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Computational and Mathematical Methods... 2022Data from single-cell RNA sequencing (RNA-seq) of CLL patients were obtained from the Gene Expression Omnibus database. The R package was utilized to analyze the data,...
Analysis of Data on Fludarabine, Cyclophosphamide, and Rituximab Chemoimmunotherapy for Chronic Lymphocytic Leukemia Shows High Patient Heterogeneity and the Need for More Consideration of Individualized Treatment.
METHODS
Data from single-cell RNA sequencing (RNA-seq) of CLL patients were obtained from the Gene Expression Omnibus database. The R package was utilized to analyze the data, and the relation of results was predicted via the GeneMANIA website. The information of 7 samples covered three stages: observation stage, pretreatment by CIT with rituximab, fludarabine, and cyclophosphamide (pre-CIT), and post-CIT. The differentially expressed genes (DEGs) were identified, and functional enrichment analyses were performed. B cell subpopulations and pseudotime trajectories analysis was conducted.
RESULTS
A total of 70,659 DEGs were identified. Each patient's DEGs presented their own characteristics, with low similarity. Therefore, it is difficult to identify potential hub genes. Similarly, pathway enrichment analysis showed significant tumor heterogeneity among CLL patients. Analysis of relapsed post-CIT compared to the observation stage suggested that the pathway should be taken seriously as it is closely related to treatment strategy and patient prognosis.
CONCLUSIONS
Tumor heterogeneity may be a more common manifestation of CLL. Individualized treatment should be considered for CLL. abnormality and its regulatory factors should still be the focus of CLL diagnosis and treatment.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Vidarabine
PubMed: 36226246
DOI: 10.1155/2022/7451395 -
Bone Marrow Transplantation Jan 2023For acute lymphoblastic leukemia (ALL) patients, total body irradiation (TBI)- based conditioning regimens are the first choice specially in young population. However,...
Thiotepa, busulfan and fludarabine conditioning-regimen is a promising approach for older adult patients with acute lymphoblastic leukemia treated with allogeneic stem cell transplantation.
For acute lymphoblastic leukemia (ALL) patients, total body irradiation (TBI)- based conditioning regimens are the first choice specially in young population. However, several studies have shown an equivalence in clinical outcomes with thiotepa-based conditioning regimen. We performed a retrospective study to evaluate the outcome of adult ALL patients who received allogeneic hematopoietic stem cell transplantation (allo-HCT) with a thiotepa-busulfan-fludarabine (TBF) myeloablative conditioning regimen with reduced toxicity. Fifty-five patients received a TBF regimen. The median age of the patients was 51 years (range, 17 to 72.4). Most patients had a diagnosis of B-ALL (93%) with 7% having T-ALL. Two - and 5-year overall survival was 73.2% and 64%, respectively. At 2 years, leukemia-free survival and GVHD-free, relapse-free survival were 59.5% and 57.6%, and at 5 years, 53.4% and 51.8%, respectively. The 5-year non-relapse mortality was 15%. The day 180 cumulative incidence (CI) of grade II-IV acute GVHD and grade III-IV acute GVHD were 38.2% and 5.5%, respectively. At 2 years, the CI of chronic GVHD and extensive chronic GVHD was 16.9% and 1.9%, respectively. Our study results do suggest that using TBF as the conditioning regimen in adult ALL patients is a promising option with acceptable toxicity.
Topics: Humans; Aged; Adolescent; Young Adult; Adult; Middle Aged; Busulfan; Thiotepa; Retrospective Studies; Leukemia, Myeloid, Acute; Hematopoietic Stem Cell Transplantation; Vidarabine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Graft vs Host Disease; Transplantation Conditioning
PubMed: 36224494
DOI: 10.1038/s41409-022-01841-0 -
ChemMedChem Dec 2022Repurposing of antiviral drugs affords a rapid and effective strategy to develop therapies to counter pandemics such as COVID-19. SARS-CoV-2 replication is closely...
Effects of the 5'-Triphosphate Metabolites of Ribavirin, Sofosbuvir, Vidarabine, and Molnupiravir on CTP Synthase Catalysis and Filament Formation: Implications for Repurposing Antiviral Agents against SARS-CoV-2.
