patients achieved complete hematological remission after salvage chemotherapy including InO. Negative minimal residual disease was confirmed in all four evaluable patients. Eight patients were successfully bridged to the subsequent HCT. After HCT, veno-occlusive disease (VOD) developed in three patients, and caused the death of one. No patient received maintenance therapy. At present, five patients are disease-free and alive, and the overall and progression-free survival rates at 1 year were 60% and 40%, respectively. High rates of disease remission and bridging to HCT with comprehensive treatments including InO may have contributed to favorable outcomes. However, further investigation is needed to reduce post-HCT complications including VOD.

Chronic myeloid leukemia (CML) is a form of myeloproliferative neoplasm caused by the oncogenic tyrosine kinase BCR-ABL. Although tyrosine kinase inhibitors have dramatically improved the prognosis of patients with CML, several problems such as resistance and recurrence still exist. Immunological control may contribute to solving these problems, and it is important to understand why CML patients fail to spontaneously develop anti-tumor immunity. Here, we show that differentiation of conventional dendritic cells (cDCs), which are vital for anti-tumor immunity, is restricted from an early stage of hematopoiesis in CML. In addition, we found that monocytes and basophils, which are increased in CML patients, express high levels of PD-L1, an immune checkpoint molecule that inhibits T cell responses. Moreover, RNA-sequencing analysis revealed that basophils express genes related to poor prognosis in CML. Our data suggest that BCR-ABL not only disrupts the “accelerator” (i.e., cDCs) but also applies the “brake” (i.e., monocytes and basophils) of anti-tumor immunity, compromising the defense against CML cells.

White blood cell count (WBC) at diagnosis is the conventional prognostic factor in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Nevertheless, little is known about the impact of WBC at diagnosis considering the minimal residual disease (MRD) status at allogeneic hematopoietic cell transplantation (HCT). We evaluated adult patients with Ph+ ALL who achieved negative-MRD and received HCT in first complete remission between 2006 and 2018. The entire cohort was temporally divided into derivation (n = 258) and validation cohorts (n = 366). Using a threshold of 15,000/μL, which was determined by a receiver operating characteristic curve analysis in the derivation cohort, high WBC was associated with an increased risk of hematological relapse in both the derivation cohort (25.3% vs. 11.6% at 7 years, P = 0.004) and the validation cohort (16.2% vs. 8.5% at 3 years, P = 0.025). In multivariate analyses, high WBC was a strong predictor of hematological relapse in the derivation cohort (HR, 2.52, 95%CI 1.32-4.80, P = 0.005) and in the validation cohort (HR, 2.32, 95%CI, 1.18-4.55; P = 0.015). In conclusion, WBC at diagnosis with a new threshold of 15,000/μL should contribute to better risk stratification in patients with negative-MRD at HCT.

Molecular relapse after allogeneic hematopoietic cell transplantation (allo-HCT) has been thought to predict clinical relapse in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (PhALL). Tyrosine kinase inhibitor (TKI) administration after allo-HCT may dynamically change the status from molecular relapse to molecular remission, but these state changes cannot be accurately represented by conventional survival indicators such as relapse-free survival, where events are usually considered irreversible. We aimed to develop novel indicators of transplant outcomes for allo-HCT recipients with PhALL and to visualize current molecular-relapse-free survival (CMRFS) and current on-TKI status (CTKI), treating molecular relapse or TKI administration after allo-HCT as a reversible event. We retrospectively analyzed 286 patients with PhALL who received allo-HCT between 2000 and 2016 in order to develop the indicators. CMRFS was defined as the probability of molecular remission without clinical relapse or death at any time after allo-HCT. Similarly, CTKI was defined as the probability of TKI administration without clinical relapse or death at any time after allo-HCT. The 1- and 5-year CMRFS rates were 67% and 59%, respectively, whereas the 1- and 5-year conventional molecular relapse-free survival rates were 42% and 37%. The 1- and 5-year CTKI rates were 14% and 8%, respectively. In a post hoc analysis focusing on patients who had achieved a molecular complete remission within 6 weeks (n = 201), the 5-year CMRFS rate (71%) was similar to the 5-year conventional molecular relapse-free survival (molRFS) rate (70%) in the non-TKI group. On the other hand, the 5-year CMRFS rate in the TKI group was 61%, whereas the 5-year conventional molRFS rate was only 38%. CMRFS and CTKI might become useful indicators of transplant success in terms of survival, leukemia-free status, and treatment-free status at any time point. Future extension of these survival models to other clinical situations is warranted.

