bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Study on the Prognosis of Patients Relapsing after Autologous Stem Cell Transplantation (auto-SCT) for Follicular Lymphoma (FL): The Impact of Remission Duration.
Authors: Stumm Julia , Dreyhaupt Jens , Kornacker Martin , Hensel Manfred , Kneba Michael , D.Ho Anthony , Schmitz Norbert , Dreger Peter 
Published: October 2019

Abstract
Although auto-SCT has been in use for treatment of advanced FL since many years, little is known about the course of those who relapse after this procedure. Because these patients may be candidates for aggressive salvage approaches, we sought to study the outcome of patients with FL relapsing after auto-SCT with particular focus on factors predicting for survival.
Methods: Relapse cases were identified retrospectively from 244 patients autografted for FL between August 1990 and November 2002 in 3 institutions. Overall survival after relapse (OS) was calculated according to Kaplan-Meier and analyzed for the prognostic impact of pre-relapse variables as well as of post-relapse salvage treatment by univariate log rank comparisons and Cox regression analyses.
Results: With a median follow-up of 88 (5–186) months post auto-SCT, 104 relapses occurred, corresponding to a 10-year relapse probability of 0.47 (95%CI 0.4–0.53). Median age of relapsed patients was 48 (22–65) years. FLIPI score at diagnosis was low in 18%, intermediate in 58%, and high in 24%. In 51%, auto-SCT had been given as part of first-line treatment, and 45% had been in complete remission at auto-SCT. Myeloablation included total body irradiation (TBI) in 57% of the cases. Median time from auto-SCT to relapse was 19 (2–128) months, with only 2 relapses occurring later than 6 years post transplant. Transformed FL was present in 14% of those 87 patients who had relapse histology available. Rituximab-containing salvage therapy was given to 50% of the patients after relapse. With 45 (1–139) months of follow-up, median OS after relapse was 100 months. Log rank comparisons identified auto-SCT as part of salvage treatment, time to relapse <12 months, and salvage without rituximab as factors adversely influencing OS, while all other variables listed above had no impact. Cox analysis considering sex, age, salvage auto-SCT, TBI, time to relapse, and rituximab salvage confirmed a possible adverse impact of time to relapse <12 months (hazard ratio 2.58 (95%CI 0.99–6.82); p 0.055) but none of the other covariates on OS.
Conclusions: The prognosis of patients relapsing after auto-SCT for FL is surprisingly good. However, those whose disease recurs within the first post-transplant year tend to have a dismal outcome and might benefit from experimental salvage approaches, such as allogeneic SCT.
Arsenic Trioxide with Ascorbic Acid and High-Dose Melphalan for Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma.
Authors: Qazilbash Muzaffar H. , Saliba Rima M. , Davis Marilyn S. , Mendoza Floralyn L. , Hosing Chitra , Couriel Daniel R. , De Lima Marcos , Kebriaei Partow , Weber Donna M. , Wang Michael , Alousi Amin M. , Matthes Steven G. , Jones Roy B. , Champlin Richard E. , Giralt Sergio A. 
Published: October 2019

Abstract
Backround: Arsenic trioxide (ATO) has been shown to be synergistic with melphalan both in vitro and in vivo. We conducted a phase I/II trial to determine the safety and efficacy of a combination of arsenic trioxide, melphalan and ascorbic acid (AA) as preparative regimen in patients undergoing high-dose therapy (HDT) and autologous hematopoietic progenitor cell transplantation for multiple myeloma (MM). We also assessed the impact ATO levels on melphalan pharmacokinetics (PK), engraftment and toxicity.
Methods: Forty-eight patients with secretory myeloma (23 females, 25 males; median age: 54, range: 3570) were treated between 4/04 and 8/05. All patient received melphalan 100 mg/m2 IV on days -4 and -3 and AA 1000 mg/day IV on days -9 to -3. Patients were randomized to 3 arms; no ATO (arm 1), ATO 0.15 mg/kg IV on days -9 to -3 (arm 2) and ATO 0.25 mg/kg IV on days -9 to -3 (arm 3). Twelve patients had disease progression or relapse after a prior autograft. Median CD34 cells dose infused was 4.5 x 106/kg (range 2.3–10.9).
