bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid Cyclosporine Tapering and Isotretinoin Usage after Unrelated Donor Hematopoietic Stem Cell Transplantation in Juvenile Myelomonocytic Leukemia.
Authors: Yoo Keon Hee , Lee Soo Hyun , Sung Ki Woong , Koo Hong Hoe , Jung Hye Lim 
Published: April 2020

Abstract
Juvenile myelomonocytic leukemia (JMML) is a rare type of childhood leukemias, and allogeneic hematopoietic stem cell transplantation (HSCT) is known to be the only way to cure the disease. Unfortunately, relapse is still the most frequent cause of treatment failure after transplant in JMML. We investigated the feasibility of inducing graft versus leukemia (GVL) effect and the use of a differentiating agent even after unrelated HSCT in children with JMML. Seven consecutive patients with JMML underwent unrelated HSCT at a median age of 17 months. The sources of grafts were bone marrows (n=3) or HLA 1- or 2-antigen mismatched cord bloods (n=4). Only 3 of the 7 patients were in complete remission before transplantation. Intravenous busulfan, cyclophosphamide, and etoposide were used as preparative agents except in one who was conditioned with TBI-based regimen. Cyclosporine was used universally for GVHD prophylaxis with additional use of short-term methotrexate in bone marrow transplants and of methyl-prednisolone in cord blood transplants. Cyclosporine was tapered rapidly from around 1 month post-HSCT and isotretinoin (75–100 mg/m2/day) was used in selected patients who have any risk factors of relapse. Cyclosporine blood levels were 247.8±91.1, 146.6±104.2, and 88.8±52.6 ng/mL at 1, 2, and 3 months post-transplant, respectively. There was no grade 3 or 4 acute GVHD and only 2 patients developed grade 2 acute GVHD which was improved without additional treatment. Chronic GVHD was developed in 3 (1 limited, 2 extensive) of the evaluable 5 patents, which was all resolved after combined use of immune suppressive agents. Initial chimeric status analysis at 1 month revealed complete donor chimerism (CC) in 4 patients, mixed chimerism (MC) in 2 and autologous recovery (AR) in one. One of the patients with MC and the one with AR were in disease-free status. One patient whose chimeric status changed from CC to MC eventually relapsed. One patient with initial MC with residual disease turned to CC with complete remission. Another patient with initial MC but with no evidence of disease is on treatment with isotretinoin without relapse for 3 months even with persistent MC. The patient with AR relapsed early after transplant. Five patients are alive relapse-free and disease-free with a median follow-up of 16 months after transplant. The Kaplan-Meier probability of event-free survival was 66.7%. We suggest that GVL induction strategy with concomittant use of a differentiating agent might have a role to suppress leukemic relapse in JMML.
Pediatric Patients Transplanted with Positive Selected Stem Cells from Alternative Donors Have a Low Incidence of CMV Dnaemia.
Authors: Lang Peter , Hamprecht Klaus , Greil Johann , Bader Peter , Einsele Hermann , Neuheuser Friederike , Handgretinger Rupert , Niethammer Dietrich 
Published: April 2020

Abstract
Human cytomegalovirus (HCMV) remains a cause of serious infectious complications after allogeneic transplantation of hematopoietic stem cells, especially in recipients of T cell depleted grafts. Here, we investigated the incidence of CMV-DNAemia in a cohort of 100 pediatric patients with leukemias and nonmalignant diseases, who received megadoses of CD34+ or CD133+ selected (and therefore highly T-cell depleted) grafts from matched unrelated or mismatched related (haploidentical) donors. Graft versus host disease was minimized with this approach (acute GvHD grade III-IV 5%) but T-cell recovery was delayed in most patients.
