97 results on '"Witte, T."'
Search Results
2. Oral decitabine plus cedazuridine versus intravenous decitabine.
- Author
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de Witte T
- Subjects
- Humans, Decitabine therapeutic use, Uridine therapeutic use, Antineoplastic Combined Chemotherapy Protocols, Azacitidine therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Abstract
Competing Interests: I declare no competing interests.
- Published
- 2024
- Full Text
- View/download PDF
3. CPX-351 for higher risk myelodysplastic syndrome: cytarabine and daunorubicin in disguise?
- Author
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Muus P and de Witte T
- Subjects
- Humans, Daunorubicin adverse effects, Cytarabine adverse effects, Antineoplastic Combined Chemotherapy Protocols, Myelodysplastic Syndromes drug therapy, Leukemia, Myeloid, Acute drug therapy
- Abstract
Competing Interests: We declare no competing interests.
- Published
- 2023
- Full Text
- View/download PDF
4. Cause of death and excess mortality in patients with lower-risk myelodysplastic syndromes (MDS): A report from the European MDS registry.
- Author
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Mądry K, Lis K, Fenaux P, Bowen D, Symeonidis A, Mittelman M, Stauder R, Čermák J, Sanz G, Hellström-Lindberg E, Langemeijer S, Malcovati L, Germing U, Holm MS, Guerci-Bresler A, Culligan D, Sanhes L, Kotsianidis I, van Marrewijk C, Crouch S, de Witte T, and Smith A
- Subjects
- Humans, Cause of Death, Disease Progression, Registries, Myelodysplastic Syndromes, Cardiovascular Diseases, Leukemia, Myeloid, Acute
- Abstract
Information on causes of death (CoDs) and the impact of myelodysplastic syndromes (MDS) on survival in patients with lower-risk MDS (LR-MDS) is limited. A better understanding of the relationship between disease characteristics, clinical interventions and CoDs may improve outcomes of patients with LR-MDS. We prospectively collected data on patients with LR-MDS in the European MDS registry from 2008 to 2019. Clinical, laboratory and CoDs data were obtained. To examine MDS-specific survival, relative survival (RS) was estimated using national life tables. Of 2396 evaluated subjects, 900 died (median overall survival [OS]: 4.7 years; median follow-up: 3.5 years). The most common CoDs were acute myeloid leukaemia/MDS (20.1%), infection (17.8%) and cardiovascular disease (CVD; 9.8%). Patients with isolated del(5q) and with red cell transfusion needed during the disease course, had a higher risk of fatal CVD. The 5-year OS was 47.3% and the 5-year RS was 59.6%, indicating that most patients died due to their underlying MDS. Older patients (aged >80 years) and the lowest-risk patients were more likely to die from competing causes. This study shows that MDS and its related complications play crucial role in the outcome of patients with LR-MDS., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2023
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5. Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial.
- Author
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Larson RA, Mandrekar SJ, Huebner LJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Voso MT, Klisovic RB, Galinsky I, Wei AH, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Gathmann I, Döhner H, and Stone RM
- Subjects
- Adolescent, Adult, Antineoplastic Agents therapeutic use, Biomarkers, Tumor genetics, Female, Follow-Up Studies, Humans, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Neoplasm Recurrence, Local pathology, Prognosis, Prospective Studies, Staurosporine therapeutic use, Survival Rate, Young Adult, Leukemia, Myeloid, Acute drug therapy, Mutation, Neoplasm Recurrence, Local drug therapy, Staurosporine analogs & derivatives, fms-Like Tyrosine Kinase 3 genetics
- Abstract
The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR = 0.71 (95% CI, 0.54-0.93); p = 0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.)
- Published
- 2021
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6. A phase I clinical trial to study the safety of treatment with tipifarnib combined with bortezomib in patients with advanced stages of myelodysplastic syndrome and oligoblastic acute myeloid leukemia.
- Author
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Muus P, Langemeijer S, van Bijnen S, Blijlevens N, and de Witte T
- Subjects
- Aged, Bortezomib administration & dosage, Dose-Response Relationship, Drug, Female, Humans, Male, Maximum Tolerated Dose, Middle Aged, Quinolones administration & dosage, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bortezomib adverse effects, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy, Quinolones adverse effects
- Abstract
Purpose: To determine the safety of tipifarnib in combination with escalating doses of bortezomib and to determine the maximum tolerated dose in patients with untreated high-risk MDS and oligoblastic acute myeloid leukemia, who were not eligible for intensive therapy., Experimental Design: In a "3 + 3″ design, patients received fixed doses of tipifarnib 200 mg bid (days 1-21) and escalating doses of bortezomib (days 8, 15, 22) every 4 weeks in 4-6 cycles., Results: The combination was tolerated well by the 11 patients in this study without reaching the maximum tolerated dose. Myelosuppression was the most frequent side effect, but usually of short duration. Interestingly a complete response with or without complete count recovery was observed in three patients and three additional patients had stable disease. The median duration of overall survival was 449 days. Two patients were still alive at 4.0 and 4.3 years, including one patient in continuing CR., Conclusions: The combination of tipifarnib and bortezomib was tolerated well and appeared to have clinical activity in patients with high-risk MDS and AML with low counts of marrow blasts. Our results warrant further evaluation in a phase II study., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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7. Impact of the type of anthracycline and of stem cell transplantation in younger patients with acute myeloid leukaemia: Long-term follow up of a phase III study.