Results: Patients in all 3 arms were evenly matched. With a median F/U of 14.0 months (range 6–25) post autograft, no dose-limiting toxicity or non-relapse mortality was seen. Toxicity was limited to grade I or II nausea, vomiting and diarrhea. Median ATO levels on day 0 in arms 1, 2 and 3 were 0.2, 26.3 and 46.2 ng/ml, respectively. Melphalan PK was not altered by ATO pretreatment. Median time to neutrophil engraftment (ANC >500/ dl) was 9 days. There were no engraftment failures or delays in the ATO arms. CR rate for the entire group was 23%, and total response rate (CR + PR) was 75%. 1-year Progression-free survival (PFS) and overall survival (OS) were 75% and 95%, respectively. There was no significant difference in CR, RR, PFS or OS between the 3 arms (p = 0.9, 0.9, 0.4 and 0.6, respectively). A prior autologous transplant (p = 0.02) and abnormal cytogenetics at transplant (p = 0.04) were associated with a significantly shorter remission.
Conclusions: ATO + melphalan + ascorbic acid is a safe, effective and well tolerated preparative regimen for patients with multiple myeloma undergoing an autotransplant. A longer follow up is needed to assess the impact of ATO on progression-free and overall survival.
Unrelated Allogeneic Stem Cell Transplantation for Severe Acquired Aplastic Anemia: Has Outcome Improved?.
Authors: Maury Sebastien , Balere-Appert M.-Lorraine , Chir Zina , Boiron J.-Michel , Galambrun Claire , Yakouben Karima , Bordigoni Pierre , Marie-Cardine Aude , Milpied Noel , Kanold Justina , Maillard Natacha , Bourhis J.-Henri , Fischer Alain , Lutz Patrick , Michallet Mauricette , Blaise Didier , Cordonnier Catherine , Raffoux Colette , Socie Gerard 
Published: October 2019

Abstract
We aimed to determine whether outcome of HSCT from an unrelated donor has improved over time for patients with severe acquired aplastic anemia (SAA) and, if so, to determine whether improvement resulted from changes in patient selection, changes in transplantation technique, or both. We thus analyzed the outcome of 89 patients (median age 17 years, range 0–52) who received such transplantations between 1989 and 2004. We compared two cohorts of patients transplanted within two successive time-periods (1989–1998 and 1999–2004) associated with probabilities (± 95% confidence interval) of 5-year survival significantly different: 29% ± 7% and 50% ± 7%, respectively (P<.01, Figure 1). Significant differences between the two cohorts concerned transplant-related, but not patient- and disease-related variables: the use of ATG and of fludarabine within conditioning and HLA matching at the allelic level for the 10 HLA-A, -B, -C, -DRB1 and -DQB1 loci (P=.0004) were more frequent in the recent 1999–2004 period. In multivariate analysis, the only 2 factors influencing survival were HLA allelic matching (P<.01) and younger age of recipient (<17 years, P<.0001). Of note, the impact of HLA matching disappeared in multivariate analysis when it was considered at the antigenic level for HLA-A, -B and -DR antigens, which underlines the importance of considering HLA matching at the allelic rather than the generic level for these transplantations. Survival reached 78% ± 11% at 5-year for the younger patients fully HLA-matched (n=14), which can be compared with survivals obtained for HLA-identical sibling transplants in similar young patients. Cumulative incidences of graft failure, grade II–IV or grade III–IV acute GVHD, and chronic GVHD were: 14% ± 4 % at 2 years, 50% ± 5 % and 24% ± 4 % at 100 days, and 28% ± 5 % at 2 years after HSCT (limited: 17% ± 4 %, extensive: 11% ± 3 %), respectively. In a competing risk analysis, allelic HLA matching - particularly incorporating HLA-C but not -DQB1 matching - but also a high cell-dose injected (> 2,6.108/kg nucleated cells, the median value of the cohort) and the use of fludarabine and/or ATG in the conditioning regimen were found as protective against graft failure and acute GVHD, respectively. Our results suggest that survival after unrelated transplantation for SAA has improved over the past 15 years, due to a better HLA matching at the allelic level for both HLA class I and class II antigens, but also to other transplant-related factors.
