bluuebunny/crossref_metadata_2025_split huggingface dataset:
Allogeneic Stem Cell Transplantation Should Be Performed in First Complete Remission in Adults with Acute Lymphoblastic Leukemia; Strong Antileukemic Activity of Chronic Graft-Versus-Host Disease.
Authors: Lee Seok , Cho Byung-Shik , Kim Sung-Yong , Eom Ki-Seong , Kim Yoo-Jin , Min Chang-Ki , Kim Hee-Je , Cho Seok-Goo , Kim Dong-Wook , Lee Jong-Wook , Min Woo-Sung , Park Jong-Won , Kim Chun-Choo 
Published: October 2019

Abstract
Purpose: The role of allogeneic stem cell transplantation (SCT) for adult acute lymphoblastic leukemia (ALL) remains unclear because interpretation of transplantation outcome is complicated by the criteria used to select patients for transplantation and by the relatively small number of patients studied. Moreover, whether SCT from an unrelated donor could be a treatment option of equal value in a case lacking a compatible related donor remains controversial. The aim of the present study was to determine the graft-versus-leukemia (GVL) effect and risk factors affecting outcome of 218 adults with ALL who received allogeneic SCT during the last 10 years (1995 to 2004).
Patients and Methods: The study population was 218 consecutive adults receiving an allogeneic SCT from matched sibling (n=162) or unrelated (n=56; 40 matched, 16 mismatched) donors at the Catholic Hematopoietic Stem Cell Transplantation Center in Korea. Their median age was 30 years (range, 15–61 years). One hundred eighty-three (83.9%) patients had high-risk criteria, and of these, 69 (31.7%) had t(9;22)/BCR-ABL and 7 (3.2%) had t(4;11)/MLL-AF4. One hundred sixty-five patients (75.7%) were transplanted in first complete remission (CR1); 23 (10.5%) in CR2; and 30 (13.8%) were resistant to chemotherapy before transplantation. Most patients (n=206, 94.5%) received a preparative treatment of total body irradiation (TBI)-containing regimen (TBI/cyclophosphamide for CR1, TBI/cytarabine/melphalan for >CR1). Graft-versus-host disease (GVHD) prophylaxis was attempted by administering calcineurin inhibitor (cyclosporine for sibling, tacrolimus for unrelated) plus methotrexate.
Results: With a median follow-up of 52 months (range, 15+ to 130+ months) after SCT, the 5-year probability of disease-free survival (DFS) was 51.3%±3.5% for all patients; 62.4%±4.3% for patients in CR1; and 11.3%±4.4% for patients in >CR1 at transplantation. There was no difference in DFS for sibling and unrelated transplant patients in CR1 (65.2%±4.3% v 62.3%±8.0%). Multivariate Cox regression analysis showed that the most powerful predictive factor affecting relapse and DFS was disease status at transplantation (CR1 v >CR1, p<0.001). The presence of chronic GVHD was also found to be significantly associated with favorable outcome (p<0.001).
Conclusion: Our data in combination with recent studies suggest that matched related or unrelated allogeneic SCT should be performed in CR1 in adults with ALL. Further studies to develop treatment strategies to reduce leukemic cell burden and to enhance GVL effect are needed. The indications for allogeneic SCT also should be continuously evaluated.
Abnormal Expression of Human Mitoferrin (SLC25A37) Is Associated with a Variant of Erythropoietic Protoporphyria.
Authors: Shaw George C. , Langer Nathaniel B. , Wang Yongming , Li Liangtao , Kaplan Jerry , Bloomer Joseph R. , Paw Barry H. 
