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Hematopoietic stem cell transplants for inherited metabolic disorders performed at Tokai University Hospital between June 5, 1986, and May 28, 2021, were analyzed and compared between the period before 2007 and the period from 2007 onward based on availability of medical resources. Transplants were performed for 38 patients with mucopolysaccharidosis, 33 with adrenoleukodystrophy, and 16 with another disorder. Before 2007, oral busulfan-based regimens were mainly used. From 2007 onward, intravenous busulfan-based regimens or 4 Gy of thoracoabdominal irradiation (TAI), fludarabine, and melphalan (Mel)/treosulfan were adopted. Between 2002 and 2010, adrenoleukodystrophy was treated with 12 Gy of TAI and Mel. HLA-identical sibling bone marrow was used in 43% of cases before 2007 and 15% from 2007 onward, while alternative donors were selected for other transplants. Overall survival and event-free survival (EFS) before 2007 and from 2007 onward were 76% and 62%, and 97% and 85%, respectively (P = 0.006 and 0.017). Transplant era predicted superior overall survival and EFS, while myeloablative conditioning also predicted EFS. The incidence of primary graft failure decreased from 2007 onward, especially in cord blood transplant when 4 Gy of TAI with 150 mg/m 2 fludarabine and 180 mg/m 2 Mel or 42 g/m 2 treosulfan were used as conditioning., (© 2024. Japanese Society of Hematology.)

The conditioning regimen is an important part of autologous hematopoietic stem cell transplantation (ASCT). We explored the efficacy and safety of an optimized BEAC (adjusted-dose, intermediate-dose cytarabine and reduced-dose cyclophosphamide, AD-BEAC) conditioning regimen for non-Hodgkin lymphoma (NHL). A total of 141 NHL patients received AD-BEAC or a standard-dose BEAC (SD-BEAC) conditioning regimen from January 2007 to December 2017, and 104 patients were included in the study after 1:1 propensity matching. The 5-year overall survival (OS) and progression free survival (PFS) rates were significantly higher with AD-BEAC than with SD-BEAC (82.7% vs. 67.3%, P = 0.039; 76.9% vs. 57.7%, P = 0.039). Transplant-related mortality (TRM) was 3.8% in both the AD-BEAC and SD-BEAC groups. The AD-BEAC group had lower incidence of oral ulcers and cardiotoxicity than the SD-BEAC group. An optimized BEAC conditioning regimen is an effective conditioning regimen for ASCT in NHL with acceptable toxicity, that is more effective and safer than a standard BEAC conditioning regimen., (© 2024. The Author(s).)

After more than 60 years of intense research in allogeneic hematopoietic cell transplantation (HCT), this therapy has progressed from one that was fraught with seemingly insurmountable complications to a standard treatment of patients with aplastic anemia. During the 1970s and 1980s, HCT donors were almost exclusively HLA-identical siblings. Subsequent advances in the understanding of the complexity of the HLA region along with the development of molecular HLA typing and the establishment of unrelated volunteer donor registries have resulted in an ever-increasing use of such donors. Most recent breakthroughs have enabled HLA-haploidentical HCT and, thereby, finding donors for nearly every patient. The outstanding outcomes reported with any of the donor options have made allogeneic HCT the preferred treatment over immunosuppressive therapy., (© 2022. Japanese Society of Hematology.)

The widespread recognition of the concept of sarcopenia, or muscle loss, has impacted the prognosis of patients undergoing high-intensity treatments. We focused on the effect of muscle loss on the prognosis of pediatric patients with hematologic diseases. A total of 65 patients with hematologic malignancies who underwent allogeneic HCT once were investigated. The change in cross-sectional psoas muscle area (PMA) measured on computed tomography (CT) images was expressed as the muscle loss index (MLI), which was calculated by dividing the pre-HCT PMA by the baseline PMA. In this study, patients with MLI values less than 0.85 were classified into the muscle loss group. Muscle loss was observed in 27 patients (41.5%). Patients who experienced muscle loss were older than those who did not. Muscle loss was an independent predictor of higher non-relapse mortality (NRM) (p = 0.012) and inferior overall survival (OS) (p = 0.045) at 5 years. Multivariate analysis showed that muscle loss was an independent risk factor for higher NRM (p = 0.046), and inferior EFS (p = 0.048). Muscle loss observed pre-HCT may be a predictor of increased NRM, poor OS and EFS in pediatric patients with hematologic malignancies undergoing allogeneic HCT., (© 2022. Japanese Society of Hematology.)

Idiopathic pneumonia syndrome (IPS) is a rare but deadly complication of hematopoietic stem cell transplantation (HSCT). This study characterized the incidence and risk factors for IPS after HSCT in Taiwan. Data from January 2009 to February 2019 was collected from the Taiwan Society of BMT national registry. Forty-three (1.1%) of 3924 HSCT patients who developed IPS were identified. Incidence of IPS was lower in patients who received autologous HSCT than patients who received allogeneic HSCT (0.68% vs 1.44%, P = 0.022). Multivariate analysis showed that use of TBI and intravenous busulfan in the conditioning regimen were each independent predictor of IPS after HSCT. In addition, development of IPS was significantly associated with increased risk of death in the first 120 days post-HSCT (HR, 2.09; 95% CI, 1.08 to 4.05, P = 0.029) and 2 years post-HSCT (HR, 1.65; 95% CI, 1.07 to 2.542, P = 0.023), but not beyond 2 years post-HSCT. However, survival outcomes did not differ significantly between patients with IPS who received autologous versus allogeneic HSCT (P = 0.52). In conclusion, despite the relatively low incidence of post-HSCT IPS in Taiwan, mortality remains high. The results of this study will help to identify high-risk patients for early intervention and guide future therapeutic research., (© 2022. Japanese Society of Hematology.)

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for patients with relapsed and refractory classic Hodgkin lymphoma (rrHL). However, the optimal conditioning regimen and GVHD prophylaxis for rrHL remain undetermined. The aim of this study was to investigate outcomes of allo-HSCT with a fludarabine plus bendamustine (FluBe) conditioning regimen and GVHD prophylaxis with posttransplantation cyclophosphamide (PTCY) in patients with rrHL., Methods: Allo-HSCT results in 58 adult patients with rrHL were analyzed retrospectively., Results: Three-year overall survival and event-free survival were 81% (95% CI 65-91) and 55% (95% CI 38-72), respectively. The cumulative incidence of relapse (CIR) at 3 years was 33% (95% CI 13-51). The cumulative incidence of aGVHD grade II-IV and severe aGVHD grade III-IV was 36% (95% CI 22-48) and 22% (95% CI 9-33), respectively. The cumulative incidence of cGVHD was 32% (95% CI 17-45), including moderate or severe cGVHD in 17% (95% CI 4-28). Patients who developed aGVHD after allo-HSCT had significantly lower CIR (24% vs 49%, p = 0.004). The use of PBSC as a graft source also significantly reduced CIR (4% vs 61%, p = 0.002)., Conclusions: FluBe-PTCY allo-HSCT facilitates favorable outcomes, low toxicity, and mortality in rrHL., (© 2022. Japanese Society of Hematology.)

