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Leukemia & Lymphoma Jan 2022Due to the evolving use of haploidentical donor grafts in hematopoietic cell transplantation, there is increased need to better understand the risks and benefits of...
Increased early mortality after fludarabine and melphalan conditioning with peripheral blood grafts in haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide.
Due to the evolving use of haploidentical donor grafts in hematopoietic cell transplantation, there is increased need to better understand the risks and benefits of using bone marrow versus peripheral blood grafts, as well as how specific pre-transplantation conditioning regimens impact patient safety and treatment outcomes. We performed a retrospective analysis of 38 patients at two centers who underwent haploidentical hematopoietic cell transplantation using fludarabine plus melphalan-based conditioning regimens with post-transplant cyclophosphamide and peripheral blood donor grafts. We observed an unexpectedly high rate of early non-relapse mortality and severe cytokine release syndrome. The poor outcomes with 1-year overall survival of 34%, disease-free survival of 29%, and non-relapse mortality of 34% motivate us to reconsider the appropriateness of the combination of fludarabine and melphalan conditioning with T-cell replete peripheral blood grafts in the setting of haploidentical hematopoietic cell transplant with post-transplant cyclophosphamide.
Topics: Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Retrospective Studies; Transplantation Conditioning; Vidarabine
PubMed: 34794373
DOI: 10.1080/10428194.2021.1978087 -
Biology of Blood and Marrow... May 2017Allogeneic hematopoietic cell transplantation conditioning regimen intensity has varied for patients with acute myeloid leukemia and myelodysplastic syndrome. A... (Comparative Study)
Comparative Study
Comparative Effectiveness of Busulfan and Fludarabine versus Fludarabine and 400 cGy Total Body Irradiation Conditioning Regimens for Acute Myeloid Leukemia/Myelodysplastic Syndrome.
Allogeneic hematopoietic cell transplantation conditioning regimen intensity has varied for patients with acute myeloid leukemia and myelodysplastic syndrome. A comparative effectiveness analysis was performed to assess outcomes of busulfan and fludarabine (BuFlu) versus those of fludarabine and 400 cGy total body irradiation (FluTBI) conditioning. Thirty-three subjects received BuFlu and 38 received FluTBI. The BuFlu group received more red blood cell transfusions (P = .02) and had a longer time to platelet recovery (P = .004). There were no differences between the regimens regarding incidence of acute or chronic graft-versus-host disease (GVHD), quality of life, or 2-year outcome estimates for relapse (48; 95% confidence interval [CI], 30 to 64 and 50; 95% CI, 33 to 65), nonrelapse mortality (29; 95% CI, 14 to 45 and 29; 95% CI, 15 to 44), relapse-free survival (27; 95% CI, 13 to 43 and 29; 95% CI, 16 to 44), and overall survival (35; 95% CI, 19 to 51; and 37; 95% CI, 22 to 52), respectively. These comparable outcomes have implications for health care resource utilization. Future prospective investigation comparing these regimens with larger patient cohorts and additional strategies to prevent relapse and limit toxicities as well as cost-effectiveness analyses are warranted.
Topics: Adult; Aged; Busulfan; Erythrocyte Transfusion; Female; Graft vs Host Disease; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Quality of Life; Recurrence; Survival Analysis; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation
PubMed: 28108271
DOI: 10.1016/j.bbmt.2017.01.077 -
Biology of Blood and Marrow... Sep 2020Allogeneic hematopoietic cell transplantation (HCT) for children with nonmalignant disorders is challenged by potential drug-related toxicities and poor engraftment....
