Therapy for chronic myelogenous leukemia in blast crisis with etoposide and 5-azacitidine administered by continuous infusion: a Cancer and Leukemia group B Study.
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Adult↗
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Chemotherapeutic trials with hamster mesothelioma 10-24: responses to azacitidine, aziridinylbenzoquinone, cisplatin, and PCNU.
Asbestos-induced peritoneal mesothelioma 10-24 serially transplanted in Syrian golden hamsters was used to test responses to seven drugs as single agents. Compared to saline-treated controls, the average survival time increased 51%-85% with azactitidine, 42%-60% with aziridinylbenzoquinone, 43% with cisplatin, and 35%-45% with PCNU. No cures were achieved. Therapeutic responses were not observed with dactinomycin, dianhydroxyanthracenedione, or DTIC.
Animals↗
Health-system burden of higher-risk myelodysplastic syndromes in England: a literature-based micro-cost analysis.
OBJECTIVES: To quantify the per-patient-per-month (PPPM) cost for each phase of care in higher-risk myelodysplastic syndromes (HR-MDS) and the overall cost of a base-case (illustrative) non-curative management pathway followed by a patient with HR-MDS in England. DESIGN: We conducted a retrospective, literature-based, micro-costing analysis from the National Health Service (NHS) England provider perspective using published sources and publicly available price lists. No individual-patient data were used. Based on literature, a base-case management pathway followed by a patient with HR-MDS was defined as a diagnostic work-up at month 0, 12 cycles of azacitidine (given for 7 days in each 28-day cycle), 5 months of post-hypomethylating agent (HMA) failure supportive care and 1 month of terminal care. SETTING: Healthcare resource utilisation was analysed for adults with HR-MDS who received first-line azacitidine in routine practice if cycle-level or phase-level transfusion and admission rates were reported in the literature. Patients who required allogeneic haematopoietic stem cell transplantation or whose HR-MDS transformed to acute myeloid leukaemia were excluded because the diagnostic and/or therapeutic pathways differ. Unit costs for 2024/2025 were taken from published English national sources and an English trust tariff. RESULTS: PPPM costs were £8721.58 during active azacitidine therapy, £5399.58 after HMA failure and £12 554.58 for hospital-dominant terminal care; a one-off diagnostic work-up with genomics cost £2710 to £2810. The total cost for the base-case management pathway was £146 921 per patient. An alternative pathway excluding genomic testing and assuming hospice-dominant terminal care reduced the total cost to approximately £136 840 to £140 990, depending on whether the lower or upper bound of hospice bed-day costs is applied. CONCLUSIONS: The direct NHS-provider cost burden of this non-curative HR-MDS management pathway is concentrated in azacitidine acquisition and administration during active treatment, transfusions and admissions after HMA failure and setting-dependent costs at the end of life. The total cost for the illustrative management pathway followed by a patient with HR-MDS (£146 921) is of a similar order to the estimate in the National Institute for Health and Care Excellence technology appraisal for azacitidine uprated to £124 848 for 2024/2025. This comparison is provided for context only and should not be interpreted as validation of the present model, given differences in population, model structure, treatment duration and price year. The phase-specific PPPM estimates can inform, subject to local validation and scenario testing, UK budget-impact analyses, service planning and future economic models.
Humans↗
Methylation inhibitor therapy in the treatment of myelodysplastic syndrome.
The class of DNA methyltransferase inhibitors is represented by azacitidine and decitabine. Azacitidine is approved for the treatment of patients in both low- and high-risk subtypes of myelodysplastic syndrome (MDS), and decitabine is currently under review by the FDA. Azacitidine phase III trial data, based upon the Cancer and Leukemia Group B (CALGB) study 9221, showed durable clinical and symptomatic improvement in bone marrow function, a reduction in the risk of leukemic transformation, and significant improvements in the quality of life of patients treated with azacitidine compared with supportive care alone. This study also provided data suggestive of improvement in survival in MDS patients. The experience with decitabine comprises a number of phase I/II studies and a phase III trial yet to be published. While there is a strong base of experience supporting the efficacy of DNA methyltransferase inhibitors in the treatment of MDS, a number of practical issues need to be explored further. These include the optimization of the timing and duration of treatment, and the prediction of response to therapy. Along with current experience, future studies will lead to the development of treatment algorithms, strategies for selecting patients (e.g. according to age, risk, classification, and cytogenetic profile), and the combination strategies, particularly with histone deacetylase inhibitors, in the management of MDS.
