14 results on '"Willemze, Roel"'
Search Results
2. Gemtuzumab Ozogamicin Versus Best Supportive Care in Older Patients With Newly Diagnosed Acute Myeloid Leukemia Unsuitable for Intensive Chemotherapy: Results of the Randomized Phase III EORTC-GIMEMA AML-19 Trial.
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Amadori S, Suciu S, Selleslag D, Aversa F, Gaidano G, Musso M, Annino L, Venditti A, Voso MT, Mazzone C, Magro D, De Fabritiis P, Muus P, Alimena G, Mancini M, Hagemeijer A, Paoloni F, Vignetti M, Fazi P, Meert L, Ramadan SM, Willemze R, de Witte T, and Baron F
- Subjects
- Age Factors, Aged, Aged, 80 and over, Female, Gemtuzumab, Humans, Hydroxyurea therapeutic use, Male, Middle Aged, Aminoglycosides therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Abstract
Purpose: To compare single-agent gemtuzumab ozogamicin (GO) with best supportive care (BSC) including hydroxyurea as first-line therapy in older patients with acute myeloid leukemia unsuitable for intensive chemotherapy., Patients and Methods: In this trial, patients at least 61 years old were centrally randomized (1:1) to receive either a single induction course of GO (6 mg/m(2) on day 1 and 3 mg/m(2) on day 8) or BSC. Patients who did not progress after GO induction could receive up to eight monthly infusions of the immunoconjugate at 2 mg/m(2). Randomization was stratified by age, WHO performance score, CD33 expression status, and center. The primary end point was overall survival (OS) by intention-to-treat analysis., Results: A total of 237 patients were randomly assigned (118 to GO and 119 to BSC). The median OS was 4.9 months (95% CI, 4.2 to 6.8 months) in the GO group and 3.6 months (95% CI, 2.6 to 4.2 months) in the BSC group (hazard ratio, 0.69; 95% CI, 0.53 to 0.90; P = .005); the 1-year OS rate was 24.3% with GO and 9.7% with BSC. The OS benefit with GO was consistent across most subgroups, and was especially apparent in patients with high CD33 expression status, in those with favorable/intermediate cytogenetic risk profile, and in women. Overall, complete remission (CR [complete remission] + CRi [CR with incomplete recovery of peripheral blood counts]) occurred in 30 of 111 (27%) GO recipients. The rates of serious adverse events (AEs) were similar in the two groups, and no excess mortality from AEs was observed with GO., Conclusion: First-line monotherapy with low-dose GO, as compared with BSC, significantly improved OS in older patients with acute myeloid leukemia who were ineligible for intensive chemotherapy. No unexpected AEs were identified and toxicity was manageable., (© 2016 by American Society of Clinical Oncology.)
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- 2016
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3. Idarubicin and cytarabine in combination with gemtuzumab ozogamicin (IAGO) for untreated patients with high-risk MDS or AML evolved from MDS: a phase II study from the EORTC and GIMEMA Leukemia Groups (protocol 06013).
- Author
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de Witte T, Suciu S, Meert L, Halkes C, Selleslag D, Bron D, Amadori S, Willemze R, Muus P, and Baron F
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- Adolescent, Adult, Aged, Allografts, Aminoglycosides administration & dosage, Antibodies, Monoclonal, Humanized administration & dosage, Autografts, Cytarabine administration & dosage, Disease-Free Survival, Female, Gemtuzumab, Hematopoietic Stem Cell Transplantation, Humans, Idarubicin administration & dosage, Male, Middle Aged, Survival Rate, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Myelodysplastic Syndromes mortality, Myelodysplastic Syndromes therapy
- Abstract
The primary objective of this trial was to assess the feasibility, toxicity profile, and antitumor activity of gemtuzumab ozogamicin (GO) combined with a chemotherapy remission-induction regimen in adults with untreated high-risk myelodysplastic syndrome (HR-MDS) or secondary acute myeloid leukemia (sAML). In this phase II trial, 30 patients with median age of 58 years received 1 day of GO as a 1-h infusion at the dose level of 5 mg/m(2) on day 7 of the remission-induction course further consisting of a continuous infusion of cytarabine 100 mg/m(2)/day for 10 days and idarubicin 12 mg/m(2)/day on days 1, 3, and 5. A consolidation course, consisting of intermediate-dose cytarabine (A) and idarubicin (I) followed by hematopoietic stem cell transplantation (HSCT) was planned for patients in complete remission (CR). The primary endpoints were response rate (CR/CRi) and severe toxicity rate. The secondary endpoint(s) were survival and progression-free survival (PFS) from start of treatment. Thirteen patients (43 %) achieved CR (eight patients) or CR with incomplete hematopoietic recovery (CRi) (five patients). In patients who achieved CR or CRi, the median time to recovery of neutrophils to 0.5 × 10(9)/l and of platelets to >50 × 10(9)/l was 29 and 30 days, respectively. Grade 3 to 4 severe toxicities occurred in nine patients. The most prominent was liver toxicity, as shown by elevated bilirubin levels in 16 patients and one case of nonfatal veno-occlusive disease (VOD). All 13 patients with CR/CRi received consolidation therapy, which was followed by allogeneic HSCT in five patients and autologous HSCT in three patients. According to the statistical design of the study, the idarubicin and cytarabine in combination with gemtuzumab ozogamicin (IAGO) regimen did not show sufficient activity to warrant further exploration of this regimen in adult patients with HR-MDS or sAML.
