bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduced Intensity Allogeneic Stem Cell Transplantation in Patients with Myelodysplastic Syndrome: Does the Conditioning Matter?.
Authors: Terriou Louis , Chir Zina , Esperou Helene , Boiron Jean-Michel , Vernant Jean-Paul , Gratecos Nicole , Michalet Mauricette , Milpied Noel , Jouet Jean-Pierre , Yakoub-Agha Ibrahim ,   Societe Francaise de Greffe de Moelle Osseuse et de Therapie Cellulaire
Published: October 2019

Abstract
Allogeneic transplantation following a reduced-intensity conditioning (RIC) has emerged as an alternative to myeloablative transplantation in pts with myelodysplastic syndrome (MDS). Given the uncertainty regarding the most appropriate conditioning regimen, SFGM-TC conducted a retrospective multicenter study in the attempt to evaluate the impact of conditioning on pts’ outcome. The record of 61 pts (37 males) with MDS who received a RIC were reviewed. The median age was 55 years (range: 18–70). According to the FAB classification, 11 pts had RA at diagnosis, of whom one had progressed to REAB and one to AML before transplantation. Thirty two pts had REAB at diagnosis, of whom 2 had progressed to REAB-T and 7 to AML before transplantation. Twelve pts had REAB-T at diagnosis and 6 CMML, of whom 8 progressed to AML before transplantation. The median time from diagnosis to RIC was 12 months (6–129). Conditioning consisted of Fludarabin (Flu) plus busulfan (FB; n=29), Flu plus 2-Gy TBI (F-TBI; n=20) and idarubicin plus aracytine and Flu (FlagIda; n=12). Donors were HLA-identical siblings (n=52) and HLA-matched unrelated (n=9). All pts received peripheral blood stem cells. The median of CD34+ infused cell dose was 5 x 106/kg (0.5–17.3). The median follow-up was 44.7 months (21–85). Estimated 3-year overall survival (OS), progression free survival (PFS), relapse and transplant-relapse mortality (TRM) were 35%, 27%, 66% and 30%, respectively. Neither of the 3 conditioning regimens used (FB, F-TBI and FlagIda) had impact on patients’ outcome. In multivariable analyses, while acute III/IV grade GVHD development was the only factor found to adversely influencing OS (HR=3.6; 95% CI: 1.1–12.2), chronic GVHD development was the only favourably influencing PFS and relapse ratios (HR=0.3; 95% CI: 0.1–0.7 and HR=0.2; 95% CI: 0.1–0.6, respectively). TRM was adversely influenced by male sex of recipient (HR=9.2; 95% CI: 1.5–66.6). RIC is an effective treatment in MDS patients irrespective of conditioning type. While acute III/IV grade GVHD appeared to be detrimental, the benefit effect of chronic GVHD was to be bound to GVL effect as demonstrated by the improvement of PFS and relapse rates in patients who developed chronic GVHD. This study shows no impact of conditioning in pts’ outcomes. New approaches with focus on immunosuppressive treatment are needed to enhance the GVL effect with an acceptable risk of GVHD.
Complete and Fast Hematologic Reconstitution with Non-Cryopreserved Stem Cell after a 5 Days BEAM Conditioning and Autologous Stem Cell Transplantation.
