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The New England Journal of Medicine Jan 2024The combination of ibrutinib and venetoclax has been shown to improve outcomes in patients with chronic lymphocytic leukemia (CLL) as compared with chemoimmunotherapy.... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The combination of ibrutinib and venetoclax has been shown to improve outcomes in patients with chronic lymphocytic leukemia (CLL) as compared with chemoimmunotherapy. Whether ibrutinib-venetoclax and personalization of treatment duration according to measurable residual disease (MRD) is more effective than fludarabine-cyclophosphamide-rituximab (FCR) is unclear.
METHODS
In this phase 3, multicenter, randomized, controlled, open-label platform trial involving patients with untreated CLL, we compared ibrutinib-venetoclax and ibrutinib monotherapy with FCR. In the ibrutinib-venetoclax group, after 2 months of ibrutinib, venetoclax was added for up to 6 years of therapy. The duration of ibrutinib-venetoclax therapy was defined by MRD assessed in peripheral blood and bone marrow and was double the time taken to achieve undetectable MRD. The primary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group, results that are reported here. Key secondary end points were overall survival, response, MRD, and safety.
RESULTS
A total of 523 patients were randomly assigned to the ibrutinib-venetoclax group or the FCR group. At a median of 43.7 months, disease progression or death had occurred in 12 patients in the ibrutinib-venetoclax group and 75 patients in the FCR group (hazard ratio, 0.13; 95% confidence interval [CI], 0.07 to 0.24; P<0.001). Death occurred in 9 patients in the ibrutinib-venetoclax group and 25 patients in the FCR group (hazard ratio, 0.31; 95% CI, 0.15 to 0.67). At 3 years, 58.0% of the patients in the ibrutinib-venetoclax group had stopped therapy owing to undetectable MRD. After 5 years of ibrutinib-venetoclax therapy, 65.9% of the patients had undetectable MRD in the bone marrow and 92.7% had undetectable MRD in the peripheral blood. The risk of infection was similar in the ibrutinib-venetoclax group and the FCR group. The percentage of patients with cardiac serious adverse events was higher in the ibrutinib-venetoclax group than in the FCR group (10.7% vs. 0.4%).
CONCLUSIONS
MRD-directed ibrutinib-venetoclax improved progression-free survival as compared with FCR, and results for overall survival also favored ibrutinib-venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.).
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cyclophosphamide; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Rituximab; Sulfonamides; Time Factors; Vidarabine; Duration of Therapy
PubMed: 38078508
DOI: 10.1056/NEJMoa2310063 -
Leukemia Research Jan 2024Limited data are available regarding efficacious antiemetic regimens to prevent chemotherapy-induced nausea and vomiting (CINV) for patients undergoing allogeneic...
Evaluation of palonosetron, fosaprepitant, and olanzapine as antiemetic prophylaxis for fludarabine and melphalan-based conditioning regimens prior to allogeneic hematopoietic stem cell transplants.
BACKGROUND
Limited data are available regarding efficacious antiemetic regimens to prevent chemotherapy-induced nausea and vomiting (CINV) for patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). In patients aged 60 years or older, allogeneic HSCT is associated with improved survival, but tolerability of the transplant is a significant barrier. Fludarabine and melphalan (Flu-Mel) is a frequently utilized multi-day reduced intensity conditioning regimen for allogeneic HSCT. However, the optimal CINV prevention regimen is unknown.
OBJECTIVE
The purpose of this study was to evaluate the efficacy of a novel CINV prophylaxis regimen prior to allogeneic HSCT with Flu-Mel compared to a historical control group.
STUDY DESIGN
This was a retrospective, single-center, cohort review of 123 patients who received a Flu-Mel preparative regimen prior to allogeneic HSCT from January 1, 2019, to September 30, 2022. Fifty-nine patients received high dose ondansetron (HDO) for CINV prevention, while sixty-four patients received a combination of palonosetron, fosaprepitant, and olanzapine (PFO). The primary outcome was average number of rescue antiemetic doses administered per day. A key secondary outcome was time to first rescue antiemetic.
RESULTS
The median number of antiemetic doses used per day was significantly lower in patients who received PFO compared to HDO (1.94 doses [0.31-3.60] vs 3.31 doses [1.61-4.92]; p = 0.002). In addition, use of PFO significantly prolonged the median time to first rescue antiemetic compared to HDO (41.3 h [24.3-122.7] vs 26.2 h [14.7-48.1]; p = 0.016).
CONCLUSION
The combination of palonosetron, fosaprepitant, and olanzapine is an effective antiemetic regimen for patients receiving a Flu-Mel-based preparative regimen.