Repurposing of antiviral drugs affords a rapid and effective strategy to develop therapies to counter pandemics such as COVID-19. SARS-CoV-2 replication is closely linked to the metabolism of cytosine-containing nucleotides, especially cytidine-5'-triphosphate (CTP), such that the integrity of the viral genome is highly sensitive to intracellular CTP levels. CTP synthase (CTPS) catalyzes the rate-limiting step for the de novo biosynthesis of CTP. Hence, it is of interest to know the effects of the 5'-triphosphate (TP) metabolites of repurposed antiviral agents on CTPS activity. Using E. coli CTPS as a model enzyme, we show that ribavirin-5'-TP is a weak allosteric activator of CTPS, while sofosbuvir-5'-TP and adenine-arabinofuranoside-5'-TP are both substrates. β-d-N -Hydroxycytidine-5'-TP is a weak competitive inhibitor relative to CTP, but induces filament formation by CTPS. Alternatively, sofosbuvir-5'-TP prevented CTP-induced filament formation. These results reveal the underlying potential for repurposed antivirals to affect the activity of a critical pyrimidine nucleotide biosynthetic enzyme.
Topics: Humans; Ribavirin; Sofosbuvir; Antiviral Agents; SARS-CoV-2; Vidarabine; Escherichia coli; COVID-19; Cytidine
PubMed: 36184568
DOI: 10.1002/cmdc.202200399 -
Bone Marrow Transplantation Dec 2022Different doses of treosulfan plus fludarabine have shown advantage over reduced intensity regimens. However, data comparing higher doses of treosulfan to myeloablative...
Comparative study of treosulfan plus Fludarabine (FT14) with busulfan plus Fludarabine (FB4) for acute myeloid leukemia in first or second complete remission: An analysis from the European Society for Blood and Marrow Transplantation (EBMT) Acute Leukemia Working Party (ALWP).
Different doses of treosulfan plus fludarabine have shown advantage over reduced intensity regimens. However, data comparing higher doses of treosulfan to myeloablative busulfan are limited. Thus, we compared outcomes between FT14 (fludarabine 150/160 mg/m and treosulfan 42 g/m, or FT14) over FB4 (fludarabine 150/160 mg/m and busulfan 12.8 mg/kg). We retrospectively studied patients from European Society for Blood and Marrow Transplantation registry: a) adults diagnosed with acute myeloid leukemia (AML), b) recipients of first allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated or sibling donor (2010-2020), c) HSCT at first or second complete remission, d) conditioning with FT14 or FB4. FT14 recipients (n = 678) were older, with higher rates of secondary AML, unrelated donors, peripheral blood grafts, and adverse cytogenetics, but lower percentage of female donor to male recipient compared to FB4 (n = 2025). Analysis was stratified on age. In patients aged < 55 years, FT14 was associated with higher relapse incidence (RI) and lower Leukemia-Free Survival (LFS). In patients aged≥55 years, acute GVHD CI was higher in FB4, without significant differences in other outcomes. Although FT14 has been used for higher-risk HSCT patients, our large real-world multicenter study suggests that FB4 is associated with better outcomes compared to FT14 in younger patients.
Topics: Adult; Humans; Male; Female; Busulfan; Retrospective Studies; Bone Marrow; Vidarabine; Transplantation Conditioning; Leukemia, Myeloid, Acute; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Acute Disease
PubMed: 36138068
DOI: 10.1038/s41409-022-01830-3 -
Bone Marrow Transplantation Dec 2022
Topics: Humans; Pentostatin; Vidarabine; Cyclophosphamide; Transplantation Conditioning; Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation
PubMed: 36115868
DOI: 10.1038/s41409-022-01819-y -
Bone Marrow Transplantation Nov 2022
Topics: Humans; Aged; Vidarabine; Hematopoietic Stem Cell Transplantation; Cyclophosphamide; Leukemia, Myeloid, Acute; Transplantation Conditioning; Graft vs Host Disease; Busulfan; Retrospective Studies
PubMed: 36097041
DOI: 10.1038/s41409-022-01821-4 -
American Journal of Hematology Dec 2022We analyzed a Japanese registry database to elucidate the incidence, risk factors, and outcomes of adenovirus (AdV) disease after autologous and allogeneic hematopoietic...
