S172: PHASE 1/2 STUDY OF ORAL DECITABINE/CEDAZURIDINE IN COMBINATION WITH VENETOCLAX IN TREATMENT-NAIVE HIGHER-RISK MYELODYSPLASTIC SYNDROMES OR CHRONIC MYELOMONOCYTIC LEUKEMIA
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SUBMITTER: Bataller A
PROVIDER: S-EPMC10428441 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Project description:On July 7, 2020, the Food and Drug Administration approved Inqovi (Otsuka Pharmaceutical Co.), an oral fixed-dose combination tablet comprising 35 mg decitabine, a hypomethylating agent, and 100 mg cedazuridine, a cytidine deaminase inhibitor (abbreviated DEC-C) for treatment of adult patients with myelodysplastic syndromes (MDS). Evidence of effectiveness of DEC-C was established in phase III ASTX727-02 (N = 133) in adults with MDS. The study involved a two-sequence crossover comparing DEC-C and intravenous (IV) decitabine 20 mg/m2 once daily for the first 5 days of each 28-day cycle in the first 2 cycles. From cycle 3 onward, patients received DEC-C. Five-day cumulative area under the curve (5-d AUC) of decitabine for DEC-C was similar to that of IV decitabine, with geometric mean ratio 0.99 (90% confidence interval: 0.93-1.06). Clinical benefit was supported by study ASTX727-02 and the similarly designed phase II study ASTX727-01-B (n = 80), with complete remission (CR) of 21% and 18% and median duration of CR 7.5 and 8.7 months, respectively. Adverse reactions were consistent with IV decitabine. Postmarketing assessments were issued to address the effect of cedazuridine on QT prolongation, food effect, moderate and severe hepatic impairment, and severe renal impairment on the pharmacokinetics and safety of DEC-C.
| S-EPMC9378483 | biostudies-literature
Project description:Hypomethylating agents (HMAs) are guideline-recommended treatment for higher-risk myelodysplastic syndromes/neoplasms (MDS). However, a prior survey of patients with MDS reported challenges with intravenous (IV) and subcutaneous (SC) HMA therapies, including pain related to treatment administration and interference with daily activities; most patients also indicated a preference to switch to an oral therapy if one were available. This study evaluated the perspectives of US patients with MDS receiving oral decitabine/cedazuridine (DEC-C), an alternative to IV/SC HMAs. An online survey was conducted among adult patients with MDS in the United States (10 November 2022 to 5 December 2022) who had filled a prescription for oral DEC-C between 2021 and 2022. A total of 150 patients completed the survey; 61% were aged ⩾60 years and 63% were male. Of these, 123 (82%) were still receiving oral DEC-C, and 27 (18%) had stopped oral DEC-C treatment. Half (50%) of patients had received oral DEC-C for ⩾6 months. The majority reported that treatment was convenient (83%) and that they were satisfied with treatment (86%). Most patients also reported very little/no interference with regular daily activities (82%), social activities (78%), and productivity (78%). When queried about negative impacts on quality of life (QOL), treatment side effects were the most commonly reported (30% of respondents). Among patients who had previously received IV/SC HMAs (n = 91), most agreed that oral DEC-C interfered less with daily life (91%) and had experienced improvement in QOL (85%) compared with previous treatment; 91% reported that oral DEC-C reduced the number of times they needed to travel to a healthcare facility. Survey results suggest very little/no impact on regular daily activities and improved QOL with oral DEC-C relative to IV/SC HMAs, highlighting the potential for oral DEC-C to reduce the treatment burden associated with parenteral HMA therapy.
| S-EPMC11292726 | biostudies-literature
Project description:Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome (MDS)/myeloproliferative disorder most commonly seen in the elderly. We describe an adolescent with monosomy 7 CMML presenting as central diabetes insipidus (DI), who was treated with venetoclax and decitabine as a bridge to hematopoietic stem cell transplantation (HSCT). Central DI is a rare manifestation of monosomy 7-associated MDS including CMML, itself a rare manifestation of GATA2 deficiency, particularly in children. Venetoclax/decitabine was effective for treatment of CMML as a bridge to HSCT.