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- 2015
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4. Specific scoring systems to predict survival of patients with high-risk myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML) after intensive antileukemic treatment based on results of the EORTC-GIMEMA AML-10 and intergroup CRIANT studies.
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Oosterveld M, Suciu S, Muus P, Germing U, Delforge M, Belhabri A, Aul C, Selleslag D, Ferrant A, Marie JP, Amadori S, Jehn U, Mandelli F, Hess U, Hellström-Lindberg E, Cakmak-Wollgast S, Vignetti M, Labar B, Willemze R, and de Witte T
- Subjects
- Adolescent, Adult, Europe epidemiology, Female, Humans, Male, Middle Aged, Predictive Value of Tests, Risk Factors, Survival Rate trends, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute mortality, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes mortality, Severity of Illness Index
- Abstract
High-risk myelodysplastic syndrome (MDS) patients have usually a less favorable outcome after intensive treatment compared with de novo acute myeloid leukemia (AML) patients. This may reflect different disease-related and patient-related factors. The purpose of this analysis is to identify disease-specific prognostic factors and to develop prognostic scores for both patient groups. A total of 692 patients in the EORTC/GIMEMA AML-10 study and 289 patients in the CRIANT study received identical remission-induction and consolidation treatment. Estimated 5-year survival rate was 34 % in the AML-10 versus 27 % in the CRIANT study, and estimated disease-free survival was 40 % versus 28 %, respectively. In multivariate analysis, cytogenetic characteristics, white blood count, and age appeared prognostic for survival in both studies. French-American-British (FAB) subtype and performance status were prognostic in the AML-10 study only, whereas number of cytopenias and duration of antecedent hematologic disorder >6 months were prognostic in the CRIANT study only. The prognostic scores distinguish three groups with a 5-year survival rate of 54, 38, and 19 % in the AML-10 study versus 69, 37, and 5 % in the CRIANT study. The prognostic value of these scores has been validated on two external series. The new scoring systems form a practical tool to predict the outcome of individual MDS and AML patients treated with intensive antileukemic therapy.
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- 2015
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5. Clinical and biological impact of TET2 mutations and expression in younger adult AML patients treated within the EORTC/GIMEMA AML-12 clinical trial.
