Low-Dose Decitabine Versus Best Supportive Care in Elderly Patients With Intermediate- or High-Risk Myelodysplastic Syndrome (MDS) Ineligible for Intensive Chemotherapy: Final Results of the Randomized Phase III Study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group

Lübbert, Michael; Suciu, Stefan; Baila, Liliana; Rüter, Björn; Platzbecker, Uwe; Giagounidis, Aristoteles; Selleslag, Dominik; Labar, Boris; Germing, Ulrich; Salih, Helmut R.; Beeldens, F.; Muus, Petra; Pflüger, Karl-Heinz; Coens, Corneel; Hagemeijer, Anne; Schaefer, Hans E.; Ganser, Arnold; Aul, Carlo; Witte, Théo de; Wijermans, Pierre W.

doi:10.1200/jco.2010.30.9245

Cited by 491 publications

(379 citation statements)

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“…Crossover to the experimental arm was prohibited. Decitabine (15 mg/m 2 in two doses over 2 h each) was given intravenously every 8 h for 3 days in 6-week cycles [8]. If regeneration of hematologic parameters was insufficient, the interval between cycles could be extended up to 10 weeks.…”

Section: Methodsmentioning

confidence: 99%

“…Eligibility criteria of trial 06011 (clinicaltrials.gov Id NCT00043134) have been previously reported [8] and included the following: patients ≥60 years old; primary or treatment-related MDS or chronic myelomonocytic leukemia (CMML) according to FAB criteria [9]; International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2, or high risk [1]; BM blasts of 11 to 30 %, or ≤10 % and poor cytogenetics according to IPSS criteria; Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; and ineligible for intensive chemotherapy as judged by the treating physician. No previous treatment with standard chemotherapy or a hypomethylating agent was allowed.…”

Section: Patientsmentioning

confidence: 99%

“…Primary endpoint was OS (measured from the date of random assignment until death from any cause or last follow-up (censored observation)) [8]. Secondary endpoints were AML-free survival (AMLFS; measured from the date of random assignment to transformation to AML [FAB] or death from any cause, whichever occurred first), progression-free survival (PFS; measured from the date of random assignment to progression, relapse after achievement of CR or partial response [PR], or death, whichever occurred first), and best response rate.…”

Section: Endpointsmentioning

confidence: 99%

“…In the phase III trial 06011, we compared the 3-day schedule of decitabine (15 mg/m 2 every 8 h for 3 days) with BSC in patients ≥60 years with MDS (FAB) not eligible for intensive therapy [8]. Decitabine administered at the 3-day schedule for MDS (FAB) is in line with its approval status in the USA.…”

Section: Introductionmentioning

confidence: 99%

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Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation (RAEBt) - results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group (GMDSSG)

et al. 2015

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In the European Organisation for Research and Treatment of Cancer (EORTC)/GMDSSG phase III trial 06011, we compared decitabine (15 mg/m 2 every 8 h for 3 days) with best supportive care (BSC) in patients ≥60 years with myelodysplastic syndromes (MDS) by FrenchAmerican-British (FAB) criteria. Here, we reinvestigate trial 06011 for the activity and efficacy specifically in patients with refractory anemia with excess blasts in transformation (RAEBt). Response rates in the decitabine arm (N=40) were as follows: complete or partial remission, 15 %; hematologic improvement, 15 %; resistant disease, 30 %. RAEBt patients in the decitabine arm had longer progression-free survival (PFS; hazard ratio (HR) 0.30, 95 % confidence interval (CI) 0.18-0.51; median, 6.2 vs 2.8 months) and overall survival (OS; HR 0.68, 95 % CI 0.42-1.11; median, 8.0 vs 6.0 months) than in the BSC arm (N=35). Censoring at allogeneic hematopoietic stem cell transplantation, the OS difference between the treatment groups increased, particularly among patients Electronic supplementary material The online version of this article (doi:10.1007/s00277-015-2489-6) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Section: Patientsmentioning

confidence: 99%

Section: Endpointsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation (RAEBt) - results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group (GMDSSG)

et al. 2015

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“…Although decitabine is another effective HMA for MDS and AML (Lübbert et al. 2011; Kantarjian et al. 2012), the prognosis after decitabine failure is also poor (Jabbour et al.…”

Section: Introductionmentioning

confidence: 99%

Lack of cross‐resistance to FF‐10501, an inhibitor of inosine‐5′‐monophosphate dehydrogenase, in azacitidine‐resistant cell lines selected from SKM‐1 and MOLM‐13 leukemia cell lines