Authors: Karduss Amado J. , Jimenez Alejo , Gomez Luis R. , Reyes Pedro , De-Ossa N Hilda 
Published: October 2019

Abstract
There are several reports published in the medical literature addressing the roll of non-cryopreserved stem cells for supporting autologous transplant in lymphoma patients. However, in most of them, the conditioning used was a modification of BEAM or CBV with important differences in dose intensity or, in fact with different drugs. We present our experience using non cryopreseved stem cells and BEAM, but without decreasing the dose intensity of it. From Jun 2004 to May 2007, after a signed inform consent, 20 patients were transplanted; 16 men, 4 women, the median age was 37 years (range 15–57), 9 with Hodgkin lymphoma, 10 with large cell lymphoma and 1 with Burkitt. 13 of them were in second complete remission and 7 in third or partial remission. The mobilization was done with filgrastin 5 mg/kg/BID without chemotherapy and in the 5th and 6th day a leukopheresis of 3 or 4 blood volume was performed, the cells obtained were stored at 4oC for 6 days, in the case of the first leukopheresis, and for 5 days in the case of the second leukopheresis The administration of BEAM began in the evening of the last leukopheresis day and it was completed in 5 days as follow: BiCNU 300 mgs/m2 on day −5, etoposide 150–200 mgs/m2 BID for 6 doses on days −5 to −2, citarabine 300–400 mgs/m2 /day from days −4 to −2 and melphalam 140/mg/m2 on day −2. The stem cells were re-infused on day zero after 6 days of refrigeration for the first leokopheresis, and 5 days for the second. All patients received filgrastin from day + 5 until neutrophil recovery or pegfilgrastin one dose The mobilization and recollection were successful in 19 out of 20 patients with a median CD34 of 2.3 x 10(6)/kg (range 1–6) but in one was necessary obtain also bone marrow stem cell. The median viability of the cells after 6 days of refrigeration, measured by trypan blue, was 82% (range 66–90). The median time to achieve an absolute neutrophil count greater than 500 /ml in all patients was 12 days (range 9–20); 18 out of 20 were evaluable for thrombopoesis, they obtained a self sustained platelets count of 20.000 or more at a median of 15 days (range 9–30). The tolerance of the 5 days BEAM was good, one patient died from weak capillary syndrome on day + 18 and another from pneumonia on day + 16 there were no other grade III or IV non hematologic toxicity. With a follow of 3 to 36 months 13 out of 20 patients are alive. We conclude that the use of non-cryopreserved stem cell for supporting autologous transplant after a 5 days BEAM conditioning is feasible, safe, and produce a rapid, complete and sustained hematopoiesis. This simple procedure is a good alternative for saving costs.
The Mobilization Effects of G-CSF, GM-CSF and Darbepoetin-α for Allogeneic Peripheral Blood Stem Cell Transplantation.
Authors: Kim Shi Nae , Sohn Sang Kyun , Kim Jong Gwang , Kim Yee Soo , Cho Yoon Young , Moon Joon Ho , Ahn Byung Min , Lee Soo Jung , Kim Yun Jeong 
Published: October 2019

Abstract
Background: Granulocyte colony-stimulating-factor (G-CSF) is widely used for the mobilization of hematopoietic stem cells from normal donors. It has been reported that the addition of granulocyte-macrophage CSF (GM-CSF) to G-CSF mobilized more primitive CD34+ subsets than did G-CSF alone. We investigated the effects of combination regimen (GM-CSF + G-CSF + darbepoetin-α) for mobilization in normal healthy donors and compared its efficacy in mobilizing stem cells with G-CSF alone.
Methods: Thirty donors were randomly assigned to one of the following regimens for mobilization: G-CSF group (G-CSF 5ug/kg/day for 5 to 7 days) and combination group (GM-CSF 10ug/kg/day on 1st and 2nd days, G-CSF 5ug/kg/day for 5 to 7 days and 40mg of dalbepoetin-α on day 1)
Results: The counts of MNC and CD34+ cells/kg were not significantly different between two groups (p=0.129 and p=0.651). The CD3+ cell counts per kilogram were 3.48±1.45×108/kg and 2.54±0.94×108/kg in a G-CSF group and a combination group, respectively (p=0.04). Red blood cell transfusion requirement was not different between two groups (p=0.469). The median time to neutrophil and platelet engraftment was 12.5 vs. 12.0 days (p=0.443) and 11.5 vs. 11.0 days (p=0.752). Red blood cell recovery was 7.5 days and 7 days in G-CSF group and combination group, respectively (p=0.231). Grade II–IV acute graft-versus-host disease (GVHD) was observed in 20% in G-CSF group and 13% in combination group (p=0.50).
Conclusion: The combination regimen was not superior to G-CSF alone in terms of acute GVHD and CD34+ cell dose. But CD3+ cell count was significantly lower in combination regimen group. The role of lower CD3+ cells in the graft need to be elucidated in the future.
Protective Abilities of Interleukin-10 in Blood-Induced Joint Damage.
