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According to recent guidelines, cytogenetically normal acute myeloid leukemia (CN AML) is divided into four molecular subgroups based on nucleophosmin-1 (NPM1) and FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations. All subgroups except for isolated NPM1mut are associated with poor prognosis. We retrospectively analyzed 223 patients with CN AML, 156 of whom were treated with standard chemotherapy. For postremission therapy, patients with available donors underwent allogeneic (allo) hematopoietic stem cell transplantation (HSCT) and the rest were treated with autologous HSCT or chemotherapy alone. We first compared the 4 conventional molecular subgroups, and then created another 4 subgroups based on WT1 expression: isolated NPM1mut, NPM1wt/FLT3-ITD-neg with low WT1 or high WT1, and FLT3-ITD-pos CN AML. We finally evaluated 89 patients who were treated with allo HSCT and achieved complete remission after standard chemotherapy. FLT3-ITD CN AML showed the worst outcome irrespective of NPM1mut, and isolated NPM1mut CN AML showed no significant differences compared with NPM1wt/FLT3-ITD-neg CN AML. In contrast, two newly stratified low-risk subgroups (NPM1wt/FLT3-ITD-neg with low WT1 and isolated NPM1mut CN AML) showed higher remission rates with superior overall survival (OS) compared with the other two high-risk subgroups, which showed a higher relapse rate even after allo HSCT. Further analysis showed that higher pre-HSCT expression of WT1 resulted in a higher relapse rate and poorer OS after allo HSCT. For CN AML, a risk-adapted approach using allo HSCT with novel agents should be evaluated with stratification specified by WT1. © 2015 Wiley Periodicals, Inc.

In relapsed or refractory non-Hodgkin lymphoma (NHL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides graft-versus-lymphoma activity resulting in fewer incidences of relapse. However, therapy-related mortality (TRM) remains an important challenge. We attempted to introduce our reduced-intensity conditioning (RIC) regimen. From 2007 to 2013, we treated 28 relapsed or refractory NHLs with allo-HSCT. All were pre-conditioned with fludarabine [FLU, 180 mg/body surface area (BSA)/6 days] and melphalan (MEL, 70 mg/BSA/1 day); 25 (all but 3) were additionally treated with total body irradiation (TBI, 800 cGy/4Fx/2 days). Peripheral blood stem cells were collected from matched siblings (n = 10) or suitably matched unrelated (n = 18) donors. There were eight diffuse large B-cell lymphomas, seven peripheral T-cell lymphoma not otherwise specified, give lymphoblastic lymphomas, two mantle cell lymphomas, and six various other lymphomas. Of these patients, 10 relapsed after auto-HSCT, 5 relapsed after chemotherapy, and 13 were refractory lymphomas. After allo-HSCT, complete remission was achieved in 22 (78.5%) patients. After a median follow-up of 24.8 months, 3-year overall survival and disease-free survival were 62.4 and 59.2% and the 3-year TRM and relapse incidence were 14.9 and 28.6% respectively. Acute and chronic graft-versus-host diseases (GVHDs) were identified in 17 (≥Grade II in 12 patients) and 18 patients respectively, and the group with chronic GVHD showed favourable survival outcomes. In relapsed or refractory NHL, RIC-allo-HSCT using FLU + MEL + 800 cGy TBI showed favourable survival outcomes with acceptable TRM and relapse incidence. Copyright © 2015 John WileySons, Ltd.

Relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is a major concern in myelodysplastic syndromes (MDS), but the role of Wilms tumor gene 1 (WT1) as a predictive marker for post-HSCT relapse remains to be validated. We measured WT1 transcript levels by real-time quantitative PCR from marrow samples of 82 MDS patients who underwent transplantation between 2009 and 2013. Pre-HSCT WT1 expression weakly correlated with marrow blast counts or International Prognostic Scoring System scores and failed to predict post-transplantation relapse. Regarding post-HSCT WT1, transcript levels of relapsed patients were significantly higher in comparison to those in remission. Further analysis using receiver operating characteristics curves showed that higher (>154 copies/104ABL) 1-month post-HSCT WT1 resulted in a higher 3-year relapse rate (47.2% versus 6.9%, P < .001) with poorer disease-free survival (DFS) and overall survival at 3 years (41.7% versus 79.0% and 54.3% versus 82.1%, P = .003 and P = .033, respectively). Multivariate analysis after adjusting for pre-HSCT karyotype and chronic graft-versus-host disease (GVHD) also revealed that higher 1-month post-HSCT WT1 was an independent predictive marker for subsequent relapse (P = .002) and poorer DFS (P = .010). In the higher 1-month post-HSCT WT1 subgroup, patients with chronic GVHD showed lower relapse rate and favorable survival outcome. One month post-HSCT WT1 expression was a useful marker for minimal residual disease and relapse prediction in association with chronic GVHD in the context of HSCT for MDS.

We analyzed the outcome of stem cell transplantation (SCT) for 59 acute myeloid leukemia (AML) patients with t(8;21). The 5-year overall and disease-free survival (OS and DFS) were 70.2 and 68.4%, respectively. The 5-year cumulative incidence of relapse (CIR) and nonrelapse mortality were 16.9 and 13.6%, respectively. OS and DFS in the reduced-intensity conditioning (RIC)-SCT group (70.4%) were not different from in the autologous SCT (ASCT) group (72.4 and 69.0%, respectively). Age was a factor affecting OS (p = 0.007) and DFS (p = 0.008) in the ASCT group, but not in the RIC-SCT group. In the ASCT group, lack of the X chromosome (-X) and an age of >50 years were associated with inferior survival; however, these differences disappeared in the RIC-SCT group. CIR was significantly higher in patients with -X than in those without -X only in the ASCT group (p = 0.038), i.e. not in the RIC-SCT group. ASCT and RIC-SCT are equally effective for the intensification of postremission treatment of AML patients with t(8;21). The subgroups with advanced age or -X should be preferentially considered for RIC-SCT, rather than ASCT. Further investigations with randomized prospective trials of a sizeable study population are warranted. © 2014 S. Karger AG, Basel

Eighty adult patients with acute myeloid leukemia (AML) received peripheral blood T cell–replete HLA haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Disease status at transplantation was either first or second complete remission (CR, n = 69) or relapse/refractory (n = 11). Identical transplant-related procedures with conditioning regimen consisting of fractionated 800 cGy total body irradiation (TBI), fludarabine (30 mg/m2/day for 5 days), busulfan (3.2 mg/kg/day for 2 days), and antithymocyte globulin (1.25 mg/kg/day on days −4 to −1) and graft-versus-host disease (GVHD) prophylaxis with tacrolimus and methotrexate were used in all patients. Recovery of neutrophil (median, 11 days) and platelet (median, 10 days) counts was achieved in all patients with full donor chimerism (≥99%), and no delayed engraftment failure was observed. The cumulative incidence of grades III to IV acute GVHD and moderate to severe chronic GVHD was 11.2% and 26.3%, respectively. A donor CD8+ and CD4+ T cell dose above the median value was significantly associated with the incidences of grades II to IV acute GHVD and moderate to severe chronic GVHD, respectively. After a median follow-up of 28 months for survivors, the 2-year cumulative incidences of relapse (n = 20) and nonrelapse mortality (n = 10) were 26.6% and 12.2%, respectively. Although all but 1 patient in relapse/refractory status died, the 2-year overall and progression-free survival of patients in first CR was 82.5% and 75.1%, respectively. We suggest the strategy of fractionated 800 cGy TBI-based conditioning with unmanipulated peripheral blood stem cell grafts seems feasible with favorable outcomes for adult patients with AML undergoing haplo-HSCT in CR.

PBSCs are increasingly being chosen as the mode of donation among unrelated donors. Pediatric patients, in particular, may receive very high CD34(+) and CD3(+) doses during unrelated PBSCT. In this work, we analyzed survival and GVHD outcomes in a cohort of 81 children who received unrelated PBSCT with uniform antithymocyte globulin (ATG)-based in vivo T-cell depletion for treatment of hematologic malignancy, with emphasis on the impact of cell dose on transplant outcomes. EFS was 61.5±5.6%, with higher CD34(+) dose (>10.0 × 10(6)/kg) and lower patient risk status predicting improved survival in multivariate study. Cumulative incidence of relapse was 30.2±5.2%; a low CD34(+) dose was the only significant factor for relapse. Neither CD34(+) nor CD3(+) dose was a significant determinant of acute or chronic GVHD. Importance of CD34(+) dose was reaffirmed in a subcohort of younger patients who received greater median cell doses than the overall cohort. In summary, for children who received unrelated PBSCT with ATG-based T-cell depletion for treatment of hematologic malignancy, the CD34(+) dose was the most important factor for relapse and EFS, and neither the CD34(+) nor the CD3(+) dose influenced incidence of acute or chronic GVHD.