Allogeneic hematopoietic stem cell transplantation (HSCT) has been used to treat patients with inherited metabolic disorders (IMDs) for more than 40 years. In the first two decades, various IMDs were treated by HSCT with a wide variety of donor sources and conditioning regimens selected at the institutional level. However, HSCT was not always successful due to post-transplant complications such as graft failure. In the third decade, myeloablative conditioning with targeted busulfan-based pharmacokinetic monitoring was established as an optimal conditioning regimen, and unrelated cord blood was recognized as an excellent donor source. During the fourth decade, further improvements were made to transplant procedures, including modification of the conditioning regimen, and the survival rate after HSCT markedly improved. Simultaneously, several long-term observational studies for patients after HSCT clarified its therapeutic effects on growth and development of cognitive function, fine motor skills, and activities of daily living when compared with enzyme replacement therapy. Although immune-mediated cytopenia was newly highlighted as a problematic morbidity after HSCT for IMDs, especially in younger patients who received unrelated cord blood, a recent study with rituximab added to the conditioning raised expectations that this issue can be overcome., (© 2022. Japanese Society of Hematology.)

Inborn errors of immunity (IEI) are caused by germline genetic mutations, resulting in defects of innate or acquired immunity. Hematopoietic cell transplantation (HCT) is indicated for curative therapy especially in patients with IEI who develop fatal opportunistic infections or severe manifestations of immune dysregulation. The first successful HCT for severe combined immunodeficiency (SCID) was reported in 1968. Since then, the indications for HCT have expanded from SCID to various non-SCID IEI. In general, HCT for IEI differs from that for other hematological malignancies in that the goal is not to eradicate certain immune cells but to achieve immune reconstitution. European Society for Blood and Marrow Transplantation/European Society for Immunodeficiencies guidelines recommend reduced-intensity conditioning to avoid treatment-related toxicity, and the optimal conditioning regimen should be considered for each IEI. We review conditioning regimens for some representative IEI disorders in Japanese and worldwide cohort studies, and future strategies for treating IEI., (© 2022. Japanese Society of Hematology.)

In this review, we will outline dimensions in which outcome of patients with myelofibrosis undergoing curative treatment can be optimized: patient selection, transplant procedure, and posttransplant prevention or treatment of relapse. For patient selection, fortunately, as with several other hematologic malignancies, the management of patients with myelofibrosis has very much entered the molecular era, with the establishment of several driver and nondriver mutations, allowing more individualized selection for treatment. For the transplant procedure itself, different conditioning intensities do not seem to play a distinctive role with regards to outcome posttransplant but still need to be compared in the molecular era. While many patients nowadays may receive ruxolitinib before transplant, recent studies may facilitate fine-tuning and integration of ruxolitinib into the transplant algorithm. The role of novel inhibitors for the transplant setting remains unclear. For the posttransplant phase, evidence remains scarce, with experiences of donor-lymphocyte infusions for relapse management but more efforts are needed in understanding relapse and identifying and treating patients at high risk for relapse., (© 2022. Japanese Society of Hematology.)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the preferred treatment for children with high-risk hematologic malignancies, but post-allo-HSCT relapse has a poor prognosis and limited treatment options. We evaluated the feasibility, outcome, and risk factors influencing survival after T-cell-replete haploidentical HSCT with low-dose anti-thymocyte globulin (ATG) in 30 patients with post-allo-HSCT relapse of acute lymphoblastic leukemia and acute myeloid leukemia. Overall, 50% of the patients had complete remission (CR) before the second transplant and the overall survival (OS) rate was 52%. In surviving patients (median follow-up 614 days), Kaplan-Meier analysis revealed estimated 2-year leukemia-free survival and OS rates of 48.1% and 61.1%, respectively. Cumulative incidences of 2-year non-relapse mortality and relapse were 24.7% and 36.3%, respectively. Achieving CR before the second allo-HSCT was a predominant independent prognostic factor identified in the multivariate analysis, with a significantly improved 2-year OS rate of 86.7%. T-cell-replete haplo-HSCT with low-dose ATG for second allo-HSCT may benefit a selected patient population., (© 2021. Japanese Society of Hematology.)

The prognosis of relapsed/refractory (R/R) pediatric acute leukemia is extremely poor. We retrospectively reviewed 20 consecutive pediatric patients with R/R acute leukemia who underwent a first HLA-haploidentical peripheral blood stem cell transplantation following reduced-intensity conditioning (haplo-RIC-PBSCT) with very low-dose antithymocyte globulin (ATG) between 2012 and 2019. Of these 20 patients, 7 patients had acute lymphoblastic leukemia, and 13 had acute myeloid leukemia. At the time of haplo-RIC-PBSCT, 15 patients had active disease. The median follow-up duration for survivors was 56 months (range 22-108 months). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus, short-term methotrexate, methylprednisolone, and ATG 1.25 mg/kg on day-2. The 2-year cumulative incidence of transplant-related mortality and relapse were 5.0% [95% confidence interval (CI) 0.7-30.5%)] and 57.8% (95% CI 37.4-79.6%), respectively. Among the 20 patients, 16 (80.0%) developed grade III-IV acute GVHD, and 2 developed severe chronic GVHD. The 2-year event-free survival and overall survival rates were 40.0% (95% CI 19.3-60.0%) and 50.0% (95% CI 27.1-69.2%), respectively. Although the sample size is small, the survival outcomes of the present study are encouraging., (© 2021. Japanese Society of Hematology.)

Graft failure is a major pitfall of unrelated umbilical cord blood transplantation (CBT) in children with rare hematological disorders other than acute leukemia, such as acquired and inherited bone marrow failure, myelodysplastic syndrome, juvenile myelomonocytic leukemia, and chronic myeloid leukemia. We developed a less-toxic conditioning regimen for CBT that achieves a higher rate of complete donor chimerism, and retrospectively compared it against two other conditioning regimens for CBT performed at our single institution. The engraftment rate with complete donor chimerism was 100% and 5-year event-free survival (5y-EFS) was 90.9% in patients using our latest regimen (n = 11) of reduced-intensity conditioning (RIC) containing fludarabine (Flu) 180 mg/m 2 , melphalan (MEL) 210 mg/m 2 , and low-dose rabbit anti-thymocyte globulin (LD-rATG) 2.5 mg/kg without irradiation (regimen C). Outcomes were better than in patients (n = 10) treated with previous regimens involving irradiation (5y-EFS 30.0%, p = 0.004): regimen A, consisting of myeloablative conditioning containing cyclophosphamide (CY) and total body irradiation (TBI) with 8-12 Gy, or regimen B, consisting of RIC with Flu, CY, horse ATG, and thoracoabdominal irradiation (TAI) with 6 Gy. In conclusion, Flu/MEL/LD-rATG (regimen C) without TBI/TAI may be preferable as RIC for unrelated CBT in children with rare hematological disorders., (© 2021. Japanese Society of Hematology.)