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Aslanyan MG, Kroeze LI, Langemeijer SM, Koorenhof-Scheele TN, Massop M, van Hoogen P, Stevens-Linders E, van de Locht LT, Tönnissen E, van der Heijden A, da Silva-Coelho P, Cilloni D, Saglio G, Marie JP, Tang R, Labar B, Amadori S, Muus P, Willemze R, Marijt EW, de Witte T, van der Reijden BA, Suciu S, and Jansen JH
- Subjects
- 5-Methylcytosine analogs & derivatives, Adolescent, Adult, Animals, COS Cells, Chlorocebus aethiops, Clinical Trials as Topic, Cytosine analogs & derivatives, Cytosine analysis, DNA (Cytosine-5-)-Methyltransferases genetics, DNA Methyltransferase 3A, DNA-Binding Proteins biosynthesis, DNA-Binding Proteins physiology, Dioxygenases, Female, Humans, Isocitrate Dehydrogenase genetics, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute mortality, Male, Multicenter Studies as Topic, Neoplasm Proteins biosynthesis, Neoplasm Proteins physiology, Prognosis, Prospective Studies, Proto-Oncogene Proteins biosynthesis, Proto-Oncogene Proteins physiology, RNA, Messenger biosynthesis, RNA, Neoplasm biosynthesis, Recombinant Fusion Proteins metabolism, Transfection, Young Adult, DNA-Binding Proteins genetics, Gene Expression Regulation, Leukemic, Leukemia, Myeloid, Acute genetics, Mutation, Neoplasm Proteins genetics, Proto-Oncogene Proteins genetics
- Abstract
We assessed the prognostic impact of TET2 mutations and mRNA expression in a prospective cohort of 357 adult AML patients < 60 years of age enrolled in the European Organization For Research and Treatment of Cancer (EORTC)/Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) AML-12 06991 clinical trial. In addition the co-occurrence with other genetic defects and the functional consequences of TET2 mutations were investigated. TET2 mutations occurred in 7.6 % of the patients and were an independent marker of poor prognosis (p = 0.024). TET2 and IDH1/2 mutations strongly associated with aberrations in the DNA methyltransferase DNMT3A. Functional studies confirmed previous work that neither nonsense truncations, nor missense TET2 mutations, induced 5-hydroxymethylcytosine formation. In addition, we now show that mutant TET2 forms did not act in a dominant negative manner when co-expressed with the wild-type protein. Finally, as loss-of-function TET2 mutations predicted poor outcome, we questioned whether low TET2 mRNA expression in cases of AML without TET2 mutations would affect overall survival. Notably, also AML patients with low TET2 mRNA expression levels showed inferior overall survival.
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- 2014
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6. Value of allogeneic versus autologous stem cell transplantation and chemotherapy in patients with myelodysplastic syndromes and secondary acute myeloid leukemia. Final results of a prospective randomized European Intergroup Trial.
- Author
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de Witte T, Hagemeijer A, Suciu S, Belhabri A, Delforge M, Kobbe G, Selleslag D, Schouten HC, Ferrant A, Biersack H, Amadori S, Muus P, Jansen JH, Hellström-Lindberg E, Kovacsovics T, Wijermans P, Ossenkoppele G, Gratwohl A, Marie JP, and Willemze R
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Humans, Leukemia, Myeloid, Acute mortality, Middle Aged, Myelodysplastic Syndromes mortality, Neoplasms, Second Primary mortality, Neoplasms, Second Primary therapy, Survival Analysis, Transplantation, Autologous, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute therapy, Myelodysplastic Syndromes therapy
- Abstract
Background: Allogeneic stem cell transplantation is usually considered the only curative treatment option for patients with advanced or transformed myelodysplastic syndromes in complete remission, but post-remission chemotherapy and autologous stem cell transplantation are potential alternatives, especially in patients over 45 years old., Design and Methods: We evaluated, after intensive anti-leukemic remission-induction chemotherapy, the impact of the availability of an HLA-identical sibling donor on an intention-to treat basis. Additionally, all patients without a sibling donor in complete remission after the first consolidation course were randomized to either autologous peripheral blood stem cell transplantation or a second consolidation course consisting of high-dose cytarabine., Results: The 4-year survival of the 341 evaluable patients was 28%. After achieving complete remission, the 4-year survival rates of patients under 55 years old with or without a donor were 54% and 41%, respectively, with an adjusted hazard ratio of 0.81 (95% confidence interval [95% CI], 0.49-1.35) for survival and of 0.67 (95% CI, 0.42-1.06) for disease-free survival. In patients with intermediate/high risk cytogenetic abnormalities the hazard ratio in multivariate analysis was 0.58 (99% CI, 0.22-1.50) (P=0.14) for survival and 0.46 (99% CI, 0.22-1.50) for disease-free survival (P=0.03). In contrast, in patients with low risk cytogenetic characteristics the hazard ratio for survival was 1.17 (99% CI, 0.40-3.42) and that for disease-free survival was 1.02 (99% CI, 0.40-2.56). The 4-year survival of the 65 patients randomized to autologous peripheral blood stem cell transplantation or a second consolidation course of high-dose cytarabine was 37% and 27%, respectively. The hazard ratio in multivariate analysis was 1.22 (95% CI, 0.65-2.27) for survival and 1.02 (95% CI, 0.56-1.85) for disease-free survival., Conclusions: Patients with a donor and candidates for allogeneic stem cell transplantation in first complete remission may have a better disease-free survival than those without a donor in case of myelodysplastic syndromes with intermediate/high-risk cytogenetics. Autologous peripheral blood stem cell transplantation does not provide longer survival than intensive chemotherapy.
