-
Critical Reviews in Oncology/hematology Mar 2022Therapy-related acute myeloid leukemia (t-AML), defined as AML arising from prior cytotoxic, radiation, or immunosuppressive therapy for an unrelated disease, accounts... (Review)
Review
Therapy-related acute myeloid leukemia (t-AML), defined as AML arising from prior cytotoxic, radiation, or immunosuppressive therapy for an unrelated disease, accounts for 7 %-8 % of AML cases and primarily occurs in elderly patients. t-AML is associated with an increased probability of adverse cytogenetics and shortened survival compared with de novo AML. Factors predicting poorer prognosis in t-AML include older age, unfavorable karyotype, presence of certain mutations, poor performance status, and poor bone marrow reserve. Few clinical studies have focused specifically on patients with t-AML, and the choice of induction therapy for t-AML is thus typically based on subset analyses of larger studies or on extrapolation. In patients deemed fit, t-AML treatment can involve CPX-351 (liposomal daunorubicin and cytarabine) or conventional chemotherapy, ideally followed by hematopoietic cell transplantation. Patients who are not candidates for intensive therapy may benefit from lower-intensity therapies. Additional agents and combination regimens are being evaluated in clinical studies.
Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Mutation; Prognosis
PubMed: 35101585
DOI: 10.1016/j.critrevonc.2022.103607 -
BJU International Apr 2022To compare the urinary pH, recurrence-free survival (RFS), and safety of adjuvant intravesical therapy in patients with non-muscle-invasive bladder cancer (NMIBC)... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To compare the urinary pH, recurrence-free survival (RFS), and safety of adjuvant intravesical therapy in patients with non-muscle-invasive bladder cancer (NMIBC) receiving mitomycin C (MMC) therapy and MMC + cytosine arabinoside (Ara-C) therapy.
PATIENTS AND METHODS
A total of 165 patients with NMIBC from six hospitals were randomly allocated to two groups: weekly instillation of MMC + Ara-C (30 mg/30 mL + 200 mg/10 mL) for 6 weeks and the same instillation schedule of MMC (30 mg/40 mL). The primary outcome was RFS, and secondary outcomes were urinary pH and toxicity in the two groups.
RESULTS
A total of 81 and 87 patients were randomised into the MMC and MMC + Ara-C groups, respectively. Overall, the RFS in the MMC + Ara-C group was significantly longer (P = 0.018) than that in the MMC group. A similar significant difference was detected in patients with intermediate-risk NMIBC, but not in those with high-risk NMIBC. The mean (SD) urinary pH was significantly higher in the MMC + Ara-C group than in the MMC group, at 6.56 (0.61) vs 5.78 (0.64) (P < 0.001), and the frequency of a urinary pH of >7.0 in the MMC and MMC + Ara-C groups was 6.3% and 26.7%, respectively (P < 0.001). Multivariate analysis models including clinicopathological features and second transurethral resection demonstrated that increased urinary pH was associated with better outcomes (hazard ratio 0.18, 95% confidential interval 0.18-0.038; P < 0.001). In all, there were 14 and 10 adverse events in the MMC and MMC + Ara-C groups, respectively, without a significant difference (P = 0.113).
CONCLUSIONS
Our randomised clinical trial suggested that intravesical therapy with MMC and Ara-C is useful and safe for patients with intermediate-risk NMIBC. Increase in urinary pH with Ara-C is speculated as a mechanism for increased anti-cancer effects.