| S-EPMC9357463 | biostudies-literature
Project description:BackgroundHypomethylating agents (HMAs) have shown efficacy in the treatment of hematological malignancies and are indicated for the treatment of chronic myelomonocytic leukemia (CMML). While the HMA decitabine, in its intravenous formulation, has been used since 2006 for the treatment of CMML, use of its oral formulation has been limited by poor bioavailability due to first-pass metabolism by the enzyme cytidine deaminase. The dose of intravenous decitabine is limited by toxicities such as cardiomyopathy and heart failure. Therefore, cedazuridine was developed as an inhibitor of cytidine deaminase. Cedazuridine decreases the first-pass metabolism of oral decitabine allowing therapeutic levels to be achieved at lower doses, and thus, the novel oral combination of cedazuridine with decitabine was developed. While cardiomyopathy and heart failure are well-established adverse effects associated with intravenous decitabine alone, there to our knowledge there have been no documented incidences of reversible cardiomyopathy in the literature or in patients who participated in the phase 2 and phase 3 clinical trials of oral decitabine-cedazuridine.CaseThis case study presents an 85 year-old Caucasian female with CMML who developed cardiomyopathy and heart failure with reduced ejection fraction after completing 5 cycles of therapy with decitabine/cedazuridine. Furthermore, her symptoms and cardiac function recovered upon discontinuation of the drug.ConclusionsWe present an occurrence of reversible cardiomyopathy in a patient who completed 5 cycles of decitabine/cedazuridine, an oral combination therapy developed to enhance oral bioavailability of decitabine thereby limiting its adverse effects. As the decitabine/cedazuridine combination therapy rises in popularity due to its convenient oral formulation, more trials are needed to understand the prevalence of cardiomyopathy with this drug and to discover preventative strategies for cardiotoxic effects.
| S-EPMC9845814 | biostudies-literature
Project description:BackgroundThe molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear.MethodsWe enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols.ResultsOf the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles.ConclusionsPatients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).
| S-EPMC5217532 | biostudies-literature
Project description:Chronic myelomonocytic leukemia (CMML) is a complex clonal hematological disorder classified among myelodysplastic (MDS)/myeloproliferative neoplasms. Prognosis is poor and there is a lack of effective treatments. The hypomethylating agent decitabine has shown activity against MDS and elderly acute myeloid leukemia, but there is little data focusing specifically on its efficacy in CMML. In this prospective, phase 2 Italian study, CMML patients received intravenous decitabine 20 mg/m2 per day on Days 1-5 of a 28-day treatment cycle. Response was evaluated after four and six cycles; patients responding at the end of six cycles could continue treatment with decitabine. Forty-three patients were enrolled; >50% were high-risk according to four CMML-specific scoring systems. In the intent-to-treat population (n=42), the overall response rate after six cycles was 47.6%, with seven complete responses (16.6%), eight marrow responses (19%), one partial response (2.4%) and four hematological improvements (9.5%). After a median follow-up of 51.5 months (range: 44.4-57.2), median overall survival was 17 months, with responders having a significantly longer survival than non-responders (P=0.02). Grade 3/4 anemia, neutropenia and thrombocytopenia occurred in 28.6%, 50% and 38% of patients, respectively. Decitabine appears to be an effective and well-tolerated treatment for patients with high-risk CMML.
| S-EPMC5808077 | biostudies-literature
Project description:A fixed dose oral combination (FDC) of decitabine and cedazuridine (Inqovi®), is being developed by Astex Pharmaceuticals (a subsidiary of Otsuka Pharmaceuticals) for the treatment of various cancers like myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemia (AML), glioma and solid tumours. Decitabine, a DNA methyltransferase inhibitor approved for the treatment of MDS and CMML, is degraded by cytidine deaminase in the gastrointestinal tract and liver, thereby limiting oral bioavailability. Cedazuridine is a proprietary, patented cytidine deaminase inhibitor that, when added to decitabine, increases oral bioavailability of the drug. In July 2020, decitabine/cedazuridine received its first approval in the USA and Canada for the treatment of MDS and CMML. In the USA, it is indicated for use in adults with MDS and CMML, including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anaemia, refractory anaemia with ringed sideroblasts, refractory anaemia with excess blasts and CMML) and intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System groups. Clinical studies for AML, glioma and solid tumours are underway in several countries worldwide. This article summarizes the milestones in the development of decitabine/cedazuridine leading to this first approval for the treatment of MDS and CMML.