All patients received prophylactic acyclovir. PCR screening for CMV was performed weekly from leukocytes and plasma and additional antiviral treatment was started in the case of positive findings. Cumulative incidence of CM-DNAemia at day 100 was 29%. Seropositive recipients (n=44) had a significantly higher incidence of CMV-DNAemia than seronegative recipients (n=56) (64% vs. 0.05%; p=0.0001). In contrast, the incidence was not influenced by the serostatus of the donors (patients with seropositve donors (n=41): 33%; patients with seronegative donors (n=59): 28%; p=0.6). D+R+ pairs were not superior to D-R+ pairs. CMV related over-all mortality was&lt;10%. Conclusions: the incidence of CMVDNAemia was remarkably low in our transplanted patients, despite profound T-cell depletion. Donor seropositivity had no influence. An explanation for these observations may be, that only purified stem cells were transplanted (representing less than 1% of the total cell number of an unmanipulated graft) and therefore, patients received a minimal number of potentially CMV infected leukocytes.We suppose, that this effect may counterbalance the transiently impaired T-cell function in our patients and supports the use of CD34+ or CD133 selection in order to prevent GvHD.
Impact on Short and Long-Term Hematopoiesis of G-CSF Administered Posttransplant in Function of the Amounts of Peripheral Blood CD34+38− Cells Reinfused.
Authors: Henon Philippe R.G. , Sovalat Hanna , Ojeda-Uribe Mario , Arkam Yazid , Eisenmann Jean-Claude 
Published: April 2020

Abstract
We previously suggested that a reinfused threshold dose of CD34+38− cells = 5x104/kg b.w. better predict both short- and long-term engraftment after PBSCT than total CD34+ cells assessment, and should thus avoid unecessary postransplant (Tx) G-CSF administration. Therefore, we have further conducted a prospective study comparing postTx data from cancer patients undergoing autologous PBSCT and were administered or not G-CSF depending on the amount of CD34+38− cells reinfused. 48 patients (mean age 49y) were transplanted with, on average 2.5x104 CD34+38− cells/kg b.w. (range 1–49) and were consequently administered G-CSF 5 μg/kg daily from d5 to ANC = 109/1 (Group-I). 46 patients (mean age 50y) received an average of 20.5x104 CD34+38− cells/kg (range 5.5–162) without postTx G-CSF (Group-II). These 2 groups were compared and paired two by two with 2 groups of "historical" patients referred as controls : 11 patients (mean age 44y) had received, on average, 2.5x104 CD34+38− cells/kg b.w. (range 1.1–4.8) without G-CSF (Group-III); 29 patients (mean age 51y) received an average of 15.2x5x104 CD34+38− cells/kg b.w. (range 5.5–60) systematically associated with G-CSF for protocolar reasons (Group-IV). PostTx trilineage hematopoietic engraftment (up to 2 years), clinical and economical parameters were systematically recorded for each group of patients and statistically compared. PostTx ANC recovery occurred sooner, was faster and reached higher levels in the G-CSF groups (II and IV) compared to the others; platelets recovery kinetics was significantly faster in Group-III compared to the others; reticulocytic recovery was not statistically different whichever the group. When age, sex, disease, TBI did not significantly influence trilineage engraftment, a multiparametric study showed strong positive impacts of total CD34+ cells reinfused on ANC kinetics and of CD38− subset amounts on platelet kinetics, which was on the contrary slowered by G-CSF administration. Group-I patients received more transfusions, stayed longer hospitalized and costed more than those of the 3 other groups. Regarding long-term hematopoiesis, platelets and hemoglobin levels were globally higher in Group-III compared to the other groups, but still more dramatically compared to Group-IV from 1 to 9 months, which might be explained by differences in BM CD34+ and 38− subset differentiation.
In conclusion, if postTx G-CSF certainly accelerates ANC recovery, it seems to be to the detriment of short- an d median-term platelets and hemoglobin recovery, even in case of reinjection of CD34+38− cell doses = 5x104/kg b.w., which appears thus to be significantly discriminant for G-CSF administration decision.
A Single Center Analysis over a Ten Year Period on Transplant Related Mortality (TRM), Early Relapse (ER) and Failure of Blood Cell Reconstitution (FBR) in High-Risk (HR) Cancer Patients (PTS) Undergoing Autologous PBSCT (auto-PBSCT): Frequency, Outcome and Prognostics.