The prognostic impacts of BCR-ABL1 fusion gene mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) remain unknown. Using data from a nationwide Japanese registry, we have evaluated the prognostic impact of BCR-ABL1 mutations prior to the first allogeneic hematopoietic cell transplantation (HCT). The cohort included 289 patients with a median of 48 years of age (range: 16-70). Point mutations were detected in 110 patients. Of these, 90 (82%) harbored T315I mutations, while 20 had other mutations. With a median follow-up period of 29 months (range: 1-125), outcomes after 2 years were worse with mutations than without (overall survival [OS]: 34% vs 68%, p < 0.001; relapse rate [RR]: 48% vs 18%, p < 0.001), particularly with the presence of the T315I mutation (OS: 29% vs 68%, p < 0.001; RR: 54% vs 18%, p < 0.001). OS was significantly worse in the T315I group even among the cohort with hematological (p < 0.001) or molecular complete remission (p = 0.025) as compared to the no mutation group. Multivariate analysis determined the prognostic impact of the T315I mutation (OS: hazard ratio [HR] = 2.19, 95% confidence interval [CI]: 1.5-3.3, p < 0.001; RR: HR = 2.51, 95% CI: 1.5-4.2, p < 0.001). This study is the first to report on the prognostic significance of BCR-ABL1 mutations in Ph + ALL.

Allogeneic peripheral blood stem cell transplantation (PBSCT) is associated with an increased risk of severe acute and chronic graft-versus-host disease (GVHD) compared to bone marrow transplantation. Anti-thymocyte globulin (ATG) can reduce severe acute and chronic GVHD in PBSCT; however, an optimal dose of ATG remains undefined. We conducted a multicenter phase II study to investigate safety and efficacy of low-dose ATG (a total of 2 mg/kg Thymoglobulin) in patients undergoing HLA-matched PBSCT after myeloablative conditioning. The primary endpoint was grades III-IV GVHD at 100 days. Seventy-seven patients were enrolled and 72 patients with a median age of 46.5 years were eligible for analysis. The primary endpoint, cumulative incidence of grades III-IV acute GVHD at 100 days was 1.4% (95% CI, 0.1-6.7%), which was greatly less than our pre-defined statistical threshold value (18.0%). The incidence of chronic GVHD at 1 year was also low (all-grade; 15.3%, moderate to severe; 5.6%). Non-relapse mortality, relapse, overall survival, disease-free survival, and GVHD-free, relapse-free survival at 1 year were 4.2%, 20.8%, 84.7%, 75.0%, and 69.4%, respectively. Low dose thymoglobulin is promising to reduce severe acute and chronic GVHD in HLA-matched PBSCT following myeloablative conditioning.

A single-center retrospective study was performed with consecutive patients who received salvage therapy using ponatinib for the aim of allogeneic hematopoietic cell transplantation (HCT) for relapsed or refractory Ph-leukemia between January 2017 and July 2018. A total of ten patients-seven with Ph-acute lymphoblastic leukemia (ALL) and three with chronic phase (CP)/accelerated phase chronic myeloid leukemia (CML)-were eligible. Eight patients had a history of a single tyrosine kinase inhibitor (TKI) use prior to ponatinib. Any mutation of the tyrosine kinase domain was detected in eight patients, including seven of T315I. The median dose of ponatinib was 15 mg with a median duration of 7 weeks (range 4-23 weeks). The median duration from the start of ponatinib to HCT was 54 days (range 35-175 days). Hematological remission was obtained in five Ph-ALL patients. Maintenance therapy of ponatinib was applied to five patients. No vascular occlusion event has occurred over this series of treatments. Salvage therapy with low-dose ponatinib appears to be safe and effective in patients with relapsed or refractory Ph-leukemia, which may immediately bridge to HCT.