- Author
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Baron F, Efficace F, Cannella L, Muus P, Trisolini S, Halkes CJM, Fazi P, Vignetti M, Marie JP, Chiusolo P, van der Velden W, La Sala E, Vitolo U, Thomas X, Lefrère F, Di Raimondo F, Bourhis JH, Specchia G, Guimarães JE, Allione B, Vrhovac R, Ferrara F, Stevens-Kroef M, Meert L, de Witte T, Willemze R, Amadori S, and Suciu S
- Subjects
- Adolescent, Adult, Age Factors, Allografts, Cytarabine administration & dosage, Cytarabine adverse effects, Daunorubicin administration & dosage, Daunorubicin adverse effects, Etoposide administration & dosage, Etoposide adverse effects, Female, Follow-Up Studies, Humans, Idarubicin administration & dosage, Idarubicin adverse effects, Male, Middle Aged, Mitoxantrone administration & dosage, Mitoxantrone adverse effects, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Hematopoietic Stem Cell Transplantation, Induction Chemotherapy, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy
- Abstract
We provide a long-term evaluation of patients enrolled in the EORTC/GIMEMA AML-10 trial which included a total of 2157 patients, 15-60 years old, randomized to receive either daunorubicin (DNR, 50 mg/m
2 ), mitoxantrone (MXR, 12 mg/m2 ), or idarubicin (IDA, 10 mg/m2 ) in addition to standard-dose cytarabine and etoposide for induction chemotherapy and intermediate dose cytarabine for consolidation. Younger patients who reached complete remission with complete (CR) or incomplete (CRi) recovery were then scheduled to receive an allogeneic hematopoietic stem cell transplantation (HSCT). That was if they had a HLA-identical sibling donor; in all other cases, an autologous HSCT had to be administered. At an 11-year median follow-up, the 5-year, 10-year and 15-year overall survival (OS) rates were 33.2%, 30.1% and 28.0%, respectively. No significant difference between the three randomized groups regarding OS was observed (P = .38). In young patients, 15-45 years old, no treatment difference (P = .89) regarding OS was observed, while in patients 46-60 years old, MXR and IDA groups had a trend for a longer OS as compared to the DNR group (P = .029). Among younger patients without a favorable MRC cytogenetic risk subgroup who achieved a CR/CRi after induction chemotherapy, those with a HLA-identical sibling donor had higher 10-year and 15-year OS rates than those without. In older patients who reached CR/CRi, the long-term outcomes of those with or without a donor was similar. In conclusion, long-term outcomes of the study confirmed similar OS in the three randomized groups in the whole cohort of patients., (© 2020 Wiley Periodicals, Inc.)- Published
- 2020
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8. Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia.
- Author
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Döhner K, Thiede C, Jahn N, Panina E, Gambietz A, Larson RA, Prior TW, Marcucci G, Jones D, Krauter J, Heuser M, Voso MT, Ottone T, Nomdedeu JF, Mandrekar SJ, Klisovic RB, Wei AH, Sierra J, Sanz MA, Brandwein JM, de Witte T, Jansen JH, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Gathmann I, Benner A, Pallaud C, Stone RM, Döhner H, and Bloomfield CD
- Subjects
- Europe, Female, Genotype, Hematopoietic Stem Cell Transplantation, Humans, Leukemia, Myeloid, Acute therapy, Male, Middle Aged, Multivariate Analysis, Nucleophosmin, Prognosis, Proportional Hazards Models, Risk Factors, Treatment Outcome, Gene Duplication, Genetic Predisposition to Disease, Leukemia, Myeloid, Acute genetics, Nuclear Proteins genetics, Tandem Repeat Sequences genetics, fms-Like Tyrosine Kinase 3 genetics
- Abstract
Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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9. Long-term follow-up of a trial comparing post-remission treatment with autologous or allogeneic bone marrow transplantation or intensive chemotherapy in younger acute myeloid leukemia patients.
- Author
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Baron F, Efficace F, Cannella L, Willemze R, Vignetti M, Muus P, Marie JP, Ferrero D, Fazi P, La Sala E, Bourhis JH, Fabbiano F, Bosi A, Sborgia M, Martinelli G, Wittnebel S, Trisolini S, Petti MC, Halkes CJM, van der Velden WJFM, de Witte T, Amadori S, Zittoun RA, and Suciu S
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Bone Marrow Transplantation, Cytarabine therapeutic use, Follow-Up Studies, Humans, Remission Induction, Transplantation, Autologous, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute drug therapy
- Published
- 2020
- Full Text
- View/download PDF
10. Impact of induction regimen and allogeneic hematopoietic cell transplantation on outcome in younger adults with acute myeloid leukemia with a monosomal karyotype.
- Author
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Baron F, Stevens-Kroef M, Kicinski M, Meloni G, Muus P, Marie JP, Halkes CJM, Thomas X, Vrhovac R, Albano F, Lefrère F Sr, Sica S, Mancini M, Venditti A, Hagemeijer A, Jansen JH, Amadori S, de Witte T, Willemze R, and Suciu S
- Subjects
- Adolescent, Adult, Age Factors, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Combined Modality Therapy, Female, Humans, Induction Chemotherapy, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Odds Ratio, Prognosis, Survival Analysis, Transplantation, Homologous, Treatment Outcome, Young Adult, Abnormal Karyotype, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Monosomy genetics
- Abstract
Monosomal karyotype confers a poor prognosis in patients with acute myeloid leukemia. Here, we determined the impact of the type of remission-induction chemotherapy and the impact of having a donor in younger acute myeloid leukemia patients with a monosomal karyotype included in two phase III trials. In the first trial patients were randomized to receive either daunorubicin, mitoxantrone, or idarubicin in addition to standard-dose cytarabine and etoposide for induction chemotherapy. In the second trial patients were randomized to standard-dose cytarabine or high-dose cytarabine induction, both with daunorubicin and etoposide. In both trials, patients who achieved a complete remission with or without complete hematologic recovery underwent allogeneic hematopoietic stem cell transplantation if they had a donor; otherwise, they underwent autologous transplantation. In comparison to patients with intermediate-risk cytogenetics without a monosomal karyotype (n=1,584) and with adverse cytogenetics without a monosomal karyotype (n=218), patients with a monosomal karyotype (n=188) were more likely not to achieve a complete remission with or without count recovery [odds ratio=2.85, 95% confidence interval (95%, CI): 2.10-3.88] and had shorter overall survival [hazard ratio, (HR)=2.44, 95% CI: 2.08-2.88]. There was no impact of the type of anthracycline or of the dose of cytarabine on outcomes in patients with a monosomal karyotype. Among monosomal karyo type patients who achieved a complete remission with or without count recovery, HLA-identical related donor availability was associated with longer survival from complete remission with or without count recovery (HR=0.59, 95% CI: 0.37-0.95). ClinicalTrials.gov identifiers: AML-10: NCT00002549; AML-12: NCT00004128., (Copyright© 2019 Ferrata Storti Foundation.)