We analyzed a Japanese registry database to elucidate the incidence, risk factors, and outcomes of adenovirus (AdV) disease after autologous and allogeneic hematopoietic cell transplantation (HCT) in contemporary real-world patients. We evaluated the cumulative incidence of AdV disease, as well as risk factors, survival, and treatment details, among 25 233 patients who underwent autologous HCT and 48 380 patients who underwent allogeneic HCT between 2005 and 2019. The 1-year cumulative incidences of AdV disease after autologous and allogeneic HCT were 0.18% and 1.52%, respectively, in children, and 0.49% and 2.99%, respectively, in adults. Among patients with AdV disease, renourinary infection was the most common manifestation, and viremia or disseminated disease occurred in 6% of those after autologous HCT and 19% of those after allogeneic HCT. In multivariate analysis, age ≥50 years and lymphoma were associated with AdV disease after autologous HCT, while patients age ≥50 years, male patients, lymphoma, HCT-specific comorbidity index ≥3, human leukocyte antigen-mismatched or haploidentical donors, cord blood, in vivo T-cell depletion, HCT from 2005 to 2009, acute graft-versus-host disease (GVHD), and chronic GVHD were associated with AdV disease after allogeneic HCT. The 1-year probabilities of survival after disease diagnosis were 65% in autologous HCT and 44% in allogeneic HCT. Regardless of the AdV disease burden, there was an increased risk of mortality after both autologous and allogeneic HCT. The most commonly used antiviral agents were cidofovir and vidarabine. The probabilities of improvement and survival with currently available agents were suboptimal. AdV disease after HCT remains a challenge. Better antiviral modalities are necessary.
Topics: Adult; Child; Humans; Male; Middle Aged; Graft vs Host Disease; Japan; Hematopoietic Stem Cell Transplantation; Transplantation Conditioning; Lymphoma; Registries; Adenoviridae
PubMed: 36087061
DOI: 10.1002/ajh.26723 -
American Journal of Hematology Nov 2022Fludarabine, cytarabine, GCSF (FLAG)-based induction/consolidation results in high remission rates in core binding factor (CBF) acute myelogenous leukemia. We treated... (Clinical Trial)
Clinical Trial
Retrospective comparison of survival and responses to Fludarabine, Cytarabine, GCSF (FLAG) in combination with gemtuzumab ozogamicin (GO) or Idarubicin (IDA) in patients with newly diagnosed core binding factor (CBF) acute myelogenous leukemia: MD Anderson experience in 174 patients.
Fludarabine, cytarabine, GCSF (FLAG)-based induction/consolidation results in high remission rates in core binding factor (CBF) acute myelogenous leukemia. We treated 174 consecutive patients with newly diagnosed CBF-AML in a prospective clinical trial of FLAG-based induction/consolidation in combination with gemtuzumab ozogamicin (FLAG-GO; N = 65) or in combination with idarubicin (FLAG-IDA; N = 109). The 5 year RFS in the FLAG-GO cohort was significantly better than the FLAG-IDA cohort, 78% versus 59%, respectively (p-value = .02). In multivariate analysis for RFS, age (p = .0001), FLAG-GO regimen (p = .04), 4 log reduction in CBF-related fusion transcript by quantitative polymerase chain reaction (qPCR) in bone marrow samples at end of consolidation therapy (p = .03), and additional cytogenetic abnormalities (p = .03) were significant variables. Lower age (p = .0001) and 3 log or more transcript reduction at end of induction (p = .04) were significant variables predicting for better overall survival (OS), while there was strong trend for better OS with FLAG-GO (p = .06) regimen. FLAG-GO regimen was superior in optimal disease specific fusion transcript reduction at end of induction (p = .002), mid-consolidation (p < .01), and end of consolidation (p < .001) therapy. Induction/consolidation with FLAG-GO regimen results in better clinical outcomes in newly diagnosed patients with CBF-AML compared to FLAG-IDA and achieves deeper molecular clearance by qPCR assessment of the fusion transcripts.