Background: Although introduction of pediatric-type Berlin-Frankfurt-Munster (BFM) chemotherapy has markedly improved the prognosis of adolescent and young adult (AYA) patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph-negative ALL), their higher toxicity has become an emerging issue with an increased post-remission mortality in AYA patients than pediatric patients. Allogeneic stem cell transplantation (allo-SCT) with myeloablative conditioning (MAC) regimens containing total body irradiation (TBI) is recognized as an important treatment option for patients with higher risk diseases. However, safety and efficacy of allo-SCT with TBI-MAC have not been fully investigated among AYA patients who received pediatric-type chemotherapy. Patients and methods: AYA was defined as 16 to 39 years old. Of the 143 AYA patients with Ph-negative ALL who underwent the first allo-SCT in the first remission between 2007 and 2016 at the 20 institutions, 106 patients who were treated with one BFM chemotherapy regimen before transplant and were conditioned with MAC regimens containing more than or equal to 8 Gy of TBI dose. The reasons for the transplant were surveyed with a multi-answer questionnaire. Overall survival (OS) was defined as the interval from the date of transplant to the date of death. Fisher's exact test was used to compare binary variables. The cumulative incidence (CI) of non-relapse mortality (NRM) and relapse were evaluated with Gray's test, considering relapse and NRM as a competing risk, respectively. OS was estimated with the Kaplan-Meier method and compared using the log-rank test. Factors associated with at least borderline significance (p < 0.20) in univariate analyses were subjected to multivariate analysis. The Fine-Gray and Cox proportional hazard model were used for multivariate analysis of risk factors and prognostic factors, respectively. Values of p < 0.05 were considered to indicate statistical significance. Results: Of the 106 patients included in this study, 61 were male, and 45 were female. The median age at transplant was 29 years (range, 16-39 years). Donor types were related, unrelated, and cord blood in 47 (44%), 47 (44%), and 12 (12%) patients, respectively. The difficulty of continuing chemotherapy due to side effects as the reason for transplant was included in 13 patients (12%). As chemotherapy before transplant, pediatric-type and adult-type regimens were used in 56 (53%) and 50 patients (47%), respectively. There was no significant difference in baseline characteristics and transplant procedures between the pediatric-type group and the adult-type group, except for proportion of patients over 30 years (14% vs. 64%, respectively; p < 0.01), those with more than or equal to 2 of hematopoietic cell transplant comorbidity index (13% vs. 36%, respectively; p < 0.01), and transplant between 2007 and 2011 (36% vs. 64%, respectively; p < 0.01). The CI of NRM, the OS rates, and the CI of relapse were not significantly different between two groups (NRM: 4% vs. 12% at three years after transplant, respectively; p = 0.26), (OS: 86% vs. 70%, respectively; p = 0.14), and (relapse: 16% vs. 24%, respectively; p = 0.32), respectively. Multivariate analysis for NRM revealed that more than or equal to 1 of performance status at transplant (hazard ratio [HR] = 4.8; p < 0.01) and transplant due to side effects of chemotherapy (HR = 3.5; p = 0.04) were identified as independent risk factors, but not pediatric-type chemotherapy (HR = 0.48; p = 0.23). The proportions of transplant due to side effects of chemotherapy were similar between two groups (13% vs. 12%, respectively; p = 1). No independent prognostic factor for OS was found, while transplant between 2007 and 2011 (HR = 2.5; p = 0.04) was extracted as an independent risk factor of relapse. Regarding transplant complications, significant differences were not shown in CI of grade II to IV acute graft-versus-host disease (GVHD), chronic GVHD, bacteremia, cytomegalovirus reactivation, hemorrhagic cystitis, and avascular necrosis between two groups. No characteristic cause of NRM was found in the pediatric-type group. Conclusion: These findings suggested that conventional allo-SCT with TBI-MAC can be performed without increasing NRM in AYA patients with Ph-negative ALL even after pediatric-type chemotherapy. Disclosures Kimura: MSD: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Kyowa Kirin: Honoraria; Chugai Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Ono Pharmaceutical: Honoraria; Eisai: Honoraria; Nippon Kayaku: Honoraria; Takeda Pharmaceutical: Honoraria; SymBio Pharmaceutical: Honoraria. Usuki: MSD: Speakers Bureau; Alexion: Speakers Bureau; Pfizer: Research Funding; Kyowa Kirin: Research Funding, Speakers Bureau; Eisai: Speakers Bureau; Nippon shinyaku: Research Funding, Speakers Bureau; Astellas-Amgen-Biopharma: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Takeda: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Janssen: Research Funding; Ono: Research Funding, Speakers Bureau; Brisol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Otsuka: Research Funding, Speakers Bureau; Sumitomo Dainippon: Research Funding; Daiichi Sankyo: Research Funding, Speakers Bureau; Symbio: Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Astellas: Research Funding, Speakers Bureau; Mundipharma: Research Funding; Yakult: Speakers Bureau; PharmaEssentia: Speakers Bureau. Sakaida: Bristol Myers Squibb: Research Funding; Chugai: Research Funding; Ono: Research Funding; Kyowa Kirin: Research Funding. Fujisawa: Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Handa: Abbvie: Honoraria; MSD: Research Funding; Shionogi: Research Funding; Sanofi: Honoraria, Research Funding; Ono: Honoraria; BMS: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Research Funding; Celgene: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding; Takeda: Honoraria, Research Funding. Hatta: Bristol-Myers Squibb: Honoraria; Novartis KK: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical.: Honoraria. Kanda: Otsuka Pharmaceutical: Honoraria, Research Funding; Sanofi: Research Funding; MSD: Honoraria.