Figure 1 Figure 1.
Purified T Depleted Peripheral Blood and Bone Marrow Cd34 Transplantation from Haploidentical Mother to Child with Thalassemia.
Authors: Sodani Pietro , Erer Buket , Gaziev Javid , Polchi Paola , Roveda Andrea , Spitaleri Luca , Pagliai Francesca , Paciaroni Katia , Adorno Gaspare , Lanti Alessandro , Isacchi Giancarlo , Zinno Francesco , Lucarelli Guido 
Published: October 2019

Abstract
Approximately 60% of thalassemic patients can not apply to “gene therapy today” which the insertion of one allogenic HLA identical stem cell into the empty bone marrow as the vector of the normal gene for beta globin chain synthesis. We studied the use of the haploidentical mother as the donor of hematopoietic stem cells assuming that the immuno-tollerance established during the pregnancy will help to bypass the HLA disparity and allow the hemopoietic allogeneic reconstitution in the thalassemic recipient of the transplant.
We have employed a new preparative regimen for the transplant in fourteen thalassemic children aged 3 to 12 years (median age 5 years) using T cell depleted peripheral blood stem cell (PBSCTs) plus bone marrow (BM) stem cells. All patients received hydroxyurea (OHU) 60 mg/kg and azathioprine 3 mg/kg from day -59 until day-11, fludarabine (FLU) 30 mg/m 2 from day -17 to day -11, busulphan (BU) 14 mg/kg starting on day -10, and cyclophosphamide(CY) 200mg/kg, Thiotepa 10 mg/kg and ATG Sangstat 2.5 mg/kg, followed by a CD34 + t cell depleted (CliniMacs system), granulocyte colony stimulating factor (G-csf) mobilized PBSC from their HLA haploidentical mother. The purity of CD34+ cells after MACS sorting was 98–99%, the average number of transplanted CD34+ cells was 15, 4 x 10 6/kg and the average number of infused T lymphocytes from BM was 1,8 x 10 5/Kg.The patients received cyclosporin after transplant for graft versus host disease(GVHD) prophylaxis during the first two months after the bone marrow transplantation.
Results. Thirteen patients are alive. Four patients rejected the transplant and are alive with thalassemia One patients died six months after bone marrow transplant for central nervous system diffuse large B cell lymphoma EBV related. Nine patients are alive disease free with a median follow up of 30 months (range12–47). None of the seven patients showed AGVHD and CGVHD. This preliminary study suggest that the transplantation of megadose of haploidentical CD34+ cell from the mother is a realistic therapeutic option for those thalassemic patients without genotipically or phenotipically HLA identical donor.
Impaired Survival after Unrelated Hematopoietic Stem Cell Transplantation from KIR2DS1 and KIR2DS2 Positive Donors.
Authors: Giebel Sebastian , Czerw Tomasz , Nowak Izabela , Wojnar Jerzy , Kruzel Tomasz , Dziaczkowska Joanna , Markiewicz Miroslaw , Holowiecka-Goral Aleksandra , Karolczyk Agnieszka , Wylezol Iwona , Kusnierczyk Piotr , Holowiecki Jerzy 
Published: October 2019

Abstract
The function of NK cells is regulated by a balance between signals transmitted via actvating and inhibitory receptors, including killer-immunoglobulin-like receptors (KIRs). Activating KIRs (KIR2DS1 and KIR2DS2) are also present on subsets of T cells, which has recently been demonstrated to play a role in several autoimmune conditions. The goal of this analysis was to determine the relationship between donor activating KIRs genotype and outcome after unrelated donor hematopoietic stem cell transplantation (URD-HSCT).
Seventy five patients (age 30y; range 14–57) with hematological malignancies treated with URD-HSCT in a single centre between 2000 and 2006 were included in the analysis. Donors were selected using DNA-high resolution typing for both HLA class I and II alleles. KIR2DS1 and KIR2DS2 genes were examined in all donors. Additionally, in 16 cases a subpopulation of KIR2DS2/DL2/DL3-positive T cells in peripheral blood was monitored in donors as well as in recipients for 6 months after transplantation.