Topics: Administration, Intravesical; Antibiotics, Antineoplastic; Cytarabine; Female; Humans; Male; Mitomycin; Urinary Bladder Neoplasms
PubMed: 34383381
DOI: 10.1111/bju.15571 -
Biomolecules Nov 2019Cancer is the second leading cause of death worldwide. The main modality to fight against cancer is surgery, radiotherapy, and chemotherapy, and more recently targeted... (Review)
Review
Cancer is the second leading cause of death worldwide. The main modality to fight against cancer is surgery, radiotherapy, and chemotherapy, and more recently targeted therapy, gene therapy and immunotherapy, which play important roles in treating cancer patients. In the last decades, chemotherapy has been well developed. Nonetheless, administration of the drug is not always successful, as limited drug dosage can reach the tumor cells.. In this context, the possibility to use an encapsulated anti-cancer drug may potentially solve the problem. Liposomal cytarabine is a formulation with pronounced effectiveness in lymphomatous meningitis and reduced cardiotoxicity if compared to liposomal anthracyclines. Thus, the future liposomal cytarabine use could be extended to other diseases given its reduction in cytotoxic side effects compared to the free formulation. This review summarizes the chemistry and biology of liposomal cytarabine, with exploration of its clinical implications.
Topics: Animals; Antineoplastic Agents; Cytarabine; Drug Compounding; Humans; Liposomes; Neoplasms
PubMed: 31771220
DOI: 10.3390/biom9120773 -
British Journal of Cancer Sep 1974Seventy-eight adult patients with acute leukaemia were classified cytologically into 3 categories: acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML)...
Seventy-eight adult patients with acute leukaemia were classified cytologically into 3 categories: acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML) or acute undifferentiated leukaemia (AUL). The periodic acid-Schiff stain was of little value in differentiating the 3 groups. The treatment response in each group was different: 94% of patients with ALL (16/17) achieved complete remission with prednisone, vincristine and other drugs in standard use in childhood ALL; 59% of patients with AML (27/46) achieved complete remission with cytosine arabinoside and daunorubicin (22 patients), or 6-thioguanine and cyclophosphamide (2 patients), 6-thioguanine, cyclophosphamide and Adriamycin (1 patient), and cytosine and Adriamycin (1 patient); only 2 out of 14 patients (14%) with acute undifferentiated leukaemia achieved complete remission using cytosine and daunorubicin after an initial trial of prednisone and vincristine had failed. Prednisone and vincristine would seem to be of no value in acute undifferentiated leukaemia. It would seem also that no benefit is obtained by classifying all patients with acute leukaemia over 20 years of age as "adult acute leukaemia" and treating them with the same polypharmaceutical regimen. The problems posed by each disease are different and such a policy serves only to obscure them.
Topics: Acute Disease; Administration, Oral; Adult; Aged; Antineoplastic Agents; Cyclophosphamide; Cytarabine; Cytosine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Humans; Injections, Intravenous; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Middle Aged; Prednisone; Remission, Spontaneous; Staining and Labeling; Thioguanine; Vincristine
PubMed: 4141625
DOI: 10.1038/bjc.1974.191 -
BMC Cancer May 2020Langerhans Cell Histiocytosis (LCH) is a rare disease puzzling both children and adults, however outcome of adult patients is unfavorable. This prospective...
BACKGROUND
Langerhans Cell Histiocytosis (LCH) is a rare disease puzzling both children and adults, however outcome of adult patients is unfavorable. This prospective interventional trial aims to test the efficacy and safety of the combination of methotrexate and cytosine arabinoside in adult LCH patients.
METHOD
A total of 36 patients enrolled diagnosed with LCH and treated in our center from 1st Jan, 2014 to 30th Jun, 2016.
RESULT
Nineteen patients underwent the detection of BRAF mutation, with a positive rate of 21.1%. The overall response rate was 100%, only 16.7% achieved complete response. The overall regression rate of osseous lesions was 100%. Regression of central nervous system involvement was also favorable. After a median follow-up of 44 months, the estimated event-free survival was 48.9 months, the overall survival rate was 97.2%. The risk organ involvement showed strong prognostic value, EFS was 34.1 or 54.6 months (p = 0.001) in groups with/without risk organ involvement respectively. Neutropenia and thrombocytopenia were the most common adverse effects.