Body mass index (BMI), which represents the proportion of weight to height, is a controversial prognostic factor for acute myeloid leukemia (AML). We evaluated prognostic value of BMI in Japanese AML. The study included 369 adult patients with newly diagnosed AML who were administered either daunorubicin or idarubicin with cytarabine as induction chemotherapy. The patients were categorized into two groups according to their BMI: the NW group (BMI

Introduction Despite recent developments on various transplantation procedures and supportive therapy, nonrelapse mortality (NRM) after allogeneic stem cell transplantation (allo-SCT) remains an essential issue. In choosing the appropriate regimen for allo-SCT, decision-making information that considers the complexity of different risk factors is vital. The Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), which was initially derived and validated by investigators at the Fred Hutchinson Cancer Research Center to predict NRM, has become a widely validated tool for predicting outcomes in many transplant settings (Sorror et al. Blood. 2005). It can also stratify patients for the risk of other outcomes, including overall survival and graft versus host disease. Patients with a high HCT-CI score tend to prefer allo-SCT with reduced-intensity conditioning. Conversely, for those who prefer allo-SCT with myeloablative conditioning (MAC) and has a low HCT-CI score, a prognostic indicator is unnecessary. Furthermore, the risk factors for NRM may differ among various conditioning regimens. Therefore, the current study aimed to establish a new prognostic model for patients specific to each MAC regimen before allo-SCT. Methods We performed a retrospective cohort study to develop prognostic models of NRM in patients conditioned with cyclophosphamide/total body irradiation (Cy/TBI) or busulfan/cyclophosphamide (Bu/Cy). We selected patients who had leukemia and lymphoma in remission or had untreated or stable myelodysplastic syndrome and experienced initial allo-SCT relapse between 2007 and 2017 in the Kanto Study of Group for Cell Therapy (KSGCT). The primary outcome measure was 2-year NRM. Furthermore, we evaluated variables such as patient age, albumin, liver function, renal function, respiratory function, ejection fraction (EF), C-reactive protein (CRP), stem cell source, donor type, antithymocyte globulin use, performance status, recipient/donor sexes, time interval from diagnosis to transplant, and HCT-CI score. To identify a set of variables for Cox proportional hazards, we used an Akaike Information Criterion (AIC)-based variable selection procedure. We assigned weights to individual parameters according to their prognostic significance in Cox proportional hazard models. The identified model's discriminative ability was assessed by Harrell's C-statistic calculated using the bootstrap method. Results Among the 555 patients analyzed, 338 received Cy/TBI, and 217 received Bu/Cy. In Cy/TBI and Bu/Cy, the median age was 39 (11-60) and 44 (18-62) years, the HCT-CI score ≤ 2 was observed in 82.1% and 87.6%, and 2-year NRM was found in 13.5% and 16.0% of the patients, respectively. Before transplantation, the most dominant parameters in Cy/TBI were abnormal liver function (AST/ALT or bilirubin >upper limit of normal) and albumin value < 4.5g/dL, whereas