- Published
- 2010
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7. Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia.
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Lim Z, Brand R, Martino R, van Biezen A, Finke J, Bacigalupo A, Beelen D, Devergie A, Alessandrino E, Willemze R, Ruutu T, Boogaerts M, Falda M, Jouet JP, Niederwieser D, Kroger N, Mufti GJ, and De Witte TM
- Subjects
- Age Factors, Aged, Humans, Middle Aged, Retrospective Studies, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute therapy, Myelodysplastic Syndromes therapy
- Abstract
Purpose: This study was performed to examine the characteristics of transplant activity for patients with myelodysplastic syndromes (MDS) older than 50 years within the European Group for Blood and Marrow Transplantation, and to evaluate the factors predicting outcome within this group of patients., Patients and Methods: We performed a retrospective multicenter analysis of 1,333 MDS patients age 50 years or older who received transplantation within the EBMT since 1998. The median recipient age was 56 years, with 884 patients (66%) age 50 to 60 years and 449 (34%) patients older than 60 years. There were 811 HLA-matched sibling (61%) and 522 (39%) unrelated donor transplants. Five hundred patients (38%) received standard myeloablative conditioning (SMC), and 833 (62%) received reduced intensity conditioning (RIC)., Results: The 4-year estimate for overall survival of the whole cohort was 31%. On multivariate analysis, use of RIC (hazard ratio [HR], 1.44; 95% CI, 1.13 to 1.84; P < .01) and advanced disease stage at transplantation (HR, 1.51; 95% CI, 1.18 to 1.93; P < .01) were associated with an increased relapse rate. In contrast, advanced disease stage at transplantation (HR, 1.43; 95% CI, 1.13 to 1.79; P = .01), use of an unrelated donor (P = .03), and RIC (HR, 0.79; 95% CI, 0.65 to 0.97; P = .03) were independent variables associated with nonrelapse mortality. Advanced disease stage at transplantation (HR, 1.55; 95% CI, 1.32 to 1.83; P < .01) was the major independent variable associated with an inferior 4-year overall survival., Conclusion: Allogeneic hematopoietic stem-cell transplantation remains a potential curative therapeutic option for many older patients with MDS. In this analysis, disease stage at time of transplantation, but not recipient age or the intensity of the conditioning regimens, was the most important factor influencing outcomes.
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- 2010
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8. Higher incidence of relapse with peripheral blood rather than marrow as a source of stem cells in adults with acute myelocytic leukemia autografted during the first remission.
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Gorin NC, Labopin M, Blaise D, Reiffers J, Meloni G, Michallet M, de Witte T, Attal M, Rio B, Witz F, Fouillard L, Willemze R, and Rocha V
- Subjects
- Adolescent, Adult, Aged, Female, Humans, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Multivariate Analysis, Prognosis, Recurrence, Transplantation, Autologous, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute therapy, Peripheral Blood Stem Cell Transplantation
- Abstract
Purpose: The cell source for autologous stem cell transplantation has shifted from bone marrow (BM) to peripheral blood (PB). In acute myelocytic leukemia (AML), for patients who receive transplants during first complete remission (CR1), no prospective randomized study has compared relapse incidence (RI) to cell source., Patients and Methods: We analyzed 2,165 patients who received autografts (1,607 PB and 558 BM) from 1994 to 2006 and were reported to the European Cooperative Group for Blood and Marrow Transplantation with complete research data. Relative to the time of CR1, PB transplants were performed earlier than BM transplants. Because a poorer outcome was associated with a shorter interval from CR1 to transplantation, patients were divided into three groups: BM, early PB (< or = 80 days after CR1), and late PB (> 80 days after CR1) transplantation., Results: In a multivariate analysis adjusted for differences between groups and center, RI was higher with both early PB (56% +/- 3%; hazard ratio [HR], 1.45; 95% CI, 1.11 to 1.9; P = .006) and late PB transplantation (46% +/- 2%; HR, 1.3; 95% CI, 1.06 to 1.59; P = .01) as compared with BM transplantation (39% +/- 2%). This translated into a significantly worse leukemia-free survival (LFS) for early PB transplantation (36% +/- 3%; HR, 0.75; 95% CI, 0.58 to 0.96; P = .02) and a trend for a poorer LFS for late PB (46% +/- 2%; HR, 0.84; 95% CI, 0.7 to 1.01; P = .06) as compared with BM (52% +/- 2%)., Conclusion: For patients with AML in CR1, risk of relapse is greater with PB transplantation rather than BM, independent of the interval from CR1 to transplantation.