Allogeneic hematopoietic cell transplantation (HCT) for children with nonmalignant disorders is challenged by potential drug-related toxicities and poor engraftment. This retrospective analysis expands on our single pediatric medical center experience with targeted busulfan, fludarabine, and intravenous (IV) alemtuzumab as a low-toxicity regimen to achieve sustained donor engraftment. Sixty-two patients received this regimen for their first HCT for a nonmalignant disorder between 2004 and 2018. Donors were matched sibling in 27%, 8/8 HLA allele-matched unrelated in 50%, and 7/8 HLA allele-mismatched in 23% (some of whom received additional immunoablation with thiotepa or clofarabine). Five patients experienced graft failure for a cumulative incidence of 8.4% (95% CI, 1 to 16%). In engrafted patients, the median donor chimerism in whole blood and CD3, CD14/15, and CD19 subsets at 1-year were 96%, 90%, 99%, and 99%, respectively. Only one patient received donor lymphocyte infusions (DLIs) for poor chimerism. Two patients died following disease progression despite 100% donor chimerism. The 3-year cumulative incidence of treatment-related mortality was 10% (95% CI, 2 to 17%). Overall survival and event-free-survival at 3-years were 87% (95% CI, 78 to 95%) and 80% (95% CI, 70 to 90%), respectively. The 6-month cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 7% (95% CI, 3 to 13%), while the 3-year cumulative incidence of chronic GVHD was 5% (95% CI, 0 to 11%). These results suggest that use of targeted busulfan, fludarabine and IV alemtuzumab offers a well-tolerated option for children with nonmalignant disorders to achieve sustained engraftment with a low incidence of GVHD.
Topics: Busulfan; Child; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Retrospective Studies; Transplantation Conditioning; Vidarabine
PubMed: 32534101
DOI: 10.1016/j.bbmt.2020.06.004 -
Leukemia & Lymphoma Jun 2015The combination of fludarabine, cyclophosphamide and rituximab (FCR) has been widely used in the treatment of lymphoproliferative disorders, and is now considered as the... (Review)
Review
The combination of fludarabine, cyclophosphamide and rituximab (FCR) has been widely used in the treatment of lymphoproliferative disorders, and is now considered as the standard first-line therapy for fit, young patients with chronic lymphocytic leukemia (CLL). However, in routine practice, the majority of patients with lymphoproliferative disease are over the age of 70 years, and most studies involving FCR have included younger, "fitter" patients, on average in their sixth decade of life. It is not easy to extrapolate the results of these studies to routine practice. In general, the impression is that FCR is less well tolerated in more elderly patients (> 70 years) with good organ function. However, there is a relative paucity of evidence to support this. In this review we aimed to critically examine evidence of the efficacy and toxicity of FCR in the elderly patient.
Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Humans; Lymphoproliferative Disorders; Rituximab; Vidarabine
PubMed: 25213181
DOI: 10.3109/10428194.2014.963083 -
Leukemia Research Feb 2016
Fludarabine-IV busulfan, dose-intensity and progression-free survival: Are we finally finding the way to reach a consensus opinion?: Higher busulfan dose intensity appears to improve leukemia-free and overall survival in AML allografted in CR2: An analysis from the acute leukemia working party of...
Topics: Antineoplastic Agents, Alkylating; Busulfan; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Transplantation Conditioning; Vidarabine
PubMed: 26733443
DOI: 10.1016/j.leukres.2015.11.015 -
Bone Marrow Transplantation Sep 2023
Treosulfan, thiotepa and fludarabine conditioning regimen prior to first allogeneic stem cell transplantation in acute myeloid leukemia and high-risk myelodysplastic syndromes: a single center experience.
Topics: Humans; Thiotepa; Busulfan; Hematopoietic Stem Cell Transplantation; Vidarabine; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Transplantation Conditioning; Graft vs Host Disease
PubMed: 37355712
DOI: 10.1038/s41409-023-02023-2 -
Biology of Blood and Marrow... Jun 2020While allogeneic hematopoietic stem cell transplantation (allo-HCT) currently offers the only curative option for patients with myelodysplastic syndrome (MDS), there is...