those in Bu/Cy were age >40 years, EF < 65 %, and CRP ≥ 0.2 mg/dL. Internal validation with bootstrap resampling showed good discrimination, with C-statistic values of 0.70 (95% CI: 0.69-0.71) in Cy/TBI and 0.68 (95% CI: 0.67-0.69) in Bu/Cy. Each of the abovementioned parameters, including age >40 years, was scored as 1 point. To evaluate the 2-year NRM, we divided the total scores into three risk groups. In the Cy/TBI group, the NRM was 6.9% in low (score 0-1, n = 186), 19.5% in intermediate (score 2, n = 127), and 35.3% in high (score 3, n = 25) scores. In the Bu/Cy group, the NRM was 8.3% in low (score 0-1, n = 93), 21.7% in intermediate (score 2, n = 98), and 29.8% in high (score 3, n = 26) scores (Figure). Higher scores were strongly associated with worse NRM and survival. Conclusions Our prognostic models for NRM estimation can distinguish patients with a high NRM risk. To our knowledge, these models are the first prognostic models used to estimate NRM for standard-risk patients specific to each MAC regimen. This new simple index may help predict NRM and choose an appropriate conditioning regimen before allo-SCT. Figure 1 Disclosures Nakasone: Takeda Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Janssen Pharmaceutical: Honoraria; Eisai: Honoraria; Chugai Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria. Fujisawa:Takeda Pharmaceutical Company Limited.: Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Speakers Bureau; Novartis Pharma KK: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Janssen Pharmaceutical K.K: Speakers Bureau; NIPPON SHINYAKU CO.,LTD.: Research Funding. Nakaseko:Novartis Pharma KK: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau. Kanda:Novartis: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Honoraria; Shire: Honoraria; Daiichi Sankyo: Honoraria; Ono Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Mochida Pharmaceutical: Honoraria; Mundipharma: Honoraria; Sanofi: Honoraria, Research Funding; Meiji Seika Kaisha: Honoraria; Shionogi: Research Funding; Otsuka: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharma: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Janssen: Honoraria; Astellas Pharma: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Pfizer: Honoraria, Research Funding; Merck Sharp & Dohme: Honoraria.

A 29-year-old man was diagnosed with acute myeloid leukemia at 20 years of age; he achieved a second complete remission at 22 years of age after an allogeneic unrelated bone marrow transplantation. After 14 months, he developed bronchiolitis obliterans (BO) due to chronic graft-versus-host disease. Home ventilator management was continuously performed for 3 years, but the patient required extracorporeal membrane oxygenation (ECMO) after progression to type 2 respiratory failure. A matched brain-dead lung donor was found after 5 months of intensive care management on ECMO, and bilateral lung transplantation was successfully performed. BO is a progressive refractory respiratory disease with poor prognosis. Careful management of infection, monitoring organ function, and lung transplantation at the appropriate time of initiation of mechanical ventilation or ECMO may save a patient's life. However, it is crucial to collaborate with higher education institutions or medical professionals in other departments.