CONCLUSION
The regimen of methotrexate and cytosine arabinoside (MA) is effective and safe in treating adult LCH patients, and timely preventions may be considered for the high incidence of hematological adverse effects.
TRIAL REGISTRATION
Trial No. NCT02389400 on Clinicaltrials.gov, registered on 10th Mar. 2015.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Early Medical Intervention; Female; Follow-Up Studies; Histiocytosis, Langerhans-Cell; Humans; Male; Methotrexate; Middle Aged; Prognosis; Prospective Studies; Remission Induction; Survival Rate; Young Adult
PubMed: 32423455
DOI: 10.1186/s12885-020-06872-8 -
Journal of Experimental & Clinical... Dec 2022Acute myeloid leukemia (AML) is an aggressive hematological cancer resulting from uncontrolled proliferation of differentiation-blocked myeloid cells. Seventy percent of...
BACKGROUND
Acute myeloid leukemia (AML) is an aggressive hematological cancer resulting from uncontrolled proliferation of differentiation-blocked myeloid cells. Seventy percent of AML patients are currently not cured with available treatments, highlighting the need of novel therapeutic strategies. A promising target in AML is the mammalian target of rapamycin complex 1 (mTORC1). Clinical inhibition of mTORC1 is limited by its reactivation through compensatory and regulatory feedback loops. Here, we explored a strategy to curtail these drawbacks through inhibition of an important effector of the mTORC1signaling pathway, the eukaryotic initiation factor 4A (eIF4A).
METHODS
We tested the anti-leukemic effect of a potent and specific eIF4A inhibitor (eIF4Ai), CR-1-31-B, in combination with cytosine arabinoside (araC) or the BCL2 inhibitor venetoclax. We utilized the MOLM-14 human AML cell line to model chemoresistant disease both in vitro and in vivo. In eIF4Ai-treated cells, we assessed for changes in survival, apoptotic priming, de novo protein synthesis, targeted intracellular metabolite content, bioenergetic profile, mitochondrial reactive oxygen species (mtROS) and mitochondrial membrane potential (MMP).
RESULTS
eIF4Ai exhibits anti-leukemia activity in vivo while sparing non-malignant myeloid cells. In vitro, eIF4Ai synergizes with two therapeutic agents in AML, araC and venetoclax. EIF4Ai reduces mitochondrial membrane potential (MMP) and the rate of ATP synthesis from mitochondrial respiration and glycolysis. Furthermore, eIF4i enhanced apoptotic priming while reducing the expression levels of the antiapoptotic factors BCL2, BCL-XL and MCL1. Concomitantly, eIF4Ai decreases intracellular levels of specific metabolic intermediates of the tricarboxylic acid cycle (TCA cycle) and glucose metabolism, while enhancing mtROS. In vitro redox stress contributes to eIF4Ai cytotoxicity, as treatment with a ROS scavenger partially rescued the viability of eIF4A inhibition.
CONCLUSIONS
We discovered that chemoresistant MOLM-14 cells rely on eIF4A-dependent cap translation for survival in vitro and in vivo. EIF4A drives an intrinsic metabolic program sustaining bioenergetic and redox homeostasis and regulates the expression of anti-apoptotic proteins. Overall, our work suggests that eIF4A-dependent cap translation contributes to adaptive processes involved in resistance to relevant therapeutic agents in AML.
Topics: Humans; Cytarabine; Leukemia, Myeloid, Acute; Proto-Oncogene Proteins c-bcl-2; Cell Line, Tumor; Eukaryotic Initiation Factor-4A; Antineoplastic Agents
PubMed: 36482393
DOI: 10.1186/s13046-022-02542-8 -
Hematology/oncology and Stem Cell... Mar 2018Primary central nervous system lymphoma (PCNSL) is associated with worst prognosis compared with other aggressive non-Hodgkin's lymphomas. However, recent trials have...
