bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hematopoietic Stem Cell Transplantation after Reduced Intensity Conditioning in Acute Myeloid Leukemia Patients Older Than 40 Years.
Authors: Huisman Cynthia , Meijer Ellen , Petersen Eefke J. , Lokhorst Henk M. , Verdonck Leo F. 
Published: October 2019

Abstract
Reduced intensity conditioning (RIC) protocols are increasingly used for allogeneic hematopoietic stem cell transplantation (HSCT) in elderly patients. We retrospectively analyzed the outcome of RIC HSCT in a homogeneous group of acute myeloid leukemia (AML) patients over the age of 40. Forty-three AML or high-risk myelodysplastic syndrome patients were treated with a fludarabine and low dose total body irradiation (TBI) based regimen, followed by a full peripheral stem cell graft. Antithymocyte globulin was given to matched unrelated recipients (34%) before infusion of fludarabine. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin and mycophenolate mofetil. All but 2 AML patients were in complete remission at the time of transplantation. Seventy-six percent of patients had a poor risk profile. Hematologic recovery was fast and primary graft failure occurred in one patient. Two patients with active disease at the time of HSCT experienced ongoing relapse. Infections were diagnosed in 9 patients (21%) and 6 patients (14%) were treated for CMV reactivation. Sixty percent of patients developed acute GVHD, which was grade 2 in 40% and grade 3 in 12%. Chronic GVHD occurred in 33% of patients. The incidence and severity of both acute and chronic GVHD was similar in patients with related and unrelated donors (P = 0.84 and 0.74, respectively). Treatment-related mortality (TRM) was low (9%), total nonrelapse mortality was 19%. After a median follow-up of 571 days, 16 patients (37%) experienced relapse. One-year progression-free and overall survival were 61% and 67%, respectively. Median disease-free survival has not been reached yet (> 58 months) and median overall survival was 31 months (Fig 1 and 2, respectively). Poor risk AML was significantly associated with disease-free survival in multivariate analysis (P = 0.02). Age > 60 years, gender, donor type, timing of RIC HSCT (upfront or after relapse) and acute GVHD were not identified as prognostic factors. In conclusion, fludarabine plus low-dose TBI-based RIC HSCT is effective in AML patients over the age of 40 without active disease at the time of transplant and is associated with low TRM.
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Brazilian Experience Using High Dose Sequential (HDS) Followed by Autologous Hematopoietic Stem Cell Transplantation (AHSCT) for Relapse/Refractory Aggressive Non-Hodgkin Lymphoma (NHL).
Authors: Duarte Bruno K.L. , Valente I.S. , Vigorito Afonso C. , Aranha Francisco J.P. , Oliveria Gislaine B. , Miranda Eliana C.M. , Lorand-Metze Irene , Pagnano Katia B.B. , De Souza Carmino A. 