The objective of this study was to evaluate the efficacy and safety of micafungin for the prevention of invasive fungal infection (IFI) during the neutropenic phase of allogeneic hematopoietic SCT (allo-HSCT) in children and adolescents. This was a prospective, multicenter, open-label, single-arm study. Micafungin was administered i.v. at a dose of 1 mg/kg/day (max 50 mg) from the beginning of conditioning until neutrophil engraftment. Treatment success was defined as the absence of proven, probable, possible or suspected IFI through to 4 weeks after therapy. From April 2010 to December 2011, 155 patients were enrolled from 11 institutions in Korea, and 147 patients were analyzed. Of the 147 patients, 121 (82.3%) completed the protocol without premature interruption. Of the 132 patients in whom micafungin efficacy could be evaluated, treatment success was achieved in 119 patients (90.2%). There was no proven fungal infection in any patient. The number of patients with probable, possible and suspected IFI was two, two and nine, respectively. Thirty-five patients (23.8%) experienced 109 adverse events (AEs) possibly related to micafungin. No patients experienced grade IV AEs. Two patients (1.4%) discontinued micafungin administration due to adverse effects. None of the deaths were related to the study drug.

To determine the roles of CD4+ T-cell (Th) subsets, including Th17 cells, in the development of chronic graft-versus-host disease (cGVHD), we used a Th-dependent cGVHD model comprising B10.D2 donor and BALB/c recipient mice. The clinical GVHD score increased beginning at day +14, peaked at day +42, and remained elevated until day +70. In the skin, increased dermal thickness was apparent at day +14, and maintained with few changes until day +70. In contrast, the liver had peak pathologic scores at day +28, and the tissue damage began to improve at day +56. To determine possible associations between improvement of liver pathology and changes in Th subsets, we analyzed Th subsets using flow cytometry. Th1 frequencies in the livers were greater than other Th subsets throughout the disease course, but the frequencies decreased over time. Notably, Th17 cells were rarely detected during earlier periods, but emerged at day +56, which correlated with the improved hepatic inflammation. In contrast, other Th subsets (Th2 and regulatory T cells) did not change significantly during the disease course. These results indicate the association of attenuation on cGVHD with a later emergence of Th17 cells and concomitant decrease of Th1 cells.

Purpose Posaconazole is a second-generation triazole with a broad spectrum. However, there is a lack of data to support a significant role for posaconazole in the treatment of invasive fungal infection (IFI), especially in Korea. Until recently, posaconazole was available only through the Korean Orphan Drug Center. This study was designed to review the use of posaconazole at a single-center in Korea. Materials and methods Data from patients who received posaconazole treatment at Catholic Blood and Marrow Transplantation Center were retrospectively reviewed between January 2007 and September 2012. Results A total of 11 cases (3 males and 8 females, median age 52 years) received posaconazole. Five patients were given the drug for mucormycosis, two for invasive aspergillosis, and four for unspecified IFI for which galactomannan (GM) assays were negative. The treatment duration ranged from 4-250 days. Three patients received posaconazole for management refractory IFI, two for intolerance of previous antifungal therapy, and six for long-term maintenance treatment. The overall successful response rate to posaconazole was 55% (six of eleven patients). Five of eleven patients died during the study period. However, only one death was attributed to the progression of IFI. None of the patients discontinued posaconazole therapy due to adverse events. Conclusion Posaconazole is an attractive oral antifungal agent for salvage treatment of IFI, particularly upon diagnosis of mucormycosis or in cases in which mucormycosis cannot be ruled out due to a negative GM.

Karyotype is a powerful prognostic factor for complete remission (CR) and overall survival (OS) in acute myelogenous leukemia (AML). Adverse-risk karyotype AML is now treated with intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) to overcome relapse. We attempted to stratify patients with this disease using a combination of known factors. We evaluated clinical correlates in 211 adults with AML and adverse-risk karyotypes. We divided the patients into several subgroups based on the number of chromosomal aberrations (NCAs), normal karyotype (NK) mosaicism, and monosomal karyotype (MK) status. CR rates and survival outcomes were compared among the subgroups, and the relapse rate was calculated in the allo-HSCT subgroup. The cutoff of NCA ≥5 showed the worst OS (P

Summary The major limitation of autologous stem cell transplantation (auto-SCT) in non-Hodgkin lymphoma (NHL) is relapse. Although autologous graft contamination may be a potential cause, prior purging of the autograft remains controversial. Therefore, we retrospectively analysed 56 consecutive patients with NHL receiving auto-SCT at complete (n = 41) or partial remission (n = 15). Among them, 24 patients underwent autograft manipulation with positive selection of CD34+ cells using a CliniMACS device (purged group). Twenty-five patients had received ≥2 previous chemotherapy regimens before auto-SCT. After a median follow-up of 41·4 months, transplant-related mortality was observed only in unpurged group (n = 2; 3·6%). The 3-year overall survival (91·7% vs. 56·1%, P = 0·009) and progression-free survival (78·7% vs. 53·1%, P = 0·034) favoured CD34+ purification. While neutrophil recovery was similar, platelet recovery was delayed in the purged group. Cytomegalovirus reactivation was predominantly observed in the purged group, although no other clinically unmanageable infectious complications occurred. Although this study has the inevitable limitations of heterogeneity in previous treatment and NHL subtypes, and a small number of patients analysed, the high survival rate in the purged group may suggest the need for prospective randomized trials to determine the role of CD34+ purification in auto-SCT for NHL.

In Asia, the incidence of chronic lymphocytic leukaemia (CLL) is lower than in Western countries. Only a few studies of CLL have been conducted in Korea, and no long-term clinical outcome data are available. We assessed the frequency of common chromosomal aberrations in Korean CLL patients using interphase fluorescence in situ hybridization (FISH) and investigated their relationship to clinical outcomes. Between 2000 and 2011, conventional cytogenetic studies were performed in 58 patients, and FISH results were available in 48 patients. We used six DNA probes for the detection of del(13q14), trisomy 12, del(11q22), del(17p13), IGH rearrangement and del(6q23). Chromosomal aberrations were identified in 15 of 58 patients (26%) with conventional cytogenetic studies and in 25 of 48 patients (52%) with interphase FISH, including six patients with complex karyotypes. In contrast with the results of Western studies, trisomy 12 was the most common aberration, followed by IGH rearrangement, del(13q14), del(11q22) and del(17p13). Deletion of 6q23 was not observed, and isolated del(13q14) was less frequent than in Western studies. Compared with the other types of chromosomal aberrations, patients with del(11q22) and del(17p13) were more likely to be Rai stage 3-4 and Binet stage C, resulting in poor responses to chemotherapy and worse outcomes. In contrast, patient with trisomy 12 and isolated del(13q14) showed better responses and superior survival outcomes. The incidence of CLL is lower in Korea than in Western countries, and the frequency of chromosomal aberrations differs, perhaps reflecting differences in the pathogenic mechanism between ethnicities. Large prospective studies are needed to further assess the prognostic value of these results in Korean CLL patients.

The aim of this study was to evaluate the impact of the response to induction therapy on the long-term prognosis of multiple myeloma (MM) after autologous stem cell transplantation (ASCT) in the era of novel agents (NAs). A total of 171 patients who were newly diagnosed with MM and underwent early ASCT were analyzed. One hundred ten had a NA-based induction therapy, and 61 patients had a non-NA-based induction therapy. After a median follow-up of 45.4 months, the 4-year overall survival (OS) and progression-free survival (PFS) from transplantation were 60.5 and 25.5 %, respectively, for the NA-based induction group and 54.6 and 15.6 %, respectively, for the non-NA-based induction group. Multivariate analyses revealed that the patients who had NA-based induction had a significantly shorter OS (P < 0.001) and PFS (P < 0.001) when at least a partial response (PR) was not achieved. In patients who did not receive NAs before ASCT, lack of at least a PR to induction therapy was not associated with a survival disadvantage. These findings suggest that, unlike pretransplantation induction before NAs, patients who do not respond to induction treatment using NAs may not derive a benefit from ASCT. The relevance of induction failure differs for corticosteroid- and NA-based induction.

The aim of this study was to estimate the prognostic factors for the outcomes of chronic myeloid leukemia (CML) patients receiving allogeneic stem cell transplantation (SCT) in chronic phase (CP) in the era of tyrosine kinase inhibitors (TKIs). Ninety-seven patients who underwent allogeneic SCT in CP were analyzed. Forty-seven were TKI-naive at the time of transplant, and 50 received TKI(s) treatment before transplantation. After a median follow-up of 115.8 months, the 4-year overall survival and event-free survival were 80.4 and 58.8%, respectively. Multivariate analysis showed that there were no differences in survival outcomes based on prior TKI therapy. Older age was a prognostic factor for higher treatment-related mortality (TRM), and the type of graft source and younger age were associated with relapse, but prior TKI therapy and disease status at the time of transplant were not associated with either TRM or relapse. Additionally, a major molecular response at 1 month and an MR(4.5) at 3 months were important predictors of favorable long-term outcomes. This study demonstrates the prognostic factors for the outcomes of allogeneic SCT in CP CML and shows that survival outcomes were not affected by the administration of long-term multi-TKI treatment prior to transplantation.