Published: October 2019

Abstract
Mitoferrin (mfrn, slc25a37) is the high-affinity transporter of iron into mitochondria of developing erythroblasts and is essential for normal erythropoiesis. Recently, we described the cloning and characterization of mfrn in the zebrafish frascati (frs) mutant, in which homozygous null mutation leads to profound hypochromic anemia and embryonic lethality (Shaw GC, et al. 2006 Nature 440:96–100). Here we characterize the human MFRN orthologue and implicate a specific disease process purportedly caused by defects in MFRN expression. We studied human MFRN expression by a) analysis of human-tissue northern blots, b) fluorescent immunohistochemistry and confocal microscopy for subcellular localization, c) genetic complementation in MRS3/4 deficient yeast strains, and d) microinjection and rescue efficiency of frs mutant zebrafish. Human MFRN, mapping to chromosome 8p21, shows 82% and 64% similarity at the amino acid level to orthologous mouse and zebrafish Mfrn proteins respectively, and 60% similarity to a paralogous MFRN2 (SLC25A28). MFRN mRNA is highly expressed in fetal and adult hematopoietic tissues, including fetal liver and bone marrow, similar to zebrafish and mice. The MFRN protein localizes to the mitochondria like other SLC25 solute carriers. Ectopic expression of human MFRN capably restores hemoglobinized cells in anemic frs embryos, programs increased 55Fe-labeled heme synthesis in K562 cells, and rescues MRS3/4 mutant yeast for growth on iron-deficient media, demonstrating conservation of MFRN function. We evaluated 6 unrelated probands with a variant of erythropoietic protoporphyria (EPP) who harbor no mutations in ferrochelatase, the genetic cause of classic EPP. Five of the 6 index cases had severe hepatic disease necessitating liver transplantation. Our analysis of all 6 patients revealed the presence of an aberrantly spliced MFRN transcript, which was absent in normal individuals and patients with classic EPP. This aberrant spliceoform results in insertion of a 477 bp fragment from intron 2 and leads to an early nonsense codon after amino acid 156, prematurely truncating the MFRN protein. In contrast to normal MFRN cDNA, the variant MFRN cDNA from EPP patients fails to complement MRS3/4 mutant yeasts in low-iron media, demonstrating its loss-of-function activity. Our data demonstrate conserved function of human MFRN in erythroid mitochondrial iron metabolism and an association between a loss-of-function MFRN transcript and a variant of erythropoietic protoporphyria.
Favourable Overall Survival with Myeloablative Allogeneic Stem Cell Transplantation for Follicular Lymphoma.
Authors: Kuruvilla John , Bao Qikun , Messner Erica , Gupta Vikas , Kiss Thomas L. , Lipton Jeffrey H. , Minden Mark D. , Messner Hans A. 
Published: October 2019

Abstract
Introduction
Allogeneic stem cell transplantation (Allo-SCT) remains an option for patients with follicular lymphoma (FL). Our program employs a strategy using allo-SCT for patients (pts) with high risk disease based on clinical characteristics. We performed a retrospective analysis to examine long-term disease control and treatment-related mortality.
Methods
41 pts with indolent FL (follicular small cleaved [FSC], follicular mixed [FM] or FL grade 1,2 by WHO criteria) underwent allo-SCT at our institution between Jan 1989 and Dec 2005. Patients were in a chemosensitive remission at the time of SCT. The conditioning regimen consisted of busulfan (1 mg/kg PO q6h X4 days between 1989–200 and 3.2 mg/kg IV daily X 4days subsequently) and cyclophosphamide 60 mg/kg X 2 days. Cyclophosphamide 60 mg/kg X 2 days and TBI 12 Gy was used for unrelated donor SCT. GVHD prophylaxis was with cyclosporine A and methotrexate.
Results
There were 21 males and 20 females. The median age at the time of transplant was 45 years (range 24 to 58). Histologic subtype was: unclassified indolent FL: 3, Grade 1 or FSC: 17, Grade 2 or FM: 21. The median number of prior chemotherapy regimens was 2 (range 1 – 6) and was unavailable in 5. Prior anthracycline: 37, prior purine analog: 9, prior platinum-based: 20, prior auto-SCT: 1, prior rituximab: 11. The median time from diagnosis to allo-SCT was 23 months (range 6 – 161). 38 pts received BuCy conditioning. 2 patients underwent RIC SCT. Graft source was: matched related (MRD) bone marrow (BM): 28, MRD peripheral blood stem cells (PBSC): 4, Mismatch related (MMRD) bone marrow (BM): 1, MMRD PBSC: 2, matched unrelated donor (MUD) BM: 1, MUD PBSC: 1, and syngeneic BM: 4. The five year overall survival is 77% (95% confidence intervals 73 – 91%) with a median follow-up of 48 months post-SCT. Treatment-related mortality was 5 of 41 pts (12%). Non-relapse mortality was seen in one patient (3%). One patient has relapsed at over 3 years post-SCT while all recipients of syngeneic SCT remain in remission.
