bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparable Leukemia-Free Survival after Autologous Hematopoietic Cell Transplantation Versus HLA-Identical Sibling Hematopoietic Cell Transplantation for Adult Acute Myeloid Leukemia in First Complete Remission: A Registry Study By the Adult AML Working Group of the Japan Society for Hematopoietic Cell Transplantation
Authors: Mizutani Motonori , Hara Masahiko , Fujita Hiroyuki , Aoki Jun , Kanamori Heiwa , Machida Shinichiro , Yamasaki Satoshi , Ohashi Kazuteru , Usuki Kensuke , Fukuda Takahiro , Chou Takaaki , Tanaka Junji , Atsuta Yoshiko , Takami Akiyoshi 
Published: November 2019

Abstract
Allogeneic hematopoietic cell transplantation (HCT) from a matched sibling donor (MSD) may provide a cure for acute myeloid leukemia in first complete remission (AML/CR1), although the procedure is associated with a higher rate of treatment-related mortality (TRM) than autologous HCT, and it remains uncertain which modality is preferable as post-remission treatment. We therefore conducted a retrospective registry-based analysis to compare the outcomes of patients with AML/CR1 receiving autologous peripheral blood (PB) grafts (n=398, median age: 47, range: 17-80) and those receiving allogeneic MSD bone marrow (BM) grafts (n=633, median age: 38, range: 16-73) or allogeneic MSD PB grafts (n=475, median age: 42, range: 16-74) between 1995 and 2011. Consequently, the 5-year overall survival (OS) rates for the autologous PB, allogeneic BM and allogeneic PB recipients were 62% (95% confidence interval [CI], 57-67%), 61% (95% CI, 57-65%; P=0.90) and 54% (95% CI, 49-59%; P=0.07), respectively (Fig. 1-A), and the 5-year leukemia-free survival (LFS) rates were 57% (95% CI, 52-62%), 58% (95% CI, 54-63%; P=0.49) and 51% (95% CI, 46-56%; P=0.12), respectively(Fig. 1-B). Meanwhile, the 5-year cumulative incidence of TRM was 8% (95% CI, 5-11%), 16% (95% CI, 13-19%; P=0.009) and 19% (95% CI, 15-23%; P=0.0001), respectively, while that of relapse was 35% (95% CI, 30-40%), 26% (95% CI, 22-29%; P=0.003) and 30% (95% CI, 26-35%; P=0.08), respectively. A multivariate analysis performed with autologous PB HCT as the reference showed a hazard ratio (HR) for OS of 0.93 (95% CI, 0.73-1.18; P=0.53) for allogeneic BM HCT and 1.08 (95% CI, 0.83-1.39; P=0.57) for allogeneic PB HCT and an HR for LFS of 0.86 (95% CI, 0.69-1.09; P=0.21) and 0.98 (95% CI, 0.77-1.24; P=0.85), respectively. Stratifying the patients according to cytogenetics (favorable, intermediate and poor) and age (<50 years and ≥ 50 years) did not influence the results. Accordingly, autologous PB HCT may be a viable alternative as post-remission therapy in patients with AML/CR1 in the absence of MSD.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Evaluation of the Disease Risk Index on Outcomes Following Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes
Authors: Michelis Fotios V. , Messner Hans A. , Uhm Jieun , Alam Naheed , Loach David , McGillis Laura , Lambie Anna , Gupta Vikas , Kuruvilla John , Lipton Jeffrey H. , Seftel Matthew D. , Kim Dennis D. 
Published: November 2019