| S-EPMC7708383 | biostudies-literature
Project description:PurposeTo determine the maximum-tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and clinical activity of an oral formulation of azacitidine in patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML).Patients and methodsPatients received 1 cycle of subcutaneous (SC) azacitidine (75 mg/m2) on the first 7 days of cycle 1, followed by oral azacitidine daily (120 to 600 mg) on the first 7 days of each additional 28-day cycle. Pharmacokinetic and pharmacodynamic profiles were evaluated during cycles 1 and 2. Adverse events and hematologic responses were recorded. Cross-over to SC azacitidine was permitted for nonresponders who received ≥ 6 cycles of oral azacitidine.ResultsOverall, 41 patients received SC and oral azacitidine (MDSs, n = 29; CMML, n = 4; AML, n = 8). Dose-limiting toxicity (grade 3/4 diarrhea) occurred at the 600-mg dose and MTD was 480 mg. Most common grade 3/4 adverse events were diarrhea (12.2%), nausea (7.3%), vomiting (7.3%), febrile neutropenia (19.5%), and fatigue (9.8%). Azacitidine exposure increased with escalating oral doses. Mean relative oral bioavailability ranged from 6.3% to 20%. Oral and SC azacitidine decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. Hematologic responses occurred in patients with MDSs and CMML. Overall response rate (i.e., complete remission, hematologic improvement, or RBC or platelet transfusion independence) was 35% in previously treated patients and 73% in previously untreated patients.ConclusionOral azacitidine was bioavailable and demonstrated biologic and clinical activity in patients with MDSs and CMML.
| S-EPMC3675699 | biostudies-literature
Project description:Failure of hypomethylation agent (HMA) treatments is an important issue in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Recent studies indicated that function of wildtype TP53 positively impacts outcome of HMA treatments. We investigated the combination of the HMA azacitidine (AZA) with DS-3032b and DS-5272, novel antagonists of the TP53 negative regulator MDM2, in cellular and animal models of MDS and CMML. In TP53 wildtype myeloid cell line, combinational effects of DS-3032b or DS-5272 with AZA were observed. In Tet2-knockout mouse model of MDS and CMML, DS-5272 and AZA combination ameliorated disease-like phenotype. RNA-Seq analysis in mouse bone marrow hematopoietic stem and progenitors indicated that DS-5272 and AZA combination caused down-regulation of leukemia stem cell marker genes and activation of pathways of TP53 function and stability. These findings demonstrate that combining an MDM2 antagonist with AZA has potential to improve AZA treatment in TP53 wildtype MDS and CMML.
| S-EPMC10088064 | biostudies-literature
Project description:Prior studies have investigated patients' characteristics, treatments, and outcomes for older adults with myelodysplastic syndromes, but most failed to distinguish chronic myelomonocytic leukemia. Recognizing potentially important differences between the diseases, we undertook a population-based comparison of baseline characteristics, treatments, and outcomes between older adults with chronic myelomonocytic leukemia and myelodysplastic syndromes. The patients' data were obtained from Surveillance Epidemiology and End Results registry data from 2001-2005, linked to Medicare claims. Baseline characteristics, treatment (red blood cell transfusions, hematopoietic growth factors, hypomethylating agents, chemotherapy or transplantation), progression to acute myeloid leukemia, and overall survival were compared using bivariate techniques. Multivariate logistic regression estimated differences in treatments received. Cox proportional hazard models estimated the effects of chronic myelomonocytic leukemia relative to myelodysplastic syndromes on progression-free survival. A larger proportion of patients with chronic myelomonocytic leukemia (n=792), compared to patients with myelodysplastic syndromes (n=7,385), failed to receive any treatment (25% versus 15%; P<0.0001), or only received red blood cell transfusions (19.8% versus 16.7%; P=0.037). A larger percentage of patients with chronic myelomonocytic leukemia progressed to acute myeloid leukemia (42.6% versus 15.5%, respectively; P<0.0001), with shorter time to progression. Chronic myelomonocytic leukemia patients had a shorter median survival (13.3 versus 23.3 months; P<0.0001) and lower 3-year survival rate (19% versus 36%; P<0.0001). Adjusted estimates, controlling for baseline characteristics and selected treatments, indicate that chronic myelomonocytic leukemia was associated with an increased risk of progression to acute myeloid leukemia or death (HR 2.22; P<0.0001), compared to myelodysplastic syndromes. In conclusion, chronic myelomonocytic leukemia is less frequently treated in older adults and is associated with worse outcomes, even after controlling for the patients' baseline characteristics and selected treatments. Our data suggest the need for continued evaluation of the biological differences between these diseases and clinical trials targeting chronic myelomonocytic leukemia.
| S-EPMC3659989 | biostudies-literature