Topics: Humans; Antiemetics; Palonosetron; Olanzapine; Melphalan; Retrospective Studies; Vomiting; Nausea; Ondansetron; Hematopoietic Stem Cell Transplantation; Morpholines; Vidarabine
PubMed: 38043326
DOI: 10.1016/j.leukres.2023.107431 -
Bone Marrow Transplantation Feb 2024Conditioning protocols for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) are being developed continuously to improve their anti-leukemic...
Comparison of fludarabine/melphalan (FluMel) with fludarabine/melphalan/BCNU or thiotepa (FBM/FTM) in patients with AML in first complete remission undergoing allogeneic hematopoietic stem cell transplantation - a registry study on behalf of the EBMT Acute Leukemia Working Party.
Conditioning protocols for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) are being developed continuously to improve their anti-leukemic efficacy and reduce their toxicity. In this study, we compared the conditioning protocol of fludarabine with melphalan 140 mg/m (FluMel) with conditioning protocols based on this same backbone but with an additional alkylating agent i.e., either fludarabine/BCNU (also known as carmustine)/melphalan (FBM), or fludarabine/thiotepa/melphalan (FTM) 110 mg/m. We included 1272 adult patients (FluMel, n = 1002; FBM/FTM, n = 270) with acute myeloid leukemia (AML) with intermediate/poor cytogenetic risk in first complete remission (CR) from the registry of the EBMT Acute Leukemia Working Party. Despite patients in the FBM/FTM group were older (64.1 years vs. 59.8 years, p < 0.001) and had a worse Karnofsky performance score (KPS < 90, 33% vs. 24%, p = 0.003), they showed a better overall survival (OS) (2 y OS: 68.3% vs. 58.1%, p = 0.02) and less non-relapse mortality (NRM) (2 y NRM: 15.8% vs. 22.2%, p = 0.009) compared to patients treated with FluMel. No significant differences were observed in relapse incidence (RI) (2 y RI: 24.9% vs. 23.7%, p = 0.62). In conclusion, the addition of a second alkylating agent (BCNU/carmustine or thiotepa) to FluMel as FBM/FTM conditioning, improves OS in AML patients in first CR with intermediate/poor risk cytogenetics after allo-HCT.
Topics: Humans; Adult; Melphalan; Carmustine; Thiotepa; Busulfan; Antineoplastic Combined Chemotherapy Protocols; Transplantation Conditioning; Transplantation, Homologous; Leukemia, Myeloid, Acute; Recurrence; Pathologic Complete Response; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Alkylating Agents; Retrospective Studies; Vidarabine
PubMed: 38040842
DOI: 10.1038/s41409-023-02150-w -
Methods in Molecular Biology (Clifton,... 2024Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapeutic treatment for many patients with high-risk hematologic malignancies and...
Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapeutic treatment for many patients with high-risk hematologic malignancies and bone marrow failure syndromes. While allo-HCT can be highly effective, it is met with significant bone marrow conditioning regimen-related toxicities and complications such as infections related to poor immune reconstitution. This chapter describes the measurement of clofarabine and fludarabine concentrations to support clinical trials whose goal is to determine the optimal therapeutic ranges in order to maximize effectiveness while minimizing variability and regimen-related adverse events and toxicities. Moreover, the same holds true for patients receiving fludarabine as part of their lymphodepleting chemotherapy for chimeric antigen receptor T-cells (CAR T-cells). It is believed that one of the causes of variable outcomes after CAR T-cell therapy is lymphodepletion due to the variable fludarabine concentrations.This chapter describes a HPLC-MS/MS method to measure both compounds simultaneously. Clofarabine and fludarabine are extracted with solvent from plasma by the addition of deuterated internal standards prepared in methanol. Chromatographic separation is attained using a reversed-phase column followed by mass spectrometry which is performed in the positive ion mode. Herein, the described method to quantify both compounds in plasma is fast, accurate, and sensitive and allows for rapid drug concentration monitoring and timely dose adjustments.
Topics: Humans; Clofarabine; Chromatography, High Pressure Liquid; Tandem Mass Spectrometry; Vidarabine
PubMed: 38036821
DOI: 10.1007/978-1-0716-3541-4_17 -
Heliyon Nov 2023Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, which is distinguished by the loss of dopaminergic (DA) neurons in the...
Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, which is distinguished by the loss of dopaminergic (DA) neurons in the substantia nigra and the formation of intraneuronal. Numerous studies showed that the damage and dysfunction of mitochondria may play key roles in DA neuronal loss. Thus, it is necessary to seek therapeutic measures for PD targeting mitochondrial function and biogenesis. In this study, through screening the purchased compound library, we found that marine derived vidarabine had significant neuroprotective effects against rotenone (ROT) induced SH-SY5Y cell injury. Further studies indicated that vidarabine pretreatment significantly protected ROT-treated SH-SY5Y cells from toxicity by preserving mitochondrial morphology, improving mitochondrial function, and reducing cell apoptosis. Vidarabine also reduced the oxidative stress and increased the expression levels of PGC-1α, NRF1, and TFAM proteins, which was accompanied by the increased mitochondrial biogenesis. However, the neuroprotective effects of vidarabine were counteracted in the presence of SIRT1-specific inhibitor Ex-527. Besides, vidarabine treatment attenuated the weight loss, alleviated the motor deficits and inhibited the neuronal injury in the MPTP induced mouse model. Thus, vidarabine may exert neuroprotective effects via a mechanism involving specific connections between the SIRT1-dependent mitochondrial biogenesis and its antioxidant capacity, suggesting that vidarabine has potential to be developed into a novel therapeutic agent for PD.
PubMed: 38027872
DOI: 10.1016/j.heliyon.2023.e21695 -
Mini Reviews in Medicinal Chemistry Nov 2023Nucleoside analogs have been widely used as antiviral, antitumor, and antiparasitic agents due to their ability to inhibit nucleic acid synthesis. Adenosine, cytidine,...
Nucleoside analogs have been widely used as antiviral, antitumor, and antiparasitic agents due to their ability to inhibit nucleic acid synthesis. Adenosine, cytidine, guanosine, thymidine and uridine analogs such as didanosine, vidarabine, remdesivir, gemcitabine, lamivudine, acyclovir, abacavir, zidovusine, stavudine, and idoxuridine showed remarkable anticancer and antiviral activities. In our previously published articles, our main intention was to develop newer generation nucleoside analogs with acylation-induced modification of the hydroxyl group and showcase their biological potencies. In the process of developing nucleoside analogs, in silico studies play an important role and provide a scientific background for biological data. Molecular interactions between drugs and receptors followed by assessment of their stability in physiological environments, help to optimize the drug development process and minimize the burden of unwanted synthesis. Computational approaches, such as DFT, FMO, MEP, ADMET prediction, PASS prediction, POM analysis, molecular docking, and molecular dynamics simulation, are the most popular tools to culminate all preclinical study data and deliver a molecule with maximum bioactivity and minimum toxicity. Although clinical drug trials are crucial for providing dosage recommendations, they can only indirectly provide mechanistic information through researchers for pathological, physiological, and pharmacological determinants. As a result, in silico approaches are increasingly used in drug discovery and development to provide mechanistic information of clinical value. This article portrays the current status of these methods and highlights some remarkable contributions to the development of nucleoside analogs with optimized bioactivity.
PubMed: 37957918
DOI: 10.2174/0113895575258033231024073521 -
British Journal of Haematology Jan 2024Sickle cell disease affects the whole body through acute and chronic organ damage and results in significant physical and neurological constraints. The report by Cseh...
Sickle cell disease affects the whole body through acute and chronic organ damage and results in significant physical and neurological constraints. The report by Cseh et al. demonstrates in a retrospective multinational study that allogeneic haematopoietic stem cell transplantation from HLA-identical siblings using a contemporary conditioning regimen is safe and effective in more than 96% of patients. Commentary on: Cseh et al. Busulfan-fludarabine- or treosulfan-fludarabine-based conditioning before allogeneic HSCT from matched sibling donors in paediatric patients with sickle cell disease: A study on behalf of the EBMT Paediatric Diseases and Inborn Errors Working Parties. Br J Haematol 2024;204:e1-e5. [Correction added on 23 November 2023, after first online publication: In the preceding sentence, the article title and doi have been updated in this version.].
Topics: Humans; Child; Retrospective Studies; Transplantation Conditioning; Hematopoietic Stem Cell Transplantation; Busulfan; Tissue Donors; Anemia, Sickle Cell; Vidarabine; Graft vs Host Disease
PubMed: 37957026
DOI: 10.1111/bjh.19175 -
International Journal of Hematology Jan 2024Various reduced-intensity conditioning (RIC) regimens are used to decrease toxicity while providing comparable outcomes to myeloablative regimens. We compared toxicity...
Fludarabine melphalan versus fludarabine treosulfan for reduced intensity conditioning regimen in allogeneic hematopoietic stem cell transplantation: a retrospective analysis.