Abstract
Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment option when indicated for myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The Disease Risk Index (DRI, Armand et al, 2012) has been developed to predict overall survival and progression-free survival on the basis of differences in relapse risk. The purpose of this single-center study was to retrospectively investigate the prognostic value of the DRI on the outcome of 470 patients that underwent HCT for AML and MDS between 2000 and 2013.
AML patients (n=381) underwent HCT in first and second complete remission and MDS patients (n=89) underwent HCT untreated or in remission. Median age at HCT was 51 (range 18-71), 219 (47%) patients were female. Myeloablative conditioning (MAC) was used in 304 (65%) patients, reduced-intensity (RIC) in 166 (35%) patients. Donors were related for 287 (61%) patients, unrelated for 183 (39%) patients. Grafts were peripheral blood stem cells (PBSC) in 377 (80%) patients and bone marrow in 93 (20%) patients. Median follow-up of patients alive was 44 months (range 1-134). In accordance with the DRI criteria, all 470 patients were in the low risk group concerning disease stage. Concerning disease biology characterized by cytogenetic risk, 11 patients were low risk, 396 patients were intermediate risk and 63 patients high risk. Based on the DRI overall risk stratification, 11, 396 and 63 patients were low, intermediate and high risk respectively.
Univariate analysis demonstrated that the DRI was significantly prognostic for overall survival (OS) with a 3-year OS of 82%, 48% and 29% for low, intermediate and high risk patients respectively (p=0.005, Figure A). For cumulative incidence of relapse (CIR), DRI was again prognostic with 3-year CIR 0%, 21% and 30% for low, intermediate and high risk patients respectively (p<0.0001, Figure B). For non-relapse mortality (NRM), DRI did not demonstrate significant prognostic relevance with 3-year NRM 18%, 32% and 43% for low, intermediate and high risk patients respectively (p=0.14).
Multivariable analysis for OS confirmed the prognostic significance of the DRI with hazard ratio (HR) 3.3 and 4.9 for intermediate and high risk respectively compared to low risk (p=0.01). For CIR, DRI was highly significant (p<0.0001) while for NRM, the DRI was not predictive (p=0.22). This study confirms the prognostic relevance of the DRI for OS and CIR in our cohort of patients undergoing HCT for AML and MDS.
Figure 1 Figure 1.
Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.
Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Children and Young Adults with Chronic Myeloid Leukemia: A CIBMTR Cohort Analysis
Authors: Chaudhury Sonali , HiJiya Nobuko , Hu Zhenhuan , Sparapani Rodney , Kalaycio Matt E. , Alyea Edwin P. , Popat Uday R. , Saber Wael 
Published: November 2019

Abstract
Chronic myeloid leukemia (CML) in pediatrics is rare accounting for 2–3% of leukemias. Data on allogeneic hematopoietic cell transplantation (HCT) in this group is scarce. Since the introduction of tyrosine kinase inhibitors (TKI), HCT in patients with CML especially with early disease has decreased. Children and young adults have long life expectancies, lower morbidity with HCT and are likely to recieve prolonged TKI therapy with increased risk for complications. HCT for early disease may still benefit this population.
We retrospectively evaluated outcomes in CML patients receiving myeoloablative HCT reported to the CIBMTR, comparing pediatric patients (n= 212) to young adults (n=200). Table 1 describes patient variables.
5 y overall survival (OS) and leukemia free survival (LFS) in <18 y was 71% (95%CI 65-77) and 51% (95%CI 43-58) respectively. In adjusted analysis, there was a statistically insignificant effect of prior TKI therapy on LFS (P=0.07), OS (0.06), transplant related mortality (TRM) (P=0.47) or relapse (P=0.88). Favorable factors for OS were early disease, matched sibling donors (MSD), bone marrow (BM) or cord blood (CB) grafts. LFS was superior with total body irradiation (TBI), non alemtuzumab based regimens and recent (>2006) HCTs. 5 year OS and LFS for the 18-25y group was 71 (95%CI 65-77)% and 53 (45-60)% respectively. In adjusted analysis there was no difference in OS (P=0.7), LFS (P=0.4) for 18-25y group compared to the pediatric group. Favorable factors for OS/DFS remained early disease, MSD and BM grafts.
Allogeneic HCT outcomes were comparable in children and young adults. HCT should remain an option for young patients with CML especially with a MSD using TBI containing regimens with BM as the stem cell source. We could not show an advantage for TKI use prior to HCT. Long term toxicities of TKI and allogeneic HCT need to be further evaluated in this group.
Table1 Description of variables for Allogeneic HCT in CML Table1. Description of variables for Allogeneic HCT in CML
Figure 1 Adjusted OS and LFS for <18y vs. 18-25y Figure 1. Adjusted OS and LFS for <18y vs. 18-25y