Data for 125 patients with cytogenetically normal acute myeloid leukemia (CN-AML) regarding BAALC and combinatorial molecular markers at diagnosis were evaluated. Fewer patients with higher BAALC expression at diagnosis achieved a complete remission (CR) (49.2 vs. 75.8%, p = 0.002) after the first cycle of chemotherapy, and there were more primary refractory cases (37.3 vs. 18.2%, p = 0.017). In a combinatorial analysis, FLT3-ITD-positive patients with higher BAALC showed more refractoriness and the worst overall survival (OS) (p0.001) and disease-free survival (DFS) (p0.001) in CN-AML. When NPM1-mutated CN-AML was combined with either FLT3-ITD mutation or higher BAALC expression, both OS (p = 0.043) and DFS (p = 0.008) were worse; when combined with both, it showed the worst OS (p0.001) and DFS (p = 0.004). Higher BAALC expression and FLT3-ITD mutation, both individually and in combination, were associated with worse survival outcomes in CN-AML, and this was also applicable in NPM1-mutated CN-AML, known as a favorable-risk group.

Background Few studies have been performed to identify factors that are associated with an increased risk of infections during the neutropenic period in patients undergoing allogeneic stem cell transplantation (allo-SCT). The aim of this study was to identify the host immune cells responsible for infections before engraftment. Methods A total of 282 patients who underwent allo-SCT were enrolled. Peripheral blood samples were collected before conditioning therapy. Expression of CD161- expressing T cells, natural killer cells, and immature myeloid cells was analyzed by flow cytometry. Microbially and clinically defined infections, and fevers of unknown origin as proposed by the Immunocompromised Host Society were included in this study. Results The median age was 45 years (range, 16–68 years). Patients had various hematologic disorders and were transplanted from human leukocyte antigen (HLA)-matched siblings, unrelated donors, and familial HLA-mismatched donors. In univariate analysis, younger age and a familial HLA-mismatched donor were risk factors for the occurrence of infections. After adjusting for potential variables in univariate analysis, multivariate analyses revealed that a lower frequency of CD3+CD4+CD161+ cells was significantly associated with the occurrence of neutropenic infections. An age of 35 years or younger and allo-grafting from familial HLA-mismatched donors showed a trend toward higher infection rates. Conclusion Our data indicated that a lower frequency of CD3+CD4+CD161+ T cells in peripheral blood before conditioning therapy was associated with a higher incidence of infection during the neutropenic period. These results suggest that recipient innate T cells with expression of C-type lectin CD161 can guard against infections before engraftment. This article is protected by copyright. All rights reserved.

Background Standard remission induction chemotherapy consisting of anthracycline plus cytarabine (3+7) is administered for adult acute myeloid leukemia (AML). However, the effects of intensified regimen on complete remission (CR), relapse and overall survival (OS) remain unknown. Methods We analyzed 1195 patients treated with idarubicin plus cytarabine/BHAC (3+7) from 2002 to 2013. Among them, 731 received early intensification with 3-day cytarabine/BHAC (3+10, N=363) or 2-day idarubicin plus cytarabine/BHAC 3 days (5+10, N=368). The 3+10 and 5+10 strategies were applied to patients with bone marrow blast counts of 5–20% and >20% on day 7 of 3+7, respectively. Results Early intensification correlated with a younger age (median: 40 vs. 45 yr) and higher t(8;21) frequency (20.4% vs. 7.1%), compared to 3+7. After early intensification, the early death rates were higher among the elderly (3+10 [15.7%], 5+10 [21.7%] vs. 3+7 [6.3%], P=0.038), while the post-induction CR rate was higher in young patients (3+10 [79.8%], 5+10 [75.1%] vs. 3+7 [65.1%], P

Background Acute myeloid leukemia (AML) with t(8;21)(q22;q22) is classified into a favorable-risk group. Extramedullary (EM) involvement has frequently been reported in this subgroup as resulting in a poor prognosis. However, characteristics or standard treatments of t(8;21) AML with EM involvement (EM-positive t(8;21)) have not yet been elucidated. Patients and Methods We retrospectively analyzed 154 adult AML patients with t(8;21). Among them, 17 were EM positive and 137 were EM negative at the time of diagnosis. EM involvement was evaluated only when a patient showed suspicious signs or symptoms. All EM-positive patients were treated according to a strategy based on allogeneic hematopoietic cell transplantation (allo-HCT). Results Central nervous system was the most frequently involved site (70.6%). EM-positive t(8;21) was associated with age ≤ 45 years, leukocytosis (≥ 30 × 10 9 /L), and c-kit mutation compared to EM-negative t(8;21) in multivariate analysis. After intensive chemotherapy with or without local therapy, high-risk t(8;21) AML including EM-positive t(8;21) underwent allo-HCT for postremission therapy. Three-year OS (52.3% vs. 60.0%, P = .658) and event-free survival (51.5% vs. 58.0%, P = .496) were not different between the 2 groups. The subgroup of patients who underwent allo-HCT also showed similar outcomes. Conclusion EM-positive t(8;21) was associated with young age, leukocytosis, and c-kit mutation, and central nervous system was frequently involved. Allo-HCT resulted in good outcomes in EM-positive t(8;21).

Pretransplant imatinib can improve the outcome of nonmyeloablative stem cell transplantation without increasing the morbidity in Philadelphia chromosome-positive chronic myeloid leukemia

Background Novel agents (NAs) such as thalidomide and bortezomib have been administered in combination with autologous stem-cell transplantation (ASCT) to effectively treat multiple myeloma (MM). However, whether NAs perform better as induction treatments prior to transplantation, or as post-transplant maintenance therapies remains unclear. Methods We retrospectively analyzed 106 consecutive patients with MM who underwent ASCT within 1 year of diagnosis as first-line therapy. Results Eighty-seven (82.1%) patients received NAs before ASCT, whereas 68 (64.2%) received NAs after ASCT. NAs were administered to each patient as follows: before ASCT alone (N=29, 27.4%), after ASCT alone (N=10, 9.4%) or both before and after ASCT (N=58, 54.7%). High-quality rates before and after ASCT were significantly higher for patients who received NAs as induction treatment compared to those who did not receive pre-transplant NAs. At a median follow-up of 37.9 months, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 42.8% and 70.2%, respectively. The PFS and OS were significantly higher in patients with NAs as post-transplant maintenance treatment (P=0.03 and P=0.04, respectively), but not in those with NAs as pre-transplant induction treatment. The PFS of patients with NAs before and after ASCT was higher than that of the patients with NAs as induction therapy alone (P=0.05). Age, serum β2-microglobulin level, complete response after ASCT, and NA use post-ASCT independently predicted survival outcomes. Conclusion These findings suggest that integration of NAs post-ASCT could benefit patients with MM undergoing ASCT. Induction therapy using NAs also improves high-quality response rates before and after ASCT.

Objectives For patients with acute myeloid leukemia in first complete remission (AML CR1) lacking HLA-matched sibling donors (MSD), 8/8-matched unrelated donors (URD) are mostly used in cases with poor-risk features. For AML CR1 with intermediate cytogenetics, however, the benefit of 8/8-matched URD should be compared with non-allogeneic therapies as well as MSD. Methods To address this issue, we assessed the transplantation outcomes of 8/8-matched URD (n = 54) compared with MSD (n = 145) or autologous transplantation (n = 89) for AML CR1 with intermediate cytogenetics. Results In multivariate analyses, 8/8-matched URD had comparable 6-yr overall survival (OS, P = 0.997), disease-free survival (DFS, P = 0.951), and relapse (P = 0.672) to MSD, whereas 8/8-matched URD had a higher OS (P = 0.070) and DFS (P = 0.035) with lower relapse (P = 0.009) than autologous transplantation. No difference in non-relapse mortality was observed according to donor type. Notably, these equivalent or superior outcomes of 8/8-matched URD compared with MSD or autologous transplantation, respectively, were particularly evident in patients without poor-risk features (n = 200), such as older age, hyperleukocytosis at diagnosis, and myelodysplasia-related changes, who are not usual candidates for URD transplantation. Conclusions These results indicate that 8/8-matched URD are feasible next option in AML CR1 with intermediate cytogenetics, when lacking MSD, even in patients without poor-risk features.