Fludarabine with intravenous busulfan (6.4 mg/kg; FB2) and fludarabine with intermediate-dose melphalan (140 mg/m 2 ; FM140) are the most widely used reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation. FM140 generally has a lower relapse rate and higher non-relapse mortality (NRM), resulting in overall survival (OS) comparable to that seen with FB2. To evaluate the effect of reducing the melphalan dose, we retrospectively compared transplant outcomes in 156 patients who received FB2 (n = 103) or FM80 (n = 53) at our center (median age: 63 years; range 27-72 years). All patients received 4-Gy total body irradiation. Three-year OS, the cumulative incidence of relapse, and NRM were comparable between groups (FB2 vs. FM80, 58% vs. 47%, p = 0.24; 30% vs. 36%, p = 0.57; 17% vs. 21%, p = 0.44, respectively). There was no significant difference in the cumulative incidence of graft-versus-host disease (GVHD) at day 100, chronic GVHD at 3 years, or the 3-year GVHD-free/relapse-free survival rate. In the high-risk disease group, patients receiving FM80 tended to have lower 3-year OS (FB2 vs. FM80, 48% vs. 17%, p = 0.06). In summary, transplant outcomes following FB2 or FM80 were comparable except in patients with high-risk disease., (© 2021. Japanese Society of Hematology.)

Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of peripheral T-cell lymphoma that occurs most often in adolescents and young adults and is rare in children. Because of the aggressive clinical course, resistance to conventional chemotherapy and poor prognosis of HSTCL, an effective treatment has not been established. We report the case of a 3-year-old girl with HSTCL presenting with trilineage myelodysplasia. Although the HSTCL was refractory to conventional chemotherapy, remission was achieved with salvage chemotherapy that included fludarabine and cytarabine, which were shown to be effective in the drug sensitivity assay. After undergoing umbilical cord blood transplantation with a conditioning regimen consisting of etoposide, cyclophosphamide and total body irradiation, the patient has remained in complete remission for 8 years. Single-nucleotide polymorphism array analysis revealed heterozygous deletions of PAX5 (9p), ETV6 (12p) and homozygous deletions of CDKN2A (9p). Exome analysis showed a heterozygous nonsense c.2961C>G (p.Tyr987Ter) variant of the KMT2C gene. To improve the poor prognosis of HSTCL, the chemotherapeutic regimen can be selected for each patient on the basis of drug sensitivity and molecular genetic characteristics., (© 2021. Japanese Society of Hematology.)

The efficacy of pharmacokinetically (PK) guided, once-daily administration of busulfan (BU) was evaluated in elderly patients with acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). Twenty-one patients (median age 61) received 30 mg/m 2 fludarabine for 6 days and BU for 4 days, starting from 3.2 mg/m 2 and subsequently adjusted to the target area under the curve (AUC) of 6000 µmol-min/L. The median AUC of day 1 (AUC1), AUC4, and their average were 4871.3, 6021.0, and 5368.1 µmol-min/L, respectively. Veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) occurred in five patients (24%) but all recovered well. Four patients (20%) had non-infectious pulmonary complications (NIPCs). Patients with high AUC1 had frequent gastrointestinal adverse events, but similar incidence of VOD/SOS and NIPCs. Two-year overall survival (OS), non-relapse mortality (NRM), and relapse rates were 44.4%, 28.6%, and 29.1%, respectively. Patients with high AUC1 had significantly high NRM (57.1% vs. 14.3%, P = 0.04) and inferior OS (14.3% vs. 60.1%, P = 0.002), while patients with high AUC4 had a significantly low relapse rate (8.3% vs. 55.6%, P = 0.02). In conclusion, once-daily BU and a PK-guided dose intensification were beneficial for reducing relapse in elderly patients with AML/MDS. However, caution should be exercised as rapid BU dose elevation may contribute to NRM., (© 2021. Japanese Society of Hematology.)

Standard operating procedures for autologous stem cell transplantation (SCT) aim to guarantee best possible engraftment. Three procedures are routinely used for transplant infusion: regular bag infusion (Procedure 1), injection via syringe (Procedure 2), and combination of regular bag infusion and syringe (Procedure 3). We conducted a retrospective analysis of all autologous stem cell transplants done in the hematology department of the Vivantes Clinic Neukoelln in Berlin, Germany, between January 1, 2016 and March 4, 2017. Of the total of 69 patients, 17 underwent Procedure 1, 32 Procedure 2, and 20 Procedure 3. Although speed of transplant reinfusion differed significantly between procedure types, these differences had no effect on duration of leukopenia. However, duration of leukopenia did correlate with need for blood transfusion and use of antibiotics. Our findings contradict the general perception that very rapid reinfusion is necessary. Nevertheless, considering the limitations of this study (retrospective, single center, small sample size) and that longer duration of aplasia is associated with greater need for intervention, efficient transplant reinfusion is advisable. More research is needed regarding timeliness and type of procedure used., (© 2021. Japanese Society of Hematology.)

Objective: To explore the incidence and risk factors of late-onset hemorrhagic cystitis (LOHC) in patients undergoing single umbilical cord blood transplantation for hematological malignancies., Methods: Clinical data from 234 patients who consecutively underwent single UCBT using a myeloablative conditioning regimen without antithymocyte globulin in our center were retrospectively analyzed., Results: In total, 64 (27.4%) patients developed LOHC with a median onset time of 40.5 (range 8-154) days, and 15 (6.4%) patients gradually developed grade III-IV LOHC. The incidence of LOHC was marginally higher in adults (31.0%) than in children (23.7%) (p = 0.248). HLA matching ≤ 6/8 (HR = 2.624, 95% CI 1.112-6.191, p = 0.028) was an independent risk factor for LOHC. The overall survival of LOHC patients (59.8%, 95% CI 61.7-85.5%) was significantly lower than that of patients without LOHC (86.8%, 95% CI 79.6-91.6%) at 130 days post transplantation (p = 0.036)., Conclusion: Patients with less well-matched grafts have a higher incidence of LOHC. Inherent deficiencies in immunity in the context of HLA disparity and more intense pharmacologic immunosuppression after severe acute graft-versus-host disease may contribute to viral activation. Prevention and treatment of LOHC have the potential to prolong long-term survival., (© 2021. Japanese Society of Hematology.)

The optimal conditioning regimen for stem cell transplantation in elderly patients remains to be established. We developed a novel preparative regimen using fludarabine 180 mg/m 2 , intravenous busulfan 12.8 mg/m 2 , cytarabine 8 g/m 2 , and 4-Gy total body irradiation before cord blood transplantation (CBT) in patients older than 55 years with various hematological malignancies. All but one patient received graft-versus-host disease (GVHD) prophylaxis consisting of cyclosporine (CsA) and short-term methotrexate (sMTX). Thirty-three patients were included in this study, with a median age of 64 years (range 56-70). The disease risk index was high or very high in 67% of patients, and 73% had a disease status other than complete remission. The probabilities of overall survival and disease-free survival at 3 years were 60 and 57%, respectively. The cumulative incidences of relapse and non-relapse mortality at 3 years were 18 and 25%, respectively. Regimen-related toxicities were generally tolerable. Disease-free survivors (n = 20) stopped immunosuppressants at a median of 7.4 months (range 2.6-25.0), in all cases by the time of the last follow-up. In conclusion, this highly myeloablative conditioning regimen resulted in a high probability of disease-free, GVHD-free, immunosuppressant-free survival after single CBT.(190 words).