Disclosures
HiJiya: Pfizer: Consultancy; Jazz: Consultancy; Enzon: Consultancy; Sanofi: Consultancy.
Dysregulation of the TGF β Pathway in Induced Pluripotent Stem Cells (iPSCs) Generated from Patients with Diamond Blackfan Anemia (DBA)
Authors: Ge Jingping , Apicella Marisa , Mills Jason A. , Garcon Loic , French Deborah L. , Weiss Mitchell J. , Bessler Monica , Mason Philip J 
Published: November 2019

Abstract
DBA is an inherited bone marrow failure syndrome that usually develops in the first year of life with clinical features of red cell aplasia and sometimes variable developmental abnormalities. Most affected patients have heterozygous loss of function mutations of one of the 11 ribosomal proteins (RPs) or mutations in the GATA1 gene which encodes an erythroid specific transcription factor. We have previously demonstrated that induced pluripotent stem cells (iPSCs) from fibroblast of DBA patients with RPS19 or RPL5 mutations recapitulate the pathogenesis of DBA, with the mutant lines showing abnormal ribosome biogenesis and altered erythropoiesis. The mechanism whereby haploinsufficiency for RPs causes failure of erythropoiesis and the other DBA features is still unknown. We investigated the pathways that are affected in these DBA iPSCs using an Affymetrix human exon array, and we observed the striking dysregulation of the TGF β pathway in DBA lines. The TGF β downstream target genes, such as DKK1, BAMBI, FN1, COL3A1, COLA1A1 and PAI-1 significantly increased in the DBA iPSCs. The TGF β signaling is complex and can occur via a canonical pathway or by a number of non-canonical pathways. We measured levels of a number of intermediates in these pathways by western blot, and observed a significant increase in the levels of p-JNK, a mediator of a non-canonical pathway, in the DBA iPSCs. Moreover, when the mutant cells were corrected by ectopic expression of WT RPS19 or RPL5, levels of p-JNK returned to normal. We also investigated the SMAD family, which are mediators of the TGF β canonical pathway and are known to negatively regulate the regeneration of hematopoietic stem cells. We observed a drastic decrease in SMAD4, but no change in p-SMAD2. Again corrected lines showed normal expression levels of SMAD4. Our data suggests that the activation of a non-canonical TGF β pathway in the DBA iPSCs may lead increased expression of the downstream genes; and the decrease of anti-proliferative factor SMAD4 may explain how DBA iPSCs maintain their growth. We conclude that the mutations of RPS19 or RPL5 both affect ribosome biogenesis and TGF β signaling, which can cause the failure of erythropoiesis at the stem cell stage. We further suggest that the suppression of SMAD4 may be used as a therapeutic target for DBA treatment.

Disclosures
No relevant conflicts of interest to declare.
Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Acute Myeloid Leukemia Transformed from Ph-Negative Myeloproliferative Neoplasm: A Study from the Adult AML Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT)
Authors: Takagi Shinsuke , Masuoka Kazuhiro , Uchida Naoyuki , Kurokawa Mineo , Nakamae Hirohisa , Tsudo Mitsuru , Iwato Koji , Ichinohe Tatsuo , Atsuta Yoshiko , Takami Akiyoshi 
Published: November 2019