The role of reduced-intensity conditioning (RIC) in adult acute lymphoblastic leukemia (ALL) remains unclear because of the small sample size, short follow-up duration, various regimens for conditioning and graft-versus-host disease (GVHD) prophylaxis, and the heterogeneity of selection criteria for transplantation. We compared long-term outcomes of 60 consecutive RIC transplants (fludarabine plus melphalan) with 120 myeloablative conditioning (MAC) transplants (total body irradiation plus cyclophosphamide) for adult high-risk ALL in first or second complete remission. All transplants received a uniform strategy of pretransplant chemotherapy and GVHD prophylaxis. Compared to MAC transplants, RIC transplants had older age (46 years vs. 33 years, P

Background: Acute promyelocytic leukemia (APL) is classified into a favorable-risk group and long-term overall survival (OS) is estimated at around 80%. Relapse rate of APL is lower than another acute myeloid leukemia (AML) subtypes, but we confront higher incidence of early deaths caused by fatal complications including bleeding events and differentiation syndromes (DS) during initial therapy. Recently, although arsenic trioxide (ATO) is introduced with a better survival outcome, the results were from data of low to intermediate-risk group. Thus, patients in high-risk group still show poor survival outcome with high probability of early complications and deaths. We calculated the incidence of DS and early deaths, and tried to find out affecting factors for those early events. Methods: In this single center retrospective study, 259 APL patients (median 42 years old (16-72), follow-up was 65.4 months (11.1 - 170.5) from 2002 to 2014 were analyzed. APL was diagnosed by RT-PCR method for detection of PML-RARa and all patients were available with cytogenetic results. All except 5 patients with normal karyotype was identified with t(15;17)(q22;q21) and 77 showed combination of additional karyotypes. All patients were supported with sufficient transfusion and received ATRA. Our treatment protocol was based on the modified AIDA protocol using ATRA and idarubicin monotherapy (Sanz et al. Blood. 1999; 94: 3015-21) but some patients with comorbidity were treated with ATO, low-dose cytarabine, and ATRA alone for remission induction. For hyperleukocytosis, we conducted leukapheresis when leukocyte counts exceeded 50 (x109/L) and some were treated with hydroxyurea, cytarabine and prophylactic dexamethasone. High-risk group was determined according to the Sanz criteria which presented leukocyte count > 10 (x109/L) at diagnosis. For leukocyte count, we checked diagnostic level (WBCdx) and the maximal level (WBCmax) during initial therapy and identified a group which showed a meaningful increment of WBCmax compared to WBCdx. Results: ATRA was applied in 258 patients and 217 (84.1%) were treated with idarubicin, 13 (5.0%) were with ATO, 3 (1.2%) were with low-dose cytarabine. Eight-week cumulative incidence of early death and DS was 13.5% and 17.8%, and hematological CR was identified in 222 (86.0%) patients. Five-year OS and EFS was 76.8% and 69.8%, and CIR rate was 15.7%. Six patients showed clonal evolution to therapy-related AML and 3 patients died in CR. FLT3-TKD and FLT3-ITD mutation was identified in 12 (7.3%) and 34 (20.7%) patients, and PML-RARa BCR3 and BCR1 subtype was identified in 70 (36.8%) and 120 (63.2%) patients, respectively. For leukocyte counts, except for WBCdx higher than 43 (x109/L), which showed significantly higher rate of early death and DS, patient groups with WBCdx 43 (x109/L) and low antithrombin III were significant for DS, while old age, WBCmax, and high D-dimer were associated with early death. In our data, dexamethasone prophylaxis did not show a preventive effect for DS or early death, while leukapheresis in patients with WBCmax >43 (x109/L) showed marginally decreased early death rate `resulting superior OS without significant bleeding complications. Conclusion: Our data revealed WBCmax with higher increment ratio was a significant predictive factor for early death and DS compared to WBCdx even in the low Sanz-risk group. The role of dexamethasone, transfusion support including antithrombin III, leukapheresis or cytoreduction should be evaluated in the specific patient subset for reducing early events in APL. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background: Although recently, Eculizumab, humanized monoclonal antibody directed against complement component C5, has used increasingly for the patients with hemolytic paroxysmal nocturnal hemoglobinuria (PNH), allogeneic stem cell transplantation (allo-SCT) can be curative treatment option especially for PNH patients with combined aplastic anemia (AA). The aim of the present study was to evaluate long-term outcome of allo-SCT in patients with AA/PNH. In addition, patients with classic PNH who underwent allo-SCT in the pre-eculizumab era were also evaluated. Methods: Total of 33 patients with PNH clones underwent allogeneic SCT at our institution between Jan 1998 and Jan 2016. Among them, seven patients had classic PNH and 26 patients with cytopenia had AA/PNH (with bone marrow evidence of a concomitant AA). Results: There were 21 male and 12 female patients with a median age of 34 years (range, 13-56 years). Pre-transplant GPI-AP deficient neutrophils and erythrocytes were 5.6% (0-92) and 21% (0-98.5), respectively. Median white blood cell, absolute neutrophil count, hemoglobin, and platelet at transplant were 2.4×109/L, 0.8×109/L, 7.7 g/dL, and 27×109/L, respectively. Median LDH level was 727 U/L (232-7721 U/L) and 19 (58%) patients had LDH ≥1.5x upper limit of normal. Classic PNH (n=7) and AA/PNH [SAA (n=15), VSAA (n=9), or non-SAA (n=2)] received SCT from HLA-matched sibling (MSD, n=24), unrelated (URD, n=7), or haplo-identical donor (Haplo-SCT, n=2). Since 2003, the conditioning regimen for MSD-SCT was changed from Busulfex (12.8 mg/kg) + cyclophosphamide (CY, 120 mg/kg) to fludarabine (180 mg/m2) + CY (100 mg/kg) + rATG (10 mg/kg). The conditioning regimen for URD-SCT and Haplo-SCT were TBI (800 cGy) + CY (100-120 mg/kg) ± rATG (2.5 mg/kg) and TBI 600cGy + Fludarabine (150 mg/m2) + rATG (5 mg/kg), respectively. After a median follow-up of 57 months (range 6.0-151.3), the 5-year estimated OS rates were 87.9 ± 5.7%. Four patients died of treatment-related mortality (TRM), including acute GVHD (n=1), pneumonia (n = 2), and cerebral hemorrhage (n=1), respectively. Except one patient with early TRM, 32 patients engrafted. Two patients who experienced delayed graft-failure received second transplant and recovered. The cumulative incidence of acute GVHD (≥grade II) and chronic GVHD was 27.3 ± 7.9% and 18.7 ± 7.0%, respectively. Among 25 patients with available follow-up data, PNH clone disappeared at median 3.0 months (range 0.7-45.5) after SCT and reemerging of PNH clones was observed in two patients; one patient showed re-appearance of 2.6% GPI-negative neutrophils at 12 months without PNH symptoms, but disappeared again at 21 months. Another patient suffered from labile graft and received a booster with peripheral blood stem cells. Conclusion: This study showed that long-term transplant outcome in patients with AA/PNH were comparable to that of allogeneic SCT in SAA (the 3-year estimated OS rates were 92.7 and 89 % for MSD-SCT and URD-SCT, respectively) at our institution (ASH Annual Meeting Abstracts 2012;120:4151). Reduced-intensity conditioning regimen was sufficient for the eradication of PNH clone in allogeneic SCT. Therefore, application of allogeneic SCT should be considered in PNH patients with AA in case of availability of well matched donor. Disclosures No relevant conflicts of interest to declare.

Background: On the basis of the characteristics of extranodal natural killer T (NK/T)-cell lymphoma (ENKTL) which is predisposed to have the multidrug resistance phenotype and radiosensitivity, combined chemotherapy-radiotherapy is one of the effective options in localized early-stage, ENKTL, nasal type. However, frequent severe myelosuppression (grad 3/4 cytopenia), grade 3 radiation-related mucositis, and local/systemic relapse is a major obstacle. So we evaluated the proMACE-cytaBOM (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, and methotrexate) as a slightly less intense regimen with sandwiched radiotherapy (36 Gy). Patients and Methods: From July 2005 to December 2014, Thirty-one patients with newly diagnosed, stage IE to IIE, nasal type ENKTL were analyzed retrospectively. Twenty patients received the chemoradiotherapy sandwiched method: Initially 3 cycles of proMACE-cytaBOM, followed by radiotherapy of 36 Gy, after sandwiched radiotherapy and additional 3 cycles of proMACE-cytaBOM were administered. The other eleven patients were treated with following: Two patients received the frontline autologous hematopoietic stem cell transplantation, five patients were treated with sequential chemoradiotherapy as VIPD (etoposide, ifosfamide, cisplatin, and dexamethasone) followed by radiation of 50 Gy. Four patients received the chemotherapy alone (4 to 6 cycles of proMACE-cytaBOM). Results: In twenty patients with completely proMACE-cytaBOM and sandwiched radiotherapy schedule, median age was 50-year (range 26 to 79), with male-dominant (85%). A median of 6 (range, 4-6) cycles of proMACE-cytaBOM were administered, and sandwiched radiotherapy was received with a median 36 Gy (range 34.5 to 36) (Table1). Interim analysis after 3 courses of proMACE-cytaBOM showed that an overall response rate (ORR) of 82.6%, with complete remission (CR) and partial remission (PR) achieved in 73.9% and 8.7%, respectively. On treatment completion with chemotherapy and sandwiched radiotherapy, the ORR was increased to 90.0%, with CR rate increased to 85%. One patient experienced disease progression, and the other one was within stable disease during therapy. With a median follow-up of 42 months (range 5.5 to 81.4), the 5-year overall survival and progression-free survival were 83.6% (95% CI, 69 to 95 %) and 45.9% (95% CI, 45 to 95%), respectively (figure 1). Grade 3/4 neutropenia developed in 25% (n=5) of patients and grade 3 radiation-related mucositis in 10% (n=2). There was no regimen treatment-related mortality (TRM) (Table 2). Conclusion: The proMACE-cytaBOM regimen with sandwiched radiotherapy (36 Gy) could be a promising and feasible option in the treatment of newly diagnosed localized ENKTL due to its favorable efficacy and tolerable low toxicities including of low radiation-related mucositis and no TRM. Table 1 patient demographic and characteristics Table 1. patient demographic and characteristics Table 2 major adverse events of therapy in twenty patients with localized ENKTL Table 2. major adverse events of therapy in twenty patients with localized ENKTL Figure 1 Overall survival and progression-free survival after combined chemotherapy with sandwiched radiotherpay Figure 1. Overall survival and progression-free survival after combined chemotherapy with sandwiched radiotherpay Disclosures No relevant conflicts of interest to declare.

