bluuebunny/crossref_metadata_2025_split huggingface dataset:
Asymmetric Reconstitution of γδ T Cell Subsets after Haemopoietic Stem Cell Transplantation.
Authors: Travers Paul J. , Knight Andrea , Grace Sarah , Kottaridis Panos , Mackinnon Stephen , Madrigal J. Alejandro 
Published: October 2019

Abstract
In previous studies we and others have shown that the production of new T cells from the thymus declines after the third decade and that while patients below the age of 30 reconstitute primarily new T cells, those over thirty reconstitute primarily by expansion of pre-existing mature T cells. However little attention has been paid to the γδ subset of T cells, which form an important component of mucosal immune protection and which represent approximately 5% of peripheral T cells. Two major subsets of γδ T cells are defined by the expression of Vδ1 versus Vδ2, with Vδ1+ cells predominating in the fetal circulation and in mucosal sites, while Vδ2+ cells predominate in adult life and in the peripheral circulation. In light of the differerential preponderance of the two subsets in the fetal versus adult circulation, we have examined the reconstitution of these two subsets of γδ T cells following hemopoietic stem cell transplantation in a cohort of 28 patients sampled at 3 monthly intervals to ask whether both subsets recover adequately from adult stem cells.
In 44 normal individuals, the median levels of Vδ1 and Vδ2 cells are 12.46 (0.22 to 167.8) and 32.78 (4.48 to 190.1) cells/mm3 respectively. In patients under 30, the reconstitution of the Vδ1 and Vδ2 subsets follow similar kinetics, reaching a plateau at 9 months post transplant with comparable numbers of Vδ1 and Vδ2 cells (note that the normal ratio of Vδ1 to Vδ2 is 0.38, so in the patients there is a significant increase in the proportion of Vδ1 cells in the peripheral circulation). In patients over 30 years of age, there is an even more significant disparity in the reconstitution of the two subsets. The Vδ1 subset recovers with similar kinetics as is seen in the patients under 30, although to slightly lower final levels. The Vδ2 subset, however, shows very little recover y, reaching a plateau at 6 months at the bottom of the normal range for up to 2 years post transplant. In these patients the ratio between Vδ1 and Vδ2 is inverted with an increasingly greater proportion of Vδ1 cells at longer times after transplant, with ratios in excess of 10 by 24 months post transplant, a 30-fold increase in the normal proportion of Vδ1 + T cells. Given that the Vδ1 subset shows a very restricted repertoire compared to the Vδ2 subset, the overall capacity of the circulating γδ T cell population to recognise and respond to antigen will be significantly compromised in older transplant recipients.
Day 15 Natural Killer (NK) Cell Recovery Predicts Progression Free Survival after Autologous Stem Cell Transplantation in Non-Hodgkin’s Lymphoma.
Authors: Siddiqui Mustaqeem A. , Markovic Svetomir N. , Nevala Wendy K. , Uhl Cindy B. , Morice William G. , Porrata Luis F. 