Abstract
BACKGROUND/METHODS: Long-term survivors with Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) can eventually develop acute myeloid leukemia (AML, i.e. blast transformation). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be the only curative treatment for such patients. To clarify its outcome, we retrospectively studied the cases with AML transformed from Ph-neg MPNs using the national registry data of JSHCT. The cases transplanted after 2000 were collected.
RESULTS: Thirty-nine cases were extracted (male, n=21; female, n=18). Median age was 57 years (range, 22-71). Underlying Ph-neg MPNs included essential thrombocythemia (ET, n=21), primary myelofibrosis (PMF, n=11) and polycythemia vera (PV, n=7). FAB classification was M0 (n=4), M1 (n=4), M2 (n=10), M3 (n=0), M4 (n=1), M5 (n=3), M6 (n=0), M7 (n=1) and unknown (n=16). Median value of WBC at diagnosis of AML was 8300/uL (250-338000). Karyotype at diagnosis of AML was normal (n=6), complex (n=12), others (n=17) and unknown (n=4). Thirty-two cases (82%) were not in remission at the time of allo-HSCT (1st relapse, n=7; primary induction failure, n=18; untreated, n=12). Median duration between diagnosis of AML and allo-HSCT was 134 days (range, 24-369). The donors were related bone marrow or related mobilized peripheral blood stem cell (rBM/rPBSC, n=8), unrelated bone marrow (uBM, n=15) and unrelated umbilical cord blood (uCB, n=16). Myeloablative conditioning regimens (MAC) were used in 15 cases, and the remaining 24 cases were conditioned by reduced-intensity regimens (RIC), according to CIBMTR definition (Giralt S, et al, 2009). Cumulative incidence of neutrophil engraftment was 74.4% at day 60 (patients engrafted, n=29; death before day 60, n=6; relapse before day 60, n=4). At 2 years after transplant, overall survival (OS) was 29.2%. The median duration of follow up of survivors was 1989.5 days (range, 285-3270). In univariate analysis, age (>57 vs. <57, p=0.87), underlying MPNs (PMF vs. ET vs. PV, p=0.16), disease status at allo-HSCT (CR vs. non-CR, p=0.09), conditioning regimen (MAC vs. RIC, p=0.95) and donor selection (rBM/PBSC vs. uBM vs. uCB, p=0.10) had no impact on OS. The only variable that influenced on OS was chromosome at diagnosis of AML (normal vs. others vs. complex, p=0.02). The cumulative incidence of relapse and non-relapse mortality at 3 years was 34.4% and 38.1%, respectively.
CONCLUSION: Although the prognosis of AML transformed from Ph-neg MPNs is dismal in general, the study suggested a promising result that there were curable patients with allo-HSCT.
Figure 1 Figure 1.
Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.
The Association of KIR2DS4 and Its Variant KIR1D with CMV Infection after HLA-Matched Sibling Hematopoietic Stem Cell Transplantation
Authors: Yao Yao , Li Xiaoli , Xu Liangjing , Liu Bin , Han Yue , Tian Xiaopeng , Fu Chengcheng , Bao Xiaojing , He Jun , Wu Xiaojin , Depei Wu 
Published: November 2019

Abstract
Objective To expolore the association of KIR2DS4 and its variant KIR1D with cytomegalovirus(CMV) infection after HLA-matched sibling hematopoietic stem cell transplantation.
Methods Polymerase chain reaction with sequence-speciﬁc primers (PCR-SSP) method was used to genotype KIR genes in 267 donor-recipient pairs from Oct 2005 to Apr 2014. Posttransplant monitoring for CMV infection was performed by immune histochemically assays .165 donor-recipient pairs who belong to KIR gene haplotype AA were analyzed for the presence of KIR2DS4 and its variant KIR1D and then further subdivided into the following groups: 2DS4-/1D+ (homozygous for the deletion variant KIR1D), 2DS4+/1D+ (heterozygous), 2DS4+/1D- (two intact KIR2DS4 alleles). Furthermore, we investigated the influence of the KIR2DS4 variants on CMV infection of 165 patients receiving Sibling related HLA matched transplantation.
Results There were no significant differences in frequency of KIR2DS4 or KIR1D between donors and recipients in the haplotype AA group. The ratio of 2DS4+ and KIR1D in haplotype AA group was 2:1.There was no difference on neutrophil engraftment and platelet recovery among the three groups after hematopoietic stem cell transplantation. The CMV infection rate was significantly higher in 2DS4+/1D- group compared with 2DS4+/1D+ group (44.0% vs 19.0%，P=0.002)．In 2DS4-/1D+ group ，the CMV infection rate was higer than that in 2DS4+KIR1D+ group (50.0% vs 19%，P=0.028). However，there was no difference in CMV infection rate between 2DS4+/1D-group and 2DS4-/1D+ group.
Conclusion KIR2DS4 and its variant KIR1D are associated with CMV infection after HLA-matched sibling hematopoietic stem cell transplantation