Background: Human leukocyte antigen (HLA) matching between donor and recipient is a key part of successful allogeneic hematopoietic cell transplantation (allo-HCT). The HCT from the unrelated donor (UD) with one allele/antigen mismatch (MM) can be as beneficial as HCT from perfectly matched donor. For the remaining patients, the donors with permissive mismatches may be the option. In HLA-mismatched transplantation, the patient and donor can also be mismatched for their killer cell immunoglobulin-like receptor (KIR) ligands that recognize allotypic determinants shared by certain HLA class I allele groups. Recent research has accumulated evidence of the role of each HLA locus and KIR ligand MM on clinical outcomes for UD-HCT. However, HCT outcomes of the patients with permissive MM depending on KIR ligand MM (KIR-L-MM) status remain obscure in UD-HCT. In the current study, we identified permissive and nonpermissive MM allele combinations and analyzed the effects of these mismatches in combination of KIR ligand mismatches in patients with acute myeloid leukemia (AML). Methods: A total of 438 patients with AML who underwent allo-HCT from UD from 2007 to 2014 were analyzed. Alleles of patients and donors at the HLA-A, -B, -C, and -DRB1 loci were identified by the high resolution DNA typing. Nonpermissive HLA allele combinations were defined as a significant HLA risk factor for severe acute graft-versus-host disease (aGVHD). KIR-L-MM among patient-donor pairs were searched in the Immuno Polymorphism Database available at www.ebi.ac.uk/ipd/kir. Results: Median age of the patients was 45 (range 15-60) years and 117 patients (40.4%) were female. Eighty-five (19.4%) patients were high risk at the time of HCT. Reduced intensity conditioning was performed in 131 patients (29.9%) and anti-thymocyte globulin was used in 324 patients (74.0%). Primary graft source was peripheral blood stem cells (n=369, 84.2%) and median 6.0 x 106/kg cells were infused. Severe aGVDH occurred in 43 patients (9.8%) and chronic GVHD (cGVHD) in 193 (44.1%). With median follow-up duration of 19 (range, 2-96) months, treatment-related mortality (TRM) occurred in 111 patients (25.3%), relapse in 119 (27.2%) and death in 214 (48.9%). Two-hundred sixty-four patients (60.3%) were HLA full matched in the 4 loci. Mismatches in HLA-A loci observed in 64 patients, HLA-B in 35, HLA-C in 98, and HLA-DRB1 in 60. Five nonpermissive MM pairs in 33 patients were identified as donor/patient pair: A*02:06/A*02:01, C*03:03/C*08:01, C*08:01/C03:04, C*08:01/C*15:02, and DRB1*04:03/DRB1*04:05. Among 98 patients with HLA-C loci MM, 16 patients showed KIR ligand MM (KIR-L-MM) as GvH direction, which was observed in the permissive MM group. Severe aGVHD occurred in 30.4%, 22.4%, 13.4%, and 10.8% in nonpermissive, permissive MM and KIR-L-MM, permissive MM and KIR-L-M, and full match group, respectively (p=0.003). The 3-year overall survival (OS) rate was inferior in permissive MM and KIR-L-MM group (30.0%) compared to full match (53.5%), permissive MM and KIR-L-M (51.8%), and nonpermissive (42.4%) group (p=0.067). The 3-year TRM was higher in permissive MM and KIR-L-MM group (57.5%) than full match (21.0%), permissive MM and KIR-L-M (27.7%), and nonpermissive (33.3%) group (p=0.006). In the multivariate analysis, high risk at HCT (HR 2.087, p6x106/kg (HR 4.113, p=0.017) were high risk factors on severe aGVHD. Conclusion: Permissive MM for HLA could be further classified into high risk groups with regard to TRM by KIR-L matching in UD-HCT. The evaluation of KIR-L matching is warranted to reduce unfavorable outcomes among the patients with permissive MM in UD-HCT. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Background: The use of tyrosine kinase inhibitor (TKI)-based chemotherapy has demonstrated improved complete remission (CR) rates and increased applicability to allogeneic hematopoietic cell transplantation (HCT), thus allowing better survival in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). However, the sensitivity of Ph-positive ALL to reduced-intensity conditioning (RIC) versus myeloablative conditioning (MAC) by minimal residual disease (MRD) kinetics is not well established. Previously, we have confirmed that monitoring MRD kinetics is very important to predict long-term outcomes. Here, we examined a cohort of patients with Ph-positive ALL in CR1 and tried to compare the long-term outcomes of RIC-HCT vs MAC-HCT according to pre-HCT MRD kinetics. Methods: During the period between 2000 and 2014, 173 adults (median age, 39 years [range, 16-65 years]) with Ph-positive ALL were included in this analysis. All patients received allogeneic HCT (68 RIC [fludarabine 150mg/m2 + melphalan 140mg/m2] and 105 MAC [total body irradiation 13.2Gy + cyclophosphamide 120mg/kg]) in CR1 following two courses of first-line TKI (138 imatinib and 35 dasatinib)-based chemotherapy and had data on prospectively determined quantitative MRD kinetics. A total of 52 patients were excluded because of >CR1 pre-HCT status (n=26), transplants receiving umbilical cord blood grafts (n=14), and no TKI use before HCT (n=12). All but one RIC transplants received peripheral blood stem cells as a graft source (40 matched sibling donor, 11 matched unrelated donor, 17 mismatched unrelated donor), while MAC transplants used either bone marrow (n=73; 57 matched sibling donor, 8 matched unrelated donor, 6 mismatched unrelated donor) or peripheral blood stem cells (n=32; 2 matched sibling donor, 20 matched unrelated donor, 10 mismatched unrelated donor). The median time to transplant was 154 days (range, 119-291 days) in RIC transplants and 141 days (range, 112-280 days) in MAC transplants, respectively. Calcineurin inhibitors (cyclosporine for sibling donor transplants, tacrolimus for unrelated donor transplants) and methotrexate was used for graft-versus-host disease (GVHD) prophylaxis and antithymocyte globulin was administered to the patients who received mismatched unrelated donor grafts. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued. MRD monitoring was centrally evaluated by real-time quantitative PCR (4.5 log sensitivity) through handling of bone marrow samples. Results: After a median follow-up of 70.4 months (range, 16.0-176.8 mo), RIC regimen showed comparable 5-year cumulative incidence of relapse (CIR; 30.2% vs 27.9%, P=0.750), non-relapse mortality (NRM; 20.3% vs 15.5%, P=0.318), disease-free survival (DFS; 49.7% vs 56.6%, P=0.296), and overall survival (OS; 59.3% vs 62.1%, P=0.540) compared to MAC regimen. We further analyzed the impact of conditioning intensity on CIR and DFS according to MRD kinetics. Based on the MRD kinetics during the pre-HCT TKI-based chemotherapy courses, we classified patients into 3 subgroups: early-stable molecular responders (EMR, n=59), late molecular responders (LMR, n=57), and poor molecular responders (PMR, n=53). In all MRD-based subgroups of patients, no significant difference in CIR (EMR: 16.3% vs 6.2%, P=0.280; LMR: 10.5% vs 21.4%, P=0.334; PMR: 63.6% vs 59.4%, P=0.372) or DFS (EMR: 68.1% vs 78.1%, P=0.381; LMR: 49.6% vs 59.5%, P=0.369; PMR: 27.3% vs 34.2%, P=0.250) was observed between RIC and MAC. In multivariate analysis, LMR (HR, 2.36; 95% CI, 0.81-6.86; P=0.114) or PMR (HR, 9.05; 95% CI, 3.40-24.1; P Conclusion:RIC-HCT showed comparable long-term outcomes to MAC-HCT in all MRD-based subgroups of patients with Ph-positive ALL in CR1. Our data suggest that RIC-HCT is worthy of further investigation in prospective trials of adult Ph-positive ALL. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Background Although the combination of lenalidomide and low-dose dexamethasone (Len-dex) is known to preserve the efficacy with reduced toxicity than lenalidomide plus high-dose dexamethasone (Len-Dex) in patients with refractory/relapsed multiple myeloma (RRMM), infection is still a leading toxicity. Moreover, the patterns and risks for infection in patients with RRMM during Len-dex treatment remain unclear and there is a need to identify contributing factors associated with increased risk for infection. Considering the disease-related and treatment-related immune deficits in patients with RRMM, we explored the predictive implications of the revelation of the immune cell populations prior to Len-dex initiation for the occurrence of infection. In addition, the various clinical and laboratory parameters were analyzed. Methods Clinical and microbiology records of 90 RRMM patients during Len-dex treatment were reviewed and risk factors for infection were analyzed using the logistic regression. In addition, to develop the new immune cell biomarker, we prospectively examined immune cell populations (CD3, CD4CD161, CD8CD161, Lin-HLA-DR-CD11b+CD33+, CD14+HLA-DR-, NK and NKT cells) of the peripheral blood taken on baseline of Len-dex therapy. Results Forty-eight men and 42 women were enrolled in this study. The median age was 61 years (range, 29-84 years). During a median 11 cycles of Len-dex treatment, 52 (57.8%) patients experienced at least 1 infection episode. Of a total of 92 episodes of infection, 58 (63%) episodes were clinically defined, 29 (31.5%) episodes were microbiologically defined, and 5 (5.4%) episodes were fever of unknown focus. Severe episodes were frequently observed during early 3 cycles. In the univariate analyses, lower Hb ( Conclusions We demonstrated several clinical predictive factors for the occurrence of infection in patients with RRMM receiving Len-dex treatment. And we found that the frequency and absolute count of CD4+CD161+ cells may provide additional information for predicting the occurrence of infection in early period of Len/dex therapy. Disclosures No relevant conflicts of interest to declare.