Published: October 2019

Abstract
The peripheral blood absolute lymphocyte count (ALC) on day 15 after autologous stem cell transplantation (ASCT) has been shown to be an independent predictor for overall survival (OS) for many malignancies including acute myelogenous leukemia (AML), breast cancer, multiple myeloma (MM), primary systemic amyloidosis, and Hodgkin’s and non-Hodgkin’s lymphoma (NHL). However, due to the retrospective nature of previous studies, the peripheral blood lymphocyte subpopulations that predict survival are unknown. To prospectively correlate peripheral blood lymphocyte subpopulations after ASCT and progression free survival, peripheral blood lymphocytes collected from patients before and on day 15 after ASCT were analyzed by four color flow cytometry for CD3, CD4, CD8, CD16, CD 19, and CD56. Patients were then dichotomized into two groups: patients achieving normal numbers of lymphocyte subset (i.e. CD4, CD8, CD19, CD16/56) count versus those who did not. Progression free survival was then analyzed by the Kaplan-Mier method. In our cohort of 14 patients, 9 were male and 5 were female. Nine patients were diagnosed with diffuse large cell B cell lymphoma, two with mantle cell, two with follicular, and one with peripheral T cell lymphoma. On presentation, one patient had stage I, four patients had stage II, four had stage III, and five patients had stage IV disease. The median age at ASCT was 53 years (range: 26–70). The preliminary data from this ongoing prospective study of 14 patients shows that on day 15 after ASCT, 4/14 (29%) of patients achieved a normal CD3 count (median 321, range: 69–2069 cells/ml) 3/14 (21%) achieved a normal CD4 count (median 206, range: 31–1091 cells/ml), 6/14 (43%) achieved a normal CD 8 count (median 88.5, range: 13–813 cells/ml) 1/14 (7%) achieved a normal CD19 count (median 2, range:0–227 cells/ml), and 8/14 (57%) achieved a normal CD16/56 count (median 85.5, range: 10–744 cells/ml). The median follow-up was 12 months (range: 3–45 months). On univariate analysis, patients achieving an absolute NK cell count of ≥ 80 cells/μ on day 15 had significantly improved progression free survival compared to those who did not (not reached vs 3 months, p<0.006, respectively). Similar analysis evaluating the absolute CD3, CD4, CD8, and CD 19 count was not significant (p=0.1, p=0.258, p= 0.06, and p=0.55, respectively). To our knowledge, this is the first report detailing the critical role of NK cell immune reconstitution after ASCT in progression free survival.
Figure Figure
Double Cord Blood Transplantation for Patients with High Risk Hematological Diseases: Delayed Immune Recovery and High Incidence of Infections.
Authors: Rocha Vanderson , Madureira Adrienne , Robin Marie , Carmagnat Marievonick , Fernandes Juliana F. , de Latour Regis P. , Ferry Christele , Traineau Richard , Ribaud Patricia , Devergie Agnes , Rabian Claire , Gluckman Eliane , Socie Gerard 
Published: October 2019

Abstract
The possibility to perform double cord blood transplantation (dCBT) has extended its use in adults with high risk hematological disease; however there is no data on immune recovery and report on infections complications. We have performed a phase II study on 16 dCBT from 2004 to 2006. Ten patients had high risk malignant disorders (ALL=1, AML+MDS=6, CML=3) and 6 high risk of rejection (SAA=4, PNH=1 and Fanconi Anemia=1). Among those patients, 4 (25%) received a dBCT as a rescue of previous non-engrafted transplants (2 SAA, 1 AML and 1 CML). Analyses of T, B and NK cells phenotype were performed once a month during the first 3 months and ever two months until 12 months. The median age was 21 years (11–42), the median weight 63 kg (30–90) and the median follow-up was 6 months (3–18). Conditioning regimen varied according to disease (myeloablative) or second transplant (reduced intensity), all but two patients have received ATG. GVHD prophylaxis consisted in CsA + steroids in 12 patients and associated to MMF in 4.
Results: 2 patients did not engraft (both with SAA), one patient relapsed 8 days after dCBT, and 12 patients engrafted at a median of 23 days (14–42). Chimerism available in 12 patients before day 100 showed both CB units in 7 patients. After day 100, in 8 evaluable patients, 3 patients had evidence of both CB units engraftement. Acute GVHD was observed in 5 patients (grade II in 4 and grade III in 1) and chronic GVHD in 7 out of 12 at risk. During the first 100 days, 9 CMV reactivations were diagnosed; 4 HSV (resistant to acyclovir); 3 HHV6 infections; 3 EBV reactivations; 2 adenovirus diseases, 4 VRS infections, 2 septicaemias, 3 fungal infections, 1 disseminated toxoplasmosis. After day 100, we observed 4 CMV reactivations, 1 CMV disease, 1 HSV, 1 adenovirus disease and 1 EBV-PTLD. Important lymphopenia was observed in all patients (median of 259mm3 at 3 months (n=14); 389 at 6 months (n=13) and 480 at 12 months (n=8). Median numbers of CD3/CD4 at 3, 6 and 12 months were: 8, 15 and 46 mm3 respectively; of NK cells 203, 249 and 115mm3, and of B cells were 0, 0 and 110 mm3, respectively. At 6 months overall survival was 58±14% and event-free survival was 52±14%. Six patients died: 2 of relapse and 4 from infections. Three out of 4 patients have been rescued of previous non-engraftment and are alive and well (4–18 months). In conclusion, despite the short follow-up dBCT seems to be an option to treat patients with high risk diseases and without a suitable compatible HLA donor. High incidence of infections and delayed immune recovery are major problems after dCBT.