The conditioning regimen was myeloablative and based on chemotherapy alone (n=56) or TBI (n=19). Graft-vs-host disease (GVHD) prophylaxis was uniform and consisted of cyclosporin, methotrexate, and pre-transplant anti-thymocyte globulin. Twenty-five % of donors were positive for both KIR2DS1 and KIR2DS2 gene, 18% were positive for KIR2DS1 only, 25% - for KIR2DS2 only, and 32% were negative for both KIR2DS1 and KIR2DS2. In univariate and multivariate analysis, including other potential risk factors, the presence of both KIR2DS1 and KIR2DS2 genes of the donor was associated with decreased overall survival (0% vs. 80%, RR 3.2, p=0,01) and disease free survival (0% vs. 64%, RR 2.5, p=0,03), compared to the remaining subgroups. Furthermore, simultanous KIR2DS1 and KIR2DS2 positivity resulted in increased GVHD-related mortality (70% vs. 8%, p=0.01) in univariate analysis (incidence of both acute and chronic GVHD contributed to this effect). KIR2DS2/DL2/DL3-positive T cells were detected in 3/16 donors before URD-HSCT and in all recipients between day +28 and +180 after URD-HSCT. KIR-positive T cells were particularily frequent (32%–42% of all CD3 cells) in three patients who developed acute GVHD, and for whom the donors were KIR2DS2-positive.
We conclude that the simultaneous presence of both KIR2DS1 and KIR2DS2 in the donor is associated with decreased survival following URD-HSCT. The mortality may result from higher incidence of lethal GVHD. Preliminary observation suggests the role of KIR-bearing T lymphocytes in this effect.
Matched Unrelated Donor Stem Cell Transplantation for Relapsed or Refractory Mantle Cell Lymphoma. A Retrospective Analysis from the EBMT Lymphoma Working Party.
Authors: Avivi Irit , Canals Carme , Taghipour Goli , Finke Jurgen , Volin Liisa , Beguin Yves , Boogaerts Marc , Crawley Charles , Rieger Michael , Schmitz Norbert , Kobbe Guido , Milligan Donald , Niederwieser Dietger W. , Russell Nigel H. , Schwerdtfeger Rainer , Sureda Anna 
Published: October 2019

Abstract
High-dose therapy with allogeneic hematopoietic transplantation (allo-SCT) from matched sibling donors has been shown to induce durable remissions in some patients with relapsed / refractory mantle cell lymphoma (MCL). The aim of this retrospective analysis from the LWP of the EBMT was to investigate the outcome of patients with MCL treated with an unrelated donor allo-SCT (MUD-allo). From January 1994 to July 2005, 66 patients with MCL, 51 males and 15 females, with a median age of 50 years (range, 22 to 68) underwent a MUD-allo and were reported to the EBMT registry. The median time from diagnosis to MUD-allo was 34 months (range, 6–131). Thirty-five patients (53%) had previously failed an autologous procedure (ASCT). Forty-five patients (68%) had sensitive disease (including 22 patients in complete remission) at transplantation, whereas 21 patients (32%) were allografted with refractory disease. Reduced intensity conditioning regimens (RIC) were used in 44 patients (67%). Patients treated with RIC were older, more heavily pre-treated and had more frequently failed an ASCT (46% vs 30%, p = 0.01) than patients treated with a conventional conditioning protocol. Total body irradiation (TBI) was used in 68% of the patients receiving conventional protocols and low-dose TBI in 23% of the RIC patients. Grade II–IV acute graft versus host disease (GVHD) developed in 35% of the cases. The cumulative incidence (CI) of non-relapse mortality (NRM) was of 21% at 6 mo and 27% at 12 mo. The CI of relapse was 35% at 1 year and 45% at 2 years. After a median follow up of 15 months (1–73), 25 patients are alive without progression, with an estimated PFS and OS at 2 years of 28% and 42%, respectively. RIC protocols were not associated with a lower NRM or a better survival. Refractory disease at MUD-allo was an adverse prognostic factor for PFS (RR 1.7; p = 0.006). Patients allografted in sensitive disease presented a better 2-year PFS and OS (34% and 48%, respectively). In conclusion, although follow up is still short, MUD-allo is a feasible procedure in poor prognosis MCL patients, with almost one third of them being alive and progression-free in this series. RIC protocols do not seem to offer any advantage in terms of long-term outcome in relation to conventional conditioning regimens.