Authors: Jansen Nathalie W.D. , Van Roon Joel A.G. , Roosendaal Goris , Theobald Matthias , Bijlsma Johannes W.J. , Lafeber Floris P.J.G. 
Published: October 2019

Abstract
PURPOSE: Joint bleeds occur frequently in patients suffering from haemophilia or can occur as a consequence of joint trauma. Even a limited number of bleeds has been demonstrated to lead to severe joint damage in time (1,2). With respect to the mechanisms of blood induced joint damage, we have demonstrated that monocytes/macrophages within the mononuclear cell population together with the red blood cells as present in blood are responsible for the irreversible inhibition of cartilage matrix synthesis. Small amounts of IL-1 that are produced by activated monocytes/macrophages increase the production of hydrogen peroxide (H2O2) by chondrocytes. The hydrogen peroxide reacts with haemoglobin-derived iron from damaged and phagocytosed red blood cells, which results in the formation of hydroxyl radicals in the vicinity of chondrocytes. This leads to chondrocyte apoptosis and with that the irreversible inhibition of cartilage matrix synthesis (2). In search of possible interventions to prevent or limit the cartilage damaging effects of joint bleeds, we tested interleukin-10 (IL-10) as an inflammation controlling cytokine on blood-induced cartilage damage.
METHODS: Healthy human articular cartilage tissue explants were cultured in the presence or absence of 50% v/v blood for 4 days, followed by a recovery period of 12 days. IL-10 was added in 0.1, 1 or 10 ng/ml. Also cartilage and synovium in case of haemophilic arthropathy, obtained at joint replacement surgery, was cultured in the presence of IL-10 (10 ng/ml). The effect on cartilage matrix proteoglycan synthesis, -release, and -content were determined as well as the IL-1β and TNFα production by the synovium.
RESULTS: IL-10 was able to prevent the decrease in proteoglycan synthesis and the increase in proteoglycan release of cartilage exposed to blood dose dependently (p<0.05). As a consequence, the decrease in proteoglycan content after blood exposure could be prevented dose dependently (p<0.05). With 10 ng/ml IL-10, which is still a low dose for local therapeutic treatment, at least 50% reduction in adverse effects was observed (p<0.05). The matrix turnover of haemophilic cartilage improved upon addition of IL-10 and also the production of IL-1β and TNFα by haemophilic synovium decreased in the presence of IL-10 (all p<0.05).
CONCLUSIONS: The present results show that interleukin-10 prevents the direct harmful effects of blood on articular cartilage and has a beneficial effect on the matrix turnover of haemophilic cartilage and pro-inflammatory cytokine production by haemophilic synovium. Therefore, although treatment studies in addition to prevention studies have to be performed; IL-10 might be worthwhile to test in clinical practice for local treatment of joint haemorrhages, to prevent joint damage in time.
Single-Institute Comparable Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation from Unrelated and Related Donor in Patients with Myeloid Malignancies.
Authors: Yano Shingo , Usui Noriko , Dobashi Nobuaki , Takei Yutaka , Yahagi Yuichi , Takahara Shinobu , Otsubo Hiroko , Yamaguchi Yuko , Kasama Kinuyo , Minami Jiro , Kobayashi Tatsunosuke , Hoshi Yasutaka , Kobayashi Tadashi , Asai Osamu , Aiba Keisuke 
Published: October 2019

Abstract
Background: Allogeneic stem-cell transplantation (allo-SCT) from human leukocyte antigen identical related donor (RD) is taken priority over unrelated donor (URD), however, less than 30% of patients do not have a suitable RD. Transplantation from an URD should be considered for those patients. In order to investigate the role of URD, we retrospectively analyzed efficacy and safety of allo-SCT from URD and RD in patients with myeloid malignancies.
Patients and methods: One hundred six patients with myeloid malignancies (acute myeloid leukemia 48, chronic myeloid leukemia 38, and myelodysplastic syndrome 20) who received myeloablative regimens were analyzed. The stem cell source were bone marrow from URD (n=43) and peripheral blood stem cells or bone marrow from RD (n=63). Graft-versus-host disease (GVHD) prophylaxis consisted of taclorimus and short-term methotrexate (sMTX) for URD, or cyclosporine and sMTX for RD.