Authors: Engelhardt Monika , Doeing Carsten , Ihorst Gabriele , Wider Dagmar , Finke Juergen 
Published: April 2020

Abstract
The outcome of hr cancer pts undergoing intensified chemotherapy (CTx) with risk factors, such as advanced disease, incomplete remission, tumor resistance and/or prior clinical complications can be dismal and remains a challenge. The prognostic factors for determining TRM, ER and FBR in hr cancer pts undergoing auto-PBSCT, allogeneic (allo)-PBSCT or intensified CTx have not yet been identified. Here, we analysed 50 cancer pts who died within three months of auto-PBSCT or had primary FBR, with a total of 796 pts undergoing auto-transplants over a 10 year period (6/93–5/2003) at our center. Median patient (pt) age at transplant was 52 years (y; range; 18–75), with underlying lymphoma, solid tumors or leukemias in 30, 14 and 6 pts, respectively. The disease stage in 90% (n=45) was advanced, bulky disease was present in 52%. Median performance status of all pts was 70%. An elevated LDH (median 365U/l) at diagnosis was present in 78% of pts. Treatment before auto-PBSCT consisted of a median number of 7 CTx cycles and radiation in 32% of pts. A median number of 4.1x10e6/kg bw PBSCs were transfused, with total CFUs (/1.5e5) of 128. Median platelet counts before PBSCT were 98x10e9/L, with persisting BM involvement in 38% and hypocellularity in 46% of pts. Transplant complications, leading to TRM, ER or FBR were observed in 18, 25 and 7 pts, respectively and resulted in early death in all pts, except one with CML and FBR, who was salvaged with back-up PBSCs. Thirteen pts were examined post-mortem and showed hypo- vs normocellular BM in 8 vs. 3 pts, respectively. Of note, FBR was observed in older pts (59 y), who were mostly heavily pretreated and had AML or CML (4 pts). They had been retransfused with lower CD34+ cells (2.9x10e6/kg), showed lower BFU-Es, CFU-GMs and GEMMs (30, 40, 3, respectively) and low platelet counts (27x10e9/L) before PBSCT due to active underlying disease (71%) and/or BM hypocellularity (71%). During post-transplant cytopenia all pts with FBR showed serious infections. These results suggest that the above risk factors are associated with TRM, ER and FBR. LDH and low platelet counts were significantly different between the three groups. In vitro culture data (cell expansion, CFU, LTC-IC) correlated with our clinical results. With a TRM of 2.26% and FBR in 0.88% in this hr pt cohort, auto-PBSCT is in general a very safe procedure. Nevertheless distinct risk factors can be determined and need to be considered before autotransplantation. Our results may also be valid for allo-SCT and intensified dose-dense chemotherapies.
Evaluation of Body Mass Index (BMI) as a Prognostic Factor among Patients with Relapsed/Refractory Hodgkin’s Lymphoma (R/R-HL) Undergoing Autologous Bone Marrow/Peripheral Stem Cell Transplantation (Auto-BM/PSCT).
Authors: El-Khoury Christian , Kojouri Kiarash , Pant Shubham , Sylvester-Kohrt Nancy , Selby George B. , Ozer Howard , Kamble Rammurti , Kharfan-Dabaja Mohamed A. 
Published: April 2020

Abstract
Background: High-dose chemo(radio)therapy (HDC) followed by auto-BM/PSCT is considered an acceptable therapeutic option for patients (pts) with R/R-HL. Various adverse prognostic factors have been previously described in this setting, including resistance to salvage therapy, active disease at the time of transplant, decreased performance status, B symptoms, extranodal disease, and complete remission duration of less than 1 year. On the other hand, overweight state (defined as BMI &gt; or = 28) was associated with reduced overall and event-free survival among pts who received HDC followed by auto-BM/PSCT for non-Hodgkin’s lymphoma. The prognostic significance of excess body weight among pts with R/R-HL who undergo HDC followed by auto-BM/PSCT has not been reported.