Disclosures
No relevant conflicts of interest to declare.
Haploidentical Hematopoietic Stem Cell Transplantation (Haplo-SCT) with Pre-Transplant Immunosuppression (PTIS) and Post-Transplant Cyclophosphamide (Post-Cy) in Severe Thalassemia: Safe Approach and Excellent Disease Control
Authors: Hongeng Suradej , Pakakasama Samart , Anurathapan Usanarat , Andersson Borje 
Published: November 2019

Abstract
Background
Currently, the thalassemia free survival rate after hematopoietic stem cell transplant (HSCT) is about 80-90% with either matched sibling or unrelated donor. However, the probability to find a suitable door is only 25-50%. Since most of these patients (pts) could not find the potential donor, we would like to investigate the haploidentical donor HSCT (Hapo-SCT) in thalassemia.
Patients and Methods
Between Jan 2013 and August 2014, 12 thalassemia patients (pts) underwent haplo-HSCT. Six subjects were male and 6 were female. The median age was 16 yrs (range; 2-22). Nine of 12 received stem cells from mother and 3 from father. Ten of 12 were high risk class 3. These high risk class 3 pts received hydroxyurea 20 mg/kg/d for at least 3 months prior to HSCT. All pts received 2 courses of pre-transplant immunosuppression (PTIS) consisting of fludarabine (Flu) 40 mg/m2/d together with dexamethasone (dex) 25 mg/m2/d for 5 days. After 2 courses of PTIS, all pts received a reduced-toxicity conditioning regimen consisting of thymoglobulin 1.5 mg/kg/d (d-11 to d-9), Flu 35 mg/m2/d i.v. (-7 to -2) each dose immediately followed by busulfan (Bu) 130 mg/m2once daily i.v. (d-7 to d -4) for pts > 10 years and 0.95-1.2 mg/kg every 6 hr (d-7 to d-4) for pts < 10 yrs. GVHD prophylaxis consisted of cyclophosphamide (Cy) 50 mg/kg/d (d +3 to d+4). Tacrolimus was given for 6 months to 1 yr started together with mycophenolate mofetil on d+5, the latter was quickly tapered after 2 months. T-cell repleted peripheral blood stem cells (PBSC) were given to all pts, targeting a CD34+ dose of 7-10 x 106cells/kg.
Results
Eleven of 12 were engrafted with full donor chimerism (100%) while one pt suffered graft failure. However, this pt received second transplant on day +30 with minimal conditioning regimen and additional PBSC after which she achieved full donor chimerism. The median time to neutrophil engraftment was 18 days (range; 14 -22). Four pts had acute GVHD gr I, 2 grade II and 1 gr III. Only one had limited chronic GVHD. At this time, all 12 pts survive thalassemia-free and have sustained full donor chimerism (100%). Thalassemia free survial and overall survival rates are 100%. The median follow up time is 12 months (range 4-20).
Conclusion
Haploidentical HSCT for high risk thalassemia pts with our novel approach is safe and should be considered as modality to secure thalassemia-free survival with a low risk for graft rejection and treatment-related mortality. In view of our results, we suggest that all thalassemia pts even those with high risk class 3 features should be offred the chance for cure with HSCT.

Disclosures
No relevant conflicts of interest to declare.
Cyclin D1 C.870G>a Polymorphism in Patients with Multiple Myeloma after Allogeneic Stem Cells Transplantation
Authors: Blau Olga , Slonova Ekaterina , Berenstein Rimma , Nogai Axel , Rieger Kathrin , Pezzutto Antonio , Dörken Bernd , Blau Igor Wolfgang 
Published: November 2019