Unrelated Hematopoietic Blood Stem Cell Transplantation in Patients with Acute Myelogenous Leukemia (AML) in First Remission.
Authors: Ehninger Gerhard , Aulitzky Walter E. , Bodenstein Heinrich , Bornhaeuser Martin , Einsele Hermann , Faul Christoph , Finke Jurgen , Ganser Arnold , Gramatzki Martin , Haenel Mathias , Helm Gisela , Ho Anthony D. , Jakob Andreas , Knigge Owe , Link Hartmut , Mahlberg Rolf , Mahlknecht Ulrich , Neubauer Andreas , Schmitz Norbert , Schaich Markus A. , Schaefer-Eckart Kerstin , Soucek Silke , Wagner Thomas , Wandt Hannes , Zander Axel R. 
Published: October 2019

Abstract
Between 1996 and 2003, 994 patients aged under 60 years with de novo AML received a double induction chemotherapy consisting of MAV (mitoxantrone 10 mg/m2 day 4–8, Ara-C 100 mg/m2 continuous infusion day 1–8, etoposide 100 mg/m2 day 4–8) and MAMAC after an interval of at least 14 days (Ara-C 1 g/m2 q. 12 hrs day 1–5, amsacrine 100 mg/m2 day 1–5). A cytogenetic high risk profile (complex aberrations, −5/del(5q), −7/del(7q), hypodiploid karyotypes other than −5, −7, −X, −Y, abnl3q, abnl1q, abnl12p, t(6;9), t(9;22), t(9;11), +11, +13, +21, +22) was present in 252 patients (de novo AML [N=160], prior MDS [N=41], and secondary AML [N=51]). 119 out of 252 (47%) were in complete remission after 2 induction cycles. 35 (14%) additional patients showed complete remission after a further cycle. Patients with a HLA matched sibling donor (N=37) or an unrelated donor (N=34) received an allogeneic transplantation as consolidation therapy. The conditioning protocol consisted of 12 Gy TBI and cyclophosphamide. Cyclosporine and methotrexate were used as GvH prophylaxis. The actuarial survival at 5 years is 42% (CI: 26%–58%) in the related donor group and 53% (CI: 36%–70%) in the unrelated donor group. The disease free survival at 5 years is 40% (CI: 24%–56%) in the related group and 43% (CI: 26%–60%) in the unrelated group (for both, p=ns). In conclusion, the results after unrelated donor transplants are comparable with those after related donor transplants in patients with high risk AML. These data of the AML’96 study will be compared with the experience of our current upfront concept using allogeneic transplantation in aplasia after the 1st or 2nd induction cycle in high risk AML.
NK1.1+ Cells Are Involved in the Anti-Tumor Immunity Induced by the Rejection of Donor Hematopoietic Cells in Mixed Bone Marrow Chimeras.
Authors: Saito Toshiki I. , Sykes Megan 
Published: October 2019

Abstract
BACKGROUND
Surprisingly, some patients who reject donor marrow grafts following nonmyeloablative HCT sustain remissions of advanced hematologic malignancies (Br J Haematol2005, 128:351). In murine mixed chimeras prepared with nonmyeloablative conditioning, we previously showed that recipient leukocyte infusions (RLI) induced loss of donor chimerism and anti-tumor responses against host-type tumors (Blood2003, 102:2300) and that both CD4+ and CD8+ T cells are necessary to achieve maximum anti-tumor effects (J Immunol2005, 175:665). We now examined whether or not NK and/or NKT cells are required in the anti-tumor effect.