Conclusions
These results demonstrate that in selected patients, a fully myeloablative allo-SCT utilizing Busulfan-Cyclophosphamide conditioning provides excellent overall survival and disease control with low TRM. Prospective comparisons of RICSCT with myeloablative SCT should be performed in order to better evaluate these strategies.
Il-10 Polymorphism and TGF-β Haplotypes Are Associated with Rejection of Graft in Children with Beta Thalassemia Major Undergoing Matched Related Bone Marrow Transplantation (BMT).
Authors: Sellathamby Shanmugaapriya , Tamouza Ryad , Lakshmi Kavitha M , Viswabandya Auro , George Biju , Mathews Vikram , Krishnamoorthy Rajagopal , Charron Dominique , Chandy Mammen , Srivastava Alok 
Published: October 2019

Abstract
Th2 cytokines, IL-10 and TGF-β have immunoregulatory functions that can affect allograft acceptance. We have evaluated the correlation between IL-10 (-1082, -819, -592) and TGF-β codon 10C>T and 25G>C polymorphisms {(haplotype: TT/GG, TC/GG, high production); (haplotype: TC/GC, CC/GG, TT/GC, intermediate production); (haplotype: CC/GC, CC/CC, TT/CC, TC/CC, low production)}and graft rejection in 129 patients with β thalassaemia major who underwent matched related alloBMT. Patients who expired before day 15 (n=9) and for whom DNA samples was unavailable (n=18) were excluded from this study. None of these patients had graft rejection. Of the 102 patients who were evaluated, 73 (72%) patients received conditioning with Bu (16 mg/kg) / Cy (200 mg/kg) with ALG while 29 (28%) patients received Bu (600 mg/m2) / Cy (200 mg/kg) without ALG. All patients received unmanipulated bone marrow and standard cyclosporine / short course methotrexate regimen as prophylaxis against GVHD. Patients who died before day 21 after transplant (n=2) without achieving ANC >500/mm3 were not evaluated for engraftment. 9 out of 102 patients rejected their graft. Apart from the immunogenetic markers, the effect of other risk factors for rejection like recipient and donor age, sex mismatch, conditioning regimen, cell dose and Lucarelli class were also analyzed. Of these, only increasing donor age was found to mildly increase the risk of rejection (RR=1.06; p=0.019; 95% CI-1.01–1.1). Donor TGF-β haplotypes associated with intermediate or low production and IL-10 polymorphism accounting for low production were found to very significantly increase the risk of graft rejection (Table). TGF-β and IL-10 are essential for both development and the effector function of CD4 regulatory T cells which are important for tolerance induction. Therefore, it is possible that genotypes associated with lower production of these cytokines might contribute to increased graft rejection. We have previously reported that rejection in children with β thalassemia major is influenced by pharmacokinetics of busulfan and cyclophosphamide and genes implicated in their metabolism (BMT 2005 36, 839–845). We conclude that rejection of graft in this condition appears to be a multifactorial event affected not only by pharmacogenetics of the drugs used for conditioning but also by various immunogenetic factors.
Risk factors Relative risk P-value 95% CI TGFβ haplotypes Low + intermediate 6.97 0.015 1.4 – 33.6 High Reference IL-10 -819 TT 5.34 0.018 1.3 – 21.4 -819 TC + CC Reference IL-10 -592 AA 5.34 0.018 1.3 – 21.4 -592 AC + CC Reference
Conditioning with 8 Gy Total Body Irradiation and Fludarabine for Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia: Projected 4-Year Update.