Published: October 2019

Abstract
The purpose of this study was to evoluate the use of high dose cyclophosphamide HD (CY) 7 or 4g/m2 and HD etoposide (VP-16) 2g/m2 followed by AHSCT in patients affected by aggressive NHL. From January 1998 to November 2006, 106 patients, 66 males, 40 females, median age 47 (8–66) years underwent into this regimen. The diagnosis was 83 (78.3%) DLBCL, 13 (12.3%) with T-cell Lymphoma and 10 (9.4%) Mantle Cell. At diagnosis, 88 (83%) were stage III or IV, 34 (32.1%) presented bone marrow involvement, 65 (61.3%) bulky disease, 67 (63.2%) B symptoms and 45 (42.5%) were high or high intermediate risk according to IPI. Prior to HDCY patients had been submitted to a mean of 2 (1–3) therapy lines and 6 (5.7%) were in complete remission (CR), 38 (35.8%) partial remission (PR), 62 (58.5%) disease progression (PD) or relapse. Concerning CY dose 42 (39.6%) patients received 4 g/m2 and 64 (60.4%) 7 g/m2, respectively. After HDS, 13 (31%) patients who had used 4 g/m2 and 30 (47%) used 7 g/m2 were in CR (P= 0.03). After the HDCY 43 (40.6%) were in CR, 33 (31.1%) PR, 21 (19.8%) remained in PD and 9 (8.5%) died. After a median follow-up of 4.1 (1.5–57) months, 80 patients (75.5%) were submitted to AHSCT and their present status is 44 alive [33 CR, 4 PR, 7 PD]; 36 dead [4 CR, 1 PR, 2 relapse, 17 PD and 12 had death related to procedure]. Their overall survival was 45% in 8 years. Currently we have 50/106 (47%) alive patients, 35 CR, 6 PR and 9 PD. Overall Survival (OS) was 37%, Disease Free Survival (DFS) 49%, Progression Free Survival (PFS) 42%, Event Free Survival (EFS) 28%. OS by diagnosis was 42% DLBCL, 40% T-cell in 8 years whereas 20% Mantle Cell in 6 years (P=NS). OS by B symptoms patients was 22% versus 58% (P= 0.002) and EFS was 23% versus 37% (P= 0.03). Patients who were in PD prior to the HDCY compared to their status after that had a significant improvement (P< 0.001), their OS was 38% to CR-PR group (38) versus 0% PD group (24). In general, mortality was 56 (53%), their cause was 23 (41.1%) PD, 7 (12.5%) related to HDCY, 12 (21.4%) related to AHSCT, 13 (23.2%) infections and 1 (1.8%) GVHD a RIC transplant. Besides that 1 (0.9%) patient developed MDS and is alive. B symptoms at diagnosis have appeared as a predictor factor for survival. Our study suggests HDS is an efficient treatment to improve status and to reduce tumor burden. Although it presented high toxicity related mortality, we consider the treatment feasible, especially considering the patients’ poor prognosis.
Immune Mobilization with Direct In-Vivo Effector Response: Clinical Trial with Favorable Implications for Post-Transplant Outcome.
Authors: Hill John M. , Wu Jia-Yan , Webber Susan M. , Root Lynn D. , Kimtis Elizabeth A. , Williams Idalina C. , Ernstoff Marc S. , Szczepiorkowski Zbigniew M. , Sentman Charles L. , Meehan Kenneth R. 
Published: October 2019

Abstract
Autologous stem cell transplant is an effective modality for many patients with lymphoproliferative disorders. Still, the majority of patients with myeloma and many with lymphoma relapse after transplant. Innovative post-transplant immunotherapies are needed. We initiated a phase I immune mobilization trial utilizing dose escalation of IL-2, in combination with GM-CSF and G-CSF, in an attempt to mobilize autologous cytotoxic effector cells, along with peripheral CD34+ hematopoietic progenitor cells. IL-2 began on day 0 of mobilization and continued as a daily SQ injection for 11 days. On day 7 of mobilization, GM-CSF (7.5 mcg/kg/d) and G-CSF (5 mcg/kg/d) were initiated for 5 days (day 7–11). On day 11, leukapheresis was performed. Patients then received melphalan (200 mg/m2) followed by reinfusion of cryopreserved autologous peripheral hematopoietic progenitor cells. Phenotypic and functional analyses were performed using peripheral blood mononuclear cells (PBMNC) collected during mobilization on days 0, 7 and 11. Eleven of 12 patients treated to date completed the regimen (myeloma, n=11; NHL, n=1). One patient (NHL) was removed due to progressive disease. The first two dose levels of IL-2 have been well tolerated (dose level 1: 6x105 IU/m2/d; n=6 pts; dose level 2: 1x106 IU/m2/d; n=6 pts) with no ≥grade 3 toxicities noted. Dose escalation of IL-2 continues since the MTD has not been reached. Phenotypic analyses of PBMNC demonstrate an increase in CD3+CD8+ T cells from 17.5% (day 0 baseline) to 22.7% (day 11; p = 0.01). CD56+ NK cells increased from 18.9% (day 0) to 36.0% (day 11; p = 0.002), and CD8+CD56+ NKT cells increased from 8.2% (day 0) to 18.0% (day 11; p = 0.01). Cytotoxicity directed against a human myeloma cell line using peripheral blood lymphocytes was 8.6% at baseline and increased to 43% on day 11 of mobilization (p=0.03). All patients successfully mobilized and received an autologous transplant without delay in engraftment (ANC recovery: day 13 median; range 10–14 days; platelet recovery: day 12 median; range of 0–13 days). These results are encouraging and demonstrate effective mobilization with minimal toxicity and marked in vivo immunomodulatory effects. In addition, the enhanced cytotoxic effector cell number and killing of myeloma cells is quite promising, with additional follow up ongoing to determine the potential impact on survival.