- Published
- 2019
- Full Text
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11. Cytogenetic clonal heterogeneity is not an independent prognosis factor in 15-60-year-old AML patients: results on 1291 patients included in the EORTC/GIMEMA AML-10 and AML-12 trials.
- Author
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Baron F, Stevens-Kroef M, Kicinski M, Meloni G, Muus P, Marie JP, Halkes CJM, Thomas X, Vrhovac R, Specchia G, Lefrere F Sr, Sica S, Mancini M, Venditti A, Hagemeijer A, Becker H, Jansen JH, Amadori S, de Witte T, Willemze R, and Suciu S
- Subjects
- Abnormal Karyotype, Adolescent, Adult, Clonal Evolution genetics, Cytogenetic Analysis, Female, Genetic Heterogeneity, Humans, Male, Middle Aged, Prognosis, Randomized Controlled Trials as Topic, Retrospective Studies, Survival Analysis, Young Adult, Chromosome Aberrations, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality
- Abstract
The presence of cytogenetic clonal heterogeneity has been associated with poor prognosis in patients with acute myeloid leukemia (AML). Here, we reassessed this association. The study cohort consisted of all patients with an abnormal karyotype randomized in the EORTC/GIMEMA AML-10 and AML-12 trials. Abnormal karyotypes were classified as no subclones present (cytogenetic abnormality in a single clone), defined subclones present (presence of one to three subclones), and composite karyotypes (CP) (clonal heterogeneity not allowing enumeration of individual subclones). The main endpoints were overall survival (OS) and disease-free survival (DFS). Among 1291 patients with an abnormal karyotype, 1026 had no subclones, 226 at least 1 subclone, and 39 a CP. Patients with defined subclones had an OS similar to those with no subclones (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.88-1.26), but CP patients had a shorter OS (HR = 1.58, 95% CI 1.11-2.26). However, in a multivariate Cox model stratified by protocol and adjusted for age, cytogenetic risk group, secondary versus primary AML, and performance status, clonal heterogeneity lost its prognostic importance (HR = 1.10, 95% CI 0.91-1.32 for defined subclones versus no subclones; HR = 0.96, 95% CI 0.67-1.38 for CP versus no subclones). Also, the impact of having a donor on DFS was similar in the three clonal subgroups. In summary, in patients with cytogenetic abnormality, presence of subclones had no impact on OS. The dismal outcome in patients with a CP was explained by the known predictors of poor prognosis., Trial Registration: AML-10: ClinicalTrials.gov identifier: NCT00002549, retrospectively registered July 19, 2004; AML12: ClinicalTrials.gov identifier: NCT00004128, registered January 27, 2003.
- Published
- 2018
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12. Outcome after relapse of myelodysplastic syndrome and secondary acute myeloid leukemia following allogeneic stem cell transplantation: a retrospective registry analysis on 698 patients by the Chronic Malignancies Working Party of the European Society of Blood and Marrow Transplantation.
- Author
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Schmid C, de Wreede LC, van Biezen A, Finke J, Ehninger G, Ganser A, Volin L, Niederwieser D, Beelen D, Alessandrino P, Kanz L, Schleuning M, Passweg J, Veelken H, Maertens J, Cornelissen JJ, Blaise D, Gramatzki M, Milpied N, Yakoub-Agha I, Mufti G, Rovira M, Arnold R, de Witte T, Robin M, and Kröger N
- Subjects
- Adolescent, Adult, Aged, Allografts, Europe, Female, Humans, Lymphocyte Transfusion, Male, Middle Aged, Myelodysplastic Syndromes therapy, Recurrence, Registries, Reoperation, Retrospective Studies, Risk Factors, Treatment Outcome, Young Adult, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute etiology, Myelodysplastic Syndromes pathology
- Abstract
No standard exists for the treatment of myelodysplastic syndrome relapsing after allogeneic stem cell transplantation. We performed a retrospective registry analysis of outcomes and risk factors in 698 patients, treated with different strategies. The median overall survival from relapse was 4.7 months (95% confidence interval: 4.1-5.3) and the 2-year survival rate was 17.7% (95% confidence interval: 14.8-21.2%). Shorter remission after transplantation ( P <0.001), advanced disease ( P =0.001), older age ( P =0.007), unrelated donor ( P =0.008) and acute graft- versus -host disease before relapse ( P <0.001) adversely influenced survival. At 6 months from relapse, patients had received no cellular treatment, (i.e. palliative chemotherapy or best supportive care, n=375), donor lymphocyte infusion (n=213), or a second transplant (n=110). Treatment groups were analyzed separately because of imbalanced characteristics and difficulties in retrospectively evaluating the reason for individual treatments. Of the patients who did not receive any cellular therapy, 109 were alive at 6 months after relapse, achieving a median overall survival from this landmark of 8.9 months (95% confidence interval: 5.1-12.6). Their 2-year survival rate was 29.7%. Recipients of donor lymphocytes achieved a median survival from first infusion of 6.0 months (95% confidence interval: 3.7-8.3) with a 2-year survival rate of 27.6%. Longer remission after first transplantation ( P <0.001) and younger age ( P =0.009) predicted better outcome. Among recipients of a second transplant, the median survival from second transplantation was 4.2 months (95% confidence interval: 2.5-5.9), and their 2-year survival rate was 17.0%. Longer remission after first transplantation ( P <0.001), complete remission at second transplant ( P =0.008), no prior chronic graft- versus -host disease ( P <0.001) and change to a new donor ( P =0.04) predicted better outcome. The data enabled identification of patients benefiting from donor lymphocyte infusion and second transplantation, and may serve as a baseline for prospective trials., (Copyright© 2018 Ferrata Storti Foundation.)