Severe aplastic anemia and congenital amegakaryocytic thrombocytopenia are rare bone marrow failure syndromes. Treatment for aplastic anemia consists of hematopoietic stem cell transplantation (HSCT) from a matched sibling donor or immunosuppressant drugs if there is no donor available. Congenital amegakaryocytic thrombocytopenia is a rare autosomal recessive disease that causes bone marrow failure and has limited treatment options, except for transfusion support and HSCT. In the absence of a suitable matched sibling donor, matched-unrelated, haploidentical, or mismatched donors may be considered. A 2-step partial T-cell-depletion strategy can remove CD45RA+ naïve T cells responsible for graft-versus-host disease (GvHD) while preserving memory T cells. Five patients underwent transplantation using this strategy with rapid neutrophil and platelet recovery. Acute and chronic GvHD ≥ grade 2 appeared in two and one patient, respectively. No severe infections were observed before day + 100. A high (60%) incidence of transplant-associated microangiopathy was observed. Three patients (60%) remain alive, with a median follow-up of 881 (range 323-1248) days. CD45RA-depleted HSCT is a novel approach for patients lacking a suitable matched donor; however, further improvements are needed.

Data on chronic graft-versus-host disease (cGVHD) in patients with thalassemia after hematopoietic stem cell transplantation (HSCT) have not been specifically explored. The present study aimed to determine the incidence and clinical manifestations of cGVHD in children and adolescents with thalassemia who underwent HSCT and to compare healthcare utilization and medical cost between patients with and without cGVHD. We retrospectively analyzed the presentations, treatments, and outcomes of historical cGVHD (Seattle criteria), post-transplant admissions and direct medical cost for HSCT patients (n = 66). We used the 2014 NIH consensus criteria to reclassify the diagnosis of cGVHD (NIH cGVHD). Among 28 historical cGVHD patients, 13 (46.4%) fulfilled the NIH criteria. Reasons why the NIH criteria were unmet were reclassification as late acute GVHD and presence of distinctive signs without confirmatory tests. At 2 years after HSCT, the cumulative incidence of NIH cGVHD was 21.67% (95% CI, 12.31-32.74%). Lung cGVHD was associated with inferior survival with a hazard ratio of 13.6 (95% CI, 1.42-131.48). Patients with historical cGVHD had significantly increased frequency of inpatient admissions and medical cost. In conclusion, cGVHD was common in children with thalassemia receiving HSCT. Patients with cGVHD required prolonged immunosuppressive treatment and incurred high medical expenses.

Human C1q deficiency is frequently associated with systemic lupus erythematosus (SLE), which requires long-term systemic corticosteroid administration. We report the case of a 12-year-old female patient with C1q deficiency presenting with intractable SLE who successfully underwent bone marrow transplantation from a human leukocyte antigen (HLA)-mismatched unrelated donor with an immunosuppressive conditioning regimen based on fludarabine, melphalan, and anti-thymocyte globulin. She developed Grade I graft-versus-host disease, but did not have any transplantation-related morbidity. Complete donor chimerism has been maintained for 2 years after transplantation, leading to the restoration of C1q levels and the resolution of SLE symptoms. Normal C1q mRNA expression was observed in CD14 + cells. Hematopoietic stem cell transplantation from an HLA-mismatched donor is a feasible treatment for patients with C1q deficiency with refractory SLE that is dependent on systemic corticosteroid treatment who do not have an HLA-matched donor.

Busulfan (Bu) has been used in combination with fludarabine (Flu; BuFlu) or cyclophosphamide (Cy; BuCy) as conditioning for allogeneic hematopoietic stem cell transplantation (HSCT). This multi-institutional prospective study compared pharmacokinetic (PK) parameters of Bu between BuFlu and BuCy. Plasma Bu concentrations were measured by high-performance liquid chromatography at the first dose of the first and fourth days of intravenous Bu administrations (total of 16 doses of 0.8 mg/kg). Thirty-seven patients were evaluable (BuFlu, N = 18; BuCy, N = 19). The median age was significantly higher in BuFlu. In BuFlu, the median area under the blood concentration-time curve of Bu on the fourth day was 1183 μmol min/L (range 808-1509), which was significantly higher than that on the first day [1095 μmol min/L (range 822-1453), P < 0.01]. In contrast, such differences were not observed in BuCy. Consistently, there was a significant decrease in the clearance of Bu on the fourth day as compared with the first day in BuFlu. These results suggest that the PK of Bu was altered during the co-administration of Flu, which was not the case with Cy. A large-scale study is required to evaluate the significance of the differences in the PK of Bu between the conditionings on HSCT outcomes.

Autologous stem cell transplantation (ASCT) with high-dose thiotepa and busulfan is a treatment option for patients with central nervous system (CNS) lymphoma. We report here the occurrence of secondary failure of platelet recovery (SFPR) in three out of 24 patients who received high-dose thiotepa and busulfan followed by ASCT. Although there was no obvious abnormality in the primary platelet engraftment as well as the recovery of other blood cells, they developed SFPR with a median time to onset of day 38, and the platelets gradually recovered over several months with steroid therapy. During the same period, there was no development of SFPR among 50 patients who received ASCT with a conditioning regimen of MEAM (ranimustine, etoposide, cytarabine, and melphalan) or high-dose melphalan. However, one of the two patients who received a conditioning regimen of busulfan and melphalan developed SFPR, suggesting that the use of a busulfan-based conditioning regimen may be one of the risk factors for SFPR. It is important to be aware of this possible adverse effect of ASCT with high-dose thiotepa and busulfan to ensure timely diagnosis and prevention of subsequent serious complications.

An optimal pretransplant conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in older adults has not been established. Three prospective multicenter phase II studies were conducted, in which 142 patients older than 54 years (median age, 61 years; range 55-70 years) with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) received a myeloablative dose of intravenous busulfan (ivBu, 12.8 mg/kg) along with fludarabine (180 mg/m 2 ) ± low dose total body irradiation for allo-HSCT between September 2009 and February 2013. A total of 103 AML and 39 MDS patients including 21 related bone marrow (BM) or peripheral blood (PB), 50 unrelated BM, and 71 unrelated cord blood (UCB) transplantation were enrolled. Grade 3 or greater toxicities were observed in 105 patients. Neutrophil engraftment was achieved in 70 out of the 71 related PB/BM or unrelated BM recipients, and 61 out of the 71 UCB recipients. The cumulative incidence rates of relapse and non-relapse mortality after 2 years were 24.0 and 24.1%, respectively. The overall and event-free survival rates at 2 years were 53.3 and 47.4%, respectively. The myeloablative dose of ivBu was well tolerated without increased toxicity-related mortality in older adults who underwent allo-HSCT with any donor source.

Post-transplantation cyclophosphamide (PTCy) is a new method to prevent graft-versus-host disease after allogeneic hematopoietic cell transplantation. Although the use of dexamethasone is recommended as prophylaxis against chemotherapy-induced nausea and vomiting (CINV) for patients who receive high-dose cyclophosphamide, corticosteroids cannot be used during PTCy administration to exploit depletion of alloreactive T cells. Thus, CINV may not be adequately controlled in this situation. We retrospectively examined antiemetic efficacy of the combination of a 5-hydroxytryptamine-3 receptor antagonist (5-HT 3 RA) and a NK 1 receptor antagonist (NK 1 RA) in 36 patients who received PTCy, and compared this efficacy with that of the same combination together with dexamethasone in 27 patients conditioned with cyclophosphamide and total body irradiation (CY/TBI). The proportion of patients who had no vomiting during the acute phase of PTCy administration was 81%, and was lower than 100% in the CY/TBI group (p = 0.02). Our results suggest that prevention of CINV using 5-HT 3 RA and NK 1 RA during PTCy administration is suboptimal and that addition of antiemetic is necessary in patients who receive PTCy.