- Published
- 2009
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9. Identical outcome after autologous or allogeneic genoidentical hematopoietic stem-cell transplantation in first remission of acute myelocytic leukemia carrying inversion 16 or t(8;21): a retrospective study from the European Cooperative Group for Blood and Marrow Transplantation.
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Gorin NC, Labopin M, Frassoni F, Milpied N, Attal M, Blaise D, Meloni G, Iori AP, Michallet M, Willemze R, Deconninck E, Harousseau JL, Polge E, and Rocha V
- Subjects
- Adolescent, Adult, Aged, Chi-Square Distribution, Chromosome Inversion, Chromosomes, Human, Pair 16, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Female, Humans, Leukemia, Myeloid, Acute genetics, Male, Middle Aged, Prognosis, Proportional Hazards Models, Recurrence, Remission Induction, Retrospective Studies, Statistics, Nonparametric, Surveys and Questionnaires, Transplantation, Autologous, Transplantation, Homologous, Treatment Outcome, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute therapy
- Abstract
Purpose: Patients with acute myelocytic leukemia carrying inversion 16 (inv16) or t(8;21) have a better initial response to high-dose cytarabine than patients without these chromosomal abnormalities. They presently do not undergo transplantation in first remission (CR1), but there is concern about late relapses., Patients and Methods: From 1990 to 2004, 325 adult patients received transplantations in CR1 (159 patients with inv16 and 166 patients with t(8;21), including 35 and 60 patients, respectively, with additional chromosomal abnormalities). Genoidentical allografts were performed in 64 patients with inv16 and 81 patients with t(8;21), and autografts were performed in 95 patients with inv16 and 85 patients with t(8;21)., Results: In patients with inv16, after allogeneic and autologous transplantation, the 5-year leukemia-free survival (LFS) rates were 59% and 66% (P = .5), the relapse incidence (RI) rates were 27% and 32% (P = .45), and the transplantation-related mortality (TRM) rates were 14% and 2% (P = .003), respectively. Female patients had a lower RI and a higher LFS. Additional chromosomal abnormalities, compared with no additional abnormalities, were associated with lower RI rate (12% v 34%, respectively; P = .01) and higher 5-year LFS rate (78% v 59%, respectively; P = .04). In patients with t(8;21), after allogeneic and autologous transplantation, the 5-year LFS rates were 60% and 66% (P = .69), the RI rates were 15% and 28% (P = .03), and the TRM rates were 24% and 6% (P = .003), respectively. Younger age and a lower WBC count at diagnosis were associated with a lower TRM and a better LFS. The TRM was lower and the RI was higher in patients with autologous transplantations versus allogeneic transplantations., Conclusion: Both autologous and allogeneic transplantation resulted in similar outcomes.
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- 2008
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10. New CFSE-based assay to determine susceptibility to lysis by cytotoxic T cells of leukemic precursor cells within a heterogeneous target cell population.