Drug Utilization Patterns and Cost Considerations for Erythropoiesis Stimulating Agents in Cancer Chemotherapy Patients in a Managed Care Setting.
Authors: Mandel Alyson , Weininger Richard , McKenzie Scott R. , Bookhart Brahim K. , Piech Catherine T. 
Published: October 2019

Abstract
Objective and Purpose: To understand current utilization patterns, this study examined real-world dosing and drug costs for erythropoiesis-stimulating agents (ESAs), epoetin alfa (EPO) and darbepoetin alfa (DARB) in cancer patients receiving chemotherapy.
Methods: An analysis of ESA utilization in chemotherapy patients using adjudicated medical claims between 2004 and 2006 from seven health plans was conducted. Patients with ≥1 ESA claim, receiving concurrent chemotherapy identified through alphanumeric HCPCS codes, and newly initiated on EPO or DARB (no ESA administration within 90 days prior to initiation), and receiving chemotherapy were included. Those patients who received both EPO and DARB or who had myelodysplastic syndromes or end-stage renal disease were excluded. Treatment duration was defined as time from first to last ESA administration. Mean cumulative ESA dose was used to calculate drug cost (based on 1/2007 wholesale acquisition cost: EPO $12.52/1000 Units; DARB: $4.576/mcg) and dose ratio (Units EPO: mcg DARB).
Results: 1,446 EPO and 2,729 DARB patients were included. Mean treatment duration was longer in the DARB-treated group by three days (EPO:49 days; DARB:52 days; p= 0.037). The EPO-treated group reported 5.8 administrations with a mean administered dose of 42,603 Units (median 40,000, interquartile range 40,000–45,714) corresponding to a mean cumulative dose of 247,097 Units. The DARB-treated group reported 5.0 administrations with mean administered dose of 262 mcg (median 250, interquartile range 200–300) corresponding to a mean cumulative dose of 1,310 mcg. Drug costs were $2,901 lower in the EPO group compared to the DARB group (EPO $3,094; DARB $5,995) and utilization reflected a dose ratio of 189:1 (Units EPO: mcg DARB).
Conclusions: This observational study of over 4,100 cancer patients receiving chemotherapy found 48% lower drug cost in the EPO group compared to the DARB group. These findings provide greater understanding of current real-world ESA utilization and are consistent with other studies in the cancer chemotherapy population.
Treatment of Leukemic Meningeosis by CD 14 Depleted Adoptive Intrathecal Cell Therapy.
Authors: Thiel Eckhard , Blau Igor W. , Neumann Martin , Tietze-Buerger Carola , Gerbitz Armin , Uharek Lutz 
Published: October 2019

Abstract
Background: Leukemic relapse within the central nervous system (CNS) is generally difficult to treat and results in poor outcome. Limiting factors for effective treatment are mainly extended neurotoxicity and availability of only few agents that will effectively act across the blood brain barrier (BBB). Although graft versus leukemia effects after allogeneic stem cell transplantation are well documented, its application is not recommended in patients with CNS disease. Since the CNS represents an immunologically privileged organ, conventional donor lymphocyte infusion (DLI) has not proven to be effective in CNS relapse situation after stem cell transplantation. Here we present results from three patients suffering from isolated CNS relapse of CML or AML after allogeneic stem cell transplantation receiving for the first time intrathecal cell therapy using CD14 depleted peripheral blood mononuclear cells from their allogeneic donor. Besides leukemic blast cell counts of the CSF molecular genetic analyses for chimerism as well as for translocations were applied for monitoring in addition to MRI and to neuroclinical symptoms.