We report a retrospective analysis of 38 patients (age ≤ 30 years) who underwent allogeneic hematopoietic stem cell transplantation (allo-SCT) for relapsed or refractory anaplastic large-cell lymphoma (ALCL). Median follow-up for survivors after undergoing allo-SCT was 72 months (range, 35-96 months). Eight patients received reduced-intensity conditioning (RIC) regimens, including three patients with fludarabine plus melphalan-based regimens and five patients with fludarabine plus busulfan-based regimens. The remaining 30 patients received myeloablative conditioning (MAC) regimens. Median ages in the RIC and MAC groups were 24 and 15 years, respectively. The 5-year overall survival rates in the RIC and MAC groups were 100% and 49%, respectively (P = 0.018). The 5-year event-free survival rates in the RIC and MAC groups were 88% and 43%, respectively (P = 0.039). In the RIC group, four of the eight patients showed residual disease at allo-SCT, but all eight patients survived with complete remission (CR), including one patient with relapse. This result suggests that allo-SCT using the RIC regimen may be effective for relapsed or refractory ALCL in children, adolescents, and young adults, even in non-CR cases.

Advanced cutaneous T cell lymphoma (CTCL) patients have a dismal prognosis, especially those relapsing or progressing after systemic therapy. No curative therapies are available, but some new agents have prolonged disease-free survival time with a good toxicity profile. Allogeneic stem cell transplantation (allo-SCT) offers the longest disease-free survival, potentially representing the best therapeutic option for eligible patients. In the present article, we discuss current evidence about allo-SCT for CTCL patients, timing, and new therapeutic options before allo-SCT, taking into account some considerations that may impact clinical outcome.

Approximately 30-40% of patients with acute myeloid leukemia (AML) experience induction failures. In these patients who do not achieve remission with two cycles of standard induction therapies, the probability of achieving remission with subsequent inductions is very limited. Hematopoietic stem cell transplantation (HSCT) is the only curative option for these patients, but high relapse rate and transplant-related mortality often preclude them to proceed to transplant. Thus, AML not in remission at time of HSCT remains a huge unmet need in current HSCT practice, particularly if the patient does not have an HLA-matched donor identified by the time of two induction failures. We used clofarabine cytoreduction immediately followed by fludarabine (Flu) and busulfan (Bu) × 3 with total-body irradiation (TBI) conditioning (Flu/Bu3/TBI) for haploidentical peripheral blood stem cell transplant with post-transplant cyclophosphamide for two cases of refractory AML with a very high tumor burden at transplant and achieved complete remission by day + 30 in both cases.

We evaluated the efficacy and toxicity of T-cell-replete haploidentical stem cell transplantation (TCR-haploSCT) using low-dose antithymocyte globulin (ATG) in children with refractory/relapsed (R/R) acute leukemia. From October 2009 to April 2016, 39 consecutive patients with R/R acute leukemia who underwent TCR-haploSCT were included. At the time of TCR-haploSCT, 17 patients were in complete remission (CR), but 22 had active disease. Thirty-three patients received a myeloablative regimen and six received a reduced-intensity conditioning regimen. Graft-versus-host disease (GvHD) prophylaxis comprised tacrolimus, methotrexate, prednisolone, and low-dose ATG (thymoglobulin 2.5 mg/kg). Neutrophil engraftment (> 0.5 × 10 9 /L) was 95% after a median of 13 days. The median follow-up period was 527 days, with mean 3-year overall and disease-free survival rates of 45.1% [standard deviation (SD), ± 8.5%) and 33.8% (SD, ± 7.9%), respectively. The cumulative incidence of acute GvHD was 73.0%, but that of grade III-IV acute GvHD was 34.1%. The 3-year cumulative incidences of relapse and transplant-related mortality were 50.3 and 15.9%, respectively. Age < 10 years at transplantation was associated with a better overall survival in the multivariate analysis. These data suggest that TCR-haploSCT using a low-dose ATG combined with the GvHD prophylaxis described here has a significant anti-leukemic activity, particularly in younger patients.

The Japan Marrow Donor Program (JMDP) has facilitated unrelated peripheral blood stem cell transplantation (URPBSCT) since 2010. We conducted a prospective multicenter observational study to evaluate the feasibility of such transplantation. Between 2011 and 2014, 51 patients underwent URPBSCT from 8/8 allele-matched donors for hematological malignancies. The median age of the patients was 50 years; 21 had high-risk disease. Myeloablative conditioning regimens were used in 31 patients, and tacrolimus based graft-versus-host disease (GVHD) prophylaxis was used for all patients. The cumulative rate of engraftment was 96%. With a median follow-up period of 610 days for survivors, 100-day and 1-year overall survival rates were 86 and 59%, respectively. The cumulative incidence of non-relapse mortality and relapse at 1 year were 14 and 35%, respectively. The incidence of grade II to IV acute GVHD at 100 days and extensive type of chronic GVHD at 1 year were 25 and 32%, respectively. The probability of overall survival was comparable with that of bone marrow transplantation from HLA matched-unrelated donors in Japan, although the incidence of chronic GVHD was higher. Further follow-up with more patients is clearly warranted to establish the optimal use of URPBSCT together with the approaches of minimizing chronic GVHD.

We report a pilot series of five patients who received stem cell transplantation (SCT) from a spouse for post-transplant relapse or rejection. The inclusion criterion regarding HLA disparities was three or fewer antigen mismatches in the graft-versus-host direction at the HLA-A, B, and DR loci. Four patients received spousal SCT as a third transplant attempt after post-transplant relapse and one as rescue for graft rejection. The reduced intensity conditioning (RIC) regimen consisted of fludarabine, melphalan, and anti-thymocyte globulin (ATG) with 3 Gy of total body irradiation (TBI) for relapse cases and ATG plus 4 Gy of TBI for the rejection case. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus, methylprednisolone, and mycophenolate mofetil. Peripheral blood stem cells were transplanted. Granulocyte engraftment was achieved in all cases between days 9 and 11 (median, 10) with complete spousal chimerism. In three of the five patients, no acute GVHD was observed, while one case developed grade III GVHD and one case grade IV. All four patients evaluable for the anti-leukemic effect achieved complete remission; however, all relapsed between 106 and 334 day post-transplant, and died between days 152 and 548. We suggest that spousal SCT can be performed as a repetitive SCT using a RIC regimen with low-dose ATG and steroid-containing GVHD prophylaxis.

The management of relapsed/refractory mantle cell lymphoma remains challenging. Patients with relapsed mantle cell lymphoma have been treated with multi-agent salvage chemotherapies; however, outcomes are poor. Although there have been studies in the relapse/refractory setting, current data indicate that autologous hematopoietic stem cell transplantation may be an especially useful approach in the front line setting in patients in first complete or partial remission following induction chemotherapy. Allogeneic hematopoietic stem cell transplantation is the only curative option, although reduced intensity conditioning in chemo-sensitive relapse or refractory mantle cell lymphoma provides better survival rates. In addition, bortezomib, lenalidomide, temsirolimus, and ibrutinib have opened a new therapeutic era. More randomized trials should be conducted to evaluate the appropriate use of these new molecules. In this review, I discuss autologous and allo-transplant options as well as the data regarding recently approved novel agents in the relapse/refractory setting in patients with MCL.

