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Medicinal Chemistry Research : An... 2023Mysterious evolution of a new strain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the Omicron variant, led to a new challenge in the persistent...
Mysterious evolution of a new strain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the Omicron variant, led to a new challenge in the persistent coronavirus disease 2019 (COVID-19) battle. Objecting the conserved SARS-CoV-2 enzymes RNA-dependent RNA polymerase (RdRp) and 3'-to-5' exoribonuclease (ExoN) together using one ligand is a successful new tactic to stop SARS-CoV-2 multiplication and COVID-19 progression. The current comprehensive study investigated most nucleoside analogs (NAs) libraries, searching for the most ideal drug candidates expectedly able to act through this double tactic. Gradual computational filtration afforded six different promising NAs, riboprine/forodesine/tecadenoson/nelarabine/vidarabine/maribavir. Further biological assessment proved that riboprine and forodesine are able to powerfully inhibit the replication of the new virulent strains of SARS-CoV-2 with extremely minute in vitro anti-RdRp and anti-SARS-CoV-2 EC values of about 0.21 and 0.45 μM for riboprine and about 0.23 and 0.70 μM for forodesine, respectively, surpassing both remdesivir and the new anti-COVID-19 drug molnupiravir. These biochemical findings were supported by the prior in silico data. Additionally, the ideal pharmacophoric features of riboprine and forodesine molecules render them typical dual-action inhibitors of SARS-CoV-2 replication and proofreading. These findings suggest that riboprine and forodesine could serve as prospective lead compounds against COVID-19. Graphical abstract.
PubMed: 36593869
DOI: 10.1007/s00044-022-02970-3 -
American Journal of Hematology Mar 2023
Common kinase mutations do not impact optimal molecular responses in core binding factor acute myeloid leukemia treated with fludarabine, cytarabine, and G-CSF based regimens.
Topics: Humans; Cytarabine; Granulocyte Colony-Stimulating Factor; Leukemia, Myeloid, Acute; Vidarabine; Mutation; Core Binding Factors; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36565294
DOI: 10.1002/ajh.26811 -
International Journal of Hematology Apr 2023Mutations in the MECOM encoding EVI1 are observed in infants who have radioulnar synostosis with amegakaryocytic thrombocytopenia. MECOM-associated syndrome was proposed...
Mutations in the MECOM encoding EVI1 are observed in infants who have radioulnar synostosis with amegakaryocytic thrombocytopenia. MECOM-associated syndrome was proposed based on clinical heterogeneity. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for progressive bone marrow failure. However, data regarding allogeneic HSCT for this rare disease are limited. We retrospectively assessed overall survival, conditioning regimen, regimen-related toxicities and long-term sequelae in six patients treated with allogeneic HSCT. All patients received a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, cyclophosphamide or melphalan, and rabbit anti-thymocyte globulin and/or low-dose total body/thoracic-abdominal/total lymphoid irradiation, followed by allogeneic bone marrow or cord blood transplantation from unrelated donors between 4 and 18 months of age. All patients survived and achieved stable engraftment and complete chimerization with the donor type. Moreover, no patient experienced severe regimen-related toxicities, and only lower grades of acute graft-versus-host disease were observed. Three patients treated with low-dose irradiation had relatively short stature compared to three patients not treated with irradiation. Therefore, allogeneic HSCT with RIC is an effective and feasible treatment for infants with MECOM-associated syndrome. Future studies are needed to evaluate the use of low-dose irradiation to avoid risks of other long-term sequelae.
Topics: Humans; Retrospective Studies; Transplantation, Homologous; Hematopoietic Stem Cell Transplantation; Bone Marrow; Transcription Factors; Graft vs Host Disease; Unrelated Donors; Transplantation Conditioning; Vidarabine; MDS1 and EVI1 Complex Locus Protein
PubMed: 36515795
DOI: 10.1007/s12185-022-03505-7 -
Annals of Hematology Jan 2023Conditioning intensity contributes significantly to outcomes in allogeneic hematopoietic stem cell transplantation (allo-HSCT). We evaluated two myeloablative...