METHODS
Mixed chimerism was achieved in BALB/c (H-2d) mice conditioned with depleting anti-CD4 and CD8 mAbs on Day -5, cyclophosphamide 200 mg/kg on Day -1 and 7 Gy thymic irradiation on Day 0 prior to transplantation of 25x106 B10.BR (H-2k) or B10.RIII (H-2r) bone marrow cells. Some groups received RLI (3x107 BALB/c spleen cells) seven weeks post-BMT. A20 cells (5x105) were given i.v. one week after RLI. Some groups included Jα281-deficient BALB/c (Jα281 KO) mice that lack invariant NKT (iNKT) cells or NK1.1+ BALB/c mice whose NK and NKT cells can be depleted by anti-NK1.1 Ab, PK136. Some groups received a depleting dose of anti-NK1.1 antibody before and after RLI administration.
RESULTS
Untreated recipients of NK1.1-depleted RLI (n=9) showed similar tumor survival compared to recipients of NK1.1-sufficient RLI (n=9) (median survival time [MST] 52 versus 52 days respectively, p=0.68). NK1.1-depleted (with mAb in vivo) chimeras that received RLI (n=8) had shorter survival (MST 35.5 days) than NK1.1-sufficient chimeras that received RLI (n=10) (MST 68 days, P<0.01) and no anti-tumor effect was observed in the depleted group. Jα281 KO chimeric recipients receiving with Jα281 KO-derived RLI (n=12) had shorter survival than wild-type chimeric mice receiving wild-type RLI (n=11) (MST 41.0 vs 67.0 days, p<0.01) and no survival benefit of RLI was observed in Jα281 KO recipients (p=0.93).
CONCLUSION
When NK and NKT cells were depleted from NK1.1+ BALB/c recipients, no anti-tumor effect was observed. In contrast, no reduction in anti-tumor effect was observed in chimeras given NK1.1-depleted RLI. Invariant NKT cells are required to achieve anti-tumor effects in this model. Therefore, NKT cells and possibly NK cells in the recipient are essential for the anti-tumor effect of RLI, but NK and NKT cells in the RLI do not play a role. The requirement for both T cells and NK/NKT cells suggests an essential interaction between the innate and acquired immune systems.
Early CD30 Signaling Is Critical for Adoptively Transferred CD4+CD25+ Regulatory T Cells in Prevention of Acute Graft Versus Host Disease.
Authors: Zeiser Robert , Nguyen Vu H. , Hou Jing-Zhou , Beilhack Andreas , Zambricki Elizabeth A. , Buess Martin , Contag Christopher H. , Negrin Robert 
Published: October 2019

Abstract
CD4+CD25+ regulatory T cells (Treg) have been demonstrated to reduce the severity of acute graft-versus-host disease (aGvHD) in murine models of bone marrow transplantation. However, the surface molecules that are critical for suppression are unclear. The TNF-R superfamily member CD30 has been shown to be expressed on regulatory T cells that down-modulate nickel specific immune responses and to be relevant for Treg mediated protection from allograft rejection. Deficiency of the CD30 molecule (CD30−/−) is associated with impaired thymic negative selection and augmented T cell autoreactivity. Therefore, we investigated the role of CD30 signaling in Treg function in an aGvHD model. Treg derived from CD30−/ − animals were significantly less effective in preventing aGvHD lethality (wt vs. CD30−/ − p=0.002). Signal intensity derived from expanding luciferase expressing alloreactive conventional T cells (Tconv) was significantly higher if CD30−/ − Treg as compared to wt Treg (p=0.007) were transferred as assessed by bioluminescencent based imaging. Blockade of the CD30/CD153 pathway with a neutralizing anti-CD153 mAb during the early (days −2 to +4) but not late (days +4 to +10) phase of adoptive Treg transfer reduced Treg mediated protection from proinflammatory cytokine accumulation and apoptosis of donor-type CD4 and CD8 T cells. In vivo bioluminescence imaging demonstrated intact Treg homing, but reduced expansion when CD153 was blocked during the early phase after adoptive transfer. CD30 surface expression on Treg increased with alloantigen exposure and CD153 expression on recipient-type dendritic cells increased in the presence of an irradiation induced proinflammatory environment but not when T cell depleted bone marrow and Tconv were transferred into non-irradiated Rag 2−/ −γc−/ − recipients. These data are the first to demonstrate that early CD30 signaling is relevant for Treg mediated aGvHD protection after major MHC mismatch bone marrow transplantation.