Antimetabolites, Antineoplastic↗
Methylation-sensitive restriction endonuclease digestion patterns revealed in Vicia faba L. chromosomes by in situ nick-translation.
Restriction endonucleases sensitive to cytosine methylation (HpaII, MspI and HhaI) and 5-azacitidine were used to study the localization of target sequences in Vicia faba metaphase chromosomes by in situ digestion and radioactive or non-radioactive nick-translation. In control experiments, neither isolated DNA nor chromosomes in situ were digested by HpaII and MspI. Pretreatment with demethylating agent, 5-azacitidine resulted both in increased effectiveness of in situ digestion and nick-translation. In 5-azacitidine-treated material, negative bands in M chromosomes appeared. HhaI cleaved isolated DNA, digested it in situ and gave positive signals as a result of nick-translation procedure in metaphase chromosomes. In S chromosomes containing heterochromatin without target sequences for HpaII and MspI, negative bands were shown after nick-translation. Such heterochromatin contains FokI sequences and in situ nick-translation driven by that restriction enzyme resulted in positive bands.
Azacitidine↗
DNA methyltransferase inhibitors in myelodysplastic syndrome.
Myelodysplastic syndrome (MDS) resulting from a clonal stem cell is a heterogeneous disease that complicates therapeutic decisions. Most patients are of advanced age with attendant comorbities, making treatment choices difficult. Current treatment options include bone marrow transplant, which appears to be the only curative option, and supportive care. In elderly patients, risks for transplant are high and supportive-care treatments are ineffective. However, considerable progress has been made in understanding the pathology of MDS, which results from a series of progressive chromosomal assaults that lead to a release of various cytokines, loss of tumor suppressor genes, and changes in signal transduction pathways and in immune pathways. The neoplastic clone does not appear to mature; it stays in a fixed state of differentiation beyond which these cells do not progress. Hypermethylation of specific DNA sequences, which results in silencing transcription of proteins involved, has been implicated in this lack of differentiation. New clinical discoveries include the potential to block methylation, release transcriptional inactivation, and stimulate the normal myeloid cells to resume growth and differentiation. Therapies aimed at these new findings hold promise for safer treatment protocols and improved outcomes. One of these agents, azacitidine, is a nucleoside analog that has shown promising efficacy in high-risk MDS patients. Phase III studies have shown significant improvement in survival and quality of life with minimal side effects. Prolonged administration of azacitidine results in reactivation of normal hematopoiesis by its effect on inhibiting DNA methylation.
Azacitidine↗
Inhibitors of DNA methylation: beyond myelodysplastic syndromes.
DNA methyltransferase (DNMT) inhibitors, azacitidine (Vidaza, Pharmion, Boulder, CO, USA) and decitabine (Dacogen; SuperGen Inc, Dublin, CA, USA, and MGI Pharma Inc, Bloomington, MN, USA), have had a significant impact on the treatment paradigm of myelodysplastic syndromes (MDSs), previously managed mainly by supportive care and hematopoietic-stem-cell transplantation. The positive clinical experience seen in MDS to date coupled with the persistent challenges faced in the treatment of other hematologic malignancies has served as the impetus for further exploration of the therapeutic value of DNMT inhibitors beyond MDS. In that respect, the majority of data for these agents are in the setting of acute myelogenous leukemia (AML). Experience with these agents in patients with refractory anemia with excess blasts in transformation (reclassified by the World Health Organization as AML) was also reported in the clinical trials submitted to the FDA for approval of azacitidine for MDS. Some use has also been described in chronic myelogenous leukemia and acute lymphocytic leukemia. Further studies are needed to clarify the appropriate dose and the number and duration of cycles in the treatment of leukemias, and to identify ideal candidates for therapy, explore the role of DNMT inhibitors in combination with other agents, especially histone deacetylase inhibitors, delineate differences between the commercially available agents, and establish the long-term safety of these agents. To this end, experience with DNMT inhibitors in hematologic malignancies other than MDS is reviewed in an effort to better understand the therapeutic potential of these agents and to define areas of future exploration in these settings.