Conditioning intensity contributes significantly to outcomes in allogeneic hematopoietic stem cell transplantation (allo-HSCT). We evaluated two myeloablative conditioning dosing ranges of intravenous (IV) busulfan (Bu) in combination with fludarabine in 70 patients. In 2015, our practice changed to target busulfan area under the curve (AUC) of ≥ 19.7 mg*h/L. We assessed responses in patients receiving busulfan AUCs of < 19.7 mg*h/L (Low-Bu) and ≥ 19.7 mg*h/L (High-Bu). At 18-month median follow-up, no differences in overall survival (OS) and relapse-free survival (RFS) were found between Low-Bu and High-Bu groups (p = 0.35 and p = 0.29, respectively). Relapses occurred in 25.7% of patients. No differences in median time to relapse were noted. Minimal residual disease (MRD)-positive patients had a shorter median OS and RFS than MRD-negative patients. No differences were found in OS and RFS between Low-Bu and High-Bu groups in MRD-positive patients (p = 0.86 and p = 0.83, respectively), or MRD-negative patients (p = 0.56 and p = 0.38, respectively). Non-relapsed mortality (NRM) at 100 days was 3.4% vs. 4.1% in the Low-Bu vs. High-Bu groups. There were no significant differences in the incidence of acute-graft-versus-host disease (aGVHD) (71.4% vs. 63.4%) or chronic GVHD (cGVHD) (48.3% vs. 43.9%) between the groups. The cumulative incidence of grades III-IV aGVHD was 24.1% in Low-Bu group and 22.4% in High-Bu group. In conclusion, targeting a busulfan AUC of > 19.7 mg*h/L with fludarabine does not appear to add an advantage in OS and RFS.
Topics: Humans; Adult; Busulfan; Neoplasm Recurrence, Local; Vidarabine; Graft vs Host Disease; Administration, Intravenous; Hematopoietic Stem Cell Transplantation; Transplantation Conditioning; Retrospective Studies
PubMed: 36462061
DOI: 10.1007/s00277-022-05042-z -
Bone Marrow Transplantation Mar 2023Cyclophosphamide is frequently substituted with fludarabine (Flu) in conditioning regimens before allogeneic hematopoietic cell transplantation (allo-HCT). We aimed to...
Total body irradiation plus fludarabine versus busulfan plus fludarabine as a myeloablative conditioning for adults with acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation. A study on behalf of the Acute Leukemia Working Party of the EBMT.
Cyclophosphamide is frequently substituted with fludarabine (Flu) in conditioning regimens before allogeneic hematopoietic cell transplantation (allo-HCT). We aimed to compare retrospectively, total body irradiation (12 Gy) plus Flu (FluTBI12) versus busulfan (Bu) plus Flu (FB4) as a myeloablative conditioning before allo-HCT in patients with acute myeloid leukemia (AML). Out of 3203 patients who met the inclusion criteria, 109 patients treated with FluTBI12 and 213 treated with FB4 were included in a final matched-pair analysis. In both groups, median patient age was 41 years, first or second complete remission (CR1/CR2) proportion was 78%/22%, allo-HCT from an unrelated donor was performed in 78% of patients. The probabilities of leukemia-free survival and overall survival at 2 years in FluTBI12 and FB4 groups were 65% vs. 60% (p = 0.64) and 70% vs. 72% (p = 0.87), respectively. The cumulative incidence of relapse was 19% vs. 29% (p = 0.11), while non-relapse mortality was 16% vs. 11%, respectively (p = 0.13). There were no statistical differences in both acute and chronic graft-versus-host disease (GVHD) incidence. The probability of GVHD-free, relapse-free survival (GRFS) was 49% for both groups. FluTBI12 and FB4 are comparable myeloablative regimens before allo-HCT in AML patients transplanted in CR1 and CR2.
Topics: Humans; Adult; Busulfan; Whole-Body Irradiation; Retrospective Studies; Transplantation, Homologous; Leukemia, Myeloid, Acute; Acute Disease; Vidarabine; Graft vs Host Disease; Recurrence; Hematopoietic Stem Cell Transplantation; Transplantation Conditioning
PubMed: 36460819
DOI: 10.1038/s41409-022-01882-5 -
International Journal of Hematology Mar 2023Fludarabine-cyclophosphamide-rituximab (FCR) has been the gold standard front-line treatment for fit CLL patients until novel agent's introduction. Decision between...
Front-line fludarabine-cyclophosphamide-rituximab (FCR) in 110 patients with chronic lymphocytic leukaemia (CLL): real-life experience with long-term outcomes, toxicities and responses to second-line therapies.