Results: Up to eight consecutive CD14 depleted intrathecal infusions were applied in escalating doses starting at 1x106 CD3+ cells. In all cases we did not observe any immediate or delayed side effects post application. In the case of the CML patient we observed disappearance of the leukemic blasts and of bcr-abl translocations and reversal to full donor chimerism of the CSF. In one AML patient we observed a transient disappearance of leukemic blasts, followed by a delayed increase. No clear and sustained response was recorded in the other AML patient. All patients are still under observation (9–14 months) and remained full chimeras in peripheral blood and bone marrow; however, the AML patients meanwhile developed chloroma lesions.
Conclusion: Intrathecal DLI for CNS relapse of leukemia after allogeneic stem cell transplantation is a new still experimental approach. The first applications indicate no side effects e.g. cerebral or meningeal GVHD and a possible efficacy in CNS relapse of CML. This new approach merits further investigation in the setting of a clinical trial.
Genetic Polymorphism of Cytochrome P450 1B1 (C432G) Is Associated with An Increased Treatment-Related Mortality and Lower Overall Survival in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Koldehoff Michael , Elmaagacli Ahmet H. , Beelen Dietrich W. 
Published: October 2019

Abstract
Background. The human cytochrome P450 1B1 (CYP 1B1) is a key enzyme involved in the production of reactive metabolites and in the activation of environmental carcinogens. Several polymorphisms were identified in CYP 1B1 gene; four of them are single nucleotide polymorphisms and give rise to amino acidic substitutions. The CYP 1B1 codon 432 polymorphism leads to a three-fold higher 4-hydroxylase activity for the variant CYP 1B1 isozymes than the wild types. Never before the influence of genetic polymorphisms of CYP 1B1 (C432G) on patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT), was evaluated.
Methods. Here we genotyped in a retrospective study 384 recipients (R) (and their donors (D)) for CYP 1B1 (C432G) expression that underwent allogeneic HSCT for various diseases and analyzed their outcome. Genotyping of CYP 1B1 (C432G) was performed by real-time PCR.
Results. 170 R (44.3%) were genotyped as homozygous wild-type gene C/C, 157 R (40.9%) were genotyped as heterozygous genotype C/G and 57 R (14.8%) were genotype as homozygous gene mutation G/G. From the 167 D (43.5%) were C/C, 164 D (42.7%) were C/G, and 53 D (13.8%) had a homozygous gene mutation G/G. A homozygous CYP 1B1 gene mutation G/G was found on 18 R/D side (4.7%). Calculated genotype frequencies did not differ from that reported earlier by other studies for Caucasians. Five-year estimate for treatment-related mortality (TRM) and overall survival (OS) were statistically different in genotype C/G- and G/G- R with 33 ± 4%, and 49 ± 4% compared to homozygous wild-type gene C/C- R (18 ± 3%, and 59 ± 4%, respectively, [p<0.03]), whereas the five-year estimate for relapse rate (RR) was not different between the groups. No differences for five-year estimates for TRM, RR, or OS were seen in R with either genotype C/C-, C/G- or G/G- D. No statistic differences were found in the incidence of acute GVHD grade 2–4 on R- or on D- side with variant CYP 1B1 (C432G) polymorphisms. Surprisingly, the five-year estimate for TRM, RR, and OS were statistically different in homozygous gene mutation G/G on R/D site with 57 ± 2%, 81 ± 2%, and 16 ± 1% compared to all other CYP 1B1 genotypes with 28 ± 3%, 26 ± 2%, and 55 ± 3%, respectively [TRM, p<0.01; RR and OS, p<0.001]). Multivariate analysis confirmed that CYP 1B1 (C432G) homozygous gene mutation G/G on R/D site had an increased risk for TRM and RR (p<0.02), whereas the mutation G/G on R/D site revealed a worse OS (p<0.01).