Background Recent advances in controlling graft failure and graft-versus-host disease (GVHD) due to barrier of HLA incompatibilities in haplo-identical stem cell transplantation from related mismatched donor (Haplo-SCT) extended its application to severe aplastic anemia (SAA). Therefore, studies for searching optimal conditioning regimen and strategy of graft manipulations for SAA patients who receive Haplo-SCT are needed. This prospective study was aimed to explore the optimal conditioning regimen to ensure engraftment with minimal toxicity in adult patients with SAA who received Haplo-SCT. Methods We have explored a safe and sufficient dose of ATG in combination with 800 cGy TBI and fludarabine (Flu, 30 mg/m2/day) for 5 days using step by step dose de-escalation based on the transplant-related mortality (TRM) and toxicity. The dose of ATG was de-escalated from 10 mg/kg (group 1), 7.5 mg/kg (group 2), to 5 mg/kg (group 3) and from October 2014, the TBI dose also reduced to 600 cGy with fixed dose of Flu and ATG (5mg/kg) (group 4). If any patient developed TRM with engraftment in each group, we moved to next group. For GVHD prophylaxis, a combination of tacrolimus and short-course methotrexate was used. G-CSF mobilized PBSCs were used as stem cell source without manipulation. Considering the importance of both survival and GVHD rate when testing conditioning regimen, GVHD-free survival, defined as grade 3-4 acute GVHD, chronic GVHD requiring systemic treatment, or death was addressed. Results Twenty-nine patients including 18 men and 11 women were enrolled. The median age was 31 (17-52) years. Median CD34+ cells transplanted were 5.84x106/kg (1.45-16.2). All patients achieved primary engraftment. Thirteen patients (7 of 10 in the group 1-3, 6 of 19 in the group 4) had CMV DNAemia requiring pre-emptive therapy including 3 patients with CMV disease (2 pneumonia, 1 colitis). Three patients (2 in the group 1, 1 in the group 2) developed EBV-associated PTLD, of whom two patients with monomorphic type received rituximab and chemotherapy. The incidence of acute GVHD (grade ≥2) and chronic GVHD (≥ moderate) were 24% and 17%, respectively. With a median follow-up of 41.4 (31.9-48.9) months in the group 1-3 and 10.1 (1.3-20.6) months in the group 4, probability of overall survival (94.1% in the group 4 vs. 70% in the group 1-3, P = 0.292) and GVHD-free survival (73.3% in the group 4 vs. 50% in the group 1-3, P = 0.161) were improved in the group 4. Conclusions This study explored the optimal conditioning with step by step de-escalation dose of ATG and TBI to reduce TRM with sustained graft function. TBI-600 cGy/Flu/low-dose ATG resulted in feasible outcomes of Haplo-SCT for adult patients with SAA. Disclosures No relevant conflicts of interest to declare.

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by the proliferation of one or more myeloid lineages. The current study demonstrates that three driver mutations were detected in 82.6% of 407 MPNs with a mutation distribution of JAK2 in 275 (67.6%), CALR in 55 (13.5%) and MPL in 6 (1.5%). The mutations were mutually exclusive in principle except in one patient with both CALR and MPL mutations. The driver mutation directed the pathologic features of MPNs, including lineage hyperplasia, laboratory findings and clinical presentation. JAK2-mutated MPN showed erythroid, granulocytic and/or megakaryocytic hyperplasia whereas CALR- and MPL-mutated MPNs displayed granulocytic and/or megakaryocytic hyperplasia. The lineage hyperplasia was closely associated with a higher mutant allele burden and peripheral cytosis. These findings corroborated that the lineage hyperplasia consisted of clonal proliferation of each hematopoietic lineage acquiring driver mutations. Our study has also demonstrated that bone marrow (BM) fibrosis was associated with disease progression. Patients with overt fibrosis (grade ⩾2) presented an increased mutant allele burden (P

Background BK virus (BKV)-associated hemorrhagic cystitis (BKV-HC) is a severe complication after hematopoietic stem cell transplantation (HSCT). Cidofovir (CDV) has emerged as an effective agent for the treatment of BKV nephropathy, but its use for BKV-HC in pediatric HSCT recipients has not yet been established as a standard therapy. Patient and methods We retrospectively investigated the efficacy and safety of CDV therapy for patients with BKV-HC at a single institution and analyzed the clinical management outcomes. Results From April 2009 to July 2011, 12 patients developed BKV-HC at a median of 37 days after transplant (range 15-59 days). The cumulative incidence was 9% and the median peak of the urine BKV load was 2.5 × 10(10) copies/mL (range 1.4 × 10(9) -1.2 × 10(11) copies/mL). Eleven patients received intravenous CDV (5 mg/kg/dose, with probenecid), whereas 1 patient received CDV (5 mg/kg/dose, without probenecid) intravesically. The median duration of therapy was 25 days (range 9-73 days), and a median of 2 doses was given (range 1-4). A reduction of ≥ 1 log in the BKV load was found in 11 patients, while 1 patient did not have any significant change in BKV load. Clinical improvement was observed in all cases, and no HC-related death was observed. CDV-related toxicity occurred in 1 patient (8%) and spontaneously resolved. Conclusions CDV appears to be an effective and safe treatment for BKV-HC in pediatric HSCT recipients, but prospective trials are warranted to support its use.

Iron overload due to regular transfusions of packed red cells can cause multiple organ damage. Iron chelation therapy (ICT) is important in patients with aplastic anemia (AA) who require blood transfusions as supportive management. With the introduction of the oral iron chelator deferasirox, ICT has become more widely available and feasible. We studied 4 adult AA patients who had transfusion-induced iron overload and showed hematological improvement after ICT with oral deferasirox. Following deferasirox treatment, hemoglobin increased and serum ferritin levels decreased, and the patients subsequently became transfusion independent. Our experience raises the possibility of the potential benefit of ICT on hematopoiesis. Further long-term studies in larger patient cohorts are needed to clarify the effect of the restoration of hematopoiesis after iron chelation therapy.

Cytomegalovirus gastrointestinal (CMV-GI) disease in GI graft-versus-host disease (GI-GVHD) has not been properly evaluated in the era of preemptive therapy for CMV infection. We investigated 103 patients with GI-GVHD who underwent endoscopic biopsies with immunohistochemical staining for CMV. All recipients and/or donors were seropositive for CMV and monitored with a strategy of preemptive therapy based on real-time quantitative polymerase chain reaction. Twenty-six patients (25 %) developed CMV-GI disease, especially in HLA-mismatched transplants (P = 0.023) and with initial gut involvement of GVHD (P = 0.009). The CMV-GI diseases were diagnosed at follow-up endoscopies (n = 10, 39 %), comprising 19 % of 52 patients who underwent follow-up endoscopies, as well as initial endoscopies (n = 16, 61 %), comprising 16 % of all GI-GVHD patients. In seven cases, either at initial (n = 5) or follow-up endoscopies (n = 2), CMV-GI disease was diagnosed in the absence of histopathologic evidence for GI-GVHD. Notably, only 11 patients (42 %) had prior CMV DNAemia before the diagnosis of CMV-GI disease, while 12 (46 %) and three (12 %) had concurrent and no CMV DNAemia, respectively. Sixty-five percent of CMV-GI disease was resolved by additional antiviral therapies, but CMV-GI disease (P = 0.032) as well as severity of GVHD (P = 0.001) negatively affected GVHD-specific survival. In conclusion, our data demonstrate that CMV-GI disease was a cause of initial or persistent GI manifestations after the initiation of therapy in a considerable proportion of GI-GVHD. These suggest the necessity of novel strategies to reduce CMV-GI disease as well as an effort to confirm CMV with repeated endoscopies.