While allogeneic hematopoietic stem cell transplantation (allo-HCT) currently offers the only curative option for patients with myelodysplastic syndrome (MDS), there is still a high risk of relapse or transplant-related complications. We collected data on all patients who had undergone allo-HCT at our center (Copenhagen University Hospital) between 2000 and 2018. In total, 215 patients with MDS (n = 196) or chronic myelomonocytic leukemia (n = 19) were included. Estimated 1-year overall survival (OS) was 70.3% (95% confidence interval [CI], 64.2% to 77.0%), and the median survival was 7.7 years (95% CI, 4.7 to indeterminable). There was a significant improvement in OS over time (P = .011, comparing 2000 to 2010, 2010 to 2014, and 2014 to 2018). Treatment was standardized throughout the study period, allowing comparison between patients receiving nonmyeloablative (NMA, n = 124), standard myeloablative (SMA, n = 36), and fludarabine and treosulfan (FluTreo, n = 55) conditioning. FluTreo has myeloablative properties but lower toxicity and replaced standard myeloablative conditioning at our center in 2014. The FluTreo group was significantly older and had more comorbidities than the SMA group but similar disease severity. One-year OS was 84.0% (95% CI, 74.3% to 94.9%), 58.3% (95% CI, 44.3% to 76.9%), and 68.3% (95% CI, 60.2% to 77.5%) for FluTreo, SMA, and NMA, respectively (P = .04). In univariate analysis, Revised International Scoring System (IPSS-R) (high versus low), donor sex mismatch, and cytomegalovirus status mismatch were significant factors for OS. In multivariate analysis of OS including age, IPSS-R, and HCT specific comorbidity index, NMA was borderline inferior to FluTreo (P = .073) while SMA was significantly inferior to FluTreo with a hazard ratio of 6.89 (95% CI, 2.53 to 18.77, P < .001). The introduction of FluTreo allowed us to administer a myeloablative regimen to a broader patient group and shows promising results.
Topics: Busulfan; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Myelodysplastic Syndromes; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine
PubMed: 32088368
DOI: 10.1016/j.bbmt.2020.02.010 -
Journal of Clinical Pharmacy and... Dec 2020Although superseded by other antiviral agents in many Western countries, vidarabine is still widely used in some countries, including China; hence, the extent and...
WHAT IS KNOWN AND OBJECTIVE
Although superseded by other antiviral agents in many Western countries, vidarabine is still widely used in some countries, including China; hence, the extent and appropriateness of vidarabine prescriptions in children require better characterization. This study examined the rationale, extent, and health risks associated with irrational off-label vidarabine use in China.
METHODS
Data used in the study were extracted from a multi-provincial joint adverse drug reactions monitoring platform from 2002 to 2018. Descriptive statistics were used to analyse the characteristics of individual case safety reports (ICSRs) related to vidarabine use.
RESULTS AND DISCUSSION
Among 2772 individual ICSRs related to vidarabine, 2223 (80.19%) cases occurred in patients aged 0-9. In all patients, the median age and interquartile range were 2 (0-6). Although most adverse events were mild, five deaths were recorded, all in children below 7 years of age. Paediatric use is the most prominent off-label use of vidarabine. Additionally, several other irrational off-label uses were identified, including 218 (7.86%) cases of overdosing and numerous applications beyond the approved indications, dosages, routes of administration, and solvents.
WHAT IS NEW AND CONCLUSION
Data indicate that vidarabine was mainly prescribed for suspected common viral infections in paediatric patients, demonstrating serious inappropriate off-label uses. The problem was further complicated by the lack of sufficient information regarding safety, efficacy, and dosing regimens in children, as well as by several additional risk factors such as inappropriate solvents, routes of administration, and overdose. In the case of children, the physicians' lack of understanding of antiviral activities and compassionate prescriptions were mainly responsible for drug overuse. The health risks associated with the paediatric use of vidarabine in China require greater attention and further investigation.
Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Age Factors; Aged; Antiviral Agents; Child; Child, Preschool; China; Female; Humans; Inappropriate Prescribing; Infant; Infant, Newborn; Male; Middle Aged; Off-Label Use; Vidarabine; Young Adult
PubMed: 32614099
DOI: 10.1111/jcpt.13209 -
Cellular Signalling Jan 2017The transcription factors NF-κB and p53 as well as their crosstalk determine the fate of tumor cells upon therapeutic interventions. Replicative stress and cytokines...