Umbilical cord blood transplantation with a reduced-intensity conditioning regimen (RIC-UCBT) is used increasingly in patients who have comorbid organ functions and lack human leukocyte antigen-identical donors. We compared the outcomes in 35 patients who received mycophenolate mofetil plus cyclosporine (MMF/CSP, n = 17) or MMF plus tacrolimus (MMF/TAC, n = 18) for graft-versus-host disease (GVHD) prophylaxis after RIC-UCBT. Cumulative incidence of neutrophil engraftment was 94 and 89 % in MMF/CSP and MMF/TAC groups, respectively (p = 0.34). The incidence of pre-engraftment immune reaction did not differ between the MMF/CSP (41 %) and MMF/TAC (39 %, p = 1.00) groups; however, patients in the MMF/TAC group tended to have a lower incidence of grade II-IV acute GVHD than those in MMF/CSP group (28 vs 53 %, p = 0.11). Overall survival (OS) at 1 year was 43 and 60 % in MMF/CSP and MMF/TAC groups, respectively (p = 0.39). Progression-free survival, non-relapse mortality, and relapse rate were comparable between the two groups (p = 0.76, 0.59, and 0.88, respectively). In multivariate analyses, MMF/TAC GVHD prophylaxis was closely associated with improved OS, but not with incidence of engraftment and acute GVHD. These results suggest that more intensive GVHD prophylaxis with MMF/TAC decreased acute GVHD without affecting other clinical outcomes, resulting in improved OS after RIC-UCBT.

The study was aimed to explore the efficacy and safety of allo-HSCT with high-dose cyclophosphamide-induced immune tolerance for SAA. In the present study, 20 cases (12 male, 8 female; average age = 17.8 years) received reduced-intensity conditioning allo-HSCT from August 2012 to August 2014 in the Beijing Military Region General Hospital. All were HLA mismatched and received CSA; 11 received ATG-intensive immune therapy. Donors underwent mobilization with cell colony-stimulating factor. The modified preconditioning regimen included reduced-strength fludarabine combined with Busulfex and cytarabine, cyclophosphamide. Cyclophosphamide (50 mg/kg/d) induced immune tolerance 3 days after transplantation and was combined with immunosuppressive agents, including CSA, MTX, and FK506, for GVHD prophylaxis and the management of observed toxicity, GVHD and DFS. Hematopoietic reconstitution was achieved in 17 cases and engraftment after a second transplantation in an additional three cases. The average times to engraftment were 17.4 and 21.3 days, respectively, with neutrophils ≥0.5 × 10 9 /L and platelets ≥20 × 10 9 /L. Engraftment was confirmed by the evidence of 100 % donor hematopoiesis; T lymphocyte subset counts also increased significantly after transplantation. During follow-up monitoring to April 2015 (median duration = 17.7 months), three patients died of complications, while the other 17 showed disease-free survival (DFS rate = 85 %; longest DFS period = 32 months). Reduced-intensity allo-HSCT with high-dose cyclophosphamide-induced immune tolerance treatment is effective for SAA and can be the key technology extensively used in clinic, but its efficacy needs to be confirmed further with prospective randomized study with increased sample size.

Myeloablative conditioning-based allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in the treatment of adult and adolescent hemophagocytic lymphohistiocytosis (HLH) is rarely reported. We conducted a retrospective study of 30 adult and adolescent HLH transplanted for primary HLH (n = 4), tumor-HLH (n = 8), EBV-HLH (n = 14), and underlying disease-unknown (UDU)-HLH (n = 4). Peripheral blood stem cells (PBSCs) were the stem-cell source in all patients. Twenty-three patients were transplanted from HLA-haploidentical family donors, six from HLA-identical sibling donors, and one from a matched unrelated donor. Four patients appeared with mixed chimerism (MC), and no patient presented with graft failure. There was a high risk for EBV reactivation with an incidence of 47 %. Two patients developed post-transplant lymphoproliferative disorder (PTLD) and three were considered primary disease recurrent. With a median follow-up of 26 months, 19 patients survived and 11 patients died. The estimated 2-year overall survival (OS) was 63.3 ± 8.8 % in all patients, 100 % in primary HLH, 64.3 ± 12.8 % in EBV-HLH, 50.0 ± 17.7 % in tumor-HLH, and 50.0 ± 25.0 % in UDU-HLH. Myeloablative conditioning-based allo-HSCT is an effective treatment for adult and adolescent HLH to achieve complete remission and long-term survival.

Conditioning regimens that include cyclophosphamide (CY) and total body irradiation (TBI) induce severe gonadal toxicity and permanent infertility in approximately 90 % of female patients who undergo hematopoietic stem cell transplantation (HSCT). However, the use of ovarian shielding or non-myeloablative regimens may preserve ovarian function. To evaluate the ovarian reserve, serum anti-Müllerian hormone (AMH) levels were retrospectively measured in 11 female HSCT recipients aged less than 40 years, including seven with acute leukemia (AL) and four with aplastic anemia (AA), who received a myeloablative conditioning regimen with ovarian shielding or a reduced-intensity conditioning regimen. In most patients, menstruation had stopped and AMH level had decreased to an undetectable level (<0.1 ng/ml) after HSCT. Most patients showed a recovery of regular menstruation, but AMH levels did not increase immediately after the resumption of menstruation. However, in three AL patients and two AA patients who were evaluable for long-term recovery, AMH level increased gradually beyond 1 year after HSCT. In conclusion, recovery of the serum AMH level may be delayed after HSCT, and the AMH level early after HSCT may not accurately reflect ovarian reserve. A prospective study is required to address the usefulness of measuring the AMH level in HSCT recipients.

The impact of pre-transplant serum C-reactive protein (CRP) level on the outcome of reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC allo-SCT) is unclear. This study retrospectively investigated 78 patients who underwent RIC allo-SCT between 2005 and 2013. The conditioning regimen consisted of fludarabine and melphalan with/without total body irradiation. The 3-year overall survival of high CRP (43.6 % of all patients) patients was significantly worse than that of normal CRP patients in whom CRP was ≤0.3 mg/dl (26.7 vs. 74.1 %, P < 0.001). Both the CRP level before transplantation and disease risk status were independent prognostic factors for overall survival by multivariate analysis. CRP was not a significant predictor of NRM by multivariate analysis (hazard ratio 3.2, 95 % confidence interval 0.8-13.1, P = 0.100). These results suggest that measuring the CRP level before transplantation can be useful to predicting the outcome of RIC allo-SCT.