Antithymocyte globulin (ATG) is the drug of choice for immunosuppressive therapy (IST) in patients with severe aplastic anemia (SAA) ineligible for allogeneic stem cell transplantation. Recently, rabbit ATG with cyclosporine A has been used as a first-line IST regimen in patients with SAA because of unavailability of horse ATG. We retrospectively analyzed adult SAA patients who were treated with horse ATG (n=46) or rabbit ATG (n=53) between Feb 2001 and May 2010 to compare hematologic response and survival. Overall response rates at 3, 6, 12, and 18 months were similar in both the horse and rabbit ATG groups: 28.3 versus 35.8 % (P=0.421), 39.1 versus 45.3 % (P=0.537), 45.7 versus 49.1 % (P=0.735), and 47.8 versus 50.9 % (P=0.757), respectively. The complete response (CR) rate at 6 months in the horse ATG was significantly superior in comparison with the rabbit ATG (13.0 versus 1.9 %, P=0.031). But CR rates became similar in both groups after 6 months: 17.4 versus 11.3 % (P=0.387) at 12 months and 21.7 versus 22.6 % (P=0.914) at 18 months. Lymphocyte depletion after ATG was more profound and protracted in the rabbit ATG group compared to the horse ATG group. Overall survival (P=0.460) and failure-free survival (P=0.911) were not significantly different between the two groups. Our retrospective study demonstrated that the efficacy of first-line IST with rabbit ATG is similar to that with horse ATG. However, the time from treatment to CR was longer with rabbit ATG than with horse ATG, partly due to more profound and protracted lymphocyte depletion.

Background aims The aim of this study was to investigate the correlation between infused lymphocyte populations and lymphocyte subsets at engraftment, and the early clinical implications of lymphocyte subset recovery after autologous stem cell transplantation (ASCT) in multiple myeloma (MM). Methods We examined the lymphocyte populations of infused autografts and the lymphocyte subsets of peripheral blood at engraftment from 50 patients using flow cytometry. Each subset was grouped as low (below median) and high (above median) to examine the correlation with mucositis of grade 3 or more and the occurrence of infections and cytomegalovirus (CMV) reactivation. Results Using Spearman correlation coefficients, we found that cell doses of infused CD8 + ( P =0.042) and CD19 + cells ( P =0.044) were significantly associated with the absolute lymphocyte count (ALC) at engraftment. The dose of infused CD34 + cells was not associated with the change of lymphocyte subsets except for an inverse correlation with CD4 + cells ( P =0.006). After adjusting for potential variables in univariate analysis, multivariate analyzes revealed that the lower ratio of infused CD4 + to CD8 + cells ( P =0.030) was an independent factor for severe mucositis. Of lymphocyte subsets at engraftment, a higher frequency of CD3 + ( P =0.024) and a lower frequency of CD56 + ( P =0.020) were independent predictors for infections after engraftment. A higher frequency of CD8 + cells ( P =0.041) and a lower ratio of CD4 + to CD8 + ( P =0.021) were independent predictors for CMV reactivation. Conclusions Our data suggest that lymphocyte subset analysis of infused autograft and peripheral blood at engraftment may provide new predictors for early complications after ASCT in patient with MM.

To weigh the pros and cons of familial-mismatched/haploidentical transplantation (FMT) in patients with high-risk acute myelogenous leukemia, we assessed outcomes of 23 patients who underwent FMT, using reduced-intensity conditioning with total body irradiation 800 cGy/busulfan/fludarabine/antithymocyte globulin without ex vivo T cell depletion, compared to 33 patients who underwent well-matched unrelated donor transplantation (WM-UDT) and 13 who underwent partially matched unrelated donor transplantation (PM-UDT) during the same period. The FMT patients had not only a similar pattern of engraftment and immune reconstitution as the WM-UDT and PM-UDT patients but also comparable incidences and severity of acute and chronic graft-versus-host disease. The FMT patients did not experience any form of engraftment failure. However, the cumulative incidence of cytomegalovirus DNAemia was significantly higher in the FMT group compared with the other groups (P = .036). After a median follow-up of 28 months, overall survival, disease-free survival, relapse, and nonrelapse mortality were 83%, 74%, 20%, and 7%, respectively, for WM-UDT; 51%, 51%, 31%, and 18% for PM-UDT; and 66%, 64%, 26%, and 10% for FMT. This demonstrates a trend for favorable survival outcomes of WM-UDT over FMT and of FMT over PM-UDT. However, we found no significant statistical differences in survival according to donor type. These data need to be interpreted cautiously because of limited power calculations due to the small number of each donor group. This pilot study suggests the feasibility of FMT using our novel regimen with careful evaluation of CMV DNAemia compared with WM-UDT and PM-UDT. Further trials with larger numbers of patients, comparing FMT directly with transplantation with other donor types, are needed.

The aim of this study was to determine the optimum conditioning intensity for allogeneic stem cell transplantation (SCT) in young (age ≤50), lower-risk (INT-1 by IPSS) Myelodysplastic syndrome (MDS) patients without significant comorbidities (hematopoietic cell transplantation-comorbidity index score ≤3).Transplant outcomes from 46 consecutive patients were retrospectively analyzed according to the conditioning intensity: reduced-intensity conditioning (RIC; n = 14), intensified RIC by adding low-dose total body irradiation (iRIC; n = 15), and myeloablative conditioning (MAC; n = 17).After a median follow-up of 73.7 months, RIC had a better 4-yr overall survival (OS) (92.9%) compared with the iRIC (64.2%) or MAC (70.6%). Multivariate analysis showed that RIC was associated with improved OS compared with the MAC [relative risk (RR) of 0.08, P = 0.022] because of a lower transplant-related mortality (TRM) (RR, 0.08, P = 0.035). iRIC failed to show survival benefits over the MAC (RR of 0.77, P = 0.689) because of similarly high TRM (RR of 0.41, P = 0.480). Cumulative incidence of acute and chronic graft-versus-host disease (GVHD) after RIC was higher, but GVHD-specific survival was significantly better (RIC 100% vs. iRIC 45.7% vs. MAC, P = 0.018). Relapse rate was not different among the three groups, but in the RIC group, azacitidine was available and useful for inducing remission in two patients.This study shows that RIC improved OS by directly lowering TRM and indirectly giving an additional chance for relapsed MDS in the era of hypomethylating treatment. RIC-SCT should be considered for relative healthy lower-risk MDS patients.

Background : Epstein-Barr virus (EBV) is a well-known causative agent of various diseases including post-transplant lymphoproliferative disorders. Although the level of EBV viral load in donors is expected to have a direct effect on recipients after hematopoietic stem cell transplantation (HSCT), little has been studied providing a clear evidence for that. We performed EBV DNA quantitation in donors and analyzed the effect of donors’ EBV viral load on the recipients after HSCT. Methods : EBV DNA quantitation of peripheral blood in 94 healthy HSCT donors was performed by real-time PCR. We analyzed the distribution of EBV viral load in HSCT donors and EBV positivity in the recipients transplanted from donors who had detectable EBV. Results : Fifteen HSCT donors (16%) showed positive results in EBV real-time quantitative PCR. EBV viral load was below 500 copies/mL in 5 donors and above 500 (680-11,300) copies/mL in 10 donors. Five of the recipients (33.3%) transplanted from these 15 donors showed positivity in EBV PCR after HSCT. All of the EBV PCR positive recipients were transplanted from donors with viral load of >1,000 copies/mL, and 5 (71%) of 7 donors with viral load of >1,000 copies/mL was associated with posttansplant EBV PCR positivity in the recipients. Conclusions : Higher levels of EBV viral load in donors appear to be associated with EBV transmission to recipients in HSCT. EBV real-time quantitative PCR may be needed for screening EBV DNA level in HSCT donors. (Korean J Lab Med 2010;30:554-8)

Background The lack of an accepted definition of transplantation-associated thrombotic microangiopathy (TMA) has led the Blood and Marrow Transplants Clinical Trials Network (CTN) and International Working Group (IWG) to propose a definition for TMA with some differences. However, there have been few studies validating and comparing both newly proposed criteria for TMA. Methods To validate recently proposed criteria for TMA by CTN and IWG, we analyzed 672 patients who underwent allogeneic stem-cell transplantation between January 2002 and December 2006. Results The cumulative incidences of TMA by CTN and IWG were 6.1% and 2.5%, respectively. The cumulative incidence of overall TMA (O-TMA) including probable-TMA defined as meeting CTN criteria without renal or neurologic dysfunction, as well as TMA by CTN (definite-TMA), was 12.7%. Sixty-six percent of TMA by CTN did not have any degree of schistocytosis by IWG criteria (≥4%), and 18% of TMA by IWG criteria did not have renal or neurologic dysfunction. On multivariate analyses, probable-TMA as well as definite-TMA adversely affected the survival of a cohort including all patients. In patients with O-TMA, the degree of schistocytosis (≥4% or not) failed to show prognostic significance, whereas renal involvement was a significant prognostic factor associated with poor survival. Conclusions Both proposed consensus criteria have major pitfalls in their use as uniformly accepted diagnostic criteria for TMA. The use of O-TMA as a broad definition for TMA and the grading system by the presence of renal involvement may be a counterproposal for future trials.