Conclusions. These results suggest that recipients with genetic polymorphism of CYP 1B1 do have an increased TRM, RR and lower OS after transplantation. Genotyping for CYP 1B1 (C432G) might help to identify patients with higher risk for allogeneic transplantation.
KIR/HLA-I Mismatching Predicts Risk of Relapse in Pediatric Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Scquizzato Elisa , Zambello Renato , Baesso Ilenia , Varotto Stefania , Albergoni Maria Paola , Teramo Antonella , Boscaro Elisa , Cesaro Simone , Pillon Marta , Calore Elisabetta , Gazzola Maria Vittoria , Semenzato Gianpietro , Messina Chiara , Trentin Livio 
Published: October 2019

Abstract
Hematopoietic stem cell transplantation (HSCT) is a curative therapy for a variety of hematologic malignancies. Recent studies have indicated the presence of donor-derived alloreactive NK cells as an additional factor influencing transplantation outcome, NK cells being regulated by signals delivered from multiple activating and inhibitory receptors. In the allogeneic HSCT setting, several studies considered donor-recipient HLA-I mismatch as the basis for NK alloreactivity. The implication of the KIR ligand incompatibility model is that donor’s NK cells exhibit the relevant inhibitory KIR for the self HLA-I ligands. It is known, however, that the KIR genes and the HLA genes segregate independently of each other in normal mendelian fashion. This allows the possibility that individuals lack HLA ligands for their KIR receptors and indicates that NK cells alloreactivity can occur also in HLA-matched or HLA-identical transplants. Recent investigations suggest that relapse and KIR-driven alloreactivity in the transplantation setting might be better predicted if the donor KIR genotype is considered in addition to the HLA genotype of the recipient. The aim of this study was to investigate at genetic level the prognostic impact of recipient HLA-I lacking for donor KIR on allotransplanted patients outcome. We analyzed donors KIR genotype and HLA genotype of 60 pediatric patients who received related (n.15) or unrelated (n.45) transplantation. When patients were grouped on the basis of the KIR gene type involved in the KIR/HLA-I mismatch, we did not observe any relapse in the group of patients characterized by mismatches involving only inhibitory KIR. On the contrary, all relapses were observed in patients showing at least one activating gene involved in the mismatch (p<0.05). Although the biological mechanism accounting for this putative genetic rule is still to be clarified, we suggest that a careful survey of KIR/HLA-I mismatching should be taken into account in the selection of donor in related and unrelated HSCT.
A High Long-Term Survival Were Produced by Early Sequential Intensive Consolidation Chemotherapy Followed by Autologous Stem Cell Transplantation in First Complete Remission in Patients with Adult Acute Lymphoblastic Leukemia.
Authors: Zou Dehui , Qiu Lugui , Li Yenan , Zhao Yaozhong , Han Mingzhe , Feng Sizhou 
Published: October 2019

Abstract
Objective: To investigate the efficiency of our designed protocol with early sequential intensive consolidation chemotherapy followed by autologous stem cell transplantation (ASCT) in first complete remission (CR1)on adult acute lymphoblastic leukemia (ALL) patients who lack of matched sibling donors.
Methods: The ALL patients were given a median 4 intensive/ consolidation therapy courses including high-dose of methotrexate, cytarabine and/or cyclophosphamide in CR1, followed by ASCT with total body irradiation (TBI)-based conditioning regimen. A 1 to 1.5 year maintenance chemotherapy with 6-mercaptopurine, methotrexate and vincristine-prednisone in combination with interleukin-2/IFN-α immunotherapy were administered after adequate hematological recovery.