The standard conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for aplastic anemia from a human leukocyte antigen (HLA)-identical sibling has been high-dose cyclophosphamide (CY 200 mg/kg). In the present study, results for 203 patients with aplastic anemia aged 16 years or older who underwent allogeneic HSCT from HLA-identical siblings were retrospectively analyzed using the registry database of Japan Society for Hematopoietic Cell Transplantation. Conditioning regimens were defined as a (1) high-dose CY (200 mg/kg or greater)-based (n = 117); (2) reduced-dose CY (100 mg/kg or greater, but less than 200 mg/kg)-based (n = 38); and (3) low-dose CY (less than 100 mg/kg)-based (n = 48) regimen. Patient age and the proportion of patients receiving fludarabine were significantly higher in the reduced- and low-dose CY groups than the high-dose CY group. Engraftment was comparable among the groups. Five-year overall survival (OS) tended to be higher in the low-dose CY group [93.0 % (95 % CI 85.1-100.0 %)] than the high-dose CY [84.2 % (95 % CI 77.1-91.3 %)] or reduced-dose CY groups [83.8 % (95 % CI 71.8-95.8 %); P = 0.214]. Age-adjusted OS was higher in the low-dose CY group than the high- and reduced-dose CY groups with borderline significance (P = 0.067). These results suggest that CY dose can safely be reduced without increasing graft rejection by adding fludarabine in allogeneic HSCT for aplastic anemia from an HLA-identical sibling.

We compared the lomustine, cytarabine, cyclophosphamide and etoposide (LACE) and BCNU, etoposide, cytarabine, melphalan (BEAM) conditioning regimens for toxicity, engraftment kinetics, and efficacy in 139 patients undergoing autologous hematopoietic stem cell transplant for primary refractory or relapsed lymphoma. Ninety-two patients with Hodgkin lymphoma and 47 with non-Hodgkin lymphoma were enrolled. Seventy-five patients received LACE while 64 received BEAM. The incidence of grade 3-4 oral mucositis (9 vs 38%; P < 0.001) and parenteral nutrition requirement (32 vs 69%; P < 0.001) were significantly lower in the LACE cohort. The median days to myeloid (10 vs 11; P = 0.007) and platelet engraftment (13 vs 15; P = 0.026) were shorter for the LACE cohort. Transplant-related mortality in the LACE group was 9% compared to 13% in patients treated with BEAM (P = NS). The probability of overall survival (OS) and progression-free survival (PFS) at 5 years for entire cohort was 46 and 41%, respectively. Probability of OS (LACE 46% vs BEAM 47%; P = NS) and PFS (LACE 37% vs BEAM 47%; P = NS) at 5 years was comparable between two groups. We conclude that LACE has better toxicity profile compared to BEAM and results in similar long-term survival in primary refractory or relapsed lymphoma transplant.

We retrospectively evaluated single-institute outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with a reduced-intensity conditioning regimen consisting of fludarabine (125 mg/m²) and melphalan (140 mg/m²) for multiple myeloma. Twenty-three patients (median age: 46 years) were evaluated. Stem cell sources were bone marrow or peripheral blood stem cells from siblings (n = 4) and bone marrow from unrelated donors (n = 19). For graft-versus-host disease prophylaxis, cyclosporine A or tacrolimus with short-term methotrexate was given. Disease status at time of transplant was complete response in four patients, very good partial or partial response in 13, and stable or progressive disease in six. The median follow-up period of 7 survivors at analysis was 73.2 months (range 46.0-158.9 months). During the follow-up, disease recurrence or progression was observed in 21 patients, and was primary causes of death in 88% of the patients. The 5-year overall survival and progression-free survival rates were 38.6% (95% CI 19.3-57.7%) and 5.4% (95% CI 0.4-21.6%), respectively. Although allo-HSCT with this conditioning could be safely performed, further refinement of this approach aiming at more effective eradication of myeloma cells is clearly warranted.

Busulfan is a commonly used chemotherapeutic agent in myeloablative conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT). It has been associated with sinusoidal-obstructive syndrome(SOS) as a life-threatening complication of myeloablative allo-HCT, yet it has not been found to cause severe hepatocellular injury, even in cases of significant accidental overdose.We report the case of a 31-year-old male with a history of high-risk myelodysplastic syndrome transitioning to acute myeloid leukemia, who in complete remission underwent allo-HCT using myeloablative busulfan–fludarabine conditioning, and who developed hepatic failure. While he met clinical criteria for SOS and was treated with defibrotide,liver biopsy demonstrated severe subacute hepatic necrosis and lacked characteristics of SOS. Further evaluation revealed that the patient was homozygous for the HFE H63D gene mutation, associated with hereditary hemochromatosis.Both Busulfan and iron overload related to HFE H63D homozygosity can cause oxidative stress resulting in cellular injury, and the cumulative effects of these risk factors are possibly responsible for the severe hepatocellular injury in this case, making our patient the first-known case of subacute hepatic necrosis related to busulfan administration.

We retrospectively analyzed the outcomes of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) who underwent first allogeneic stem cell transplantation (allo-SCT) at complete remission (CR) with myeloablative conditioning (MAC, n = 31) or reduced-intensity conditioning (RIC, n = 15) between 2001 and 2012. All the patients had received tyrosine kinase inhibitor (TKI)-based chemotherapy prior to allo-SCT. Overall survival (OS) rates (57 vs 63%, p = 0.53), leukemia-free survival rates (50 vs 65%, p = 0.29), and non-relapse mortality rates (39 vs 35%, p = 0.62) at 2 years were similar between the MAC and RIC groups. The minimal residual disease (MRD) status evaluated by sensitive polymerase chain reaction prior to allo-SCT did not influence the OS rate (77 vs 54%, p = 0.28) and leukemia-free survival rate (69 vs 51%, p = 0.48), irrespective of the conditioning intensity. Our data suggest that the RIC regimen may represent a sufficient intensity of therapeutic pre-transplant conditioning for patients with Ph+ALL who have maintained a hematological CR with TKI-combined chemotherapy.

In Japan, intravenous busulfan (ivBu) is usually given four times per day as an infusion at 0.8 mg/kg over 2 h. However, as this requires a midnight administration, a once-daily infusion of ivBu at 3.2 mg/kg over 3 h has been investigated as a more convenient and safer method. In this study, 20 Japanese patients received once-daily ivBu in conditioning regimens before allogeneic hematopoietic stem cell transplantation (HSCT), and blood samples were obtained just before, and 3, 3.5, 5, 7, 10, and 24 h after the initiation of ivBu infusion. The outcomes of HSCT were evaluated prospectively. The median area under the plasma concentration versus time curve (AUC) of Bu was 5272 μmol × min/L (range 3491-6284 μmol × min/L), and was similar to those in previous once-daily ivBu studies and to the estimated daily AUC in previous 4-times-daily ivBu studies. All of the patients but two, who died early due to infection, achieved neutrophil engraftment at a median of 25 days after transplantation. No patient was diagnosed with veno-occlusive disease according to the criteria established by Jones. No regimen-related toxicity was significantly associated with AUC. In conclusion, once-daily administration of ivBu has a stable pharmacokinetic profile, and was safely performed in Japanese patients.

Allogeneic hematopoietic cell transplantation (HCT) is the most potent therapy for preventing relapse of acute myeloid leukemia (AML). Although its efficacy is compromised by a high risk of treatment-related morbidity and mortality, an accumulating body of evidence has led to the general recommendation favoring allogeneic HCT from a matched sibling donor during first complete remission (CR1) for younger patients with cytogenetically intermediate- or high-risk AML. Over the past few decades, this field has seen a great many advancements. The indications for allogeneic HCT have been refined by taking into account the molecular profiles of leukemic cells and the degree of comorbidities. The introduction of high-resolution human leukocyte antigen-typing technology and advances in immunosuppressive therapy and supportive care measures have improved outcomes in alternative donor transplantation, while the parallel growth of unrelated donor registries and greater use of umbilical cord blood and haploidentical donors have considerably improved the chance of finding an alternative donor. The development of reduced-intensity and non-myeloablative conditioning has made it possible to receive allogeneic HCT for patients who might once have been considered ineligible due to advanced age or comorbidities. Thanks to these advances, the role of allogeneic HCT during CR1 has become progressively more important in the treatment of AML.