- Published
- 2018
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13. Validation of the revised IPSS at transplant in patients with myelodysplastic syndrome/transformed acute myelogenous leukemia receiving allogeneic stem cell transplantation: a retrospective analysis of the EBMT chronic malignancies working party.
- Author
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Scheid C, de Wreede L, van Biezen A, Koenecke C, Göhring G, Volin L, Maertens J, Finke J, Passweg J, Beelen D, Cornelissen JJ, Itälä-Remes M, Chevallier P, Russell N, Petersen E, Milpied N, Richard Espiga C, Peniket A, Sierra J, Mufti G, Crawley C, Veelken JH, Ljungman P, Cahn JY, Alessandrino EP, de Witte T, Robin M, and Kröger N
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Databases, Factual, Disease-Free Survival, Female, Hematopoietic Stem Cell Transplantation mortality, Humans, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Male, Middle Aged, Myelodysplastic Syndromes mortality, Myelodysplastic Syndromes therapy, Retrospective Studies, Risk Factors, Survival Rate, Transplantation, Homologous, Young Adult, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute diagnosis, Myelodysplastic Syndromes diagnosis, Prognosis
- Abstract
The International Prognostic Scoring System has been revised (IPSS-R) to predict prognosis of patients with myelodysplastic syndromes at diagnosis. To validate the use of the IPSS-R assessed before transplant rather than at diagnosis we performed a retrospective analysis of the EBMT database. A total of 579 patients had sufficient information available to calculate IPSS-R at transplant. Median overall survival (OS) from transplant was significantly different according to IPSS-R: very low 23.6 months, low 55.0 months, intermediate 19.7 months, high 13.5 months, very high 7.8 months (P<0.001). In a multivariate Cox model the following parameters were significant risk factors for OS: IPSS-R, graft source, age and prior treatment. Median relapse free survival also showed significant differences according to IPSS-R: very low: 23.6 months, low: 24.8 months, intermediate 10.6 months, high 7.9 months, very high 5.5 months (P<0.001). Multivariate risk factors for relapse-free survival (RFS) were: IPSS-R, reduced intensity conditioning, graft source and prior treatment. A trend for an increased relapse incidence was noted for very high risk IPSS-R. We conclude that the IPSS-R at transplant is a useful prognostic score for predicting OS and RFS after transplantation, capturing both disease evolution and response to prior treatment before transplant.
- Published
- 2017
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14. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation.
- Author
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Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, and Döhner H
- Subjects
- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cytarabine administration & dosage, Daunorubicin administration & dosage, Female, Humans, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Mutation, Protein Kinase Inhibitors adverse effects, Staurosporine administration & dosage, Staurosporine adverse effects, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy, Protein Kinase Inhibitors administration & dosage, Staurosporine analogs & derivatives, fms-Like Tyrosine Kinase 3 genetics
- Abstract
Background: Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population., Methods: We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival., Results: A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups., Conclusions: The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261 .).
- Published
- 2017
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15. Low-dose clofarabine in combination with a standard remission induction in patients aged 18-60 years with previously untreated intermediate and bad-risk acute myeloid leukemia or high-risk myelodysplastic syndrome: combined phase I/II results of the EORTC/GIMEMA AML-14A trial.
- Author
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Selleslag D, Suciu S, Meloni G, Muus P, Halkes CJ, Venditti A, Ramadan SM, Pruijt H, Meert L, Vignetti M, Marie JP, Wittnebel S, de Witte T, Amadori S, Willemze R, and Baron F
- Subjects
- Adolescent, Adult, Clofarabine, Drug Administration Schedule, Female, Gene Expression, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes mortality, Myelodysplastic Syndromes pathology, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, Random Allocation, Remission Induction, Risk Factors, Survival Analysis, Transplantation, Homologous, Treatment Outcome, Adenine Nucleotides therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Arabinonucleosides therapeutic use, Cytarabine therapeutic use, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute therapy, Myelodysplastic Syndromes therapy
- Published
- 2017
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16. Allogeneic Stem Cell Transplantation for Patients Age ≥ 70 Years with Myelodysplastic Syndrome: A Retrospective Study of the MDS Subcommittee of the Chronic Malignancies Working Party of the EBMT.