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Jedema I, van der Werff NM, Barge RM, Willemze R, and Falkenburg JH
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- Cell Division, Clone Cells, Fluorescent Dyes, HLA-D Antigens immunology, Histocompatibility Antigens Class I immunology, Humans, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Leukemia, Myeloid, Acute pathology, Preleukemia pathology, T-Lymphocytes immunology, Fluoresceins, Leukemia, Myeloid, Acute immunology, Preleukemia immunology, Succinimides, T-Lymphocytes, Cytotoxic immunology
- Abstract
For the clinical evaluation of the efficacy of cellular immunotherapy it is necessary to analyze the effector functions of T cells against primary leukemic target cell populations which are usually considerably heterogeneous caused by differential maturation stages of the leukemic cells. An appropriate assay should not only allow the quantitative analysis of rapid cell death induction as measured by the conventional 51Cr release assay but also of the more slowly executing pathways of T-cell-induced apoptosis occurring within days instead of hours which cannot be measured using this method. Furthermore, it should dissect the differential susceptibility to T-cell-induced cell death of various target cell subpopulations and characterize the malignant precursor cells capable of producing malignant progeny. To fulfill these requirements we developed a new assay based on carboxyfluorescein diacetate succinimidyl ester (CFSE) labeling of the target cell population combined with antibody staining of specific cell populations and addition of fluorescent microbeads to quantitatively monitor target cell death occurring within a longer time frame up to at least 5 days. This new assay facilitates the analysis of differential recognition of distinct cell types within a heterogeneous target cell population and allows simultaneously evaluation of the proliferative status of surviving target cells in response to relevant cytokines.
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- 2004
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11. Acute myeloid leukemia cells in G0 phase of the cell cycle that are unresponsive to conventional chemotherapy are sensitive to treatment with granulocyte-macrophage colony-stimulating factor/diphtheria toxin fusion proteins.
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Jedema I, Barge RM, Frankel AE, Willemze R, and Falkenburg JH
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- Cell Division drug effects, Cell Line, Tumor, Humans, Leukemia, Myeloid, Acute pathology, Diphtheria Toxin therapeutic use, Granulocyte-Macrophage Colony-Stimulating Factor therapeutic use, Leukemia, Myeloid, Acute drug therapy, Recombinant Fusion Proteins therapeutic use, Resting Phase, Cell Cycle drug effects
- Abstract
Objective: Unresponsiveness to chemotherapy is a major problem in the treatment of leukemia, which can be caused by unresponsiveness of noncycling cells to cell cycle-dependent cytotoxic agents. Targeted toxins consisting of a targeting and activating cytokine (granulocyte-macrophage colony-stimulating factor [GM-CSF]) and diphtheria toxin (DT) can be used to overcome this kind of resistance of leukemic cells. In this study we manipulated the cell cycle and proliferative status of leukemic cells, explored the effect on sensitivity to DT, and determined the ability of DT388GMCSF fusion proteins to activate and subsequently kill leukemic cells., Materials and Methods: We used the GM-CSF-dependent myeloid leukemic cell line AML-193 as a model. GM-CSF or granulocyte colony-stimulating factor (G-CSF) was used to manipulate the cell cycle and proliferative state of AML-193 cells. Cell death was quantified by 51Cr release assays. The results obtained in the AML-193 cell line model were confirmed using primary leukemic blasts., Results: Similar to treatment with chemotherapy and immunotherapy, leukemic cells in resting G0 phase were relatively resistant to DT-induced cell death. Synchronized recruitment of leukemic cells into activated phases of the cell cycle by low concentrations of GM-CSF or G-CSF resulted in significant increased DT sensitivity. DT388GMCSF fusion proteins specifically targeted GM-CSF receptor-expressing cells, resulting in recruitment of leukemic cells from G0 phase of the cell cycle and subsequent kill of these cells., Conclusion: Leukemic cells in G0 phase, which are resistant to conventional chemotherapy, Fas-induced immunotherapy, and DT alone, can be synchronically activated and subsequently killed by DT388GMCSF fusion proteins.
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- 2004
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12. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia.
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Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Löwenberg B, Sanz MA, Head DR, Ohno R, and Bloomfield CD
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- Humans, Leukemia, Myeloid, Acute classification, Leukemia, Myeloid, Acute therapy, Remission Induction, United States, Clinical Trials as Topic standards, Leukemia, Myeloid, Acute diagnosis
- Abstract
An International Working Group met to revise the diagnostic and response criteria for acute myelogenous leukemia originally published in 1990, as well as to provide definitions of outcomes and reporting standards to improve interpretability of data and comparisons among trials. Since the original publication, there have been major advances in our understanding of the biology and molecular genetics of acute leukemia that are clinically relevant and warrant incorporation into response definitions. Differences from the 1990 recommendations included a category of leukemia-free state, new criteria for complete remission, including cytogenetic and molecular remissions and remission duration. Storage of viable blasts for correlative studies is important for future progress in the therapy of these disorders.