The characteristics and clinical outcome of 600 adult patients with aplastic anemia (AA) that had successful cytogenetic studies at the time of diagnosis were retrospectively evaluated. Among these, 572 (95.3%) had normal cytogenetics and 28 (4.7%) had abnormal cytogenetics. The most frequent abnormality was trisomy 8 (n = 15), followed by monosomy 7/deletion of 7q (n = 5), and deletion of 1q (n = 5). There were no statistically significant differences with respect to gender, hepatitis viral infection, paroxysmal nocturnal hemoglobinuria, or severity of disease between the patients in the normal and abnormal cytogenetics groups; however, the patients with abnormal cytogenetics were generally younger than those with normal cytogenetics (P < 0.001). Abnormal cytogenetics was associated with a higher cumulative leukemic transformation rate (P < 0.001) and lower leukemic transformation-free survival (P = 0.021). Furthermore, abnormal cytogenetics was an independent predictor of a poor response to immunosuppressive therapy (HR = 0.255; 95% CI = 0.077–0.839; P = 0.024). These analyses suggest that patients with AA and abnormal cytogenetics have different clinical characteristics compared to patients with AA and normal cytogenetics. © 2010 Wiley-Liss, Inc.

This study presents 12 patients (7 women and 5 men) with vitamin B(12)-responsive pancytopenia who had discordant laboratory findings and were misdiagnosed as having myelodysplastic syndrome (MDS). The median hemoglobin level was 6.5 g/dl, and the leukocyte and platelet counts were 2.85 × 10(9)/l and 55.5 × 10(9)/l, respectively. The median serum lactate dehydrogenase level was high (3,204.5 IU/l). The serum vitamin B(12) levels were within normal limits at the initial evaluation, but a serial follow-up of the vitamin B(12) levels revealed either fluctuations or a gradual decrease. The patients were initially diagnosed with MDS and responded rapidly to a 7-day parenteral B(12) treatment with normal complete blood counts (CBCs). We propose that patients suspected to have MDS may suffer from vitamin B(12) deficiency and that this can be revealed by a normalization of CBCs following 7 days of treatment with parental vitamin B(12).

Traditional transplant conditioning regimens have a limiting factor regarding co-morbidities or old age. Therefore, reduced-intensity conditioning (RIC) regimens have been increasingly used. To define the role of RIC in AML with old age (or=55 years) and/or co-morbidities (HCT-CI scoresor=2), we analyzed patients who received allogeneic stem cell transplantation (SCT) with Flu/Bu/TBI 400 cGy/+/-antithymocyte globulin (ATG) conditioning regimen. Seventeen men and 15 women were enrolled. The median age was 45 years (range 17-65 years). All patients were in first (n = 25) or second (n = 7) complete remission before undergoing allogeneic SCT. Patients were transplanted from HLA-mismatched unrelated donors (n = 5), matched unrelated donors (n = 10), and matched sibling (n = 17). Calcineurin inhibitor and a short course of standard dose methotrexate were used to prevent graft-versus-host disease (GVHD). All patients achieved engraftment. At a median follow-up of 18 months (range 4-40) for survivors, the estimated 2-year rates of overall survival, event-free survival, transplantation-related mortality, and relapse were 66, 63, 26, and 16%, respectively. The incidence of acute (grades II-IV) and chronic GVHD by NIH consensus criteria was 34.4 and 62.5%. This study suggests that the Flu/Bu/TBI 400 cGy or Flu/Bu/TBI 400 cGy/ATG-based conditioning regimens maybe a feasible therapeutic approach for AML with old age and/or co-morbidities.

The efficacy of fludarabine in combination with an intermediate dose of cytosine arabinoside, mitoxantrone, and G-CSF (FLANG; fludarabine 30 mg/m(2)/day, cytosine arabinoside 1 g/m(2)/day, mitoxantrone 10 mg/m(2)/day, and G-CSF 300 μg/day for 5 days) was evaluated in patients with refractory or relapsed acute myelogenous leukemia (AML). Between January 2004 and December 2006, 27 patients with relapsed or refractory AML were enrolled in the present study. In total, 14 patients had experienced an early relapse, 10 had experienced a late relapse, and the remaining three (11%) had developed primary refractory leukemia at the time of study entry. Most patients (n = 17, 63%) had post-transplant relapse, and 10 of them relapsed after allogeneic hematopoietic stem cell transplantation (SCT). After FLANG treatment, 15 patients (56%) achieved a complete response (CR), and three patients died during reinduction chemotherapy. After achieving a CR, eight patients received SCT (seven allogeneic (sibling = 4, unrelated = 2, and haploidentical familial = 1) and one autologous SCT), one received donor lymphocyte infusion, three received consolidation chemotherapy, and the remaining three refused further therapy. Eight patients were alive during continuous CR, with an event-free survival (EFS) rate of 30% after a median follow-up of 42.1 months. The survival outcome of patients who received SCT was remarkable (EFS of 75%). Additionally, no toxicity severe enough to preclude transplantation was evident after or during FLANG. The findings of the present study suggest that FLANG salvage chemotherapy is an effective regimen and that it offers a safe bridge to SCT. Furthermore, this regimen prompts efforts to proceed to SCT as post-remission therapy for patients in greater than first CR.

We describe a 5-year-old girl who had multiple fibrofolliculomas with an unusual annular configuration, present since birth, localized to the mid-back. She had no family history of similar skin lesions. Examination showed a depigmented patch on her left buttock and other congenital anomalies, i.e. deformity of the auricle of the ear and ventricular septal defect. There has been no previous report of congenital multiple fibrofolliculomas occurring with congenital malformations such as deformity of the auricle of the ear and ventricular septal defect. The congenital occurrence and unusual configuration of the lesions in our patient may suggest a naevoid origin for these tumours.

In this study, we investigated the effects of low-dose antithymocyte globulin (ATG, thymoglobulin) in the prevention of acute graft-versus-host disease (aGVHD) in mismatched, unrelated hematopoietic stem cell transplantations (uHSCTs) in patients with the single disease entity of acute myelogenous leukemia (AML). Patients (n = 103) with a variable risk for AML who received uHSCTs from available Asian and Caucasian donors were enrolled. First, we compared HLA-matched (group 1, n = 54) and HLA-mismatched (group 2, n = 49) transplantation patients. Then, we divided the patients in group 2, who had received transplants from allele(s)/antigen-mismatched donors, into 2 subgroups: patients who used ATG (group 3, n = 24) and those who did not (group 4, n = 25). To prevent the development of aGVHD, the patients in group 3 received ATG at a dose of 1.25 mg/kg body weight per day for 2 consecutive days, together with our standard regimen of methotrexate (MTX) and tacrolimus. The median CD34(+) cell infusion was 4.2 x 10(6)/kg (range: 1.2-34.4). The median patient age was 41 years (range: 16-57), and the median follow-up duration of patients who were event-free survivors was 23 months (range: 2-72). The overall incidences of aGVHD and chronic GVHD (cGVHD) were 38% and 56%, respectively. Of 48 evaluable patients in group 2, 10 (21%) developed moderate to severe aGVHD (grades II-IV). In contrast, 2 (8%) of the 24 patients in group 3 and 7 (29%) of the 24 evaluated patients in group 4 required therapy for aGVHD (grades II-IV; P = .038). The incidence of cGVHD was not different between groups 3 and 4. The estimated probabilities of overall survival (OS) and event-free survival (EFS) at 2 years for group 2 were 55% and 44%, respectively. In comparison, the estimated probabilities of OS and EFS at 2 years for groups 3 and 4 were 68% versus 38% (P = .043) and 58% versus 38% (P = .103), respectively. The overall cumulative incidence of nonrelapse mortality (NRM) was 29% in group 2. The cumulative incidence of NRM differed markedly between group 3 (16%; 95% confidence interval [CI], 4%-28%) and group 4 (44%, 95% CI, 34%-54%) (P = .013). We found no difference in cytomegalovirus (CMV) reactivation between groups 3 and 4. These results suggest that in mismatched uHSCT, a low dose of ATG (total 2.5 mg/kg) may prevent moderate to severe aGVHD, with comparable rates of relapse and CMV reactivation and a greatly decreased rate of NRM.

Purpose The development of bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (HSCT) deteriorates patients' quality of life. This study aimed to analyze the prevalence, clinical features, risk factors and prognostic factors of BOS. Materials and Methods This retrospective study included patients who underwent allogeneic HSCT from January 2002 to December 2008 and survived for ≥100 days after transplantation. Results Of 860 patients who survived for ≥100 days, 36 (4.2%) met the diagnostic criteria. The duration of BOS development after transplantation was 466.00 (284.00–642.75) [median (interquartile range)] days. The risk factor for the development of BOS was peripheral blood as the stem cell source with a hazard ratio (HR) of 2.550 [95% confidence interval (CI): 1.274–5.104, p=0.008]. In multivariate analysis, pretransplant FEV1/FVC (HR: 0.956, 95% CI: 0.921–0.993, p=0.020) and time from HSCT to diagnosis of BOS (HR: 0.997, 95% CI: 0.994–0.999, p=0.009) were independent prognostic factors associated with mortality. Conclusion Peripheral blood as a stem cell source is a risk factor for the development of BOS. A decreased pretransplant FEV1/FVC and shorter duration of time from transplantation to diagnosis of BOS are poor prognostic factors for BOS.

The genetic characterization of acute promyelocytic leukemia with cryptic t(15;17) including a new recurrent additional cytogenetic abnormality i(17)(q10)