Improving the Pharmacokinetic Analysis of the Once Daily IV Busulfan Regimen for Allogeneic Stem-Cell Transplants: A Scientific Method Modification.
Authors: Naveed Farrukh , Kangarloo Shahbal , Chaudhry Ahsan , Geddes Michelle , Quinlan Diana , Russell James 
Published: October 2019

Abstract
Derivitization, a chemical technique used to transform a compound into a similar product with a different structure required by certain detection methods, was carried out for the detection of Busulfan (Bu) in human plasma. Using a proficient scientific method and enhancing its clinical association our method furthered the pre-column derivitization technique based on isocratic high performance liquid chromatography with ultraviolet detection (HPLC-UV). In-house adjustments have been made over the course of the last two years in order to increase the efficiency and turn-around of the method assay for clinical purposes. The concentration of drug in human plasma was measured with UV detection at 278nm by employing a Waters Nov-Pak C-18 analytical column heated to 40°C. The mobile phase, run at 1.5mL/min, consisted of a mixture of 20:80 deionized water and methanol respectively. All concentration-time plasma Bu data were analyzed by a non-compartmental analysis employing linear kinetics using WinNonlin Version 4.1 software (Pharsight Corporation, Mountain View, CA, USA). Analyses were performed on 155 allogeneic Stem-Cell Transplant (SCT) patients (pts). All pts received fludarabine 50mg/m2 on days -6 to -2 and IV Bu at a “myeloablative” dose of 3.2mg/kg daily, on days -5 to -2 inclusive. Additional TBI 200cGy × 2 was given to 74 pts. Graft-vs.-host disease prophylaxis for all pts comprised cyclosporine A, “short course” methotrexate with folinic acid and Thymoglobulin (Genzyme) 4.5mg/kg administered in divided doses over 3 consecutive days pre-transplant finishing on D0. The range of area under the curve (AUC) per dose was 2184 to 7513μM·min (median 4509μM·min). Twenty nine pts (19%) had AUC < 3600μM·min and 17 (11%) had AUC > 6000μM·min. The remaining 109 (70%) were between 3600 and 6000μM·min, equivalent to an exposure of 900 – 1500μM·min per dose established as desirable from studies of qid oral Bu given with cyclophosphamide. We found that IV Bu resulted in a 3–4 fold variability in AUC with a significant number of pts with exposures deemed either too high or low. High exposures (> 6000uM*min) increase the risk of transplant-related death and there is justification for therapeutic monitoring. Our predicted adjustments obtained from a streamlined method are based on day -5 Bu doses. The adjusted doses are administered on days -3 and -2, allowing for a 24 hour turn around time between days -5 and -3.
Defibrotide Effectively Prevents Veno-Occlusive Disease of the Liver (VOD) after Allogeneic Stem Cell Transplantation. An Extended Study.
Authors: Chalandon Yves , Roosnek Eddy , Helg Claudine , Verholen Frank , Knipp Sabine , Ozsahin Hulya , Passweg Jakob R. 