The transcription factors NF-κB and p53 as well as their crosstalk determine the fate of tumor cells upon therapeutic interventions. Replicative stress and cytokines promote signaling cascades that lead to the co-regulation of p53 and NF-κB. Consequently, nuclear p53/NF-κB signaling complexes activate NF-κB-dependent survival genes. The 18 histone deacetylases (HDACs) are epigenetic modulators that fall into four classes (I-IV). Inhibitors of histone deacetylases (HDACi) become increasingly appreciated as anti-cancer agents. Based on their effects on p53 and NF-κB, we addressed whether clinically relevant HDACi affect the NF-κB/p53 crosstalk. The chemotherapeutics hydroxyurea, etoposide, and fludarabine halt cell cycle progression, induce DNA damage, and lead to DNA fragmentation. These agents co-induce p53 and NF-κB-dependent gene expression in cell lines from breast and colon cancer and in primary chronic lymphatic leukemia (CLL) cells. Using specific HDACi, we find that the class I subgroup of HDACs, but not the class IIb deacetylase HDAC6, are required for the hydroxyurea-induced crosstalk between p53 and NF-κB. HDACi decrease the basal and stress-induced expression of p53 and block NF-κB-regulated gene expression. We further show that class I HDACi induce senescence in pancreatic cancer cells with mutant p53.
Topics: Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cellular Senescence; DNA Damage; DNA, Neoplasm; Etoposide; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxyurea; Models, Biological; Mutation; NF-kappa B; Neoplasms; Signal Transduction; Tumor Suppressor Protein p53; Vidarabine
PubMed: 27838375
DOI: 10.1016/j.cellsig.2016.11.002 -
Reproductive Biology Sep 2017Trophoblast proliferation and invasion are controlled by cytokines and growth factors present at the implantation site. Members of the Interleukin-6 (IL-6) family of...
Trophoblast proliferation and invasion are controlled by cytokines and growth factors present at the implantation site. Members of the Interleukin-6 (IL-6) family of cytokines trigger their effects through activation of intracellular cascades including the Janus Kinase/Signal Transducer and Activator of Transcription (JAK-STAT) pathway. Functions of several STAT molecules in trophoblast cells have been described, but the role of STAT1 remained unclear. Here, potential functions of STAT1 and its activation by Oncostatin M (OSM) have been investigated in an in vitro model. STAT1 expression and phosphorylation were analyzed in human term placenta tissue by immunohistochemistry. HTR-8/SVneo cells (immortalized human extravillous trophoblast cells) were stimulated with OSM, IL-6, IL-11, Leukemia Inhibitory Factor (LIF) and Granulocyte Macrophage Colony-Stimulating Factor. Expression and phosphorylation of STAT1 were analyzed by Western blotting and immunocytochemistry. Fludarabine and STAT1 siRNA were employed for STAT1 depletion. STAT1 transcriptional activity was evaluated by DNA-binding capacity assay. Cell viability and invasion were assessed by MTS and Matrigel assays, respectively. STAT1 was expressed in villous and extravillous trophoblast cells. Low phosphorylation was detectable exclusively in extravillous trophoblast cells. Only OSM and LIF induced phosphorylation of STAT1 in the in vitro model. Challenge with OSM increased cell invasion but not proliferation. Inhibition of STAT1 by fludarabine treatment or STAT1 siRNA transfection reduced cell viability and invasiveness in presence and absence of OSM. These results indicate the potential involvement of STAT1 in the regulation of trophoblast behavior. Furthermore, STAT 1 functions are more efficiently inhibited by blocking its expression than its phosphorylation.
Topics: Cell Line; Cell Movement; Cell Proliferation; Gene Expression Regulation; Humans; Interleukins; Oncostatin M; Phosphorylation; RNA Interference; RNA, Small Interfering; STAT1 Transcription Factor; Signal Transduction; Trophoblasts; Vidarabine
PubMed: 28552376
DOI: 10.1016/j.repbio.2017.05.005