Antimetabolites, Antineoplastic↗
A novel retinoic acid receptor beta isoform and retinoid resistance in lung carcinogenesis.
BACKGROUND: We previously reported that all-trans-retinoic acid (RA) treatment can prevent in vitro transformation of immortalized human bronchial epithelial (HBE) cells. METHODS: To determine whether methylation inhibits RARbeta expression in HBE cells, we used sodium bisulfite sequencing to compare RARbeta P2 promoter methylation patterns in RA-sensitive (BEAS-2B) and RA-resistant (BEAS-2B-R1) HBE cells. Immunoblotting was used to assess induction of the RARbeta, placental transforming growth factor beta (PTGF-beta), Fos-related antigen 1 (Fra-1), and transglutaminase II (TGase II) proteins by RA following treatment with azacitidine, a DNA demethylating agent. The expression, transcriptional activity, and growth suppressive activity of RARbeta1', a novel RAR isoform, were evaluated in lung cancer cells transfected with RARbeta1', and expression was also studied in paired normal lung tissues and lung tumors. All statistical tests were two-sided. RESULTS: Hypermethylation was observed in the 3' region of the RARbeta P2 promoter of BEAS-2B-R1 but not BEAS-2B cells. Azacitidine treatment of BEAS-2B-R1 cells restored RA-inducible RARbeta2 and PTGF-beta expression but not that of RARbeta1', Fra-1, or TGase II. RARbeta1' expression was repressed in RA-resistant BEAS-2B-R1 cells and in lung cancers, compared with adjacent normal lung tissues. BEAS-2B-R1 cells transiently transfected with RARbeta1' had increased RA-dependent activation of a retinoic acid receptor element (RARE)-containing reporter plasmid compared with vector control (mean = 3.2, 95% confidence interval [CI] = 3.1 to 3.3 versus mean = 1.4, 95% CI = 1.3 to 1.5; P<.001). In H358 lung cancer cells transiently transfected with RARbeta1', RA treatment restored target gene expression compared with that in vector-transfected cells and suppressed cell growth compared with that in untreated cells (4 microM; treated mean = 0.49 versus untreated mean = 1.0, difference = 0.51, 95% CI = 0.35 to 0.67, P = .003; 8 microM: treated mean = 0.50 versus untreated mean = 1.0, difference = 0.50, 95% CI = 0.26 to 0.74, P = .015). CONCLUSION: Restoration of RARbeta1' expression may overcome retinoid resistance in lung carcinogenesis.
Antimetabolites, Antineoplastic↗
5-azactidine and zorubicin for patients with previously treated acute nonlymphocytic leukemia: a Cancer and Leukemia Group B pilot study.
Twenty-nine adults with advanced acute nonlymphocytic leukemia were treated with an intensive chemotherapy program consisting of 5-azacitidine and zorubicin. Overall, eight patients (28%) achieved a complete remission. Although only one of 19 patients with refractory leukemia responded, seven of ten patients who were treated immediately following relapse from a prior remission achieved another complete remission. The duration of remission ranged from 5 to 33 weeks (median, 14). Treatment resulted in severe toxic reactions including myelosuppression, renal tubular dysfunction, and elevations in liver enzymes. In addition, each of the 15 patients who died of treatment-associated complications had a severe infection. This combination of 5-azacitidine and zorubicin is relatively ineffective for truly refractory leukemia, but it may be a useful alternative following relapse.
Acute Disease↗
Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes.