Published: October 2019

Abstract
VOD of the liver is reported to occur in 10–30% of patients after allogeneic HSCT, with mortality rates up to 50%. We previously reported a pilot study of defibrotide (Prociclide® Crinos, Como, Italy) VOD prophylaxis showing a significantly lower rate of VOD as compared to historical controls. We now report the results of an extended study.
Between 2000 and 2005, 157 consecutive patients were transplanted for hematological diseases. Median age was 43 y (range 5–61 y), M/F: 96/61; diagnosis was AML=42, ALL=19, CML=28, MDS/MPS=24, lymphoma=22, MM=12, AA=7, solid tumor=3. Donors were HLA-identical siblings (65%), unrelated (32%) mismatched relatives (3%). Stem cell source was peripheral blood (87%) and bone marrow (13%). The transplants were T-cell depleted by CAMPATH-1H in vitro, with (69%) or without (7%) T-cell add-back or left unmanipulated (24%). Conditioning was myeloablative with CyTBI (50%), BuCy (9%) other myeloablative (11%) or non-myeloablative (30%) using Fludara/Bu/ATG. GVHD prophylaxis was CSA with or without MTX or MMF. Nine pts received a second transplant for relapse or graft failure.
Defibrotide was given intravenously 6 hourly starting prior to conditioning up to day +20 posttransplant (dose range 20–30 mg/kg) in addition to low dose heparin. The Baltimore criteria were used to score VOD.
Results: No VOD was observed after 165 transplants. Defibrotide was well tolerated and no side effects were attributed to this medication. Median peak levels of bilirubin were 21 umol/l (range 9–286 umol/l), aPTT: 35 sec (range 24–83 sec) and fibrinogen: 7.1 g/l (range 3.1–9.5 g/l). Day 100 survival was 91±5%. With a median follow-up of 25 mths (range 3–80 mths), 1 year OS, TRM and RR were 74±7%, 13±5% and 29±8% respectively. The incidence of aGVHD >=II was 32±7 %.
Conclusion: The results of this study suggest that defibrotide is an effective prophylaxis for VOD.
The Use of Recombinant Human Erythropoietin (rHuEpo) after Reduced Intensity Conditioning (RIC) Allogeneic Hematopoietic Peripheral Blood Stem Cell Transplantation (ASCT) Reduce Red Blood Cell (RBC) Transfusion Requirements.
Authors: Ivanov Vadim , El Cheikh Jean , Faucher Catherine , Furst Sabine , Mohty Mohamad , Ladaique Patrick , Lemarie Claude , Charbonnier Aude , Coso Diane , Schiano Jean Marc , Viret Frederic , Blaise Didier 
Published: October 2019

Abstract
We previously reported that hemoglobin (Hb) recovery was hastened after RIC ASCT as compared with ASCT after myeloablative conditioning (Transfusion, 44:501–8, 2004). In this setting pretransplant Hb level becomes the major predictive factor for early Hb recovery posttransplant and RBC transfusion (RBCT) requirements. We subsequently reported the efficacy of early rHuEpo administration after RIC ASCT to hasten Hb reconstitution (BMT, 36:901–6, 2005). Here we further confirm the efficacy of early posttransplant administration of rHuEpo after RIC reducing RBC requirements and maintaining high levels of posttransplant Hb in the 2 months following transplant.Forty patients surviving at least 60 days were analyzed. Patients characteristics were as follow: age: 50 (27–64); M/F: 28/12; with myeloid (4), lymphoid (29) or solid (7) malignancies. They received a RIC (Fludarabin (150 mg/m²; Busulfan (8mg/kg) and thymoglobulin (2.5 to 5 mg/kg)) followed with an ASCT (all PBSC) from a HLA identical sibling. Aranesp® (Amgen, France) was started on day 1. The 20 first patients received an infusion of 150 mcg/week while the 20 last patients were subsequently treated with 500 mcg/3 weeks. Aranesp® was administered intravenously when inpatient and subcutaneously when outpatient. Aranesp® administration was sustained until day 60 or when patients reached a Hb level of 140 g/L, whichever occurred first. Overall patients were treated for a median of 