Results: Median follow-up was 6.3 (0.3–17.2) years, and median age of patients was 37 (15–55) years old. Hematological studies demonstrated donor engraftment in all patients. Incidence of grades II to IV of acute GVHD was 32% in URD and 18% in RD, and extended chronic GVHD was 31% in URD and 28% in RD. Probability of 8-year actuarial survival was 62% in URD and 54% in RD (p=0.4225), and 8-year disease-free survival was 64% in URD and 47% in RD (p=0.1412). There were no apparent differences in transplant-related mortality (TRM) (14% in URD and 24% in RD), relapse (14% in URD and 32% in RD) between both groups.
Conclusion: These results suggested that allo-SCT from URD has comparable safety and effectiveness for adult patients with myeloid malignancies.
Multi-Center Prospective Trial on Conditioning with Treosulfan, Fludarabine and ATG Before Allogeneic HSCT from Unrelated Donors.
Authors: Michallet Mauricette , Le Quoc-Hung , Thiebaut Anne , Ducastelle Sophie , Nicolini Franck E. , Raus Nicole , Tabrizi Reza , Bouabdallah Krimo , Blaise Didier , Mohty Mohamad , Faucher Catherine , Furst Sabine , Bay Jacques-Olivier , Hermet Eric , Milpied Noel 
Published: October 2019

Abstract
This prospective multi-center trial (MiniMud) concerns 27 patients (13 females, 14 males - 56 years[18–65]) who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated donors. The diagnosis and disease status pre-transplant were AML (n=12; 5 CR1, 7 CR2), ALL (n=1; 1 CR2), MM (n=5; 3 PR2,1 PR3, 1 PR4), NHL (n=4; 1 CR1, 2 PR3, 1 PR4), MPS (n=3; 2 stable disease (SD), 1 Relapse), acute RAEB (n=1; 1 progressive disease (PD) and CLL (n=1; 1 PR2). In total, 14 patients were in CR, 9 in PR, 2 in SD, 2 in PD. The median interval between diagnosis and transplant was 27 months [5;171], 24 patients received PBSC and 3 received bone marrow from unrelated 10/10 antigen HLA-identical (high-resolution level). All patients received Fludarabine 30 mg/m2/dx5d, Treosulfan 12 g/m2/dx3d and ATG 2,5 mg/kg/dx3d. After transplant, we observed 2 graft failures, 7 patients developed an AGVHD ≥ grade II (30%). Only 23 patients were eligibile to be analysed after 3 months of follow-up post transplant, 7 patients developed cGVHD (30%) (5 limited and 2 extensive), 12 patients died (7 from TRM causes and 5 from relapse) and 12 patients are alive in CR with a median follow-up of 14 months. Among the global population we defined a low risk subgroup: 17 patients [12 AML (5 CR1, 7 CR2), 1 ALL (CR2), 3 MM (3 PR2) and 1 NHL (CR1)], 2 patients presented an AGVHD ≥ grade II (13%). With a median follow-up of 18 months, 2 patients had a follow-up of less than 3 months, 3 patients developed a cGVHD (20%), 6 patients died (40%) and 9 patients are alive in CR. At one year, the probability of overall survival (OS) and event-free survival (EFS) were 50.4% [32;79], 40% [23;70] for the total population and 60% [37;96], 51.5% [29;90] for the low risk subgroup respectively. To try to demonstrate if Treosulfan allowed a better transplant outcome we performed a paired match-analysis [center and 4 out of 5 other parameters (age, gender, HSC, pre-transplant status and diagnosis] comparing our Treosulfan series and RIC transplants receiving Fludarabine, Busulfan and ATG (2.5–12.5mg/kg) from the SFGM-TC registry. This paired match-analysis found only RICT from related donors in the SFGM-TC database and showed no difference in term of OS and EFS between our unrelated donor-Treosulfan and related donor-SFGM-TC series.
Figure Figure Figure Figure
In conclusion, these results demonstrate that Treosulfan appears to be a very promising drug that could be included in the conditioning regimen before HSCT from either related or unrelated donors.