- Author
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Heidenreich S, Ziagkos D, de Wreede LC, van Biezen A, Finke J, Platzbecker U, Niederwieser D, Einsele H, Bethge W, Schleuning M, Beelen DW, Tischer J, Nagler A, Glass B, Maertens J, Yáñez L, Beguin Y, Sill H, Scheid C, Stelljes M, Ganser A, Zachée P, Selleslag D, de Witte T, Robin M, and Kröger N
- Subjects
- Aged, Cytomegalovirus immunology, Europe, Female, Hematopoietic Stem Cell Transplantation mortality, Humans, Karnofsky Performance Status, Leukemia, Myeloid, Acute mortality, Male, Myelodysplastic Syndromes mortality, Recurrence, Registries, Retrospective Studies, Survival Analysis, Tissue Donors, Transplantation Conditioning mortality, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute therapy, Myelodysplastic Syndromes therapy, Transplantation Conditioning methods
- Abstract
In this retrospective analysis we evaluated the outcome of 313 patients aged ≥ 70 years in the registry of the European Group for Blood and Marrow Transplantation with myelodysplastic syndrome (MDS; n = 221) and secondary acute myeloid leukemia (n = 92) who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from related (n = 79) or unrelated (n = 234) donors. Median age at HSCT was 72 years (range, 70 to 78). Conditioning regimen was nonmyeloablative (n = 54), reduced intensity (n = 207), or standard intensity (n = 52). Allogeneic HSCT for MDS patients ≥ 70 years was increasingly performed over time. Although during 2000 to 2004 only 16 patients received HSCT, during 2011 to 2013 the number of transplantations increased to 181. The cumulative incidence of nonrelapse mortality at 1 year and relapse at 3 years was 32% and 28%, respectively, with a 3-year overall survival rate of 34%. Good performance, determined by Karnofsky performance status, and recipients' seronegativity for cytomegalovirus was associated with 3-year estimated overall survival rates of 43% (P = .01) and 46% (P = .002), respectively. Conditioning intensity did not impact survival. After careful patient selection, allogeneic HSCT can be offered to patients older than 70 years with MDS., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
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- 2017
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17. The optimal dosing of gemtuzumab ozagamicin: where to go from here?
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de Witte T and Amadori S
- Subjects
- Aged, Aged, 80 and over, Aminoglycosides adverse effects, Antibodies, Monoclonal, Humanized adverse effects, Female, Gemtuzumab, Humans, Male, Middle Aged, Aminoglycosides therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy
- Published
- 2016
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18. 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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19. 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
- Subjects
- 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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20. High numbers of mobilized CD34+ cells collected in AML in first remission are associated with high relapse risk irrespective of treatment with autologous peripheral blood SCT or autologous BMT.
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Hengeveld M, Suciu S, Chelgoum Y, Marie JP, Muus P, Lefrère F, Mandelli F, Pane F, Amadori S, Fioritoni G, Labar B, Baron F, Cermak J, Bourhis JH, Storti G, Fazi P, Hagemeijer A, Vignetti M, Willemze R, and de Witte T
- Subjects
- Adolescent, Adult, Disease-Free Survival, Female, Humans, Leukemia, Myeloid, Acute blood, Male, Middle Aged, Recurrence, Remission Induction, Risk Factors, Transplantation, Autologous, Young Adult, Antigens, CD34 metabolism, Bone Marrow Transplantation methods, Hematopoietic Stem Cell Mobilization methods, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute therapy, Transplantation Conditioning methods
- Abstract
The faster hematopoietic recovery after autologous peripheral blood SCT (APBSCT) in patients with AML may be offset by an increased relapse risk as compared with autologous BMT (ABMT). The EORTC and GIMEMA Leukemia Groups conducted a trial (AML-10) in which they compared, as second randomization, APBSCT and ABMT in first CR patients without an HLA compatible donor. A total of 292 patients were randomized. The 5-year DFS rate was 41% in the APBSCT arm and 46% in the ABMT arm with a hazard ratio (HR) of 1.17; 95% confidence interval=0.85-1.59; P=0.34. The 5-year cumulative relapse incidence was 56% vs 49% (P=0.26), and the 5-year OS 50% and 55% (P=0.6) in the APBSCT and ABMT groups, respectively. APBSCT was associated with significantly faster recovery of neutrophils and platelets, shorter duration of hospitalization, reduced need of transfusion packed RBC and less days of intravenous antibiotics. In both treatment groups, higher numbers of mobilized CD34+ cells were associated with a significantly higher relapse risk irrespective of the treatment given after the mobilization. Randomization between APBSCT and ABMT did not result in significantly different outcomes in terms of DFS, OS and relapse incidence.
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- 2015
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21. Impact of the revised International Prognostic Scoring System, cytogenetics and monosomal karyotype on outcome after allogeneic stem cell transplantation for myelodysplastic syndromes and secondary acute myeloid leukemia evolving from myelodysplastic syndromes: a retrospective multicenter study of the European Society of Blood and Marrow Transplantation.
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Koenecke C, Göhring G, de Wreede LC, van Biezen A, Scheid C, Volin L, Maertens J, Finke J, Schaap N, Robin M, Passweg J, Cornelissen J, Beelen D, Heuser M, de Witte T, and Kröger N
- Subjects
- Adolescent, Adult, Aged, Antineoplastic Agents therapeutic use, Bone Marrow drug effects, Bone Marrow pathology, Cytogenetic Analysis, Europe, Female, Humans, Karyotype, Leukemia, Myeloid, Acute etiology, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Myelodysplastic Syndromes complications, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes mortality, Prognosis, Proportional Hazards Models, Recurrence, Retrospective Studies, Risk, Societies, Medical, Survival Analysis, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute therapy, Monosomy, Myelodysplastic Syndromes therapy, Research Design
- Abstract
The aim of this study was to determine the impact of the revised 5-group International Prognostic Scoring System cytogenetic classification on outcome after allogeneic stem cell transplantation in patients with myelodysplastic syndromes or secondary acute myeloid leukemia who were reported to the European Society for Blood and Marrow Transplantation database. A total of 903 patients had sufficient cytogenetic information available at stem cell transplantation to be classified according to the 5-group classification. Poor and very poor risk according to this classification was an independent predictor of shorter relapse-free survival (hazard ratio 1.40 and 2.14), overall survival (hazard ratio 1.38 and 2.14), and significantly higher cumulative incidence of relapse (hazard ratio 1.64 and 2.76), compared to patients with very good, good or intermediate risk. When comparing the predictive performance of a series of Cox models both for relapse-free survival and for overall survival, a model with simplified 5-group cytogenetics (merging very good, good and intermediate cytogenetics) performed best. Furthermore, monosomal karyotype is an additional negative predictor for outcome within patients of the poor, but not the very poor risk group of the 5-group classification. The revised International Prognostic Scoring System cytogenetic classification allows patients with myelodysplastic syndromes to be separated into three groups with clearly different outcomes after stem cell transplantation. Poor and very poor risk cytogenetics were strong predictors of poor patient outcome. The new cytogenetic classification added value to prediction of patient outcome compared to prediction models using only traditional risk factors or the 3-group International Prognostic Scoring System cytogenetic classification., (Copyright© Ferrata Storti Foundation.)