Treatment with methotrexate, rituximab, and cytosine arabinoside followed by autologous stem cell transplantation in primary central nervous system lymphoma: A single-center experience.
OBJECTIVE/BACKGROUND
Primary central nervous system lymphoma (PCNSL) is associated with worst prognosis compared with other aggressive non-Hodgkin's lymphomas. However, recent trials have demonstrated that long-term progression-free survival can be achieved by immunochemotherapy. Our goal is to present our experience in aggressive PCNSL in this study.
METHODS
We retrospectively evaluated the clinical features and management of 13 PCNSL patients who were diagnosed and treated between 2006 and 2015.
RESULTS
Nine patients received rituximab (R) 375mg/m/day on Day 1, methotrexate (MTX) 3.5g/m/day and cytosine arabinoside (ARA-C) 4.4g/m/day on Day 2, as well as ARA-C 4.4g/m/day on Day 3 every 28days, and underwent autologous stem cell transplantation. Two patients received procarbazine instead of ARA-C. One patient relapsed, and allogeneic hematopoietic stem cell transplantation was performed. All nine patients are followed in complete remission. Two of 13 patients received one course of MTX and 36-45Gy radiotherapy and died. One patient with renal transplantation had progressive disease and died. Grade 3-4 hematological toxicity was detected in 11 (85%), Grade 3-4 mucositis in 11 (85%), and febrile neutropenia in 12 (92%) patients. The median overall survival in the R-MTX-ARA-C/procarbazine group was 28±16months.
CONCLUSION
R-MTX-ARA-C followed by autologous stem cell transplantation seems a promising strategy with high response rates in PCNSL.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Autografts; Central Nervous System Neoplasms; Cytarabine; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Methotrexate; Middle Aged; Retrospective Studies; Rituximab
PubMed: 28633037
DOI: 10.1016/j.hemonc.2017.05.030 -
The Journal of Clinical Investigation Feb 1985Cytosine arabinoside (araC) has proven efficacy in acute myeloid leukemia (AML), but its place in the treatment of acute lymphoblastic leukemia (ALL) and T lymphoblastic... (Comparative Study)
Comparative Study
Cytosine arabinoside (araC) has proven efficacy in acute myeloid leukemia (AML), but its place in the treatment of acute lymphoblastic leukemia (ALL) and T lymphoblastic lymphoma is uncertain. The therapeutic potential of araC has been assessed in patients with AML, ALL, and T lymphoblastic lymphoma by measuring the conversion of araC to its active metabolite, the 5'-triphosphate of araC (araCTP), in purified blasts from patients as well as in normal polymorphs and lymphocytes. In all leukemias, araCTP was the major intracellular metabolite of araC. The highest araCTP formation was in blasts from T lymphoblastic lymphoma, which formed threefold more nucleotide than myeloblasts, and in turn myeloblasts formed twofold more araCTP than lymphoblasts from ALL. The mean araCTP formation in myeloblasts was sixfold greater than polymorphs, but in contrast, lymphoblasts and lymphocytes formed low and similar amounts of this nucleotide. Reasons for the sixfold range in araCTP accumulation in the various leukemic blasts were studied. The mean size of myeloblasts was 35-70% larger than lymphoblasts when compared on the basis of protein or intracellular water content, but T lymphoblastic lymphoma blasts and lymphoblasts were the same size. Activities of deoxycytidine kinase, deoxycytidylate deaminase, and pyrimidine nucleoside monophosphate kinase were not different between any of the leukemic cell types. The number of nucleoside transport sites on blasts was estimated by measuring the equilibrium binding of [3H]nitrobenzylthioinosine (NBMPR), which binds with high affinity to the transporter. Scatchard analysis yielded mean values of 27,500 sites/cell for T lymphoblastic lymphoma blasts, 10,000 sites/cell for myeloblasts, and 2,300 sites/cell for lymphoblasts. Our previous work has shown that araC influx correlates with the maximum number of 3H-NBMPR binding sites in leukemic and normal white cells. A strong correlation was observed between the number of nucleoside transport sites per leukemic blast cell and the accumulation of intracellular araCTP from extracellular araC at 1 microM. Membrane transport of araC at the low concentrations (approximately 1 microM), which are achieved therapeutically, is a major rate-limiting step in its conversion to araCTP by leukemic blast cells. Myeloblasts form more araCTP than lymphoblasts because of both higher nucleoside transport capacity and larger cell size. The highest nucleoside transport capacity and largest conversion of araC to araCTP is in T lymphoblastic lymphoma, which suggests that araC may be effective in the treatment of this disease.