Authors: Stelljes Matthias , Bornhaeuser Martin , Kroger Matthias , Beyer Joerg , Sauerland Maria C. , Heinecke Achim , Berning Bjorna , Scheffold Christian , Silling Gerda , Buchner Thomas , Neubauer Andreas , Fauser Axel Arthur , Ehninger Gerhard , Berdel Wolfgang E. , Kienast Joachim 
Published: October 2019

Abstract
Seventy-one patients with acute myeloid leukemia (AML), most of them (63/71) considered ineligible for conventional allogeneic hematopoietic stem cell transplantation (HSCT), were enrolled into a phase II study on reduced intensity myeloablative conditioning with fractionated 8 Gy total body irradiation (TBI) and fludarabine (120 mg/m2) (Blood. 2005 Nov 1;106(9):3314–21). Patients received mobilized peripheral blood stem cells (n=68) or bone marrow (n=3) from siblings (n=39) or unrelated donors (n=32). HLA-typing was performed for HLA-A, -B, -Cw (serological matching or intermediate resolution DNA typing), DRB1 and DQB1 (high resolution DNA typing). Three patients had unrelated donors with an allele mismatch in HLA DRB1 (2 with an additional mismatch in HLA Cw) and 7 patients were transplanted from unrelated donors with an antigen mismatch in HLA Cw. Thirty-six patients were transplanted in complete remission (CR) and 35 with untreated or refractory disease (non-CR). Median patient age was 51 years (range, 20–66). Sustained engraftment was attained in all evaluable patients. With a median follow-up of now 41.3 months (range, 20.4–70.4) in surviving patients, probabilities of overall survival for patients transplanted in CR and non-CR were 80% (95% CI, 66 to 94%) and 17% (95% CI, 5 – 29%) at 4 years, respectively. Relapse-free survival rates were 57% (95% CI, 39 – 75%) and 14% (95% CI, 2 – 26%). Of the 35 evaluable patients transplanted in CR, 10 patients suffered a relapse between days 68 and 868 after transplantation (cumulative incidence 29%). Five patients with late relapse (>1 year after transplantation) achieved a subsequent CR after conventional chemotherapy, blood stem cell boost and treatment with granulocyte-macrophage colony-stimulating factor, lasting 2000+, 1841+, 909+, 847+ and 480 days, respectively. Depending on donor type, relapse-free survival was similar in patients transplanted from unrelated or sibling donors. Overall survival in patients transplanted in complete remission from unrelated vs. sibling donors was 84% (95% CI, 73 – 95%) vs. 77% (95% CI, 68 – 86%). The cumulative incidence of non-relapse mortality (NRM) in CR patients was 11% at 4 years and beyond (3 patients deceased before day 100 and 1 patient 25 months after transplantation), but amounted to 37% at 4 years in non-CR patients. Nine of the 33 surviving patients (27%) have actually active chronic GvHD (5 limited and 4 extensive disease). This update confirms that allogeneic HSCT from related or unrelated donors with 8 Gy TBI/fludarabine conditioning is feasible with low NRM and preserved long-term antileukemic activity in AML patients in first or later CR.
Long Remission Are Possible after Non Myeloablative Transplant in Patients with Follicular Non-Hodgkin’s Lymphoma (NHL): Results of Two Prospectives Multicenter Trials.