Abstract
Introduction: Over the last decade, the cyclin D1 (CCND1) c.870G>A polymorphism has been variously reported to confer risk for a large number of cancers. Deregulation of a D-group cyclin is a key feature of multiple myeloma (MM). Previously published meta-analysis shown a relationship between CCND1 c.870G>A and risk of t(11;14) in MM (Wienhold, 2013). Allogeneic stem cell transplantation (AlloSCT) is a potential curative treatment for MM patients. There are no data with regard to the role of CCND1 c.870G>A polymorphism in stem cells donors and outcome of transplantation in MM patients.
Methods: In this study we developed an endonuclease restriction method to identify CCND1 c.870G>A polymorphism. Directly Sanger sequencing were used to confirm the results.
Results: At first, we analyzed 130 MM patients and 100 healthy donors as a control. CCND1 c.870G>A polymorphism was strongly associated with the t(11;14)(q13;q32) (P<0.001). In addition, we have analyzed CCND1 c.870G>A polymorphism 55 pairs of MM patients and their allogeneic stem cell donors, retrospectively. Interestingly, c.870G-genotype in related and unrelated donors was statistically correlated with poor outcome after AlloSCT (P<0.01). Moreover, only patients transplanted with “G-Genotype” donors developed secondary cancer after AlloSCT (P<0.01). No secondary tumors were diagnosed in the group of MM patients received grafts from “A-, AG-genotype” donors.
Conclusion: Our data suggest the published data that constitutive genetic factor (CCND1 c.870 G>A polymorphism) is associated with a specific chromosomal translocation in patients with MM. Despite the fact that our group of patients after AlloSCT is small, we found a statistical association between the c.870G-genotype in donor and a poor prognosis after transplantation.

Disclosures
No relevant conflicts of interest to declare.
Updated Outcomes of NF-08-TM Protocol in HSCT for Patients with b-Thalassemia Major: A Large Prospective Study from Single Center
Authors: Li Chunfu , Wu Xuedong , He Yuelin , Feng Xiaoqin , Liao Jianyun , Zhou Xiaohui 
Published: November 2019

Abstract
Background: The optimization of both erythrocyte transfusion and iron chelating has resulted in a remarkable improvement in the life expectancy of patients with thalassemia major (TM). However, only curative therapy remains allogeneic hematopoietic stem cell transplantation (HSCT). HLA matched sibling transplant (MST) has been commonly used for TM patients with well results. However, this option is unavailable to many patients as a result of a lack of compatible MS, especially in China. Matched unrelated-donor transplant (MUT) and Haploidentical-donor transplant (HIT) have be well performed in malignant disease. But in few thalassemia patients because of high risk of transplantation so far. To expand donor pool and to lower risk of HSCT from alterative donor, we designed a NF-08-TM protocol for MST, MUT and HIT for TM patients since 2009. Outcomes before June 2011 have published in “Blood” in 2012. Here we updated these outcomes.
Aims: to check stability and reliability of NF-08-TM protocol in MST, MUT and HIT for thalassemia patients.
Methods: 293 consecutive patients with TM underwent HSCT between January, 2009 and December, 2013 in our center, including 143 in MUT, 21 in HIT (≥ one HLA mismatch) and 105 in MST. Rate of male to female is 185:108. The median age at transplant was 6 years (rang:0.6-16), The median follow-up time is 29 months (range: 6-64). All patients received the NF-08-TM protocol, which included a new risk classification to adjust dose of IV Busulfex (Bu) and Cyclophosphamide (Cy), and a conditioning regimen of Bu following Cy instead of Cy following Bu. Simultaneously, a intensify graft versus host disease (GVHD) prophylaxis consisted of ATG, Cs A, MMF and short MTX was given.
Results: The estimated 5-year overall survival and TM-free survival were 92.6%, 89.5% and 94.1%, and 90.5%, 89.5% and 92.2% in the MUT, HIT and MST, respectively. The cumulative incidence of graft rejection was 2.1% in total. The cumulative transplant-related mortality was 7.4%, 10.5% and 5.9%, respectively, in the MUT, HIT and MST. Incidence of cytopenia post-transplant (white cell count less than 3.0x109/L for 4 weeks or longer but CMV infection) was 20.6%.
Conclusion: Our large sample prospective study provides results comparing MUT or HIT with the MST for TM patients, which showed that MUT or HIT was comparable with MST when using NF-08-TM-HSCT protocol.

Disclosures
No relevant conflicts of interest to declare.