Various reduced-intensity conditioning (RIC) regimens are used to decrease toxicity while providing comparable outcomes to myeloablative regimens. We compared toxicity and outcomes between two RIC regimens, fludarabine with melphalan (Flu-Mel) and fludarabine with treosulfan (Flu-Treo), retrospectively over a 10-year period in two donor groups, matched related donor (MRD)/matched unrelated donor (MUD) and haploidentical (Haplo) transplants. The study included 138 patients, of which 105 received MRD/MUD (Flu-Mel: 94, Flu-Treo: 11) and 33 Haplo (Flu-Mel: 17, Flu-Treo: 16) transplants. In the MRD/MUD group, 44 (47%) of patients who received Flu-Mel had grade 3/4 oral mucositis compared to 1 (9%) who received Flu-Treo (P = 0.02). Corresponding numbers in the Haplo group were 7 (41%) and 1 (6%). Grade 3/4 diarrhoea was more frequent with Flu-Mel than Flu-Treo in the Haplo group (41% vs 6%; P = 0.039), but not the MRD/MUD group. Median follow-up time for all patients was 4.8 years. Five-year OS in the MRD/MUD group was 62% with Flu-Mel versus 53% with Flu-Treo (P = 0.0694). Similarly, 5-year OS was 41% with Flu-Mel and 28% with Flu-Treo (P = 0.770) in the Haplo group. Severe mucositis and diarrhoea were significantly less frequent with Flu-Treo than Flu-Mel. Flu-Treo provided comparable outcomes to Flu-Mel in all donor transplants.
Topics: Humans; Melphalan; Retrospective Studies; Hematopoietic Stem Cell Transplantation; Vidarabine; Unrelated Donors; Transplantation Conditioning; Diarrhea; Graft vs Host Disease
PubMed: 37952243
DOI: 10.1007/s12185-023-03674-z -
Leukemia & Lymphoma Feb 2024In humans, AMPylation of cellular proteins is carried out by Huntingtin yeast-interacting protein E (HYPE), activated under conditions of endoplasmic reticulum stress,...
In humans, AMPylation of cellular proteins is carried out by Huntingtin yeast-interacting protein E (HYPE), activated under conditions of endoplasmic reticulum stress, such as in cancer cells. Extracts of the human chronic lymphocytic leukemia cell line, OSU-CLL, were fractionated using immuno-precipitation with antibodies against adenosine-phosphate and then AMP-Tyr. The proteins isolated were modified with AMP, the 'AMPylome.' AMP-labelled peptides isolated from HYPE wild-type (WT) and HYPE knock-out (KO) cells were identified using tandem mass spectrometry. A total of 213 proteins were identified from WT cell extracts, while only 23 of these were pulled down from KO cells, consistent with the presence of another AMPylator, besides HYPE. The KO cells were more sensitive to fludarabine nucleoside (2-FaraA) than WT cells. Ingenuity Pathway Analysis of the AMPylated proteins identified in WT cells clustered actin binding proteins of the cytoskeleton, and proteins of the RHO GTPase pathway that would jointly stimulate cell proliferation.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Cell Line; Endoplasmic Reticulum Stress; Adenosine Monophosphate; Vidarabine
PubMed: 37933638
DOI: 10.1080/10428194.2023.2275530 -
Bone Marrow Transplantation Jan 2024Optimal conditioning prior to allogeneic hematopoietic stem cell transplantation for children with non-malignant diseases is subject of ongoing research. This... (Randomized Controlled Trial)
Randomized Controlled Trial
Optimal conditioning prior to allogeneic hematopoietic stem cell transplantation for children with non-malignant diseases is subject of ongoing research. This prospective, randomized, phase 2 trial compared safety and efficacy of busulfan with treosulfan based preparative regimens. Children with non-malignant diseases received fludarabine and either intravenous (IV) busulfan (4.8 to 3.2 mg/kg/day) or IV treosulfan (10, 12, or 14 g/m/day). Thiotepa administration (2 × 5 mg/kg) was at the investigator's discretion. Primary endpoint was freedom from transplantation (treatment)-related mortality (freedom from TRM), defined as death between Days -7 and +100. Overall, 101 patients (busulfan 50, treosulfan 51) with at least 12 months follow-up were analyzed. Freedom from TRM was 90.0% (95% CI: 78.2%, 96.7%) after busulfan and 100.0% (95% CI: 93.0%, 100.0%) after treosulfan. Secondary outcomes (transplantation-related mortality [12.0% versus 3.9%]) and overall survival (88.0% versus 96.1%) favored treosulfan. Graft failure was more common after treosulfan (n = 11), than after busulfan (n = 2) while all patients were rescued by second procedures except one busulfan patient. CTCAE Grade III adverse events were similar in both groups. This study confirmed treosulfan to be an excellent alternative to busulfan and can be safely used for conditioning treatment in children with non-malignant disease.
Topics: Child; Humans; Busulfan; Prospective Studies; Transplantation Conditioning; Hematopoietic Stem Cell Transplantation; Vidarabine; Graft vs Host Disease
PubMed: 37925531
DOI: 10.1038/s41409-023-02135-9