Preliminary Results of Phase II Trial of Clofarabine with Parenteral Busulfan Followed by Allogeneic Related or Unrelated Donor Transplantation for the Treatment of Hematologic Malignancies and Diseases.
Authors: Agura Edward D. , Berryman R. Brian , Fay Joseph W. , Pineiro Luis A. , Vance Estil A. , Tadic-Ovcina Mirjana 
Published: October 2019

Abstract
Background: Nonablative transplant regimens are useful to treat patients who are elderly or too ill to undergo a full-intensity ablative allogeneic transplant regimen. However, this approach is limited by a higher relapse rate in some situations. We developed a novel conditioning regimen using the nucleoside analogue clofarabine (CLO) with busulfan (BU) to treat elderly patients with acute leukemia or high risk MDS who are not in remission or are at high risk of relapse.
Methods: Five patients were enrolled on this single institution; phase II, IRB-approved trial, so far. The diagnoses at the time of transplant were two with AML, one with ALL, and two with MDS. All patients received CLO 40mg/m2/day iv on d-7 through d-4 followed by BU 3.2 mg/m2/day iv on d-3 and -2, followed by infusion of HLA matched related or unrelated donor PBSC on day 0. GVHD prophylaxis consisted of oral FK506 and MTX 5mg/m2 iv d + 1, +3 and +6. BU and CLO pharmacokinetic samples were collected on all patients for later PK analysis.
Results: Primary endpoints included toxicity and response to therapy. There were no cases of hepatic, cardiac, or renal toxicity attributed to the conditioning regimen by d+30. Acute toxicities included hand/foot syndrome, n=2 (one grade 1, and one grade 3 by CTCAE v 3.0); fluid retention, n=3 (2 grade 1 and 1 grade 2). All patients had hematologic nadirs lasting 12 to 15 days. GCSF was used in 4 of 5 subjects. 5 of 5 patients achieved allogeneic engraftment with myeloid cells by day +30. Response to therapy was documented in 4 patients by d+30, one is not yet evaluated. One (1) patient relapsed by d+62. 3 of 4 remain in remission with follow up ranging from 60 to 117 days.
Conclusions: CLO + BU is a novel allogeneic conditioning regimen that seems to be well tolerated by the small number of subjects treated so far at our institution. The follow up is not long enough to conclude more at this time. The study continues to accrue patients and will be updated at the meeting.
Intra-Arterial Catheter Directed Immunosuppressive Therapy for Steroid Resistant or Dependent Graft vs. Host Disease (GVHD).
Authors: Shapira Michael Y. , Bloom Allan I. , Or Reuven , Resnick Igor B. , Aker Memet , Slavin Shimon , Verstandig Anthony 
Published: October 2019

Abstract
Introduction: Prolonged treatment of graft vs. host disease (GVHD) is extremely immunosuppressive. Local therapy with intra-arterial (IA) injection of steroids may induce remission with lower extent of systemic immune suppression. Here, we present our experience with IA treatment of gastrointestinal (GI) and/or hepatic steroid resistant/dependent GVHD with 2 consecutive protocols.
Patients and methods: Thirty five patients (37 GVHD events (hepatic, n=15), (GI, n=16), (combined, n=6)) were treated with 53 IA sessions. Most side effects were minor.
Results: We found that IA steroid therapy was associated with partial and complete remission among patients with steroid resistant/dependent hepatic or GI GVHD. Hepatic partial response was observed in 14 (66.6%) patients among whom 7 (33.3%) reached complete response. GI partial response was observed in 19 (86.4%) patients among whom 12 (54.4%) reached complete response. Early administration of the local therapy, female gender, myeloid basic disease, and a non-active status of the basic disease at the day of transplantation were found related for predicting a better response for the intra-arterial treatment. The use of high dose steroids in the hepatic IA protocol from was at least as good as intermediate dose steroids with methotrexate (table 1, figure 1) and may be safer.
Conclusions: Intra-arterial catheter guided steroid therapy is safe and effective in steroid resistant/dependent GVHD. Hepatic artery treatment with methotrexate can be safely substituted with high dose IA methylprednisolone. Further research is warranted characterizing the patients benefit most.