The myelodysplastic syndrome (MDS) comprises a group of clonal hematopoietic disorders derived from an abnormality affecting a multipotent hematopoietic stem cell. Despite trials testing numerous agents in patients with MDS, no single drug has yet emerged as the accepted standard of treatment. Observation and supportive care with blood products and antibiotics, when necessary, continue to be the mainstays of therapy. We administered 5-azacytidine, a cell-cycle specific ring analog of the pyrimidine nucleoside cytosine, as a continuous intravenous infusion, 75 mg/m2 per day for 7 days every 4 weeks. Patients had refractory anemia with excess blasts (RAEB) or refractory anemia with excess blasts in transformation (RAEB-T). Responses were seen in 21 (49%) of 43 evaluable patients: five (12%) in complete remission (CR, complete normalization of bone marrow and peripheral blood counts); 11 (25%) in partial remission (PR, > or = 50% restoration of the deficit from normal of all three peripheral blood cell lines, elimination of transfusion requirements, and a decrease in percentage bone marrow blasts by > or = 50% from prestudy values); five (12%) improved (> or = 50% restoration in the deficit from normal of one or more peripheral blood cell lines and/or a > or = 50% decrease in transfusion requirements). A trilineage improvement (CR and PR) occurred in 37% of the patients. The median survival for all patients was 13.3 months and the median duration of remission for those with CR and PR was 14.7 months. Mild to moderate nausea and/or vomiting was the most common side effect (63%). Myelosuppression, either bone marrow hypoplasia or drug related cytopenias requiring a reduction in the dose of azacitidine, occurred in only 33% of the patients. Prior to treatment, bone marrow erythroid progenitor cells were assayed in vitro. Colonies derived from erythroid burst-forming units (BFU-e) were undetectable in one patient and reduced in two. The number of colonies derived from erythroid colony-forming units (CFU-e)) were also reduced in two of the three patients. In the two patients with detectable colony growth prior to treatment, colony number decreased by day 8 of the first cycle, followed by a subsequent increase. Continued treatment with azacitidine led to normalization of the number of CFU-e derived colonies as well as an increase in the number of BFU-e derived colonies. This improvement in erythroid colony number correlated with the spontaneous rise in hemoglobin levels and red cell transfusion independence.(ABSTRACT TRUNCATED AT 400 WORDS)
Aged↗
Myelodysplasia: when to treat and how.
Myelodysplastic syndrome (MDS) is a disorder of hematopoietic stem cells characterized by ineffective hematopoiesis. The result is pancytopenia leading to transfusion-dependent anemia, an increased risk of infection or bleeding, and a potential to progress to acute myeloid leukemia (AML). MDS is most prevalent among older individuals, many of whom also suffer from other medical conditions. MDS is classified according to World Health Organization criteria and the International Prognostic Scoring System. Supportive care remains the mainstay of therapy. Those with low-risk MDS can often be monitored for an extended period of time without specific therapy, whereas those with intermediate- or high-risk MDS benefit from treatment. Currently, only azacitidine is approved for the treatment of MDS. Several new agents are being tested, including inhibitors of angiogenesis (thalidomide, lenalidomide), farnesyl transferase inhibitors (lonafarnib, tipifarnib), and DNA methyltransferase inhibitors (azacitidine, decitabine). Lenalidomide appears particularly effective in patients with low-risk MDS with the deletion of chromosome 5q31. Allogeneic stem cell transplantation is an alternative for high-risk MDS. With advances in transplantation techniques, this treatment can be offered to an increasing number of patients. However, it is necessary to assess each patient's disease individually and to evaluate prognostic factors, other treatment options, and the appropriateness and timing of transplantation.
Anemia↗
Genomic Evolution of Myeloproliferative Neoplasms and Therapy-Associated Mutagenesis.
UNLABELLED: Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts, but disease can progress to myelofibrosis or acute myeloid leukemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of hematopoietic colonies revealed age-appropriate polyclonal hematopoiesis in triple-negative essential thrombocythemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C > G mutations following azacitidine and characteristic T > A/T > G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate that progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis. SIGNIFICANCE: Longitudinal whole-genome sequencing shows MPN progression is genomically encoded years before clinical transformation, with distinct evolutionary routes to leukemia and MF. It identifies DNA mutagenesis associated with HC and 5-azacitidine, suggests some triple-negative cases are nonclonal, and supports serial clinical genomic monitoring for improved risk stratification and long-term management. See related commentary by Agarwal and Sankaran, p. 1724.