Authors: Caballero María-Dolores , Martino Rodrigo , Mateos María-Victoria , Briones Javier , de la Serna Javier , Tomás Jose-Francisco , Arranz Reyes , Díez Jose-Luis , Rubio Vicente , Ribera Josep-María , Moraleda José-María , Sanz Guillermo , Urbano Alvaro , Sarrá José , Sampol Antonia , Sierra Jordi , Miguel J. F. San 
Published: October 2019

Abstract
Myeloablative transplant has been investigated in poor prognosis indolent lymphoma; although recurrence rate is low it is associated with high mortality; the use of non-myeloablative conditioning regimens could reduce TRM maintaining the GVH effect. Up to May 2006, 35 patients with follicular NHL received a Non Myeloablative related allogeneic according to two prospective multicenter trials; conditioning regimen consisted of Fludarabine 150 mg and Melphalan 70–140 mg. GVHD prophylaxis consisted of CSA plus short-course MTX. All patients received filgrastim-stimulated peripheral blood stem cells from a HLA related identical donor. Median age at transplant was 50 years (34–62) and 16 (46%) had received a previous autologous transplant. At transplant, 5 patients (14%) were in CR1 (after several lines of chemotherapy), 9 (25%) in >CR1, 12 (34%) in PR, 1 (3%) had stable disease (after 3 chemotherapy lines) and 8 (23%) progressive disease. All patients engrafted. Acute GVHD developed in patients 19 (54%) (17patients (48%) grade II-IV). Chronic GVHD developed in 18 out of 27 patients at risk (67%), being extensive in 11 (41%). Disease was evaluated at day +100 and at that moment 23 patients were in CR, (85%) 1 (4%) in PR, two (7%) had stable disease and 9 patients ( 26%) have died. With a median follow up of 60 months (range: 32–80 months), 20 patients (57%) are alive disease free, and 14 (43%) have died, 12 of them (37%) due to transplant toxicity and 2 patients (6%) due to progression. Overall Survival (OS) and Event Free Survival (EFS) are 57 and 54 % respectively. Analysing variables which influence on OS and EFS, patients 55 years have a OS significantly shorter than those <55 years old (22% vs 69%; p:0,007). Moreover, patients who develop chronic GVHD have an EFS significantly better than those which do not develop it (78 % vs 44%; HR: 3,9 (1,0–14,6); p: 0,03). In conclusion, our results demonstrates high efficacy of non-myeloablative transplant in follicular NHL with a very low relapse rate, indicating the important role of chronic GVHD in the control of the disease; however, mortality rate is still high, mainly in patients 55 years. Although follicular lymphoma is considered as an incurable disease, our results after a large follow-up suggest that allogeneic effect could change this concept.
A Retrospective Single Institute Analysis of 127 Lymphoma Patients Who Underwent Allogeneic Stem Cell Transplantation: Impact on Peripheral T-Cell Lymphoma (PTCL) Including ATLL.
Authors: Tanosaki Ryuji , Kim Sung-Won , Yamazaki Satoshi , Fukuda Takahiro , Mori Shin-ichiro , Heike Yuji , Tobinai Kensei , Takaue Yoichi 
Published: October 2019

Abstract
Background Clinical application of allogeneic stem cell transplantation (allo-SCT) for lymphoma patients (pts) has been hampered by its high mortality rate. In order to explore and establish safe and efficient procedures, reduced-intensity stem cell transplantation (RIST) has been incorporated in recent protocols for lymphoma. Here we retrospectively analyzed our single institute experiences of allo-SCT for lymphoma.
Results Between 1999 and 2005, 127 allo-SCTs, including 94 RIST (74%), were performed for lymphoma in our single institute. The number of each pathological classification and the one in which RIST was used, which is shown in each parenthesis, were PTCL (non-ATLL) 15 (RIST 13), ATLL 25 (18), NK/T 3 (2), FL 36 (29), MCL 6 (5), DLBCL 23 (17), LPL 1(1), HL 5 (5) and LBL 13 (4). Most patients were not eligible for autologous transplantation (auto-SCT) because of relapse after auto-SCT or chemo-resistant disease. Transplant-related mortality (TRM) were 16% in RIST and 45% in conventional stem cell transplant (CST) (p<0.001), and it was as high as 54% in aggressive lymphoma pts treated with CST (n=26). 3-year OS and PFS of FL, PTCL including 2 ALCL and 1 AILT, and ATLL were 80.6±6.6% and 80.6±6.6%, 46.7±12.9% and 60.0±12.6%, 46.5±10.3 and 57.1±10.6%, respectively, with the median follow-up of 737 days (range, -4–2628) in all these pts. Pts with other histology had poor outcomes and the numbers of pts surviving more than 1 year were HL 1 (20%), MCL 2 (33%), DLBCL 7 (30%), NK/T 1 (33%) and LBL 3 (23%). 5 pts with DLBCL were treated with auto-SCT/RIST tandem transplantation according to in-house protocol, and 4 out of 5 were alive in current CR with median follow-up of 749 days (range, 580–1038).