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- 2015
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22. 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.
- Published
- 2015
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23. 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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24. Clofarabine in combination with a standard remission induction regimen (cytosine arabinoside and idarubicin) in patients with previously untreated intermediate and bad-risk acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS): phase I results of an ongoing phase I/II study of the leukemia groups of EORTC and GIMEMA (EORTC GIMEMA 06061/AML-14A trial).
- Author
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Willemze R, Suciu S, Muus P, Halkes CJ, Meloni G, Meert L, Karrasch M, Rapion J, Vignetti M, Amadori S, de Witte T, and Marie JP
- Subjects
- Adenine Nucleotides administration & dosage, Adenine Nucleotides adverse effects, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Arabinonucleosides administration & dosage, Arabinonucleosides adverse effects, Clofarabine, Consolidation Chemotherapy, Cytarabine administration & dosage, Cytarabine adverse effects, Fatigue chemically induced, Female, Gastrointestinal Diseases chemically induced, Humans, Hydroxyurea therapeutic use, Hyperbilirubinemia chemically induced, Idarubicin administration & dosage, Idarubicin adverse effects, Male, Middle Aged, Remission Induction, Risk, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy
- Abstract
This study aims to determine the maximum tolerated dose (MTD) of clofarabine combined with the EORTC-GIMEMA 3 + 10 induction regimen (idarubicin + cytosine arabinoside) in adults with untreated acute myelogenous leukemia or high-risk myelodysplastic syndrome. In this phase I trial, 25 patients (median age 56 years) received 5 days of clofarabine as 1-h infusion (arm A) or push injection (arm B) at the dose level of 5 × 10 or 5 × 15 mg/m(2)/day in an algorithmic dose escalation 3 + 3 design. A consolidation course (intermediate dose cytosine arabinoside, idarubicin) was planned for patients in complete remission (CR). Primary endpoint was safety and tolerance as measured by dose limiting toxicity (DLT); secondary endpoints were response rate, other grade III/IV toxicities, and hematological recovery after induction and consolidation. Five DLTs were observed (in arm A: one DLT at 10 mg/m(2)/day, three at 15 mg/m(2)/day; in arm B: one DLT at 15 mg/m(2)/day). Three patients receiving 15 mg/m(2)/day were withdrawn due to adverse events not classified as DLT. Prolonged hypoplasia was observed in five patients. CR + complete remission with incomplete recovery were achieved in 21 patients (11/12 (92 %) receiving clofarabine 10 mg/m(2)/day; 10/13 (77 %) receiving clofarabine 15 mg/m(2)/day). Clofarabine, 5 × 10 mg/m(2)/day, resulted in one DLT and no early treatment withdrawals. MTD of clofarabine combined with cytosine arabinoside and idarubicin is 5 × 10 mg/m(2)/day.
- Published
- 2014
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25. Allogeneic hematopoietic stem cell transplantation in patients with polycythemia vera or essential thrombocythemia transformed to myelofibrosis or acute myeloid leukemia: a report from the MPN Subcommittee of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation.
- Author
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Lussana F, Rambaldi A, Finazzi MC, van Biezen A, Scholten M, Oldani E, Carobbio A, Iacobelli S, Finke J, Nagler A, Volin L, Lamy T, Arnold R, Mohty M, Michallet M, de Witte T, Olavarria E, and Kröger N
- Subjects
- Adult, Aged, Cause of Death, Female, Follow-Up Studies, Graft vs Host Disease etiology, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Primary Myelofibrosis diagnosis, Primary Myelofibrosis mortality, Recurrence, Tissue Donors, Transplantation, Homologous, Treatment Outcome, Young Adult, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Myeloid, Acute etiology, Leukemia, Myeloid, Acute therapy, Polycythemia Vera complications, Primary Myelofibrosis etiology, Primary Myelofibrosis therapy, Thrombocythemia, Essential complications
- Abstract
The clinical course of polycythemia vera and essential thrombocythemia is potentially associated with long-term severe complications, such as evolution to myelofibrosis or acute myeloid leukemia. Allogeneic stem cell transplantation is currently the only potentially curative treatment for advanced polycythemia vera or essential thrombocythemia. We analyzed 250 consecutive patients with an initial diagnosis of polycythemia vera (n=120) or essential thrombocythemia (n=130), who underwent transplantation due to progression to myelofibrosis (n=193) or acute myeloid leukemia (n=57) and who were reported to the European Group for Blood and Marrow Transplantation registry between 1994 and 2010. Their median age was 56 years (range, 22-75) and in 52% of cases the interval between diagnosis and transplantation was 10 years or more. With a median follow-up from transplantation of 13 months, the 3-year overall survival rate and relapse incidence were 55% and 32%, respectively. In univariate analysis, the main parameters that negatively affected post-transplantation outcomes were older age (>55 years), a diagnosis at transplant of acute myeloid leukemia and the use of an unrelated donor. The overall 3-year cumulative incidence of non-relapse mortality was 28%, but was significantly higher in older patients than in younger ones (>55 years, 35% versus 20%, P=0.032), in those transplanted from an unrelated donor rather than a related donor (34% versus 18%, P=0.034) and in patients with a diagnosis of acute myeloid leukemia compared to myelofibrosis (29% versus 27%, P=0.045). This large retrospective study confirms that transplantation is potentially curative for patients with end-stage polycythemia vera/essential thrombocythemia progressing to myelofibrosis or acute myeloid leukemia. Relapse and non-relapse mortality remain unsolved problems for which innovative treatment approaches need to be assessed.