Topics: Aminoglycosides; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Core Binding Factors; Cytarabine; Gemtuzumab; Granulocyte Colony-Stimulating Factor; Humans; Idarubicin; Leukemia, Myeloid, Acute; Prospective Studies; Retrospective Studies; Vidarabine
PubMed: 36053747
DOI: 10.1002/ajh.26700 -
Bone Marrow Transplantation Nov 2022Data regarding the safety and efficacy of reduced-toxicity conditioning regimen (RTC) prior to allogeneic stem cell transplantation (allo-SCT) to treat hematological...
Reduced-toxicity myeloablative conditioning regimen using fludarabine and full doses of intravenous busulfan in pediatric patients not eligible for standard myeloablative conditioning regimens: Results of a multicenter prospective phase 2 trial.
Data regarding the safety and efficacy of reduced-toxicity conditioning regimen (RTC) prior to allogeneic stem cell transplantation (allo-SCT) to treat hematological malignancies in pediatric patients are limited. This prospective multicenter, phase 2 trial investigated a RTC regimen based on the combination of intravenous busulfan (3.2 mg/kg/d x 4 days), fludarabine (30 mg/m/d x 5 days) and antithymocyte globulin (Thymoglobulin®, Genzyme; 5 mg/kg total dose) with the aim of delivering high dose myeloablation that would allow optimal disease control while minimizing toxicity, in a subgroup of children at very high risk of non-relapse mortality (NRM). The primary endpoint was NRM at 1 year after allo-SCT. A total of 48 high risk patients were included (median age, 13 years; range, 3-24). At 1 year, the cumulative incidence of recurrence/disease progression and NRM were 33% and 8%, respectively. With a median follow-up of 23 months, the Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) at 1 year were 69% and 58%, respectively. We conclude that the RTC regimen used in this prospective trial is safe, with a < 10% NRM rate noted among high-risk children and adolescents, paving the way for larger phase 3 trials incorporating novel agents pre- and post-allo-SCT.(ClinicalTrials.gov Identifier: NCT01572181).
Topics: Adolescent; Child; Humans; Busulfan; Hematopoietic Stem Cell Transplantation; Prospective Studies; Transplantation Conditioning; Vidarabine; Child, Preschool; Young Adult
PubMed: 36028757
DOI: 10.1038/s41409-022-01769-5 -
Bone Marrow Transplantation Nov 2022Therapeutic options for patients with AML relapsing after allogeneic HCT range from chemotherapy or hypomethylating agents with or without donor lymphocyte infusions to...
Therapeutic options for patients with AML relapsing after allogeneic HCT range from chemotherapy or hypomethylating agents with or without donor lymphocyte infusions to a 2nd allogeneic HCT. Available data are based on retrospective single center or registry studies. The aim of this multicenter trial was to investigate prospectively intensive conditioning with Thiotepa, Fludarabine and Treosulfan (TFT) for 2nd allogeneic HCT from an alternative unrelated donor in patients with AML relapse > 6 months after a 1st allogeneic HCT. Primary endpoint was disease-free survival (DFS) at one year after 2nd HCT. 50 patients median age 53.5 years, in CR/PR (34%) or active relapse (66%) were included. 33 of 38 patients (86.8%) with available data achieved CR 100 days post transplant. 23 patients were alive and free of relapse at primary endpoint one year after 2nd HCT (DFS rate 0.46, 95%-CI (0.32-0.61). Three-year rates of DFS, relapse, non-relapse mortality, and overall survival were 0.24, 95%-CI (0.13-0.36); 0.36 (0.25-0.52); 0.40 (0.29-0.57); and 0.24 (0.13-0.37). Second HCT with TFT conditioning is feasible and has high anti-leukemic efficacy in chemosensitive or refractory AML relapse after prior allogeneic HCT. Still, relapse rates and NRM after 2nd allogeneic HCT remain a challenge. The trial is registered in the German Clinical Trials Registry (number DRKS00005126).
Topics: Humans; Middle Aged; Thiotepa; Transplantation Conditioning; Unrelated Donors; Retrospective Studies; Prospective Studies; Neoplasm Recurrence, Local; Vidarabine; Hematopoietic Stem Cell Transplantation; Leukemia, Myeloid, Acute
PubMed: 35982219
DOI: 10.1038/s41409-022-01777-5