- Published
- 2003
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13. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial.
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Suciu S, Mandelli F, de Witte T, Zittoun R, Gallo E, Labar B, De Rosa G, Belhabri A, Giustolisi R, Delarue R, Liso V, Mirto S, Leone G, Bourhis JH, Fioritoni G, Jehn U, Amadori S, Fazi P, Hagemeijer A, and Willemze R
- Subjects
- Adolescent, Adult, Age Factors, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Combined Modality Therapy, Disease-Free Survival, Female, Humans, Leukemia, Myeloid, Acute drug therapy, Male, Middle Aged, Proportional Hazards Models, Tissue and Organ Procurement, Transplantation, Autologous, Transplantation, Homologous, Treatment Outcome, Leukemia, Myeloid, Acute therapy, Stem Cell Transplantation methods
- Abstract
In the European Organization for Research and Treatment of Cancer Leukemia Group and Gruppo Italiano Malattie Ematologiche dell' Adulto (EORTC-LG/GIMEMA) acute myeloid leukemia (AML)-10 trial, patients in first complete remission (CR1) received a single intensive consolidation (IC) course. Subsequently, those patients younger than 46 years with an HLA-identical sibling donor were assigned to undergo allogeneic (allo) stem cell transplantation (SCT), and patients without such a donor were planned for autologous (auto) SCT. Between November 1993 and December 1999, of 1198 patients aged younger than 46 years, 822 achieved CR. The study group constituted 734 patients who received IC: 293 had a sibling donor and 441 did not. Allo-SCT and auto-SCT were performed in 68.9% and 55.8%, respectively. Cytogenetic determination was successfully performed in 446 patients. Risk groups were good (t(8;21), inv16), intermediate (NN or -Y only), and bad/very bad (all others). Median follow-up was 4 years; 289 patients relapsed, 66 died in CR1, and 293 died. Intention-to-treat analysis revealed that the 4-year disease-free survival (DFS) rate of patients with a donor versus those without a donor was 52.2% versus 42.2%, P =.044; hazard ratio = 0.80, 95% confidence interval (0.64, 0.995), the relapse incidence was 30.4% versus 52.5%, death in CR1 was 17.4% versus 5.3%, and the survival rate was 58.3% versus 50.8% (P =.18). The DFS rates in patients with and without a sibling donor were similar in patients with good/intermediate risk but were 43.4% and 18.4%, respectively, in patients with bad/very bad risk cytogenetics. In younger patients (15-35 years), the difference was more pronounced. The strategy to perform early allo-SCT led to better overall results than auto-SCT, especially for younger patients or those with bad/very bad risk cytogenetics.
- Published
- 2003
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14. The treatment of acute myeloid leukemia in first relapse: a comprehensive review of the literature.
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Leopold LH and Willemze R
- Subjects
- Adult, Age Factors, Aged, Clinical Trials as Topic, Humans, Leukemia, Myeloid, Acute drug therapy, Middle Aged, Mucous Membrane pathology, Remission Induction, Retrospective Studies, Time Factors, Leukemia, Myeloid, Acute therapy, Recurrence
- Abstract
Twenty years of published literature was reviewed for chemotherapy regimens used to treat patients with acute myeloid leukemia (AML) in first relapse. Thirty-one trials containing at least 20 patients in first relapse and information on patient age, duration of first complete remission (CR1), and rate of second complete remission (CR2) were analyzed. These trials included 10 retrospective studies with CR2 rates ranging from 30 to 64%, two phase II single-agent studies with CR2 rates of 8 and 25%, 15 phase II combination-agent studies with CR2 rates ranging from 14 to 87%, and four phase III randomized studies with CR2 rates ranging from 40 to 89%. When reported, median duration of CR2 was < or = 14 months and overall median survival was < or = 12 months. The probability of 3-year survival ranged from 8 to 29%. Combination therapies resulted in higher CR2 rates but were associated with longer duration of myelosuppression and greater incidence of mucositis. None of the reviewed regimens provided durable remissions for the majority of AML patients in first relapse. The CR2 rates were closely associated with age and duration of CR1. Therefore, considering the poor clinical outcomes of patients with AML in first relapse, improved therapies need to be developed.
- Published
- 2002
- Full Text
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