7 weeks post transplant. No serious adverse effect or thrombosis episode related to Aranesp® was reported in these patients. This cohort of 40 patients experienced a quicker Hb recovery and lower RBCT requirements than a historical and comparable control group of 27 patients (Day +30 Hb: 114 (94–141) vs. 100 (80–129), p<.0001; patients with 0 or 1 RBCT: 83% vs. 55% (p=.02)). Thirteen of the 40 patients (33%) presented with an Hb level of 120 g/L or more prior to conditioning. Over the first 60 days, these patients received 0 (0–2) RBCT as compared with 1 (0–2) RBCT for patients with a pre-RIC Hb level < 120 g/L (p=.05). On this basis, we hypothesized the interest of increasing Hb level prior to RIC by adequate rHuEpo stimulation. With this perspective, we have treated 13 patients with Aranesp® (500 mcg, SC) 3 weeks prior RIC. Nine of these 13 pts (69%) reached an Hb level of 120 g/L or more on day −7 as compared to 35% in patients not receiving Aranesp ® prior to RIC (p=.04). This indicates that Aranesp® post RIC ASCT is efficient to hasten Hb recovery and decrease RBCTs. In addition, a comprehensive strategy to minimize RBCT in this setting might include pre-transplant stimulation. We will prospectively assess this hypothesis.
Platelets Recovery and Transfusion Needs after Reduced Intensity Conditioning (RIC) Allogeneic Peripheral Blood Stem Cell (PBSC) Transplantation (allo-SCT).
Authors: Prebet Thomas , Mohty Mohamad , Ladaique Patrick , Chabannon Christian , Faucher Catherine , Furst Sabine , de Lavallade Hugues , El-Cheikh Jean , Viens Patrice , Gastaut Jean-Albert , Blaise Didier 
Published: October 2019

Abstract
Few data are currently available regarding platelets trasfusion needs and the kinetics and predicitive factors for platelets recovery after RIC allo-SCT. In this study, we analyzed the profile of platelets recovery and transfusion needs in the first 100 days after sibling PBSC RIC in a single institution series of 166 consecutive transplantations. Patients and graft characteristics were: age 49 y. (range: 18–70), diagnoses: 66 myeloid malignancies (40%), 64 lymphoid malignancies (39%), and 36 metastatic solid tumors (21%). 112 pts (67%) received an ATG-based RIC, while 54 pts (33%) received a low dose irradiation-based RIC. 75 pts (45%) developed grade 2–4 acute GVHD. Platelets recovery (>20 G/L) was observed at a median of 9 days (range: 0–99). The kinetics profile of platelets recovery is shown in the figure below. In the whole study population, the nadir was observed around day +7 after allo-SCT, and a plateau was reached about day +35. Filtered and irradiated donor apheresis platelets were used and patients needed a median of 1 unit (range: 0–53). In this series, 83 pts (50%) did not require any platelets transfusion during the follow-up period (median follow-up: 442 days) and 83 patients (50%) received at least one transfusion of platelets (54 were not transfused beyond day +100 after allo-SCT). Platelets count prior to RIC allo-SCT (median count 144 G/L; HR 0.44 (0.28–0.7) p=0.002), conditioning regimen (use of ATG; HR 1.86 (1.08–3.2) p=0.025) and the occurrence of acute (HR 1.54 (1.17–2.01); p=0.001) and severe GVHD (HR 2.36 (1.38–3.05) p=0.0006; 82% of patients with grade 3–4 acute GVHD were transfused) were the parameters significantly associated with platelets transfusion needs in multivariate analysis. In this cohort, 145 pts could be assessed for platelets recovery at day +100: among them, 99 (68%) had a platelet count >99 G/L. Univariate analysis found a significant impact of acute GVHD (p=0.0001) and platelet count prior to conditioning (p=0.012) but only acute GVHD (HR 5.52 (2.48–12.25); p=0.001) was associated with a delayed platelet recovery in a multivariate model. No impacts of pathology, GVHD prophylaxis regimen or CD34+ cell dose were demonstrated.