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- 2014
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26. Allogeneic stem cell transplantation for myelofibrosis with leukemic transformation: a study from the Myeloproliferative Neoplasm Subcommittee of the CMWP of the European Group for Blood and Marrow Transplantation.
- Author
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Alchalby H, Zabelina T, Stübig T, van Biezen A, Bornhäuser M, Di Bartolomeo P, Beelen D, Cahn JY, Dreger P, Schroyens W, de Witte T, Olavarria E, and Kröger N
- Subjects
- Adult, Aged, Cohort Studies, Europe, Female, Humans, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Neoplasm Recurrence, Local, Remission Induction, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Myeloid, Acute therapy, Myeloproliferative Disorders complications, Primary Myelofibrosis therapy, Transplantation Conditioning adverse effects, Transplantation, Autologous adverse effects
- Abstract
Transformed acute myeloid leukemia in myelofibrosis results in a median survival of less than 5 months. We identified 46 of 1048 myelofibrosis patients in the European Group for Blood and Marrow Transplantation registry who received allogeneic stem cell transplantation for acute leukemia evolving from myelofibrosis. The cumulative incidence of treatment-related mortality at 1 year was 28% (95% confidence interval, 14 to 42) and of relapse at 3 years was 47% (95% confidence interval, 31 to 63). The 3-year progression-free (PFS) and overall survival (OS) rates were 26% and 33%, respectively. The only significant factor for survival was complete remission versus no complete remission before transplantation (69% versus 22%, P = .008); however, complete remission was achieved only in 8 patients. Allogeneic stem cell transplantation can cure myelofibrosis patients transformed to leukemia., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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27. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: results of the EORTC-GIMEMA AML-12 trial.
- Author
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Willemze R, Suciu S, Meloni G, Labar B, Marie JP, Halkes CJ, Muus P, Mistrik M, Amadori S, Specchia G, Fabbiano F, Nobile F, Sborgia M, Camera A, Selleslag DL, Lefrère F Sr, Magro D, Sica S, Cantore N, Beksac M, Berneman Z, Thomas X, Melillo L, Guimaraes JE, Leoni P, Luppi M, Mitra ME, Bron D, Fillet G, Marijt EW, Venditti A, Hagemeijer A, Mancini M, Jansen J, Cilloni D, Meert L, Fazi P, Vignetti M, Trisolini SM, Mandelli F, and de Witte T
- Subjects
- Adolescent, Adult, Consolidation Chemotherapy, Daunorubicin administration & dosage, Drug Administration Schedule, Etoposide administration & dosage, Europe, Female, Humans, Infusions, Intravenous, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Male, Middle Aged, Mutation, Risk Assessment, Risk Factors, Treatment Outcome, Antimetabolites, Antineoplastic administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cytarabine administration & dosage, Induction Chemotherapy methods, Leukemia, Myeloid, Acute drug therapy
- Abstract
Purpose: Cytarabine plays a pivotal role in the treatment of patients with acute myeloid leukemia (AML). Most centers use 7 to 10 days of cytarabine at a daily dose of 100 to 200 mg/m(2) for remission induction. Consensus has not been reached on the benefit of higher dosages of cytarabine., Patients and Methods: The European Organisation for Research and Treatment of Cancer (EORTC) and Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) Leukemia Groups conducted a randomized trial (AML-12; Combination Chemotherapy, Stem Cell Transplant and Interleukin-2 in Treating Patients With Acute Myeloid Leukemia) in 1,942 newly diagnosed patients with AML, age 15 to 60 years, comparing remission induction treatment containing daunorubicin, etoposide, and either standard-dose (SD) cytarabine (100 mg/m(2) per day by continuous infusion for 10 days) or high-dose (HD) cytarabine (3,000 mg/m(2) every 12 hours by 3-hour infusion on days 1, 3, 5, and 7). Patients in complete remission (CR) received a single consolidation cycle containing daunorubicin and intermediate-dose cytarabine (500 mg/m(2) every 12 hours for 6 days). Subsequently, a stem-cell transplantation was planned. The primary end point was survival., Results: At a median follow-up of 6 years, overall survival was 38.7% for patients randomly assigned to SD cytarabine and 42.5% for those randomly assigned to HD cytarabine (log-rank test P = .06; multivariable analysis P = .009). For patients younger than age 46 years, survival was 43.3% and 51.9%, respectively (P = .009; multivariable analysis P = .003), and for patients age 46 to 60 years, survival was 33.9% and 32.9%, respectively (P = .91). CR rates were 72.0% and 78.7%, respectively (P < .001) and were 75.6% and 82.4% for patients younger than age 46 years (P = .01) and 68.3% and 74.8% for patients age 46 years and older (P = .03). Patients of all ages with very-bad-risk cytogenetic abnormalities and/or FLT3-ITD (internal tandem duplication) mutation, or with secondary AML benefitted from HD cytarabine., Conclusion: HD cytarabine produces higher remission and survival rates than SD cytarabine, especially in patients younger than age 46 years.
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- 2014
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28. Comparison of conditioning regimens of various intensities for allogeneic hematopoietic SCT using HLA-identical sibling donors in AML and MDS with <10% BM blasts: a report from EBMT.