The optimal pre-transplant conditioning for aplastic anemia (AA) remains unclear. We performed a prospective study on allogeneic transplantation from a related or unrelated donor for adult patients with AA. We assessed whether reduced-dose cyclophosphamide (CY) could decrease toxicity while maintaining engraftment, and low-dose thymoglobulin could safely prevent graft-vs-host disease (GVHD). The pre-transplant conditioning regimen consisted of fludarabine 120 mg/m2 , CY 100 mg/kg, and thymoglobulin 2.5 mg/kg with or without 2 Gy of total body irradiation. Twenty-seven patients with a median age of 36 years were analyzed. Sixteen patients received graft from related donors. The stem cell source was bone marrow in 26 patients. All of the patients but one, who died early, achieved neutrophil engraftment at a median of 19 days. Mixed chimerism was observed in six and five patients at days 30 and 90, respectively. Only one patient experienced secondary engraftment failure with complete donor-type chimerism. None of the patients developed severe acute GVHD. The cumulative incidence of chronic GVHD was 37.7% at 1 year. The overall survival rate was 96.3% at 1 year and 3 years. A high EB virus-DNA load was detected in one patient at days 60. No one developed EBV-lymphoproliferative disorder within a year. The results suggest that the conditioning regimen in this study was safe and effective. However, relatively high incidence of chronic GVHD needs further improvement.

Natural killer (NK) cells expressing killer cell immunoglobulin-like receptors (KIRs) can recognize specific HLA class I molecules as their ligands. By studying a large Japanese transplant registry, we compared transplant outcomes between patients heterozygous for HLA-CAsn80/CLys80 (HLA-C1/C2) and those homozygous for HLA-C1 (HLA-C1/C1) among patients who had undergone HLA-matched hematopoietic stem cell transplantation (HSCT). A high frequency of KIR2DL1 with strong HLA-C2 binding capacity and a low frequency of HLA-C2 and KIR haplotype B are characteristic of the Japanese population. In our previous report, HLA-C1/C1 patients with myeloid leukemia were less likely to relapse than HLA-C1/C2 patients. We newly assessed 2884 patients with acute lymphoblastic leukemia (ALL) who received HLA-matched allogeneic HSCT and analyzed their leukemia relapses by using adjusted competing-risk methods. HLA-C1/C1 patients with ALL experienced significantly higher relapse rates than HLA-C1/C2 patients (hazard ratio [HR] = 1.55, P = .003), contrary to our results in patients with myeloid leukemia. We allocated patients with ALL to several subgroups and found a higher frequency of relapse (HR >1.8) in the HLA-C1/C1 group than in the HLA-C1/C2 group among patients with Ph-negative ALL, those who had no cytomegalovirus reactivation, those who received transplants from donors who were aged 41 years or older, and those who experienced acute graft-versus-host disease, especially if it required systemic treatment. One interpretation of our results is that KIR2DL1-positive NK cells disrupt T cells, antigen-presenting cells, or both from working efficiently in transplant immunity in HLA-C1/C1 patients with ALL. Another is that KIR2DS1-positive NK cells directly attack HLA-C2-positive ALL blasts in HLA-C1/C2 patients. Whether HLA-C2 can cause recurrence to decrease or increase in patients depending on the disease (ALL or myeloid leukemia) will be a very important finding. We hope that our results will provide clues to the real mechanisms behind relapse after transplantation in patients with different HLA profiles.

A multicenter retrospective study was performed to explore a prognostic scoring index in order to identify a population who are least likely to benefit from allogeneic hematopoietic cell transplantation (HCT) in patients with relapsed or refractory acute myeloid leukemia (AML). The cohort included 519 patients with AML, who received HCT between 2005 and 2015 at a status of relapse or primary induction failure. Multivariate analysis demonstrated five independent predictors for OS, including C-reactive protein ≥ 1 mg/dL, peripheral blood blast fraction ≥ 20%, poor-risk karyotype, performance status ≥ 2, and bone marrow unrelated donor as a stem cell source. A prognostic scoring index was explored based on these predictors, and successfully separated the cohort into four groups. At 2 years, OS was 47%, 24%, 8%, and 0% for Good (Score 0, 1: n = 118), Intermediate-1 (Score 2: n = 75), Intermediate-2 (Score 3: n = 39), and Poor (Score 4: n = 24), respectively (P 0.001). The predicting value of the index was confirmed in a validation cohort. Although a further validation study is warranted, the scoring index may be useful to predict survival and to identify the population with the lowest survival prior to HCT in patients with relapsed or refractory AML.