Murase

Iwamura

Komatsu

et al. 2016

Pharmacology Res & Perspec

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Resistance to azacitidine is a major issue in the treatments of myelodysplastic syndrome and acute myeloid leukemia, and previous studies suggest that changes in drug metabolism are involved in the resistance. Therefore, drugs with mechanisms resistant or alternative to such metabolic changes have been desired for the treatment of resistant disease. We generated azacitidine‐resistant cells derived from SKM‐1 and MOLM‐13 leukemia cell lines in vitro, analyzed the mechanisms, and examined the impact on the efficacy of other antimetabolic drugs. It appeared that the cell growth‐inhibitory effect of azacitidine, expression levels of uridine–cytidine kinase 2, and the concentrations of azacitidine triphosphate were remarkably decreased in the resistant cells compared with those in parent cells. These results were consistent with previous observations that azacitidine resistance is derived from metabolic changes. Cross‐resistance of greater than 10‐fold (shift in IC50 value) was observed in azacitidine‐resistant cells for decitabine and for cytarabine, but not for gemcitabine or the inosine‐5′‐monophosphate dehydrogenase (IMPDH) inhibitors FF‐10501 and mycophenolate mofetil (cross‐resistance to 5‐fluorouracil was cell line dependent). The IMPDH inhibitors maintained their cell growth‐inhibitory activities in the azacitidine‐resistant cell lines, in which the levels of adenine phosphoribosyltransferase (which converts FF‐10501 to its active form, FF‐10501 ribosylmonophosphate [FF‐10501RMP]), FF‐10501RMP, and the target enzyme, IMPDH, were equivalent to those in the parent cell lines. These results suggest that an IMPDH inhibitor such as FF‐10501 could be an alternative therapeutic treatment for leukemia patients with acquired resistance to azacitidine.

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Diagnosis and Treatment of Myelodysplastic Syndromes

Sekeres

Taylor

2022

JAMA

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he myelodysplastic neoplasms (MDS), formerly known as myelodysplastic syndromes, are a group of cancers characterized by failure of bone marrow stem cells to mature into normal-functioning blood cells. MDS are characterized by reduced numbers of peripheral blood cells, an increased risk of acute myeloid leukemia transformation, and reduced survival, with a 5-year survival rate of approximately 37%. 1,2 The yearly incidence of MDS is approximately 4 per 100 000 people. 3 MDS are more common in men (with yearly incidence rates of approxi-mately 5.4 per 100 000 vs 2.9 per 100 000 for women) and are more common among people who are White compared with people who are Asian/Pacific Islander (4.0 per 100 000), Black (2.7 per 100 000), or Hispanic (2.9 per 100 000), and among people who are older. 3 The median age of diagnosis is approximately 70 years, and the yearly incidence rate increases to 25 per 100 000 in people aged 65 years and older. 3 Older age is associated with clonal hematopoiesis of indeterminate potential, which is considered a precursor to MDS. 4 Additional risk factors IMPORTANCE Myelodysplastic neoplasms (MDS), formerly known as myelodysplastic syndromes, are clonal hematopoietic malignancies that cause morphologic bone marrow dysplasia along with anemia, neutropenia, or thrombocytopenia. MDS are associated with an increased risk of acute myeloid leukemia (AML). The yearly incidence of MDS is approximately 4 per 100 000 people in the United States and is higher among patients with advanced age.OBSERVATIONS MDS are characterized by reduced numbers of peripheral blood cells, an increased risk of acute myeloid leukemia transformation, and reduced survival. The median age at diagnosis is approximately 70 years, and the yearly incidence rate increases to 25 per 100 000 in people aged 65 years and older. Risk factors associated with MDS include older age and prior exposures to toxins such as chemotherapy or radiation therapy. MDS are more common in men compared with women (with yearly incidence rates of approximately 5.4 vs 2.9 per 100 000). MDS typically has an insidious presentation, consisting of signs and symptoms associated with anemia, thrombocytopenia, and neutropenia. MDS can be categorized into subtypes that are associated with lower or higher risk for acute myeloid leukemia transformation and that help with therapy selection. Patients with lower-risk MDS have a median survival of approximately 3 to 10 years, whereas patients with higher-risk disease have a median survival of less than 3 years. Therapy for lower-risk MDS is selected based on whether the primary clinical characteristic is anemia, thrombocytopenia, or neutropenia. Management focuses on treating symptoms and reducing the number of required transfusions in patients with low-risk disease. For patients with lower-risk MDS, erythropoiesis stimulating agents, such as recombinant humanized erythropoietin or the longer-acting erythropoietin, darbepoetin alfa, can improve anemia in 15% to 40% of patients for a median of 8 to 23 months. For th...

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Abstract: Decitabine administered in 6-week cycles is active in older patients with higher-risk MDS, resulting in improvements of OS and AMLFS (nonsignificant), of PFS and AML transformation (significant), and of QOL. Short MDS duration was an independent adverse prognosticator.

Cited by 491 publications

References 22 publications

Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation (RAEBt) - results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group (GMDSSG)

Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation (RAEBt) - results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group (GMDSSG)

Lack of cross‐resistance to FF‐10501, an inhibitor of inosine‐5′‐monophosphate dehydrogenase, in azacitidine‐resistant cell lines selected from SKM‐1 and MOLM‐13 leukemia cell lines

Diagnosis and Treatment of Myelodysplastic Syndromes

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