Table 1 - comparison between 1st and 2nd hepatic IA treatment protocols 1st protocol 2nd protocol Significance Median age (range) 25 years (7–42) 32 years (18–59) P=0.09 Sex (M:F) 6:1 8:5 NS family donor vs MUD 6:1 9:4 NS Median time in days SCT-GVHD (range) 27 (13–133) 45 (13–248) NS Median time in days GVHD-IA (range) 15 (6–218) 190 (12–2615) P=0.09 Median peak GVHD grade (range) 3 (3–4) 3 (2–4) NS Highest pre-IA treatment bilirubin level (in mmol/L; normal<17) (range) 186 (138–321) 225.5 (83–672) NS Median time to initial response in days (range) 14.5 (4–100) 8 (1–31) P=0.073 Median time to complete response in days (range) 130.5 (35–226) 49 (17–80) Figure 1A, Figure 1B Figure 1A, Figure 1B.
Increased Interleukin-17 Proportion in Helper T Cell (Th17) in Patients Post Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Lange Andrzej , Dlubek Dorota , Sedzimirska Mariola , Drabczak-Skrzypek Daria , Jaskula Emilia , Lange Janusz 
Published: October 2019

Abstract
Cytokines belonging to interleukin -17 family (IL-17A, B, C, D, E and F) are produced mainly by activated and memory CD4+ cells which are described as Th17. These cells (IL-17+CD4+) promote autoimmune reaction (mouse model), were found in tissues involved in autoimmune process in man and produce IFNgamma. Therefore, Th17 cells constitute a population which may contribute to aGvHD together with Treg cells (FoxP3+). In this study we examined the cytoplasmic expression of IL-17A and FoxP3 in CD4+ lymphocytes in 6 pts post HSCT (3 MUD and 3 SIB, median (mean) age: 35 (33,9) years, 3 AML, 2 ALL-T, 1 SCID). Three of them developed aGvHD. All consecutive pts were included to the study. Peripheral blood lymphocytes were examined or at the very first day of aGvHD manifestation either at the beginning of hematological reconstitution and thereafter in one week intervals. Nine healthy individuals served as controls. PBMC were stimulated with BD Leukocyte Activation Cocktail containing mixture of PMA, Ionomycin and brefeldin A in the presence of BD GolgiStop then stained with CD4, IL-17A and FoxP3 monoclonal antibodies and analyzed in CD4+ and CD4- lymphocytes gates by three colour flow cytometry. Therefore, all results reflect the situation in stimulated cells. FoxP3 mRNA was measured in unstimulated PBMC with the use of qPCR. We found:
Patients post HSCT (during 6 weeks period post transplant) had higher percentages of IL-17A+ cells in CD4+ lymphocytes as compared to healthy controls (2.0%±1.08 vs 0.2%±0.06, p=0.006) independently whether they developed or not aGvHD. In contrast to the lower proportion of total CD4+ cells in pts post HSCT then in controls (18.5%±2.1 vs 34.9%±0.7, p=0.0006) proportions of a subset of CD4+ lymphocytes which produced IL-17A+ were rather higher in pts post HSCT as compared to controls (0.2%±0.06 vs 0.07%±0.02, ns). IL-17A+ cells contributed rather to CD4+ then CD4- lymphocytes in controls (0.2%±0.06 vs 0.05%±0.01, p=0.007) as well as in pts post HSCT (2.0%±1.08 vs 0.05%±0.01, p=0.00004) FoxP3 positive cells in stimulated CD4+ lymphocytes were in lower proportions in pts post HSCT then in healthy individuals (51.6%±3.9 vs 62.2%±2.9, ns). Percentages of FoxP3+CD4+ in stimulated lymphocytes (cytometry) correlated with quantities of FoxP3 mRNA in unstimulated PBMC (qPCR) (R=0,42, p=0,065). Notably, there was a negative correlation between proportions of FoxP3 and IL-17A positive cells in CD4+ lymphocytes in patients post HSCT (R= − 0,55; p=0,012).
In conclusion, HSCT was associated with:
an increase in proportion of Th17 cells, a higher contribution of IL-17A+ cells to the pool of CD4+ cells as compared to healthy individuals and a network in the immune system in which CD4+ FoxP3 + cells and Th17 cells play an opposite role.