High-dose melphalan with autologous stem cell transplantation (HDM/ASCT) is a promising treatment option for eligible patients with systemic immunoglobulin light chain (AL) amyloidosis. We present the results of ASCT following risk-adapted melphalan conditioning on the basis of criteria proposed by our group, including B-type natriuretic peptide (BNP). Ten patients with primary systemic AL amyloidosis treated at our institute were evaluated. A full dose of melphalan (200 mg/m(2)) was administered to patients who met all the following: performance status, 0 or 1; number of organs involved, 2 or less; serum creatinine, 1.5 mg/dL or less; EF 50 % or more and BNP 200 pg/mL or less; otherwise 140 mg/m(2). The hematologic complete response was achieved in four and organ response was seen in two patients. The median event-free survival (EFS) of all patients was 21.5 months, and median overall survival (OS) was 47.0 months. EFS and OS were significantly longer for patients who received 200 mg/m(2) of melphalan than for those who received lower dose (EFS: not reached vs. 13.9 months, P = 0.0217; OS: not reached vs. 13.8 months, P = 0.0186). No treatment-related mortality within 100 days from ASCT was observed. Evaluation of cardiac diastolic function may contribute to safer HDM/ASCT and improve outcome of AL amyloidosis.

In the present study we compared outcomes of patients with myeloid neoplasms undergoing allogeneic hematopoietic stem cell transplantation after fludarabine-based regimens with melphalan (FM140) or 3-day busulfan (FB3). The FM140 and FB3 combinations were administered to 21 and 27 patients, respectively. Efforts for early reduction (from day +30 to 60) and discontinuation (until day +100 to 130) of prophylactic immunosuppression were a component of the post-transplant approach. Following FB3 patients suffered from more severe stomatitis (P = 0.013). In contrast, other manifestations of regimen-related toxicity were more frequent in the FM140 group (P = 0.048). There were no statistically significant differences in the development of graft-versus-host disease, non-relapse mortality, post-transplant remission rate, or relapse incidence. Two-year disease-free survival rates were comparable in the two cohorts (66 vs. 55 %; P = 0.751), and so were the overall survival rates (64 vs. 62 %; P = 0.715). The outcomes of allografted patients with myeloid neoplasms were comparable after the FM140 and FB3 regimens. Relatively high therapeutic response in both groups may have been influenced by early reduction and discontinuation of prophylactic immunosuppression followed by effective immunological control of the malignant clone.

Five young patients with a long history of severe aplastic anemia (SAA) who had failed initial CSA treatment and lacked a HLA-matched sibling donor, underwent co-transplantation of unrelated donor peripheral blood stem cells (UD-PBSCs) and umbilical cord mesenchymal/stroma stem cells (UC-MSCs). After FLU + CTX + ATG ± 2GY TBI conditioning, all patients received UD-PBSCs and UC-MSCs. There were no side effects attributable to the infused MSCs, and no severe complications or infections were observed in any patient after transplantation. After transplantation, one patient experienced primary graft failure, the reason for which may be related to a long history (>17 years) of SAA. The other four patients achieved complete hematopoietic recovery and complete donor hematopoietic chimerism. We did not observe severe aGVHD or cGVHD. These data suggest that co-transplantation of UD-PBSCs and UC-MSCs is an acceptable alternative treatment for young patients with a long history of intensively treated SAA.

Although anti-T lymphocyte globulin-Fresenius (ATG-F) is commonly used as prophylaxis for graft-versus-host disease (GVHD), the appropriate dosage of ATG-F in the setting of a reduced-intensity conditioning (RIC) regimen has not been determined. In the present study, we retrospectively analyzed the clinical outcomes of 103 patients after unrelated bone marrow transplant (uBMT) with RIC regimens. RIC regimens consisted of purine analogue plus busulfan with low-dose TBI or ATG-F (5-10 mg/kg in total). Median age was 57 years (range 20-68). The incidence of grade II-IV acute GVHD and chronic GVHD with ATG-F was significantly lower than that with TBI 2 Gy (15 vs. 61 %, P < 0.05; 33 vs. 57 %, P < 0.05). The incidence of 2-year NRM with ATG-F was significantly lower than that with TBI 2 Gy (6 vs. 28 %, P < 0.05). There was no statistically significant difference in the cumulative incidence of 2-year relapse between the ATG-F and TBI 2 Gy groups (37 vs. 20 %, P = 0.13). In conclusion, the addition of low-dose ATG-F to GVHD prophylaxis in patients who received uBMT resulted in decreased incidence of acute and chronic GVHD, which led to a significantly reduced risk of NRM without compromising overall survival. The beneficial effect of low-dose ATG-F should be assessed in a prospective clinical trial.

Reports from multiple centers have shown that reduced-intensity allogeneic hematopoietic cell transplantation (RIC-HCT) is able to benefit some adult patients suffering from Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL). However, the relationship between donor cell source and outcome of RIC-HCT in (Ph-)ALL patients has not been elucidated. In this study, we present the outcome of 57 (Ph-)ALL patients treated with reduced-intensity conditioning (RIC) followed by HCT from HLA-matched related (MRD, n = 34) or HLA partially matched related (PMRD, n = 23) donors from a multicenter cohort. Neutrophil recovery at day 100 occurred in 91.3 % of the PMRD group and 97.1 % of the MRD group (P = 0.84). One hundred days after treatment, the cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 30.4 % (95 % confidence interval [CI], 13.0-53.0 %) in patients who received PMRD grafts, and 27.3 % (95 % CI, 15.0-48.0 %) for those who received MRD grafts (P = 0.76). The cumulative risk of developing chronic GVHD was 59.4 % (95 % CI, 31.0-72.0 %) in the MRD group and 23.4 % (95 % CI, 4.0-43.0 %) in the PMRD group (P = 0.03). The cumulative incidence of relapse in patients who received PMRD grafts was 18.8 % (95 % CI, 3.0-34.0 %), while for those who received MRD grafts it was 37.2 % (95 % CI, 15.0-48.0 %) (P = 0.32). Overall treatment-related mortality was 41.6 % (95 % CI, 20.0-62.0 %) in the PMRD group and 19.9 % (95 % CI, 7.0-35.0 %) in the MRD group (P = 0.08). Relapse was the most common cause of mortality in the MRD group, while infection contributed to the majority of deaths in the PMRD group. The 3-year probability of disease-free survival did not differ significantly between the two groups (55.5 % for the PMRD group vs. 48.4 % for the MRD group; P = 0.81). These data strongly suggest that RIC-HCT performed with PMRD may represent an alternative treatment option for adult patients with (Ph-)ALL.

Advanced-stage mycosis fungoides (MF) has a generally poor prognosis. Allogeneic hematopoietic stem cell transplantation improves the outcome of advanced-stage MF. Recently, cord blood has been used as an alternative stem cell source; however, there are few reports of MF patients treated using cord blood transplantation. Here, we report a rare case of refractory folliculotropic MF, which was treated with reduced-intensity conditioning followed by cord blood transplantation.