Overall, these observations show a significantly lower rate of platelets transfusions and a quicker kinetic of platelets recovery after RIC allo-SCT and point out the effect of acute GVHD. In addition, considering the low level of myeloablation observed, RIC could be an appropriated field of investigation for the testing of megakaryocytic stimulating agents, towards further improving the safety and outcome of RIC allo-SCT.
Platelets recovery after PBSC RIC allo-SCT Platelets recovery after PBSC RIC allo-SCT
Allogeneic Stem Cell Transplantation with Reduced Intensity Conditionning Regimen (RIC) for Adult Patients with AML: Same Results in Secondary and De Novo AML.
Authors: Milpied Noel-Jean , Tabrizi Reza , Guillaume Thierry , Chevallier Patrice , Pigneux Arnaud , Boiron Jean Michel , Moreau Philippe , Mahe Beatrice , Leguay Thibaut , Bouabdallah Krimo , Morineau Nadine , Delaunay Jacques , Melot Cyril , Saulquin Beatrice , Marit Gerald , Harousseau Jean Luc 
Published: October 2019

Abstract
We have evaluated the outcome of RIC in 114 adult pts with AML either de novo (74) or secondary to cancer or MDS (40). There were 43 men, median age was 55 yo (22–65). Cytogenetic was available in 104 and was abnormal in 55 (favorable: 13; intermediate: 21; poor: 21). Pts had received a median of 1 line of Tx before RIC (0–3). Twenty had a previous autologous transplant. At time of RIC, 28 patients were refractory or in relapse while 71 were in CR (1st: 48; 2d: 20). The donor was an id sib for 80 and a MUD in 34 (with1allelic mismatch in 6). The cond regimen was of Slavin type in 56, only 11 pts received the Seattle program. Overall 74 had ATG as part of cond reg. GVHD prophylaxis consisted of CSA or CSA-MTX in 95 pts, 14 had CSA-MMF.
With a median FU of surviving pts of 21 m (3–73) the 3y survival (OS) and EFS are 40% and 38% respectively. Sixty pts died with the main cause of death being relapse. The probability of TRM at 100 d and 1 y are 7% and 14% respectively. The 2y probability of relapse is 50%. These figures are strictly superimposable for pts with de-novo or secondary AML.
The factors affecting significantly (p<0.05) the 3y OS and EFS were: disease status at time of RIC (50% vs 0 to 24% in pts in CR vs not), the N° of previous lines of Tx (55% vs 0 to 24% after one line vs more), an id sib as donor ( 45% vs 32% for OS and 44% vs 19% for EFS), having an aGVHD grade 1 or 2 ( OS: 75% vs 25% if aGVHD grade 3–4 vs 38% if no aGVHD), and a CGVHD limited or extensive (OS: 50% or 78% respectively vs 29% if no CGVHD; EFS: 50% or 56% respectively vs 29% if no CGVHD). The single factors that affected the risk of relapse was the occurence of an acute and or chronic GVHD. The TRM was significantly increased in pts with previous autologous transplant, a MUD, an aGVHD and a female donor.
Conclusion: RIC allo is well tolerated ( max TRM :14% at 1 y) and allows the same result in de-novo and secondary AML. The best results are achieved in patients in CR1 ( 3y OS and EFS: 63% and 62% respectively) whatever was the type of donor. As most of the pts beyond CR1 were transplanted with a MUD, it is not possible to separate the negative impact of advanced disease or MUD. An active search of a donor at the time of diagnosis, particularly in patients with secondary AML, could allow early RIC with MUD in pts with an indication of allogeneic stem cell transplantation.