Objective: To evaluate the relationship between excess body weight and overall survival (OS) in pts with R/R-HL who receive HDC followed by auto-BM/PSCT.
Methods: A retrospective, single institution study of consecutive pts with R/R-HL who received HDC followed by auto-BM/PSCT at the University of Oklahoma over the last 19 years (1985– 2004) was performed. BMI was calculated as [weight (kg)/height2 (m)]. Overweight state was defined as BMI &gt; or = 28. OS was defined as the time period in months from the day of transplant until death, or the last of day of follow-up. Survival curves were estimated according to the Kaplan-Meier method, and were compared between the two groups (control group [BMI &lt; 28] and overweight group [BMI &gt; or = 28]) with the use of the log-rank test. Median survivals of the two groups were also compared by using Wilcoxon-Mann-Whitney test. A two-tailed P-value of &lt; 0.05 was considered statistically significant. SAS® sofware (version 8.0; Carry, NC) was used for statistical analysis.
Results: 66 pts (40 males, 26 females) were identified, who were 13–69 years old (median 29 years) at the time of transplant. 40 pts (61%) died during follow-up, 4 pts (6%) were lost to follow-up at 15, 27, 58 and 103 months after transplant, and 22 pts (33%) are alive at the time of this analysis (7/30/04), 2–187 months (median 68 months) after transplant. 65 pts were included in this analysis (BMI could not be calculated for one pt). OS for the control group (n1= 42, 26/42 died) was 30 months (95% CI: 20–69 months) and for the overweight group (n2=23, 14/23 died) was 42 months (95% C.I. 8.0- N/A months). Overall survival did not differ between the two groups (p-values for log-rank and Wilcoxon-Mann-Whitney tests, 0.8109 and 0.7367, respectively).
Conclusion: Excess body weight is not a prognostic factor in patients with R/R-HL who undergo HDC followed by auto-BM/PSCT. A prospective study to evaluate and confirm our findings is warranted.
The Efficacy and Long-Term Toxicity of Intravenous Busulfan and Cyclophosphamide Conditioning Regimen for Stem Cell Transplantation in Advanced Lymphoma.
Authors: Santos Edgardo S. , DeCesare Teresa , Goodman Mark , Rosenblatt Joseph D. , Pereira Denise L. , Fernandez Hugo F. 
Published: April 2020

Abstract
Background: Although busulfan (Bu) in combination with cyclosphosphamide (Cy) is a commonly used conditioning regimen for the treatment of patients with hematologic diseases, its toxicity profile when administered intravenously (IV) as well as efficacy remains unclear, especially in the setting of autologous transplant for lymphoma.
Objective: To determine toxicity and the efficacy of the IV Bu/Cy conditioning regimen in patients who underwent autologous peripheral stem cell transplantation (APSCT) for the treatment of lymphoma.
Methods: A retrospective analysis was performed in 37 patients (21 male; 16 female) who underwent APSCT and received IV Bu/Cy regimen between January 2000 and May 2004.
Results: The median age was 50 years old (range: 20–68). Forty-seven percent of the patients were heavily pretreated (≥ 3 previous treatment, range 2–5). The distribution of lymphoma was: diffuse large B-cell lymphoma (DLBCL, 23), follicular lymphoma (8), mantle cell lymphoma (MCL, 5), and T-cell lymphoma (1). All patients received IV busulfan 3.2 mg/kg and cyclophosphamide 120 mg/kg, and were evaluable for toxicity. The patients engrafted (ANC ≥ 500 μ/l) at a median of 11 days (range: 9–14), and sustained platelet count (≥ 20,000 μ/l) at a median of 11 days (range: 8–42). The most common toxicities encountered were grade 1–2 including nausea, vomiting, stomatitis, esophagitis, and diarrhea. Grade 3–4 toxicities included hepatic veno-occlusive disease (HVOD, n=2), SIADH (n=1), and atrial fibrillation (n=2). Treatment related mortality (TRM) was seen in 3 patients due to HVOD (n=2) and septic shock (n=1). Twenty patients are still alive and 18 have no evidence of disease progression, with a median follow up of 17 months (range: 2–54 months). Kaplan-Meir actuarial OS at 24 months was 55.3% with a 47.3% DFS. Median event-free survival was 24 months (range 2–52).