- Author
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Martino R, de Wreede L, Fiocco M, van Biezen A, von dem Borne PA, Hamladji RM, Volin L, Bornhäuser M, Robin M, Rocha V, de Witte T, Kröger N, and Mohty M
- Subjects
- Adolescent, Adult, Aged, Allografts, Anemia, Refractory, with Excess of Blasts mortality, Disease-Free Survival, Female, Follow-Up Studies, Humans, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Risk Factors, Survival Rate, Anemia, Refractory, with Excess of Blasts therapy, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute therapy, Siblings, Tissue Donors, Transplantation Conditioning methods
- Abstract
In this multicenter retrospective study, the long-term outcomes of 878 adults with AML and refractory anemia with excess blasts (RAEB) with BM blasts <10% who underwent transplantation with an HLA-identical sibling donor between 1998 and 2004 were analyzed according to four regimens of conditioning intensity: reduced-intensity conditioning (RIC) (either intermediate RIC (IntermRIC) or non-myeloablative (NMA) RIC), and myeloablative conditioning (MC) in 718 patients (either conventional MC or hyperintense MC. In multivariate cox analysis, patients undergoing NMA transplantation had lower non-relapse mortality risk in the first 100 days after transplantation (P<0.01), but a higher risk beyond day +100 (P=0.02), as well as higher relapse incidence in the first 12 months (P<0.01), but the risk was similar in all groups beyond 12 months. The probabilities of PFS and OS up to 7 years were significantly lower only in the NMA subgroup (P0.01 for both). The 7-year OS was 53%, 29%, 56% and 51%, respectively. Our data suggest that prospective studies comparing RIC regimens (especially IntermRIC) with MC are appropriate in patients with AML and RAEB who are in a non-advanced disease status.
- Published
- 2013
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29. Monosomal karyotype predicts poor survival after allogeneic stem cell transplantation in chromosome 7 abnormal myelodysplastic syndrome and secondary acute myeloid leukemia.
- Author
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van Gelder M, de Wreede LC, Schetelig J, van Biezen A, Volin L, Maertens J, Robin M, Petersen E, de Witte T, and Kröger N
- Subjects
- Adolescent, Adult, Female, Humans, Karyotyping, Leukemia, Myeloid, Acute physiopathology, Male, Middle Aged, Multivariate Analysis, Myelodysplastic Syndromes physiopathology, Chromosomes, Human, Pair 7, Leukemia, Myeloid, Acute genetics, Monosomy, Myelodysplastic Syndromes genetics, Stem Cell Transplantation, Survival Analysis
- Abstract
Treatment algorithms for poor cytogenetic-risk myelodysplastic syndrome (MDS), defined by chromosome 7 abnormalities or complex karyotype (CK), include allogeneic stem cell transplantation (alloSCT). We studied outcome of alloSCT in chromosome 7 abnormal MDS patients as this data are scarce in literature. We specifically focused on the impact of the extra presence of CK and monosomal karyotype (MK). The European Group for Blood and Marrow Transplantation database contained data on 277 adult MDS patients with a chromosome 7 abnormality treated with alloSCT. Median age at alloSCT was 45 years. Median follow-up of patients alive was 5 years. Five-year progression-free survival (PFS) and overall survival (OS) were 22% and 28%, respectively. In multivariate analysis, statistically significant predictors for worse PFS were higher MDS stages treated, but not in complete remission (CR) (hazards ratio (HR) 1.7), and the presence of CK (HR 1.5) or MK (HR 1.8). Negative predictive factors for OS were higher MDS stages treated, but not in CR (HR 1.8), and the presence of CK (HR 1.6) or MK (HR 1.7). By means of the cross-validated log partial likelihood, MK showed to have a better predictive value than CK. The results are relevant when considering alloSCT for higher-stage MDS patients having MK including a chromosome 7 abnormality.
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- 2013
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30. Parameters detected by geriatric and quality of life assessment in 195 older patients with myelodysplastic syndromes and acute myeloid leukemia are highly predictive for outcome.
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Deschler B, Ihorst G, Platzbecker U, Germing U, März E, de Figuerido M, Fritzsche K, Haas P, Salih HR, Giagounidis A, Selleslag D, Labar B, de Witte T, Wijermans P, and Lübbert M
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Outcome Assessment, Health Care, Prognosis, Geriatric Assessment, Leukemia, Myeloid, Acute epidemiology, Myelodysplastic Syndromes epidemiology, Quality of Life
- Abstract
Myelodysplastic syndromes and acute myeloid leukemia exemplify the complexity of treatment allocation in older patients as options range from best supportive care, non-intensive treatment (e.g. hypomethylating agents) to intensive chemotherapy/hematopoietic cell transplantation. Novel metrics for non-disease variables are urgently needed to help define the best treatment for each older patient. We investigated the feasibility and prognostic value of geriatric/quality of life assessments aside from established disease-specific variables in 195 patients aged 60 years or over with myelodysplastic syndromes/acute myeloid leukemia. These patients were grouped according to treatment intensity and assessed. Assessment consisted of eight instruments evaluating activities of daily living, depression, mental functioning, mobility, comorbidities, Karnofsky Index and quality of life. Patients with a median age of 71 years (range 60-87 years) with myelodysplastic syndromes (n=63) or acute myeloid leukemia (n=132) were treated either with best supportive care (n=47), hypomethylating agents (n=73) or intensive chemotherapy/hematopoietic cell transplantation (n=75). After selection of variables, pathological activities of daily living and quality of life/fatigue remained highly predictive for overall survival in the entire patient group beyond disease-related risk factors adverse cytogenetics and blast count of 20% or over. In 107 patients treated non-intensively activities of daily living of less than 100 (hazard ratio, HR 2.94), Karnofsky Index below 80 (HR 2.34) and quality of life/'fatigue' of 50 or over (HR 1.77) were significant prognosticators. Summation of adverse features revealed a high risk of death (HR 9.36). In-depth evaluation of older patients prior to individual treatment allocation is feasible and provides additional information to standard assessment. