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This study aimed to clarify the risk factors and prognosis associated with blood stream infection (BSI) in allogeneic hematopoietic cell transplantation (allo-HCT), and the relationship between BSI and acute graft-versus-host disease (aGVHD). This retrospective analysis included 11,098 patients in the Japanese national transplant registry. A total of 2172 patients developed BSI after allo-HCT, with 2332 identified pathogens. The cumulative incidences of BSI were 15.5% at 30 days and 20.9% at 100 days after allo-HCT. In a multivariate analysis, severe (grade III-IV) aGVHD was associated with a higher risk of BSI (vs. grade 0-I aGVHD: hazard ratio [HR] 3.34 [95% confidence interval (CI), 2.85-3.92; P < 0.001]). In a multivariate analysis, severe aGVHD before BSI was associated with a higher risk of overall mortality after BSI (vs. grade 0-I aGVHD: HR 2.61 [95% CI 2.18-3.11; P < 0.001]). In addition, BSI (vs. no-BSI: HR 1.20 [95% CI, 1.12-1.29; P < 0.001]) and severe aGVHD (vs. grade 0-I aGVHD: HR 1.97 [95% CI, 1.83-2.12; P < 0.001]) were independent risk factors for overall mortality after allo-HCT. In the setting of allo-HCT, severe aGVHD was associated with increases in both BSI incidence and post-BSI overall mortality. Furthermore, BSI was an independent risk factor for overall mortality.

Philadelphia chromosome-positive acute myeloid leukemia (Ph+ AML) confers a dismal prognosis when treated with chemotherapy alone. Data on allogeneic hematopoietic cell transplantation (allo-HCT) outcomes are limited. We retrospectively analyzed 4649 AML patients who received allo-HCT and were in complete remission. Outcomes of Ph+ AML (n = 30), intermediate-risk, and poor-risk AML patients were compared. The 3-year overall survival after allo-HCT was similar in intermediate-risk (62.7%; 95% CI: 61.0-64.3%) and Ph+ AML (73.3%; 95% CI: 51.5-86.4%) groups (P = 0.42); however, it differed significantly between the poor-risk (49.7%; 95% CI: 45.9-53.4%) and Ph+ AML (73.3%; 95% CI: 51.5-86.4%) groups (P = 0.049). Disease-free survival in Ph+ AML patients was comparable to that in intermediate-risk patients but better than that in poor-risk patients. Relapse rates were significantly lower in Ph+ AML patients than in other groups. Non-relapse mortality (NRM) rates were similar among groups. Multivariate analysis showed that Ph+ AML was not a significant predictor of poor prognosis in terms of overall survival, disease-free survival, relapse, and NRM. Our data showed better post-transplant outcomes for Ph+ AML patients than for those with poor-risk AML. Hence, allo-HCT could be a feasible treatment option for Ph+ AML patients.

For patients without an HLA-matched donor, an HLA-mismatched unrelated donor (MMUD) has been considered as an alternative donor in allogeneic hematopoietic cell transplantation (allo-HCT). We conducted a nationwide retrospective study to compare the transplant outcomes among 1-, 2-, and 3-locus (allele/antigen) mismatched unrelated donors (1MMUD n = 2044, 2MMUD n = 492, and 3MMUD n = 73) in allo-HCT and to assess the impact of antithymocyte globulin (ATG) in allo-HCT from 1-3MMUD. 2MMUD and 3MMUD were independent significant adverse factors for grade III–IV acute graft-versus-host disease (GVHD) (hazard ratio [HR] 1.72, p

Aya Sugiyama,1 Teruhisa Fujii,2,3 Yoshiko Okikawa,4 Fumie Sasaki,5 Masazumi Okajima,3,6 Hidekuni Hidaka,3,7 Koji Iwato,3,8 Kazuyoshi Sato,3,9 Akira Kokubunji,3,10 Noboru Takata,3,11 Masahiro Yamamoto,3,12 Junko Tanaka1,3 1Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; 2Division of Transfusion Medicine, Hiroshima University Hospital, Hiroshima, Japan; 3Joint Committee for Blood Transfusion Therapy in Hiroshima Prefecture, Hiroshima, Japan; 4Department of Oncology, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan; 5Division of Laboratory, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan; 6Department of Surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan; 7Division of Surgical Services, Fukuyama City Hospital, Hiroshima, Japan; 8Department of Hematology, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan; 9Division of Laboratory, Shobara Red Cross Hospital, Shobara, Japan; 10Department of Medical Science and Technology, Faculty of Health Sciences, Hiroshima International University, Hiroshima, Japan; 11Oda Internal Medical Clinic, Hiroshima, Japan; 12Hiroshima Red Cross Blood Centre, Hiroshima, JapanCorrespondence: Teruhisa FujiiDivision of Transfusion Medicine, Hiroshima University Hospital, 1-2-3, Kasumi, Minami-ward, Hiroshima, 734-8551, JapanTel +81-82-257-5581Email terchan@hiroshima-u.ac.jpPurpose: Given the chronic shortage of blood for transfusion in Japan, promotion of appropriate use of fresh frozen plasma (FFP) urgently needs to be addressed by the national blood project in Japan. Whether FFP transfusions are administered appropriately in Japan is currently unclear. In this study, we aimed to investigate the outcomes of patients who undergo FFP transfusion and the appropriateness of use of FFP.Patients and Methods: This multicentre, prospective, observational cohort study was conducted from September 2017 to April 2019 at the 15 medical institutions in Hiroshima Prefecture that are the top providers of FFP. All patients who underwent FFP transfusion during the study period were included, relevant data being extracted from the medical records. The indications for FFP transfusion were classified in accordance with the Guidelines of the Ministry of Health, Labour and Welfare of Japan. Factors associated with patient outcomes at day 28 after FFP transfusion were subjected to multivariable logistic regression analysis.Results: In total, data of 1299 patients were eligible for analysis. At least 63.8% of indications for FFP were in accordance with the guideline for FFP transfusions. The mortality rate at day 28 after FFP transfusion was 16.2%. Older age (65– 74 years: adjusted odds ratio [AOR]=4.3, ≥ 75 years: AOR=4.1), non-perioperative use (AOR=4.5), coagulopathy associated with liver damage (AOR=2.7), large volume of FFP transfused (AOR=2.5), and lack of improvement in blood coagulation following FFP transfusion were independently and significantly associated with death within 28 days after FFP transfusion.Conclusion: Our findings do not support the simple conclusion that FFP transfusions contribute to prognosis. However, given that coagulopathy in patients with end-stage liver disease is infrequently improved by FFP transfusion, “inappropriate” use of FFP should be avoided. It is important to promote appropriate use of FFP so as not to waste blood resources.Keywords: prognosis, coagulopathy, inappropriate use, compliance with guideline

Although the prognosis of acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is worse than that of AML not otherwise specified (AML-NOS), transplantation outcomes and prognosticators of AML-MRC patients undergoing allogeneic stem cell transplantation (allo-SCT) remain unclear. Transplantation outcomes of AML-MRC (n = 4091) were compared with those of AML-NOS (n = 3964) in patients who underwent allo-SCT between 2003 and 2016 using a nationwide registration database. The 3-year overall survival (OS; 35.5% versus 50.6%) was lower and the relapse (42.3% versus 32.1%) and nonrelapse mortality (26.3% versus 22.0%) rates were higher in the AML-MRC group than in the AML-NOS group. Based on the hierarchical AML-MRC classification, myelodysplasia as the sole criterion was associated with better OS compared with AML-NOS, whereas monosomal or complex karyotype and -5/del(5q) were associated with poor OS. A history of myelodysplastic syndrome and -7/del(7q) did not affect OS. Accordingly, AML-MRC with complex karyotype or -5/del(5q) and that with monosomal karyotype were classified as intermediate and high risks, respectively, whereas the remaining cases were classified as low risk. The 3-year OS rates were 50.7%, 36.9%, and 13.8% in the low-, intermediate-, and high-risk groups, respectively (P.001). Risk classification, older age, and low performance status score were significant risk factors for survival in AML-MRC, independently of the disease status. Grades I to II acute graft-versus-host disease significantly reduced the 3-year relapse (24.7% versus 31.6%), leading to better survival (hazard ratio, .64). Our prognostic risk stratification can potentially aid in elucidating the diverse transplantation outcomes in patients with AML-MRC.

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).

The effects of ABO incompatibility on hematopoietic stem cell transplantation remain controversial. Large cohorts are required to obtain findings that allow for definite conclusions. We previously demonstrated poor overall survival and increased treatment-related mortality (TRM) in ABO-incompatible unrelated bone marrow transplantation (UR-BMT) performed during the period from 1993 to 2005. To improve our understanding of ABO-incompatible transplantation, we reanalyzed the effects of ABO mismatch in a UR-BMT cohort in Japan after 2000. Multivariate analyses for the 2000–2006 cohort showed that major ABO mismatch was associated with poor overall survival (HR, 1.211; 95% CI, 1.062 to 1.381; p = 0.004) and increased TRM (HR, 1.357; 95% CI, 1.146 to 1.608; p

We conducted a nationwide retrospective study to evaluate the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 651 patients aged 60–69 years with de novo myelodysplastic syndrome (MDS). We divided patients into two groups: 152 and 499 patients with an early and advanced disease status, respectively. The 3-year overall survival (OS) rate of patients with an early disease status was 45.9% (95% confidence interval [CI], 37.0 to 54.2%). A multivariate analysis revealed five adverse factors for OS: performance status (PS) 2–4 (hazard ratio [HR] 4.48; P

We conducted a nationwide retrospective study to evaluate the prognostic influence of +1, der(1;7)(q10;p10) [hereafter der(1;7)] and ?7/del(7q) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for de novo myelodysplastic syndromes (MDS). In this database, 69 MDS patients with der(1;7), 75 with ?7/del(7q), and 511 with normal karyotype (NK) underwent allo-HSCT at advanced disease status. The 3-year overall survival (OS) and cumulative incidence of relapse (CIR) were 50.4 and 19.4% for those with der(1;7), 36.2 and 38.4% for ?7/del(7q),and 51.1 and 20.7% for NK, respectively. In the multivariate analysis, the presence of ?7/del(7q) correlated with a significantly shorter OS (HR [95% CI], 1.38 [1.00?1.89]; P = 0.048) and higher CIR (HR, 2.11 [1.36?3.28]; P = 0.001) than those with NK. There were 23 patients with der(1;7), 29 with ?7/del(7q), and 347 with NK who underwent allo-HSCT at early disease status.The 3-year OS and CIR were as follows: 47.3 and 9.5% for the der(1;7) group, 70.5 and 13.8% for ?7/del(7q), and 70.9 and 5.6% for NK,respectively. No significant differences were observed in OS and CIR among three groups. The impact of the loss of chromosome 7q on OS and CIR may differ based on its type and disease status after allo-HSCT for MDS., Bone Marrow Transplantation, 54(9), pp.1471-1481; 2019

The significance of low-dose total body irradiation (TBI) in HLA-mismatched reduced-intensity conditioning stem cell transplantation (RICT) remains unknown. We, retrospectively, evaluated the impact of low-dose TBI in patients with hematological malignancies who received first RICT from ≥1 antigen-mismatched donors between 2004 and 2014. Of the 575 patients, 361 patients received low-dose TBI (2 or 4 Gy). There were no significant differences in neutrophil engraftment or platelet recovery between TBI and non-TBI groups. The benefit of low-dose TBI on neutrophil engraftment was not observed in any subgroups. Low-dose TBI was not associated with decreased secondary graft failure. Suppressed mixed chimerism and autologous hematopoiesis by low-dose TBI was observed. There were no significant differences in cumulative incidences of acute GVHD or nonrelapse mortality rates in either group; however, low-dose TBI improved overall survival (OS), especially in patients with high-risk disease, multi-HLA mismatch, and fludarabine/busulfan conditioning. Multivariate analysis demonstrated that low-dose TBI was an independent prognostic factor for OS. Compared with the non-TBI group, 4 Gy TBI, but not 2 Gy TBI, was associated with increased acute GVHD and reduced relapse. These findings suggest that low-dose TBI may be beneficial for patients at high risk for relapse in HLA-mismatched RICT.

Acute panmyelosis with myelofibrosis (APMF) is a rare subtype of acute myeloid leukemia characterized by acute onset of cytopenias and bone marrow fibrosis in the absence of splenomegaly. Because the prognosis of APMF is extremely poor even after chemotherapy, hematopoietic cell transplantation (HCT) has been used to treat APMF. However, the outcome after HCT for APMF remains unclear. To evaluate the outcomes and prognostic factors after HCT as a therapeutic modality for APMF, we retrospectively analyzed the Japanese registration data of 40 APMF patients who received allogeneic and syngeneic HCT between 2005 and 2015. The median age at HCT was 53.5 years (range, 16 to 70). The disease status at HCT was first complete remission (CR1) in 13 patients (33%). The probability of overall survival and the cumulative incidence of relapse at 3 years were 24% and 59%, respectively. Univariate analysis identified that female sex and disease status CR1 at the time of HCT were significantly associated with higher overall survival. Although APMF patients have a poor long-term prognosis even after syngeneic and allogeneic HCT, these data suggested that allogeneic HCT offered a curative option for APMF.

It remains unclear how specific innovations in allogeneic hematopoietic cell transplantation (HCT) attained over the past decades have contributed to improvement in transplantation outcomes. To address this question, we conducted a registry-based study of adults with acute myeloid leukemia in first or second complete remission who underwent allogeneic HCT between 1994 and 2013 from a sibling (N = 1600) or unrelated (N = 2113) donor matched at the antigen level for HLA-A, -B, and -DR. Preliminary analysis led us to focus on comparisons between the 1994–2006 and 2007–2013 periods. Significant improvement in survival was observed in the later cohort compared to the earlier cohort for unrelated HCT (P = 0.004), but not for related HCT (P = 0.767). The improvement in unrelated HCT was solely due to diminished non-relapse mortality (P = 0.001), while incidence of relapse did not change over time (P = 0.934). The percentage of patients receiving transplants from 8/8-matched unrelated donors was significantly higher in the later cohort (P

The role of stem cell transplantation (SCT) for patients with Waldenstrom's macroglobulinemia (WM) remains undetermined. Therefore, we retrospectively evaluated the outcome of autologous and allogeneic SCT for patients with WM using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Forty-six patients receiving autologous and 31 receiving allogeneic SCT were analyzed. The allogeneic SCT group included more patients with advanced disease status at transplant and received more lines of chemotherapy. The cumulative incidences of non-relapse mortality (NRM) at 1 year were 30.0% (95% CI, 14.7-46.9%) in the allogeneic SCT and 0% in the autologous SCT group. The estimated 3-year overall (OS) and progression-free (PFS) survival rates were 84.5% (95% CI, 66.0-93.4%) and 70.8% (95% CI, 53.0-82.9%) in the autologous SCT group, and 52.2% (95% CI, 32.5-68.6%) and 45.0% (95% CI, 26.3-62.0%) in the allogeneic SCT group. No patients died after the first 2 years following allogeneic SCT. In univariate analyses, disease status at SCT was significantly associated with PFS in autologous SCT, and with OS and PFS in allogeneic SCT. These results suggest that both autologous and allogeneic SCT have each potential role in WM. Allogeneic SCT is more curative for WM, but is associated with high NRM.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapeutic option for patients with chronic myelomonocytic leukemia (CMML). We retrospectively compared the post-transplantation outcomes of 159 patients with CMML who underwent allo-HSCT using 4 types of donor sources: HLA-matched related donor graft, unrelated bone marrow (U-BM), unrelated cord blood (U-CB), and HLA-mismatched related donor graft. The median patient age at allo-HSCT was 54 years (range, 16 to 75 years). In multivariate analyses, the use of HLA-matched related donor grafts correlated with better overall survival than U-BM (hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.21 to 3.48; P = .008), U-CB (HR, 3.80; 95% CI, 2.07 to 6.95; P .001), or HLA-mismatched related donor grafts (HR, 6.18; 95% CI, 2.70 to 14.15; P .001). Mortality after the relapse or progression of CMML did not significantly differ among the 4 types of donor source. Transplantation-related mortality was highest in recipients of U-CB (HR, 3.32; 95% CI, 1.33 to 8.26; P = .010). In patients with CMML, allo-HSCT using an alternative donor may contribute to durable remission; however, further improvements in transplantation-related mortality are required for this type of transplantation.

Autologous stem cell transplantation (ASCT) has been employed for patients with relapsed multiple myeloma (MM) after up-front ASCT. The present retrospective study aimed to examine the survival benefit from salvage ASCT. Among 446 patients with relapsed MM after up-front single ASCT, 70 patients received salvage ASCT, the employment of which reduced the risk of mortality after relapse (p = 0.041). Using the parameters before initial ASCT, the advantage of salvage ASCT compared to standard therapy was confirmed in the subgroup with an international staging system stage of I or II (p = 0.040), good performance status (PS; p = 0.043), or no/mild renal comorbidity (p = 0.029). The advantage of salvage ASCT was also confirmed in the subgroup excluding those with early relapse within 7 months after initial ASCT (p = 0.026). Among patients who received salvage ASCT, a favorable prognosis is apparent for those with a time to relapse after initial ASCT of longer than 24 months. The overall survival after salvage ASCT was favorable excluding patients with the following factors: early relapse, poor PS, moderate/severe renal comorbidity, and progressive disease (p < 0.001). In conclusion, our results reinforced the evidence for encouraging salvage ASCT for eligible patients.

Allogeneic hematopoietic stem cell transplantation (HSCT) with the conventional cyclophosphamide and total body irradiation (CY/TBI) regimen is an essential therapeutic strategy for acute lymphoblastic leukemia (ALL) in adults. Medium-dose etoposide (VP16, 30-40 mg/kg) can be added to intensify this CY/TBI regimen and reduce relapse; however, differences in prognosis between the VP16/CY/TBI and CY/TBI regimens have not yet been fully analyzed. We conducted a retrospective cohort study using a Japanese transplant registry database to compare the prognosis between the VP16/CY/TBI (VP16, total 30-40 mg/kg) (N = 376) and CY/TBI (N = 1178) regimens in adult patients with ALL transplanted at complete remission (CR) between January 1, 2000 and December 31, 2014. Our analyses indicated that VP16/CY/TBI significantly reduced relapse compared with CY/TBI (risk ratio, 0.75; 95% confidence interval [CI], 0.56-1.00; P = .05) with a corresponding improvement in leukemia-free survival (hazard ratio [HR], 0.76; 95%CI, 0.62-0.93; P = .01), particularly in patients transplanted at CR1 with advanced-risk (positive minimal residual disease, presence of poor-risk cytogenetics, or an initial elevated leukocyte count) (HR, 0.75; 95%CI, 0.56-1.00; P = .05) or those transplanted beyond CR2 (HR, 0.58; 95%CI, 0.39-0.88; P = .01). The addition of VP16 did not increase post-transplant complications or nonrelapse mortality (HR, 0.88; 95%CI, 0.65-1.18; P = .38). This study is the first to reveal the efficacy of the addition of medium-dose VP16 to CY/TBI in high-risk ALL. To establish new myeloablative conditioning regimens including VP16, a large-scale prospective study is necessary.

This study aimed at determining how cytogenetic risk status affects outcomes for patients with acute myeloid leukemia (AML) after undergoing various types of allogeneic hematopoietic cell transplantation (HCT). Of 7812 patients eligible for analysis, cytogenetic risk was classified as favorable for 1088, intermediate for 5025, and poor for 1699. Overall, multivariate analysis showed significant intergroup differences in terms of relapse and survival, with the difference between poor- and intermediate-risk groups being greater than that between favorable- and intermediate-risk groups. Non-relapse mortality was identical for the three groups. Significant effects of cytogenetic risk status on survival were documented irrespective of donor type (related, unrelated, and umbilical cord blood), disease status at the time of transplantation (first or second complete remission, and more advanced disease status), and conditioning intensity (myeloablative and reduced-intensity). Our findings demonstrate robust and constant effects of cytogenetic risk status on survival after allogeneic HCT for patients with AML.

A 54-year-old woman with acute myeloid leukemia (AML) achieved complete remission by induction chemotherapy, but developed zygomycosis after consolidation therapy. As zygomycosis could not be cured by liposomal amphotericin B and micafungin, left lower lobectomy was performed. As AML relapsed 7 months after onset, she received haploidentical stem cell transplantation under administration of liposomal amphotericin B. Despite experiencing severe acute graft-versus-host disease, she remains alive with no relapse of either zygomycosis or AML. Keywords: Zygomycosis, Acute myeloid leukemia, Liposomal amphotericin B, Stem cell transplantation

The impact of HLA mismatch in hematopoietic stem cell transplantation with reduced-intensity conditioning (RIC) has not been fully examined. We analyzed a total of 1130 cases to examine the effects of HLA allele mismatch in unrelated bone marrow transplantation (BMT) with RIC in the Japan Marrow Donor Program registry cohort. Compared with HLA 8/8–allele match (n = 720, 8/8 match), both 1 (n = 295, 7/8 match) and 2 allele mismatches (n = 115, 6/8 match) were associated with significant reduction of overall survival (OS) (hazard ratio [HR], 1.34; P = .0024 and HR, 1.33; P = .035 for 7/8 and 6/8 match, respectively). The incidence of grades 2 to 4 acute graft-versus-host disease (aGVHD) increased with increasing number of mismatched alleles (HR, 1.36 and HR, 2.08 for 7/8 and 6/8 match, respectively). Nonrelapse mortality showed a similar tendency to aGVHD (HR, 1.35 for 7/8 and HR, 1.63 for 6/8). One-allele mismatches at the HLA-A or -B and HLA-C loci were significantly associated with inferior OS compared with 8/8 match (HR, 1.64 for A or B mismatch and HR, 1.41 for C mismatch), whereas HLA-DRB1 allele mismatch was not (HR, 1.16; P = .30). However, the effect of HLA-A or -B and -C mismatch on OS was not observed in those who received RIC BMT since 2010, in contrast to recipients before 2010. These results suggested that in unrelated RIC BMT, 1-allele mismatch is associated with poorer outcome, and the impact of HLA mismatch may differ depending on the HLA locus, although these HLA mismatch effects may be different in recent cases.

We present the case of a 79-year-old man who showed multiple pulmonary nodules on chest computed tomography (CT) after being treated for 6 months with ruxolitinib, an inhibitor of Janus kinase (JAK) 1 and 2, to treat primary myelofibrosis. We examined the lesions by bronchoscopy, and the biopsy specimen revealed fungus bodies of Cryptococcus with granulomatous inflammation. As a result, the patient was diagnosed with pulmonary cryptococcosis. The patient was treated with fluconazole (200 mg daily for 2 weeks) with concomitant ruxolitinib administration, but the pulmonary lesions progressed. Subsequently, the patient was treated with voriconazole (300 mg daily for 3 weeks), but the lesions worsened further. The administration of ruxolitinib was therefore discontinued, and the dosage of voriconazole was increased to 400 mg daily. Three months later, the pulmonary lesions diminished in size. The present case of pulmonary cryptococcosis occurred in a patient treated with ruxolitinib. Treatment of pulmonary cryptococcosis with concomitant JAK inhibitor administration may result in poor treatment efficacy. It might be better to stop administration of JAK inhibitors, if possible, in patients being treated for pulmonary cryptococcosis.

To clarify the outcome of allogeneic hematopoietic cell transplantation (HCT) for leukemic transformation (LT) preceded by Philadelphia chromosome–negative (Ph-neg) myeloproliferative neoplasms (MPNs), we conducted a retrospective study using the national registry database of the Japan Society for Hematopoietic Cell Transplantation. From 2000 to 2013, 39 patients underwent their first allogeneic HCT with related bone marrow or peripheral blood stem cells (n = 8), unrelated bone marrow (n = 15), and unrelated umbilical cord blood (n = 16). The median patient age was 57 years. The underlying Ph-neg MPNs included 21 cases of essential thrombocythemia, 11 cases of primary myelofibrosis, and 7 cases of polycythemia vera. The median interval between the diagnosis of LT and transplantation was 134 days. Thirty-two cases (82%) were not in remission at the time of transplantation. The 2-year overall survival rate was 29.2% (95% confidence interval [CI], 15.5% to 44.3%). The median follow-up of the surviving patients was 1989.5 days (range, 285 to 3270). The cumulative incidences of relapse and nonrelapse mortality at 2 years were 34.4% (95% CI, 19.6% to 49.8%) and 34.2% (95% CI, 19.6% to 49.4%), respectively. The study results suggested that allogeneic HCT provides long-term survival in approximately one-third of patients with LT preceded by Ph-neg MPNs.

Conditioning regimens for stem cell transplantation (SCT) involving total body irradiation (TBI) are generally preferred over busulfan (BU)-based ones for lymphoid malignancies. However, reports of favorable results using BU against lymphomas have recently emerged. This study sought to compare the effectiveness of BU and TBI regimens for SCT against lymphomas. We retrospectively analyzed 893 lymphoma patients who underwent primary SCT in Japan between 1980 and 2015. The median age of all patients was 18 years (range, 0-30 years) with 589 males, 303 females, and 1 patient whose sex was unknown. Overall survival (OS) was not different between those receiving BU and TBI (P = 0.672). OS in patients receiving autologous SCT was significantly better with BU over TBI regimens (P = 0.038), particularly in children (0-15 years) (P = 0.024). Conversely, OS in adolescents and young adults (AYAs; 16-30 years) receiving allogeneic SCT was significantly worse with BU over TBI regimens (P = 0.035). Overall, BU regiments had comparable effectiveness to TBI conditioning regimens, and, although less effective for AYAs with allogeneic SCT, were particularly more effective than TBI regimens for children who received autologous SCT.

In Japan, use of unrelated peripheral blood stem cell transplantation (uPBSCT) from HLA-mismatched unrelated donors has recently been approved. We compared outcomes between HLA-matched and 1-locus mismatched uPBSCT, as well as the impact of HLA disparity in uPBSCT and in unrelated bone marrow transplantation (uBMT). In total, 5862 uBMT recipients and 234 uPBSCT recipients were included. In terms of HLA allele disparity, 185 uPBSCT patients (79.1%) had no HLA mismatch, and 49 (20.9%) had 1-locus mismatch; in comparison, 3585 uBMT patients (61.2%) had no HLA mismatch, and 2277 (38.8%) had 1-locus mismatch. The impact of 1-locus mismatch as compared with match in uPBSCT was not significantly higher than in uBMT [hazard ratio (HR) = 1.02 and 1.27 for grade III–IV acute graft-versus-host disease, HR = 0.98 and 1.14 for non-relapse mortality, and HR = 0.87 and 1.06 for overall survival, respectively]. In conclusion, the impact of single-locus mismatch on short-term outcomes was comparable in uPBSCT and uBMT. Larger studies with longer follow-up are needed to assess long-term outcomes.

Earlier reports suggested that umbilical cord blood transplantation (UCBT) for aplastic anemia (AA) was feasible in alternative transplantation. To identify differences in outcomes of UCBT and HLA-matched or mismatched unrelated bone marrow transplantation (UBMT) in adults with AA, we analyzed registry data of the Japan Society for Hematopoietic Cell Transplantation and compared results of UCBT (n = 69) to 8/8-matched (n = 101), 7/8-matched (n = 65), or 6/8-matched (n = 37) UBMT. The transplantation period was from 2002 to 2012, and patients 16 years or older with AA were eligible. Median ages were 49, 35, 28, and 30 years for UCBT, 8/8-matched, 7/8-matched, and 6/8-matched UBMT, respectively. In multivariate analysis, risk of mortality was lower for 8/8-matched UBMT compared with that of UCBT (hazard ratio [HR], .55; 95% confidence interval [CI], .32 to .94; P = .029), adjusted for age and graft-versus-host disease (GVHD) prophylaxis, which were other associated factors. Mortality risks of 7/8-matched UBMT (HR, .55; 95% CI, .29 to 1.02) or 6/8-matched UBMT (HR, .67; 95% CI, .32 to 1.39) were not significantly different from those of UCBT. Risks of grade 3 or 4 acute and chronic GVHD were not different among the 4 groups. The most prevalent cause of death was graft failure in UCBT and 6/8-matched UBMT and infection in 8/8-matched and 7/8-matched UBMT. Under 40 years old,survival of UCBT was similar to that of UBMT (76%, 79%, 83%, and 83% for UCBT and 8/8-matched, 7/8-matched, and 6/8-matched UBMT, respectively, at 3 years), adjusted for transplantation period, which was another associated factor; however, for ages over 40 years, that of UCBT tended to be lower (47%, 64%, 64%, and 75% for UCBT, 8/8-matched, 7/8-matched, and 6/8-matched UBMT, respectively, at 3 years). To conclude, these data suggest that UCBT could be an alternative treatment option for younger adults when matched sibling or adequate UBMT donors are not available.

Acute erythroid leukemia (FAB-M6) and acute megakaryoblastic leukemia (FAB-M7) exhibit closely related properties in cells regarding morphology and the gene expression profile. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the mainstay of the treatment for both subtypes of leukemia due to their refractoriness to chemotherapy and high rates of relapse, it remains unclear whether allo-HSCT is curative in such cases due to their scarcity. We retrospectively examined the impact of allo-HSCT in 382 patients with M6 and 108 patients with M7 using nationwide HSCT data and found the overall survival (OS) and relapse rates of the M6 patients to be significantly better than those of the M7 patients after adjusting for confounding factors and statistically comparable with those of the patients with M0/M1/M2/M4/M5 disease. Consequently, the factors of age, gender, performance status, karyotype, disease status at HSCT and development of graft-vs.-host disease predicted the OS for the M6 patients, while the performance status and disease status at HSCT were predictive of the OS for the M7 patients. These findings substantiate the importance of distinguishing between M6 and M7 in the HSCT setting and suggest that unknown mechanisms influence the HSCT outcomes of these closely related subtypes of leukemia. © 2016 Elsevier Ltd., Embargo Period 12 months

Allogeneic bone marrow transplantation is an essential therapy for acquired aplastic anemia and prognosis has recently improved. However, engraftment failure and graft-versus-host disease are potential fatal complications. Various risk factors for poor prognosis have been identified, such as patient age and human-leukocyte antigen disparity, but the relationship between donor age and prognosis is still unknown. Therefore, we performed a cohort study to compare the prognosis of unrelated bone marrow transplantation from younger and older donors using the registry database in Japan. We evaluated 427 patients (age 16–72 years) with aplastic anemia who underwent bone marrow transplantation from younger (≤39 years, n=281) or older (≥40 years, n=146) unrelated donors. Overall survival of the older donor group was significantly inferior to that of the younger donor group (adjusted hazard ratio 1.64; 95% confidence interval 1.15–2.35; P

Previous studies have repeatedly reported that increasing age is a significant risk factor for worse outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) among patients with acute myeloid leukemia (AML). However, more recent studies reported conflicting results regarding the association between age and outcomes in elderly patients. Therefore, we conducted a large-scale, nationwide retrospective study to examine the impact of age on outcomes of allo-HSCT with reduced intensity conditioning (RIC) for AML patients who were older than 50 years. Of the 757 patients, 89 patients (11.8%) were 50-54, 249 patients (32.9%) were 55-59, 301 patients (39.8%) were 60-64 and 118 patients (15.6%) were ≥65 years old. The 3-year overall survival (OS) (47.8, 45.2, 37.9, and 36.6% for patients aged 50-54, 55-59, 60-64, and ≥65 years, respectively, P = 0.24) and nonrelapse mortality (NRM) (24.0, 22.8, 29.2, and 27.6% for patients aged 50-54, 55-59, 60-64, and ≥65 years, respectively, P = 0.49) were not significantly different among the four age groups. Multivariate analysis revealed that increased age had no significant effect on OS or NRM after adjusting for covariates. These results suggested that advanced patient age is not a contraindication for RIC allo-HSCT in elderly AML patients.

CASE We report a patient with hypereosinophilia-associated massive osteolytic lesion of the sacrum who was admitted to our hospital. Genetic analysis revealed that atypical eosinophilic cells were positive for FIP1-like-1-platelet-derived growth factor receptor-alpha (FIP1L1-PDGFRA) fusion gene. Treatment was initiated with oral administration of imatinib mesylate. The patient responded rapidly to this medication with a marked reduction in eosinophilia both from the peripheral blood and FIP1L1-PDGFRA fusion gene in the bone marrow within 2 weeks, followed by gradual osteosclerotic repair of the sacrum. CONCLUSIONS This case study found that the drug imatinib proved very effective in the treatment of this rare condition.

We compared the effect of HLA single-antigen and single-allele mismatched unrelated bone marrow transplantation (UBMT) without in vivo/ex vivo T cell depletion. Becasue a single DRB1 mismatch is preferred among 1-allele or 1-antigen mismatched donors, we performed mismatched allele- or antigen-specific analyses with a single DRB1 mismatch as the reference. In adjusted comparison by multivariate analyses, an HLA-DRB1 single-allele mismatch resulted in a decreased risk of nonrelapse mortality (NRM; relative risk [RR], 1.33; 95% confidence interval [CI], 1.08 to 1.63, P = .006) compared with an HLA-DR single-antigen mismatch and conferred a decreased risk of NRM (RR, 1.25; 95% CI, 1.01 to 1.57; P = .025) and overall mortality (RR, 1.16; 95% CI, 1.00 to 1.37; P = .046) compared with an HLA-C single-antigen mismatch. Relative to an HLA-DRB1 single-allele mismatch, 2-mismatch transplants, including those with 1 or more antigen mismatches, resulted in a significantly increased risk of NRM (1-antigen/1-allele mismatch: RR, 1.68; 95% CI, 1.03 to 2.05; P.001; 2-antigen mismatch: RR, 1.58; 95% CI, 1.04 to 2.02; P = .001) and overall mortality (1-antigen/1-allele mismatch: RR, 1.27; 95% CI, 1.09 to 1.47; P = .002; 2-antigen mismatch: RR, 1.27; 95% CI, 1.03 to 1.57; P = .02). NRM correlated with the combined number of mismatches and allele or antigen mismatches, with rates of 22%, 27%, 32%, 31%, and 38% at 4years for full match, single-allele mismatch, single-antigen mismatch, 2-allele mismatch, and 2 mismatches that included an antigen mismatch, respectively. Our results support the preference for an allele mismatch rather than an antigen mismatch in unrelated bone marrow donors with 1 DR mismatch or 2 mismatches for T cell-replete UBMT.

Introduction: Philadelphia chromosome-positive acute myeloid leukemia (Ph+AML) is a rare form of AML and confers a dismal prognosis when treated with chemotherapy, with limited data available on the outcome when treated with allogeneic transplantation (allo-HCT). Methods: Patients were selected from the Japanese nationwide transplantation registry database based on the following criteria: AML patients aged ≥16 years; first allo-HCT conducted between 1995 and 2016; complete remission at transplantation; and intermediate- or poor-risk cytogenetics. Patients with secondary AML or chronic myeloid leukemia in blast phase were not included. Ph+AML was defined as AML, including mixed phenotype acute leukemia (MPAL), that presented with t(9;22)(q34.1;q11.2) or BCR-ABL1 fusion transcripts at diagnosis. The primary endpoint was overall survival (OS) and secondary endpoints were relapse and non-relapse mortality (NRM). The probability of OS was estimated based on the Kaplan-Meier method and compared between the groups with log-rank test. The incidences of relapse and NRM were estimated using cumulative incidence analysis and compared between the groups with Gray's test. Multivariate analysis was performed using the Cox proportional hazards model. A matched-pair analysis was also performed based on the propensity score to minimize the confounding effect of baseline patient characteristics. Sex, age at HCT (20,000/µL), GVHD prophylaxis (cyclosporine- or tacrolimus-based), disease status at HCT (CR1/CR2 or CR>2), conditioning regimen (RIC or MAC), donor type (HLA-matched related/unrelated donor or alternative donor), MPAL or not, and performance status at HCT (0-1 or 2-4) were used to calculate the propensity score. Results: Of 5,304 eligible patients, 4,372 (82.4%), 882 (16.6%), and 50 (1.0%) were classified into cytogenetically intermediate-risk AML, cytogenetically poor-risk AML (excluding Ph+AML), and Ph+AML groups, respectively. Their median age was 47, 47, and 43.5 (range: 16-76, 16-74, and 16-85) years, respectively. The median follow-up for surviving patients was 2.3 (range, 0.0-22.4) years. MPAL accounted for 1.7% of the whole cohort, and its distribution was different among groups: 1.3%, intermediate-risk AML; 2.4%, poor-risk AML; and 26.0%, Ph+AML (p < 0.001). No significant difference was noted in OS between patients with and without MPAL (p = 0.22). OS at 3 years after allo-HCT was 62.8% for intermediate-risk AML, 51.1% for poor-risk AML, and 70.2% for Ph+AML (p < 0.001) (Fig 1A). The 3-year incidences of relapse and NRM were 19.6% and 22.2% for intermediate-risk AML, 32.6% and 21.7% for poor-risk AML, and 6.3% and 27.9% for Ph+AML, respectively (Fig 1B and 1C). Multivariate analysis revealed that the Ph+AML and intermediate-risk AML groups had comparable risk in terms of OS [hazard ratio (HR), 0.75; 95% confidence interval (CI), 0.45-1.28; p = 0.29]; for these groups, the risk of Ph+AML was significantly lower than the poor-risk AML (HR, 0.54; 95% CI, 0.31-0.91; p < 0.001). Ph+AML had significantly lower risk of relapse than poor-risk AML (HR, 0.16; 95% CI, 0.05-0.51; p < 0.001) and intermediate-risk AML (HR, 0.31; 95% CI, 0.10-0.94; p = 0.04). There was no significant difference in the risk of NRM (HR, 1.45; 95% CI, 0.86-2.45; p = 0.17 for Ph+AML vs. intermediate-risk AML; HR, 1.50; 95% CI, 0.87-2.57; p = 0.14 for Ph+AML vs. poor-risk AML). The matched-pair analysis extracted 39 and 38 patients from each group based on the propensity score using optimum matching (intermediate-risk AML vs. Ph+AML and poor-risk AML vs. Ph+AML). OS in the Ph+AML group was comparable with that in the intermediate-risk AML group (p = 0.81), whereas it was significantly better than that in the poor-risk AML group (p = 0.012). Conclusion: Our data show that post-transplant outcomes were better for Ph+AML patients than those with other poor-risk cytogenetics and were comparable with those for patients with intermediate-risk cytogenetics, suggesting that allo-HCT overcomes the poor prognosis of Ph+AML. Although our registry did not secure information on the use of tyrosine kinase inhibitors, their use may partly contribute to improvements in post-transplant outcomes. Disclosures Mizuno: Celgene Corporation: Honoraria; Bristol-Myers Squibb Corporation: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Kanda:Eisai: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; Tanabe Mitsubishi: Research Funding; Otsuka: Research Funding; Celgene: Consultancy, Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Alexion: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Nippon-Shinyaku: Research Funding; Alexion: Consultancy, Honoraria; Chugai: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Mochida: Consultancy, Honoraria; Sanofi: Research Funding; Takara-bio: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Nippon-Shinyaku: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Tanabe Mitsubishi: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; CSL Behring: Research Funding; Pfizer: Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Novartis: Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; CSL Behring: Research Funding; MSD: Research Funding; Taiho: Research Funding; Novartis: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria; Taisho-Toyama: Research Funding; Taiho: Research Funding. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria.

Autologous stem cell transplantation (ASCT) is a treatment option for HIV-positive patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). However, the prognosis after ASCT in HIV-positive Japanese patients remains unclear. The aim of this study was to evaluate the impact of HIV infection on transplant outcomes after ASCT in Japan. Using the national database of the Japan Society for Hematopoietic Cell Transplantation, we retrospectively evaluated patients with NHL (n = 3862) and MM (n = 2670) who underwent their first ASCT between 2001 and 2014. The presence of HIV antibody was used to diagnose HIV infection. Fifty-six patients with NHL (1.4%) and 23 with MM (.8%) were positive for HIV antibody. Among patients with NHL overall survival (OS) was lower in HIV-positive patients than in HIV-negative patients (5-year OS: HIV-positive patients, 44% versus HIV-negative patients, 65%; P .001). In a multivariate analysis HIV infection was significantly associated with an increased risk of overall mortality (hazard ratio, 2.30; P .001). The incidence of relapse was higher in HIV-positive patients (P = .036), whereas there was a similar incidence of nonrelapse mortality (P = .879). OS in patients with MM was similar between those with/without HIV infection (5-year OS: HIV-positive patients, 61% versus HIV-negative patients, 63%; P = .988). HIV infection was associated with a higher risk of overall mortality and relapse after ASCT for NHL in a Japanese population.

The optimal conditioning regimen for elderly patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) remains unclear. We retrospectively analyzed 1607 patients aged 50 years or older with acute myeloid leukemia (AML), acute lymphoblastic leukemia, or myelodysplastic syndrome (MDS) who underwent allo-HCT using fludarabine/busulfan (FB) or fludarabine/melphalan (FM) between 2007 and 2014. We compared the clinical outcomes among FB2 (busulfan at 6.4 mg/kg iv, n = 463), FB4 (busulfan at 12.8 mg/kg iv, n = 721), and FM140 (melphalan at 140 mg/m2, n = 423). The nonrelapse mortality (NRM) rates in the FB4 and FM140 groups were higher than that in the FB2 group (hazard ratio [HR], 1.63 [P

Several high-risk HLA allele mismatch combinations (HR-MMs) for severe acute graft-versus-host disease (GVHD) have been identified by analyzing transplantation outcomes in Japanese unrelated hematopoietic stem cell transplant recipients. In this study, we analyzed the effects of HR-MMs in 3 transplantation time periods. We confirmed that the incidence of grade III to IV acute GVHD in the HR-MM group was significantly higher than that in the low-risk (LR) MM group (hazard ratio [HR], 2.74; P

Background: Follicular lymphoma (FL) shows indolent clinical course and the optimal management strategy includes watchful waiting (WW). To define prognostic models for WW in clinical practice, we focused on serum soluble interleukin-2 receptor (sIL-2R) in the era of rituximab (R). Methods: To evaluate risk stratification of patients with FL, we employed the current retrospective study. The data and follow-up information of patients were collected from three medical centers. The diagnosis of FL is made by the WHO criteria. Eligible patients were aged 18-90 years, previously untreated, and diagnosed between 2004 and 2016. WW was considered as an initial approach for patients with asymptomatic, no organ damage by lymphoma, or lacking bulky disease. Progression-free survival from diagnosis (PFS1) was defined as the time from diagnosis to disease progression requiring therapy in WW, first progression after frontline active therapy, or death from any cause. Progression free survival after active therapy (PFSA) was defined as the time from anti-lymphoma therapy to progression or death, and PFS2 was defines as the time from diagnosis to secondary progression or death from any cause. This study was approved by the independent ethics committee or institutional review board at participating institutions. Results: Total 291 patients with newly diagnosed FL with stage II-IV and with grade 1-3a were included. Of these, 12.7% of patients were older than 75 years, 45% were men, 62.5% had stage IV disease, 18.9% were elevated LDH, 16.7% were beta 2-microglobulin (B2m) beyond 3 mg/L, 7.2% were grade3a, and 32.0% were FLIPI-high. The serum levels of B2m and sIL-2R were measured in each center, and the examination rates were 88.6% and 100%, respectively. In a simple linear regression, statistic correlation between serum B2m and sIL-2R of individual patients were confirmed with R-squared of 0.4 and P-value of 500 ≤1000, and >1000 were 18.9%, 26.8%, and 54.3%, respectively. Total 89 patients (30.6%) had a first-line management strategy of WW, and during the median follow-up of 6.9 years, 52 patients required active therapy consisted of R-CHOP like (100%). The other 202 patients received frontline active therapy, included R-CHOP like (82.7%), R-CVP (12.9%), R-bendamustine (1%), or R-monotherapy (3.4%), and only 5 patients received R-maintenance. With a median follow-up of 5.5 years, there were 8 deaths in WW and 22 in frontline active therapy, demonstrating no difference in overall survival (P = 0.3). Based on multivariate analysis, factors associated with PFS1 are sIL-2R of ≤500, >500 ≤1000 IU/mL, and >1000 IU/mL (HR, 1.34; 95% CI 1.03-1.74) and stage IV (HR 1.71, 95% CI 1.11-2.63), while gender, age >75 years, B2m >3.0 mg/L, elevated LDH, and histological grade were not significant. When divided into three groups using sIL-2R, 6-year PFS1 were 74.2%, 51.4%, and 40.3%, respectively (P 1000 IU/L, WW was associated with inferior PFS1 (HR 3.00; 95% CI 1.48-3.89; Figure 1) and PFS2 (HR 2.87; 95% CI 1.25-6.60) compared with frontline active therapy. The rate of histological transformation (HT) was similar: 5 in WW vs. 4 in frontline active therapy (P = 0.1). Median time to HT from diagnosis was 6.0 years (1.2-7.0) in WW, which was quite longer compared to 1.3 years (0.3-1.8) in frontline active therapy (P = 0.01). Secondary myeloid malignancies had developed in 4 patients at median 3.6 years (2.5-6.2) after frontline active therapy. Conclusion: For FL patients, the usefulness of sIL-2R is demonstrated for predicting intervals from starting WW until therapy requirements. In addition to general guidelines, the variable of sIL-2R ≤1000 IU/L at diagnosis was the simple indicator to recommend WW to postpone active therapy without impairing prognosis. Disclosures No relevant conflicts of interest to declare.

Background: Indications for allogeneic hematopoietic stem cell transplantation (allo-HCT) with reduced-intensity conditioning (RIC) have expanded widely for elderly patients and those with comorbidities. However, the optimal RIC regimen remains uncertain. A combination of fludarabine phosphate (Flu) and melphalan (Mel) is widely used in RIC regimen with comparable results to that of fludarabine phosphate and busulfan. In our hospital, Flu/Mel and low-dose total body irradiation (Flu/Mel/TBI) is mainly used in RIC regimen. We analyzed safety and efficacy in allo-HCT patients with Flu/Mel/TBI. Methods: This study was a retrospective analysis of patients with hematopoietic malignancies who received their first allo-HCT with Flu/Mel/TBI from between January 2005 to December 2015. Patients were included for Flu/Mel/TBI treatment for elderly, those with a recent fungal infection or organ dysfunction. Flu/Mel/TBI consists of intravenous Flu (125-150 mg/m2), Mel (140 mg/m2), and TBI (2-4 Gy). GVHD prophylaxis consists of tacrolimus and short-term methotrexate with or without low-dose anti-thymocyte globulin (ATG). The primary end point was non-relapse mortality (NRM) on day 100. As the secondary end point, we verified the effects about Flu/Mel/TBI for patients with non-remission. Results: From January 2005 to December 2015, 168 patients received conditioning regimens with Flu/Mel/TBI. The median age was 59 years (16-71 years). Hematopoietic malignancies consisted of acute myeloid leukemia (AML) (n=74), myelodysplastic syndrome (MDS) (n=63), acute lymphoblastic leukemia (ALL) (n=12), malignant lymphoma (ML) (n=10), chronic myeloid leukemia (CML) (n=5), adult T-cell leukemia (ATL) (n=2), acute myeloid/NK cell leukemia (n=1), and chronic active Epstein-Barr virus infection (CAEBV) (n=1). Twenty-eight donors were HLA matched siblings, 6 were mismatched siblings, and 2 were haplo-identical donors. Of these, 55 had matched unrelated bone marrow donors, and 47 had 1-allele mismatched unrelated donors and 30 cord blood donors. With regard to disease status at allo-HCT, 44 patients (26.0%) were in remission and 124 patients (74.0%) were non-remission. Forty-nine patients were administered low-dose ATG. The median observation period of survivors was 2021 days (758-4660 days). Neutrophil engraftment was achieved in 89.3%. Median neutrophil recovery to over 500/µl was obtained on day 19 (11-87). Cumulative incidence of NRM at day 100 was 17.4%. Early death, defined as death before day 100, from allo-HCT occurred in 32 patients. Three patients had early relapse. Causes for NRM were infection in 15 patients (8 pneumonia, 7 sepsis), acute cardiac failure in 3 patients, cerebral hemorrhage in 2 patients, thrombotic microangiopathy in 2 patients, acute GVHD in 1 patient, hemophagocytic syndrome in 1 patient, and 5 other causes. NRM rates at day 100 by disease status at allo-HCT showed no significant differences (remission: 15.9% vs non-remission: 17.9%, p=0.15). Overall survival (OS) and disease-free survival (DFS) at 2 years were 50.6% and 43.5%, respectively. Survival rates with regard to disease status showed significant differences. Patients in remission had a 2-year OS of 65.9%, whereas patients in non-remission had a 2-year OS of 45.2% (p=0.031). Patients in remission had a 2-year DFS of 59.1%, whereas patients in non-remission had a 2-year DFS of 37.9% (p=0.016). Cumulative incidences of grade 2-4 and 3-4 acute GVHD were 30.7% and 17.1%, respectively. Cumulative incidence of relapse at 2 years was 29.8%. Conclusion: The current study proved that disease status at allo-HCT were mainly in non-remission. In such a situation, RIC using Flu/Mel/TBI was well tolerated with relatively low NRM, and was sufficient to allow engraftment for elderly or frail patients with hematopoietic malignancies. Disclosures No relevant conflicts of interest to declare.

Trisomy 8 (+8) is 1 of the most common cytogenetic abnormalities in adult patients with myelodysplastic syndrome (MDS). However, the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) in adult patients with MDS harboring +8 remains unclear. To evaluate the outcome and prognostic factors in patients with MDS harboring +8 as the sole cytogenetic abnormality or in association with other abnormalities, we retrospectively analyzed the Japanese registration data of 381 adult patients with MDS harboring +8 treated with allogeneic HSCT between 1990 and 2013. With a median follow-up period of 53 months, the probability of overall survival and cumulative incidence of relapse at 4 years were 51% and 22%, respectively. In the multivariate analysis, age > 50 years, 2 or more additional cytogenetic abnormalities, and a high risk at the time of HSCT according to the FAB/WHO classification were significantly associated with a higher overall mortality. Nevertheless, no significant impact of the outcome was observed in patients with 1 cytogenetic abnormality in addition to +8. Although 221 patients (58%) had advanced MDS at the time of HSCT, allogeneic HSCT offered a curative option for adult patients with MDS harboring +8.

The prognosis for adult acute lymphoblastic leukemia (ALL) patients with central nervous system (CNS) involvement (CNS+) who received allogeneic hematopoietic stem cell transplantation (allo-SCT) remains unclear. We retrospectively compared the outcomes of allo-SCT for patients with CNS involvement and for patients without CNS involvement (CNS−) using a database in Japan. The eligibility criteria for this study were as follows: diagnosis of ALL, aged more than 16 years, allo-SCT between 2005 and 2012, and first SCT. Data for 2582 patients including 136 CNS+ patients and 2446 CNS− patients were used for analyses. As compared with CNS− patients, CNS+ patients were younger, had worse disease status at SCT and had poorer performance status (PS) at SCT (P < 0.01). Incidence of relapse was higher in CNS+ patients (P = 0.02), and incidence of CNS relapse was also higher (P < 0.01). The probability of 3-year overall survival (OS) was better in CNS− patients (P < 0.01) by univariate analysis. However, in patients who received SCT in CR, there was no difference in the probability of OS between CNS+ and CNS− patients (P = 0.38) and CNS involvement did not have an unfavorable effect on OS by multivariate analysis. CNS+ patients who achieved CR showed OS comparable to that of CNS− patients.

Reduced-intensity conditioning (RIC) regimens extend the therapeutic use of allogeneic hematopoietic cell transplantation (HCT) to older patients. The survival trend in 2325 patients aged >50 years presenting with de novo acute myeloid leukemia (AML) who underwent first reduced-intensity HCT (RIC-HCT) was assessed by retrospectively analyzing outcomes between 2000 and 2013. The annual number of RIC-HCTs in Japan was higher in the 2008–2013 period (n = 205/year [1229/6 years]) than in the 2000–2007 period (n = 137/year [1096/8 years]). Overall and disease-free survival were higher in the 2008–2013 period (P

The choice of conditioning regimen before allogeneic stem cell transplantation (SCT) in patients with acute lymphoblastic leukemia (ALL) is important. We retrospectively compared outcomes of medium-dose VP-16/cyclophosphamide/total body irradiation (VP/CY/TBI) regimen and CY/TBI. Five hundred and twenty-nine patients (VP/CY/TBI: n = 35, CY/TBI: n = 494) who met all of the following criteria were compared: first time for SCT, aged 15-59 years; first or second complete remission at SCT; bone marrow or peripheral blood as stem cell source; and HLA phenotypically matched donor. Median age of the patients was 34 years, and patients who received VP/CY/TBI were younger (28 years vs. 34 years, P = 0.02). Cumulative incidences of relapse and non-relapse mortality (NRM) were higher for patients who received CY/TBI (P = 0.01 for relapse, P < 0.01 for NRM). After a median follow-up period of 36.9 months, 5-year overall survival (OS) rates were 82.2% in the VP/CY/TBI group and 55.2% in the CY/TBI group. OS, and disease-free survival (DFS) in the VP/CY/TBI group were shown to be significantly better by multivariate analysis [hazard ratio: 0.21 (95% confidence interval: 0.06-0.49) for DFS, hazard ratio: 0.25 (95% confidence interval: 0.08-0.59) for OS]. VP/CY/TBI was associated with a lower relapse rate and no increase in NRM, resulting in better survival than that in CY/TBI for adult ALL patients.

The efficacy and safety of romiplostim, a thrombopoietin-mimetic peptibody, were evaluated in a double-blind, placebo-controlled, randomized trial of Japanese patients with chronic immune thrombocytopenia (ITP). Thirty-four ITP patients received romiplostim (n = 22) or placebo (n = 12) for 12 weeks, with a starting romiplostim dose of 3 μg/kg weekly. The primary end point was the number of weeks with platelet response, defined as a platelet count ≥50 × 10(9)/L (not including the 4 weeks after rescue medication administration). Patients received a median of 4 (range 1-19) prior ITP therapies including splenectomy in 44%. On study, 68% also received concomitant ITP therapy. Weekly responses occurred for a median of 11 weeks with romiplostim as compared to 0 weeks with placebo (p 0.0001). Most romiplostim-treated patients (95%) achieved platelet responses; two showed extended responses after the treatment period. The use of rescue medication was required in 9% of romiplostim-treated patients as compared with 17% of placebo-treated patients. Both treatment groups had similar incidences of adverse events (91% romiplostim, 92% placebo). Adverse events that occurred more frequently (10%) in romiplostim-treated patients included nasopharyngitis, headache, peripheral edema, back pain, and extremity pain. In conclusion, romiplostim significantly increased and maintained platelet counts and was well tolerated in Japanese patients with ITP.

The optimal treatment for adult Philadelphia chromosome-negative acute lymphoblastic leukemia [Ph(−)ALL] during first complete remission (CR1) remains a matter of debate. One treatment option for Ph(−)ALL is autologous hematopoietic stem cell transplantation (auto-SCT).[1][1],[2][2] Previous

Background Voiding dysfunction is a rare but important complication of lumbo-sacral herpes zoster. Although the symptoms are transient, the clinical impact on immunocompromised patients cannot be overlooked. Methods To clarify the time course of voiding dysfunction in herpes zoster, 13 herpes zoster patients with voiding dysfunction were retrospectively analyzed. Results Of 13 patients, 12 had background disease, and six of these were hematopoietic malignancies; four of these patients were hematopoietic stem cell transplant (HSCT) recipients. Ten patients had sacral lesions, two had lumbar, and one had thoracic lesions. Interestingly, patients with severe rash, or with hematopoietic malignancy had later onset of urinary retention than did patients with mild skin symptoms (Mann–Whitney U analysis, P = 0.053) or with other background disease (P = 0.0082). Patients with severe skin rash also had longer durations (P = 0.035). In one case, acute urinary retention occurred as late as 19 days after the onset of skin rash. Conclusions In immune compromised subjects, attention should be paid to patients with herpes zoster in the lumbo-sacral area for late onset of acute urinary retention even after the resolution of skin symptoms.

This nationwide, retrospective study compared the efficacy of cyclosporine and tacrolimus with methotrexate (CsA/MTX and TAC/MTX) for acute graft-versus-host disease (aGVHD) prevention and transplant-related outcomes. Data were obtained from the Transplant Registry Unified Management Program of the Japan Society for Hematopoietic Cell Transplantation for ≥ 16-year-old leukemia patients who received CsA/MTX or TAC/MTX after bone marrow transplantation and peripheral blood stem cell transplantation from serological HLA-matched related donors (MRD), HLA 8/8 allele-matched, or one allele-mismatched unrelated bone marrow (UBM), or 0-2 antigen-mismatched unrelated cord blood (UCB) transplantation between January 2005 and December 2009. Separate analyses were performed for each cohort. Adjusted multivariate analyses indicated that in the MRD (n = 1524) and the UBM (n = 1466) cohorts, TAC/MTX significantly reduced grade II-IV aGVHD risk (HR 0.58, P = 0.006 and HR 0.77, P = 0.015, respectively) without affecting the other transplant-related outcomes. In the UCB cohort (n = 925), TAC/MTX significantly reduced the risk of non-relapse mortality (HR 0.63, P = 0.027) and chronic GVHD (HR 0.60, P = 0.02) without significant effects on grade II-IV aGVHD (HR 0.83, P = 0.21). Our results may provide the most up-to-date data regarding GVHD prevention in Japan.

On the basis of transplantation data from the Japan Society for Hematopoietic Cell Transplantation, we retrospectively analyzed the impact of cytogenetics at diagnosis on the outcome of transplantation in 628 patients with acute myeloid leukemia who underwent autologous (n = 200), allogeneic related (n = 363), or allogenic unrelated (n = 65) stem cell transplantation (SCT) at first complete remission. For autologous SCT, patients at good cytogenetic risk had a significantly lower relapse rate (P = .017) and a significantly higher event-free survival (EFS) (P = .013) compared with those at intermediate risk. For allogeneic SCT, patients at good cytogenetic risk had a significantly lower relapse rate (P = .019) and insignificantly higher EFS (P = .093) than those at poor risk. For unrelated SCT, there was no significant difference in relapse rate or EFS between patients at good risk and those at intermediate risk. Comparison of the 3 transplantation modalities revealed that autologous SCT patients had a significantly higher incidence of relapse compared with related or unrelated SCT patients in the intermediate-risk group but not in the good-risk group. However, there were no significant differences in EFS among the 3 transplant modalities in either of these 2 risk groups. In multivariate analysis, cytogenetics was found to be an independent predictor of relapse as well as of treatment failure.

The reported outcome of hematopoietic stem cell transplantation (HSCT) from HLA-mismatched family members has been inconsistent. The object of this study was to evaluate the true impact of HLA-mismatch by using recent data from a homogenous population, excluding HSCT procedures that used graft manipulations, and by considering genotypic matching. Clinical data of 2947 patients who underwent allogeneic HSCT for leukemia or myelodysplastic syndrome were extracted from the database of the Japan Society for Hematopoietic Cell Transplantation. The main outcome measures were survival and the incidence of graft-versus-host disease (GVHD). The presence of serologic HLA-mismatch, higher age, and high-risk disease were identified as independent risk factors for both shorter survival and the development of grade III to IV acute GVHD. The impact of HLA-mismatch on survival was more relevant in standard-risk patients. These findings persisted when we used genotypic HLA matching. Survival after one-locus-mismatched HSCT was equivalent to that after HLA-matched unrelated HSCT. We concluded that when a one-locus-mismatched family donor is available for high-risk patients, immediate HSCT using this donor is warranted. In standard-risk patients, however, survival after one-locus-mismatched HSCT is significantly shorter than that after HLA-matched HSCT, and the indications for HSCT should be considered carefully.

The impact of the conditioning intensity and TBI on acute GVHD (aGVHD) is still a matter of debate. We analyzed 6848 adult recipients who received allogeneic hematopoietic cell transplants (HCT) between 2006 and 2011 in Japan. The subjects were divided into groups who had received myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC), either with or without TBI. There was a significant difference in the incidence of aGVHD 2-4 among the different conditioning types: 39% in TBI-MAC, 35% in TBI-RIC and 32% in both no-TBI MAC and no-TBI-RIC (P

Introduction: HLA 1-locus mismatched unrelated donor (1MMUD) has been used in allogeneic hematopoietic stem cell transplantation (HCT) for patients who lack an HLA-matched related or unrelated donor, although its outcome has been shown to be inferior to that of HLA-matched HCT. The use of anti-thymocyte globulin such as thymoglobulin (Thymo) as GVHD prophylaxis may overcome this drawback. The aims of this study were to compare the transplant outcomes between 1MMUD and matched unrelated donor (MUD) and to evaluate the effectiveness of Thymo in unrelated HCT from 1MMUD using the recent cohort. Methods: We retrospectively analyzed 3313 adult patients with acute myeloid leukemia (n=1835), acute lymphoblastic leukemia (n=830), or myelodysplastic syndrome (n=648) who underwent a first bone marrow transplantation from HLA -8/8 allele MUD or 1MMUD between 2009 and 2014. The patients who underwent allo-HCT from MUD with Thymo were excluded in this study. Clinical data for these patients were obtained from the Transplant Registry Unified Management Program (TRUMP), which includes clinical data of HCT performed in Japan. We compared the outcomes of MUD (n=2089) and 1MMUD with Thymo (n=109) with those of 1MMUD without Thymo (n=1115). Results: The median total dose of Thymo was 2.5 mg/kg (range 1.0-11.0 mg/kg) in the 1MMUD with Thymo group. The incidence of grade II-IV and III-IV acute GVHD were 44.5% (95% confidence interval (CI), 41.5- 47.4%) and 13.1% (95% CI, 11.2-15.2%), 33.4% (95% CI, 24.5-42.5%) and 5.8% (95% CI 2.4-11.6%), and 36.1% (95% CI, 34.1-38.2%) and 10.5% (95% CI, 9.2-11.9%) in the 1MMUD without Thymo group, the 1MMUD with Thymo group, and the MUD group, respectively (p4 mg/kg), and compared the outcomes of the 3 groups with those of 1MMUD without Thymo. The incidence of NRM at 2 years and the probabilities of GRFS at 1 year were 16.1% (95% CI, 3.7-36.3%) and 33.8% (95% CI, 13.9-55.1%) in the Thymo4 mg/kg group, and 24.1% (95% CI, 21.5-26.8%) and 38.8% (95% CI, 35.8-41.8%) in the 1MMUD without Thymo group (p=0.014 and p=0.053), respectively. Conclusions: The outcome of HCT from 1MMUD without Thymo was inferior to that of HCT from MUD even in the recent cohort. However, the negative impact of 1MMUD disappeared by the use of relatively low dose of Thymo without increasing the risk of relapse. A large prospective study is warranted to confirm the role of low dose of Thymo in HCT from 1MMUD. Disclosures Kanda: Otsuka Pharmaceutical: Honoraria, Research Funding.

Introduction: Reduced-intensity conditioning (RIC) regimens have been increasingly used in allogeneic hematopoietic stem cell transplantation (allo-HCT), because they can reduce non-relapse mortality in comparison with standard myeloablative conditioning regimens and allow previously ineligible patients such as older patients and patients with comorbidities to receive allo-HCT. However, the optimal RIC regimen in allo-HCT remains unclear. Therefore, we conducted a nationwide retrospective study to compare the transplant outcomes between fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens which are two most widely used RIC regimens for allo-HCT. Methods: We retrospectively analyzed 2008 patients aged 50 years or older with acute myeloid leukemia (AML) (n=1219), acute lymphoblastic leukemia (ALL) (n=209), or myelodysplastic syndrome (MDS) (n=580) who underwent allo-HCT using fludarabine/busulfan (FB) or fludarabine/melphalan (FM) between 2001 and 2014. The patients who underwent cord blood transplantation were excluded in this study, but those who received low dose of total body irradiation in addition to the FB or FM regimen were included. Acute leukemia in the first or second remission and MDS excluding refractory anemia with excess blasts or leukemic transformation were defined as standard-risk diseases. Clinical data for these patients were obtained from the Transplant Registry Unified Management Program (TRUMP), which includes clinical data of HCT performed in Japan. We compared the outcomes between FB2 (busulfan at 8 mg/kg po or 6.4 mg/kg iv, n=738), FB4 (busulfan at 16 mg/kg po or 12.8 mg/kg iv, n=749), and FM140 (melphalan at 140 mg/m2, n=521). Results: The median ages were 60 (50-74), 60 (50-75), 59 (50-71) years in the FB2, FB4, and FM140 groups, respectively. The cumulative incidences of grade II-IV and III-IV acute GVHD were 30.7% (95% confidence interval (CI), 27.3-34.1%) and 10.1% (95% CI, 8.0-12.4%), 36.8% (95% CI, 33.3-40.2%) and 12.5% (95% CI 10.2-15.0%), and 39.3% (95% CI, 35.0-43.5%) and 15.2% (95% CI, 12.2-18.4%) in the FB2 group, the FB4 group, and FM140 group, respectively (p=0.0061 and p=0.050). The incidence of relapse at 3 years was higher in the FB2 group (38.2%; 95% confidence interval (CI), 34.5- 41.9%) than the FB4 group (31.5%; 95% CI, 28.0- 35.0%) or the FM140 groups (28.3%; 95% CI, 24.2- 32.4%, p Conclusion: FM140 was associated with better OS in patients with high-risk AML and MDS than FB2 because of lower relapse rate and FB4 was not superior to FB2 in OS, although OS in patients with standard-risk disease did not differ among the 3 groups. A large prospective study is warranted to confirm these findings. Disclosures Kako: Otsuka Pharmaceutical: Honoraria. Kanda:Otsuka Pharmaceutical: Honoraria, Research Funding.