Conclusions: IV Bu/Cy is a well-tolerated conditioning regimen with acceptable TRM, when compared with other regimens in heavily pretreated patients. The risk for HVOD is low. Further prospective trials are necessary to evaluate the role of Bu/Cy regimen in autologous stem cell transplant for lymphoma.
Immunotherapy Immediately Following Transplantation for Multiple Myeloma: Early Recovery of Aggressive Cytotoxic Cells and Improved Immune Recovery.
Authors: Bengtson Elizabeth , Wu Jia-Yan , Fitzmaurice Thomas , Cornell Cornelius J. , Ely Pamela , Gautier Marc , Hill John , Lowrey Christopher H. , Meehan Kenneth 
Published: April 2020

Abstract
Autologous peripheral blood stem cell transplantation (APBSCT) is effective for the treatment of multiple myeloma (MM), however the majority of patients relapse. Recent evidence shows an improved outcome if absolute lymphocyte count is increased immediatedly following APBSCT in patients with hematologic malignancy. We designed a phase II trial evaluating a dose escalation of SQ IL-2 and standard dose GM-CSF post-transplant for myeloma patients. Patients (n=18) received melphalan 200mg/m2 with GM-CSF 250mg/m2/day beginning on day 5. IL-2 began on the day of transplant and continued 5 days per week for 4 weeks. Peripheral blood samples were obtained at baseline (pre-transplant) and every week for 4 weeks post-transplant and evaluated using flow cytometry for cell subsets using antibodies directed against CD3, CD4, CD8, CD25 and CD56. Control patients (n=11) consisted of MM patients who received melphalan 200mg/m2 with either G-CSF or GM-CSF without IL-2. IL-2 at a dose of 1 X 106IU/m2/d was not tolerated in 2 of 6 patients due to grade 4 fatique and diarrhea (n=1) and grade 4 supraventricular arrhythmia (n=1). A dose of 6 X 105 IU/m2/d was well tolerated by 12 patients. Level 3 or greater toxicities included nausea (n=5), diarrhea (n=3), anorexia (n=11), mucositis (n=9). Engraftment of neutrophils occurred on day 12 and platelets on day 18. The LOS was 21 days in IL-2 treated cohort and 18 days in control group. Absolute lymphocyte counts on days 10–15 were increased an average of 152% in the IL-2 cohort (range 25–390%) over the control group. At day 21, there was a marked increase in the number of CD3+CD8+ cytotoxic T cells (43 %, +/− 7.5%) , CD56 +NK cells ( 78.3 %, +/− 9.1), and CD8+CD56+ NKT cells (36.8 %, +/− 9.8%) compared to patients’ baseline levels. Cytotoxicity of Day #21 PBMNC in the IL-2 cohort was strikingly increased at 28.1% (18.5 – 29.2%) compared to 5.5 % (3.59 – 6.52%) at baseline when tested against a human myeloma cell line (RPMI 8226) using chromium release assays (E: T ratio = 100:1). These results demonstrate a tolerable regimen of immediate post-transplant immunotherapy with marked increase in the number and function of early cytotoxic effector cells. The enhanced immune recovery may translate into an improved outcome.
Restoration of B Cell Development after Lentiviral Transduction of CD34+ Hematopoietic Cells from RAG-1 Deficient Patient.