Results: A total of 83 patients were enrolled in this study. 78 patients reconstituted hematopoiesis except 5 patients died of early toxicity. By a median 47(3– 218) months follow-up after ASCT, the 5-year probabilities of leukemia free survival (LFS) and overall survival (OS) were 53.2%±5.9% and 54.4%±5.8%, respectively. The 5-year cumulative relapse rate (RR) was 35.7%±6.1%, and no patients relapsed more than 3 years after transplantation. According to the adverse features, age ≥35 years, WBC >30×109/L for B-cell ALL or >100×109/L for T-ALL, Pro-B and early T immunotyping, more than 4 weeks to attain remission, and high-risk karyotypes including t(9;22)/BCRABL, t(4;11)/ALL1-AF4 or t(1;19)/E2A-PBX1, the patients were identified in 3 prognostic risk groups of standard (24, 29.0%), intermediate(32, 38.5%), and high(27, 32.5%) with 0, 1, 2 or high-risk karyotypes adverse features, respectively. The 5-year probabilities of DFS were 80.36%±9.0%, 59.39%±9.2% and 24.78%±8.9% in these 3 group s, respectively. While, the 5-year cumulative incidences of relapse was 16.7%,37.5% and 70.4%, respectively.. The standard and intermediate -risk groups had significantly better OS and LFS than the high-risk group.
Conclusion: Theses results indicated our designed protocol with early sequential intensive consolidation chemotherapy followed by autologous stem cell transplantation (ASCT) in first complete remission (CR1) could produced a relatively high log-term survival in standard and intermediate-risk group of adult ALL patients.
Hematopoiesis in Chronic Phase CML emerges from Hematopoietic Stem Cells with a Transcriptional Phenotype Resembling Normal Myeloid Progenitor Cells.
Authors: Bruns Ingmar , Czibere Akos , Cadeddu Patrick , Roels Frederik , Fischer Johannes C , Büst Sebastian , Brünnert Daniela , Steidl Ulrich , Brors Benedict , Gattermann Norbert , Kronenwett Ralf , Haas Rainer 
Published: October 2019

Abstract
Introduction: Composition of cell subsets within the CD34+ cell population is markedly altered in chronic phase (CP) CML. Specifically, megakaryocyte-erythrocyte progenitors (MEP) show a proportional increase and the percentage of granulocyte-macrophage progenitors (GMP) is significantly lower in comparison to healthy bone marrow. To understand the molecular basis for this, we have used microarray technology to analyze transcriptional differences between distinct subsets from normal and CP CML bone marrow.
Methods: We examined highly purified HSCs, CMPs, GMPs and MEPs from patients with chronic phase CML and healthy volunteers by FACS for subset analyses and applied high-speed cell-sorting to obtain the distinct CD34+ subsets. Then, we performed gene expression analyses (HU-133A 2.0) of each separate subset. Further assays included quantitative RT-PCR, FISH, adhesion and migration assays and transient transfection experiments.
Results: Subset analyses showed a significant proportional expansion of CMPs and MEPs and a decrease of HSCs in chronic phase CML. When comparing the concentration of each subset by means of absolute cell counts, HSC counts were similar whereas counts for other subsets were significantly higher in CML ranging between 2.8 and 7.7-fold. When looking at the gene expression data, it was surprising to see that the CML HSC has a transcriptional profile, which is similar to CML progenitors and healthy CMP as determined by Euclidian Distance Analysis. In contrast, for normal individuals the cluster tree clearly resembled the current model for hierachical development with the HSC sitting at the top of the hierarchy, and the more differentiated subsets of MEP and GMP at the bottom. Given that differences between the determined progenitors were minor, we focused on the characterisation of the CML HSC. We found 614 genes differentially expressed including downregulation of genes encoding for adhesion molecules, transcription factors and regulators of stem cell fate as well as upregulation of proliferation-associated genes in CP CML. Impaired adhesive and migratory capacity and a novel role of the nuclear receptors NR4A1 and NR4A3 for the transcriptional regulation of c-Jun and JunB was functionally corroborated in CML HSC.
Conclusion: Based on these data we propose a loss of quiescence of CML HSC upon detachment from the niche leading to expansion of myeloid progenitors as determined by quantitative analysis.