Discussion Since RIST was associated with lower TRM than CST, it could be applied safely in heavily treated pts with refractory lymphoma. Most pts with DLBCL, NK/T, and LBL relapsed or died of disease. However, pts with FL, PTCL and ATLL, even in chemo-refractory cases, had durable remissions after RIST. In refractory DLBCL, de-bulking of the tumor by prior auto-SCT might be promising.
Conclusions RIST could be performed comparatively safely. Notably, PTCL, both ATLL and non-ATLL, were newly highlighted as a good indication of RIST and should be further investigated.
Figure Figure
Frontline High Dose Sequential Chemotherapy with Rituximab (R-HDS) and Autologous Stem Cell Transplantation Induces High Rates of Complete Response and Prolongs Survival in Mantle Cell Lymphoma (MCL).
Authors: Cortelazzo Sergio , Magni Michele , Pintimalli Milena , Mian Michael , Rossi Andrea , Billio Atto , Marchesi Maddalena , Zanni Manuela , Tarella Corrado , Boccadoro Mario , Andreini Angelo , Benedetti Fabio , Pizzolo Giovanni , Barbui Tiziano , Gianni Alessandro M. , Rambaldi Alessandro 
Published: October 2019

Abstract
We showed recently that the dismal outcome of MCL might be improved in 28 young patients (pts) (<61 years) by an up-front Rituximab supplemented high-dose sequential chemotherapy (R-HDS) supported by stem cell autograft (ASCT) (A.M. Gianni et al, Blood, 2003). Following this encouraging experience we treated other 26 pts aged<61 years with standard R-HDS and 19 aged >60 years with an age-adapted R-HDS. We report the outcome of 54 young pts (group 1), including the first 28 cases and that of 19 elderly pts (group 2). The majority of both groups had an advanced stage and bone marrow infiltration, while in elderly pts prevail B symptoms and > 1 extranodal site. One third of cases had >2 adverse prognostic features according to IPI. After 2–3 cycles of either doxorubicin- or cisplatin-containing chemotherapy, group 1 received standard R-HDS including: HD-cyclophosphamide (CTX) 7 gr/sqm and HD-Ara-C (2 g/sqm every 12 hours for 6 days). Following HDS chemotherapy a conditioning program with HD-melphalan (180 mg/sqm) and/or HD-mitoxantrone plus melphalan (60 and 180 mg/sqm) with ASCT was planned. Rituximab (375 mg /sqm) was given for a total of 6 doses, twice after HD-CTX and HD-Ara-C, as in vivo purging before CD34+ cells harvest and twice after ASCT. Elderly patients received an age-adapted R-HDS: HD-CTX (3–4 gr/sqm) and HD-Ara-C (1–1.5 g/sqm every 12 hours for 3–5 days), followed by HD-melphalan (120 mg/sqm) and HD-mitoxantrone plus melphalan (40 and 120 mg/sqm). 35 pts (65%) in group 1 and 9 (47%) in group 2 completed the planned program and a median number of 7.6 and 6.8 x 10^6 cells CD34+/kg were transplanted. After ASCT the CR rate was 88% in young and 95% in elderly patients. One young pt (2%) died during treatment, 1 developed sMDS and 5 died of late toxicity including a case of lung carcinoma. Among elderly pts only one died tardily because of cardiac disease. With a median follow-up of 48 months (range 8–101) in group 1 and 25 months (range 9–68) in group 2, the 5-year estimated OS, EFS and DFS were 77%, 60% and 71%, in group 1 and 55%, 53% and not yet achieved in group 2. The Cox multivariate analysis failed to identify within potential prognostic markers factors predictive for OS and EFS. We conclude that R-HDS is an effective regimen for the induction of complete remissions in pts with newly diagnosed MCL. The manageable toxicity of the program in elderly pts proved that an age-adjusted R-HDS regimen can be safely applied to this age subgroup still producing long-term remissions.