Authors: Lagresle-Peyrou Chantal , Charneau Pierre , Hue Christophe , Mollier Karine , Andre-Schmutz Isabelle , Bonhomme Delphine , Hacein-Bey-Abina Salima , de Villartay Jean-Pierre , Fischer Alain , Cavazzana-Calvo Marina 
Published: April 2020

Abstract
Patients lacking expression of either RAG-1 or RAG-2 suffer from a Severe Combined Immuno-Deficiency (SCID) disease characterized by an early block in T and B lymphocytes differentiation leading to the absence of both mature lymphocyte subsets. This disease accounts for about 20% of SCID and the only curative treatment is hematopoietic stem cell transplantation, usually successful when an HLA-genoidentical donor is available. In the absence of such a donor, the success rate decreases along with the degree of HLA disparity between donor and recipient. Ex-vivo gene therapy of hematopoietic stem cells can be considered as an alternative treatment as a selective advantage of transgene-expressing cells is expected. Moreover, constitutive expression of only one of the two RAG proteins should not be harmful as concomitant expression of both genes is required for the recombination activity.
We used a lentivecteur containing the RAG-1 cDNA transgene as a therapeutic vector to transduce bone marrow CD34+ cells obtained from RAG-1 deficient patients. The transduced cells were injected into N0D-SCID mice previously irradiated (3Gy) and treated with an anti-TMb1 antibody. Ten weeks after transplantation, in all treated mice, 35±15% of the bone-marrow cells express the human CD45 marker. In this population, 24±2% co-express CD19 and IgM demonstrating that B cell differentiation capacity has been restored. We also detected some CD33+ cells attesting the presence of human myeloid progenitors cells. Altogether, these results suggest that both lymphoid and myeloid precursors have been transduced and demonstrate that gene transfer into hematopoietic cells can reconstitute B cell development in vivo.
Our data support the hypothesis that gene therapy could represent a possible alternative to bone marrow transplantation in RAG-1 deficient SCID disease.
Sustained Long Term Engraftment and Transgene Expression of Peripheral Blood CD34+ Cells Transduced with Advanced Lentiviral Vectors in the Preence of ABC Inhibitors.
Authors: Piacibello Wanda , Tesio Melania , Gammaitoni Loretta , Gunetti Monica , Pignochino Ymera , Aglietta Massimo 
Published: April 2020

Abstract
Because mobilized peripheral blood (MPB) represents an attractive source of cells for gene therapy, we investigated the ability of advanced-generation lentiviral vectors (LV) to transfer the Enhanced Green Fluorescent Protein (EGFP) gene into CD34+ cells isolated from MPB in culture conditions that allowed expansion of transplantable human HSC. So far, a few studies reported transduction of MPB cells with LV pseudotyped with VSV-G. However, the critical issue remains whether primitive, hematopoietic repopulating cells have indeed been transduced.
In vitro and in vivo experiments provided here show that MPB CD34+ cells can be effectively transduced by advanced generation LV: they do not lose their proliferation potential, self renewal and multilineage differentiation ability, moreover transgene expression is maintained. Following 48 hour-exposure to FL+TPO+SCF+IL6 and overnight incubation with vector particles, MPB CD34+ cells were further cultured for up to six weeks. During this period of culture the CD34+ cells population, the CD34+/GFP+ fraction and the CFC output were maintained.
Transduction efficiency of NOD/SCID repopulating cells (SRC) was assessed by serial transplants into NOD/SCID mice. Primary mice transplanted with transduced cells showed high level of engraftment (11,5 % CD45+ cells): within the CD45+ cells 11,4% expressed GFP (n=15). Moreover, mice transplanted with transduced, week-1 expanded cells showed higher levels of human engraftment than those transplanted with transduced, non-expanded cells (range from 9.25 % to 10.5 % for transduced basal cells; range from 14, 3 % to 38,19 % for transduced 1-week expanded cells). Engraftment was multilineage, with GFP+/lineage+ cells. Serial transplants were performed with transduced, week 1-expanded cells. Secondary engraftment levels were 1.6 %; 19.3 % of human cells were GFP+ (n=3). Moreover, levels of human engraftment were higher in mice injected with transduced, 1- week expanded cells (3.5 %) rather than in those injected with transduced, non expanded cells (1.2 %). Engraftment was multilineage with GFP+/lINEAGE+ cells.
These results show that LV efficiently transduced HSC, that maintain proliferation and self-renewal ability.