Humans↗
Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome.
BACKGROUND: Therapy for patients with myelodysplastic syndrome (MDS) with hypomethylating agents, like decitabine and 5-azacitidine, has produced favorable results. In this study, the authors update their experience with decitabine in patients with MDS and analyze the cytogenetic response patterns and prognostic factors associated with decitabine therapy. METHODS: One hundred fifteen patients with higher risk MDS who received treatment with decitabine were reviewed. Patients received decitabine 100 mg/m(2) per course every 4 weeks in 3 different schedules: 1) 20 mg/m(2) intravenously daily x 5, 2) 20 mg/m(2) subcutaneously daily x 5, and 3) 10 mg/m(2) intravenously daily x 10. Decitabine was given for a median of >or=7 courses (range, 1-23 courses). RESULTS: Overall, 80 patients (70%) achieved a response according to the modified International Working Group criteria (IWG): complete response (CR), 40 patients (35%); partial response, 2 patients (2%); bone marrow CR with or without other hematologic improvements (HI), 26 patients (23%); and other HI, 12 patients (10%). Cytopenias were improved in 50% of patients. The median remission duration was 20 months, and the median survival was 22 months. Mortality was 3% at 6 weeks and 7% at 3 months. In a multivariate analysis, poor prognostic factors for achieving IWG CR were MDS (vs chronic myelomonocytic leukemia), longer duration of MDS, and prior MDS therapy. For survival, independent adverse prognostic factors were chromosome 5 and/or 7 abnormalities, older age, and prior MDS therapy (excluding growth factors). CONCLUSIONS: The longer term experience with decitabine in MDS was favorable. Pretreatment prognostic factors may predict the outcome of patients who receive decitabine therapy for MDS.
Aged↗
In vivo effects of decitabine in myelodysplasia and acute myeloid leukemia: review of cytogenetic and molecular studies.
Low-dose demethylating agents such as 5-aza-2'-deoxycytidine (decitabine, DAC) and 5-azacytidine (azacitidine, Vidaza) have been explored for the treatment of myelodysplasia, acute myeloid leukemia, and hemoglobinopathies since the early 1980s, aiming to revert a methylator phenotype. Originally, the treatment rationale in hemoglobinopathies was to achieve demethylation of the hypermethylated and hence silent gamma-globin gene locus, thus reactivating synthesis of hemoglobin F (HbF). In myelodysplastic syndrome (MDS), cytogenetic analyses are mandatory for risk stratification and for monitoring response to drug treatment. The current knowledge regarding cytogenetic subgroups as predictors of response to low-dose decitabine in MDS as well as cytogenetic responses caused by demethylating agents is summarized in this review. Decitabine treatment is associated with a response rate that is higher in patients with high-risk cytogenetics (i.e., complex karyotype and/or abnormalities of chromosome 7) than in patients with intermediate-risk cytogenetics (two abnormalities or single abnormalities excluding 5q-, 20q-, and -Y). Following decitabine treatment of patients with abnormal karyotype, approximately one-third achieve a major cytogenetic response that can be confirmed by FISH analyses, while in two-thirds of patients, the abnormal karyotype persists but hematologic improvement may be observed during continued treatment. The most frequently studied gene in myelodysplasia is the cell cycle regulator p15(INK4b). Hypermethylation of p15(INK4b) in MDS is reversed during treatment with decitabine, resulting in reactivation of this gene. In hemoglobinopathies, treatment with demethylating agents leads to reactivation of fetal HbF (the gamma-globin gene locus also possibly being another target for reactivation in MDS), and thus, HbF may potentially act as surrogate marker for activity of decitabine. Other, thus far unidentified hypermethylated genes may also be targets for demethylating agents.
Acute Disease↗
Clinical experience with decitabine in North American patients with myelodysplastic syndrome.