Fludarabine-cyclophosphamide-rituximab (FCR) has been the gold standard front-line treatment for fit CLL patients until novel agent's introduction. Decision between either time-limited FCR or "endless" Bruton's tyrosine kinase inhibitor (BTKi) therapy may be difficult in fit IGHV-mutated-non-TP53 cases. We describe the outcomes after front-line FCR in 110 CLL patients from 5 centres in Catalonia, Spain, over a period of more than 10 years. ORR was 96.3% and CR 74.5%. Median second-treatment free survival (TFS1) was 6.2 years and median OS was 10.8 years. 50 (45.5%) patients required a subsequent therapy. Median third-treatment free survival was better for BTKi than for chemotherapy ± antiCD20 strategies (not reached vs 3.1 years, p = 0.003). Only 50 (45.5%) patients completed 6 cycles of FCR, and the main reason for discontinuation was cytopenia 29 (26.4%). 15 (13.6%) patients developed a second cancer, and 5 (4.5%) patients experienced a Richter's transformation (RT). At the end of follow-up, 50 (45.5%) patients remained in CR. Response rates, TFS1, OS, RT, and second cancers did not differ between patients treated with 6 vs 4 cycles of FCR. In conclusion, front-line FCR treatment leads to very long CR in almost half of patients, and BTKi yields excellent outcomes in relapsed patients.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Vidarabine
PubMed: 36449134
DOI: 10.1007/s12185-022-03488-5 -
Acta Haematologica 2023
High Incidences of Acute and Chronic Graft-Versus-Host Disease after Hematopoietic Cell Transplants for Acute Myeloid Leukemia Using Thiotepa, Busulfan, and Fludarabine Pretransplant Conditioning.
Topics: Humans; Busulfan; Thiotepa; Hematopoietic Stem Cell Transplantation; Bronchiolitis Obliterans Syndrome; Incidence; Leukemia, Myeloid, Acute; Vidarabine; Transplantation Conditioning; Graft vs Host Disease; Retrospective Studies
PubMed: 36446340
DOI: 10.1159/000528306 -
Pediatric Transplantation Mar 2023Serine/threonine kinase 4 (STK4) deficiency is a combined immunodeficiency (CID) characterized by early onset recurrent bacterial, viral, and fungal infections.... (Review)
Review
BACKGROUND
Serine/threonine kinase 4 (STK4) deficiency is a combined immunodeficiency (CID) characterized by early onset recurrent bacterial, viral, and fungal infections. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for CID; however, little is known about the necessity and benefits of HSCT in patients with STK4 deficiency.
METHODS
We report two siblings with STK4 deficiency transplanted from two unrelated donors with the same conditioning regimen.
RESULTS
In the conditioning regimen, rituximab was given on Day -11 (375 mg/m ), and sirolimus was added on the same day. Busulfan was administered at a myeloablative dose (3.2 mg/kg; Days -7 to -4) with 150 mg/m of fludarabine (Days -7 to -3). They were transplanted with peripheral blood stem cells, and graft-versus-host disease (GVHD) prophylaxis was administered with 10 mg/m methotrexate on Days 1, 3, and 6. In addition, mycophenolate mofetil (MMF) was started on Day 1 with ongoing use of sirolimus. We did not encounter veno-occlusive disease (VOD), high-grade acute GVHD, or significant organ toxicity in either patient. Both patients were well at the end of the first year after HSCT with complete donor chimerism.
CONCLUSIONS
Serine/threonine kinase 4 deficiency is a disease with high mortality post-HSCT; therefore, the conditioning regimen and GVHD prophylaxis strategies are important considerations in these patients. In our opinion, the conditioning regimen, which includes rituximab and busulfan and fludarabine (BU-FLU), GVHD prophylaxis with sirolimus and MMF, and short-term methotrexate, offers favorable outcomes and is well tolerated in our STK4-deficient patients.
Topics: Humans; Busulfan; Methotrexate; Rituximab; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Sirolimus; Mycophenolic Acid; Unrelated Donors; Protein Serine-Threonine Kinases; Serine; Transplantation Conditioning; Vidarabine; Intracellular Signaling Peptides and Proteins
PubMed: 36394186
DOI: 10.1111/petr.14439 -
American Journal of Hematology Feb 2023
Efficacy of front-line ibrutinib versus fludarabine, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia: A retrospective multicenter "Real-World" study.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Cyclophosphamide; Vidarabine; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36349541
DOI: 10.1002/ajh.26779 -
Bone Marrow Transplantation Jan 2023
Fludarabine- and low-dose cyclophosphamide-based conditioning regimens provided favorable survival and engraftment for unmanipulated hematopoietic cell transplantation from unrelated donors and matched siblings in patients with Fanconi anemia: results from the CBMTR.
Topics: Humans; Fanconi Anemia; Unrelated Donors; Siblings; Hematopoietic Stem Cell Transplantation; Vidarabine; Cyclophosphamide; Transplantation Conditioning; Graft vs Host Disease
PubMed: 36257981
DOI: 10.1038/s41409-022-01838-9