Topics: Adolescent; Adult; Aged; Arabinofuranosylcytosine Triphosphate; Biological Transport, Active; Biotransformation; Child; Child, Preschool; Cytarabine; Humans; In Vitro Techniques; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Middle Aged; T-Lymphocytes
PubMed: 3871794
DOI: 10.1172/JCI111741 -
Neoplasia (New York, N.Y.) Mar 2013Gene transfer of drug resistance (CTX-R) genes can be used to protect the hematopoietic system from the toxicity of anticancer chemotherapy and this concept recently has... (Review)
Review
Gene transfer of drug resistance (CTX-R) genes can be used to protect the hematopoietic system from the toxicity of anticancer chemotherapy and this concept recently has been proven by overexpression of a mutant O(6)-methylguaninemethyltransferase in the hematopoietic system of glioblastoma patients treated with temozolomide. Given its protection capacity against such relevant drugs as cytosine arabinoside (ara-C), gemcitabine, decitabine, or azacytidine and the highly hematopoiesis-specific toxicity profile of several of these agents, cytidine deaminase (CDD) represents another interesting candidate CTX-R gene and our group recently has established the myeloprotective capacity of CDD gene transfer in a number of murine transplant studies. Clinically, CDD overexpression appears particularly suited to optimize treatment strategies for acute leukemias and myelodysplasias given the efficacy of ara-C (and to a lesser degree decitabine and azacytidine) in these disease entities. This article will review the current state of the art with regard to CDD gene transfer and point out potential scenarios for a clinical application of this strategy. In addition, risks and potential side effects associated with this approach as well as strategies to overcome these problems will be highlighted.
Topics: Animals; Antineoplastic Agents; Cytarabine; Cytidine Deaminase; Drug Resistance, Neoplasm; Gene Expression; Gene Transfer Techniques; Genetic Therapy; Hematopoietic Stem Cells; Humans; Leukemia; Mice; Myelopoiesis
PubMed: 23479503
DOI: 10.1593/neo.121954 -
British Journal of Haematology Mar 2024Improving outcomes for older patients with acute myeloid leukaemia remains an unmet need. As part of the LI-1 trial, we evaluated lenalidomide (LEN) in combination with...
A randomised evaluation of low-dose cytosine arabinoside plus lenalidomide versus single-agent low-dose cytosine arabinoside in older patients with acute myeloid leukaemia: Results from the LI-1 trial.
Improving outcomes for older patients with acute myeloid leukaemia remains an unmet need. As part of the LI-1 trial, we evaluated lenalidomide (LEN) in combination with low-dose cytosine arabinoside (LDAC) in patients aged >60 years unfit for intensive therapy and compared this to LDAC alone. Two hundred and two patients, randomised 1:1, were evaluable. Overall response rate (CR + CRi) was higher for LDAC + LEN versus LDAC (26% and 13.7% respectively p = 0.031). However, there was no difference in overall survival between the arms (14% and 11.5% at 2 years for LDAC + LEN and LDAC respectively). The addition of LEN was associated with increased toxicity and supportive care requirements.
Topics: Humans; Aged; Cytarabine; Lenalidomide; Remission Induction; Leukemia, Myeloid, Acute; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38016651
DOI: 10.1111/bjh.19220