Recent evidence demonstrates that epigenetic silencing of genes is associated with myelodysplasia and that a worse prognosis may be correlated with hypermethylation of certain genes, such as the cyclin-dependent kinase inhibitor p15. 5-Aza-2'-deoxycytidine (decitabine, DAC) is a nucleoside analog, which, at low doses, acts as a hypomethylating agent and is fivefold to tenfold more active than 5-azacytidine (azacitidine, Vidaza)--currently the only approved drug for treatment of myelodysplastic syndrome (MDS). Clinical studies have demonstrated that decitabine has activity in patients with MDS. Preliminary results of a phase III multicenter North American trial comparing low-dose decitabine to supportive care verified that therapy with decitabine resulted in higher response rates, improved quality of life, and prolonged time to leukemic transformation and/or death. However, further elucidation of its mechanism of action is required, as clinical response to decitabine does not correlate with demethylation of the p15 gene promoter or the repetitive DNA element LINE. Decitabine appears to upregulate both hypermethylated and nonmethylated genes. Ongoing studies aim to determine the optimal dose, schedule, and route of administration of decitabine, and to evaluate whether efficacy can be improved by using it in combination with other agents, such as histone deacetylase inhibitors.
Antineoplastic Combined Chemotherapy Protocols↗
Management of patients with higher risk myelodysplastic syndromes.
Higher risk myelodysplastic syndromes (MDS) include patients in the Intermediate-2 and high-risk categories of the International Prognostic Scoring System, as well as patients with MDS secondary to radiation or chemical exposure. Ideally, the goal of therapy is to alter the natural history of disease in these patients to achieve cure or durable remission. High-intensity chemotherapy can achieve moderate rates of complete remission, however, durability of remission and overall survival tend to be short. Hematopoietic stem cell transplantation (HSCT) offers the possibility of cure, with long-term disease-free survival inversely related to age. Patients who are elderly or have poor functional status are candidates for reduced intensity HSCT, although this is still an experimental modality. Azacitidine is a hypomethylating agent that is a reasonable option for many patients ineligible for high-intensity therapies. Other therapies, such as immunomodulatory agents, arsenic trioxide, and farnesyl transferase inhibitors have thus far shown limited usefulness in higher risk MDS. This paper reviews the various therapeutic options for higher risk MDS, providing rationale for specific management approaches for these patients.
Age Factors↗
Strategies for achieving transfusion independence in myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) are a group of complex diseases of the myeloid stem cell that result in chronic cytopenias. In some instances, these disorders may progress to acute myeloid leukemia. Patients with MDS frequently experience chronic, symptomatic anemia, and many become dependent on chronic transfusions of packed red blood cells. However, long-term transfusion dependence has clinical and economic consequences, including a potentially negative impact on patients' quality of life (QOL). Recently, studies have investigated various strategies to reduce or eliminate transfusion needs in MDS patients. Supportive measures with hematopoietic growth factors such as erythropoietin are often less effective in MDS-associated anemia than in anemia from other causes, but some patients may benefit from this approach. Treatment with other agents, such as antithymocyte globulin, azacitidine, decitabine, thalidomide, and lenalidomide, has resulted in transfusion independence in some subsets of MDS patients. Nurses who care for patients with MDS should be aware of the impact of transfusion dependence on the patient's QOL, as well as the benefits and risks of the various other treatment options available to these patients. Such knowledge will enable the nurse to provide accurate, relevant information, so that patients can make informed choices regarding treatment options for MDS.
Anemia↗
DNA methylation and gene silencing in cancer.
Epigenetic changes such as DNA methylation act to regulate gene expression in normal mammalian development. However, promoter hypermethylation also plays a major role in cancer through transcriptional silencing of critical growth regulators such as tumor suppressor genes. Other chromatin modifications, such as histone deacetylation and chromatin-binding proteins, affect local chromatin structure and, in concert with DNA methylation, regulate gene transcription. The DNA methylation inhibitors azacitidine and decitabine can induce functional re-expression of aberrantly silenced genes in cancer, causing growth arrest and apoptosis in tumor cells. These agents, along with inhibitors of histone deacetylation, have shown clinical activity in the treatment of certain hematologic malignancies where gene hypermethylation occurs. This review examines alteration in DNA methylation in cancer, effects on gene expression, and implications for the use of hypomethylating agents in the treatment of cancer.
Antimetabolites, Antineoplastic↗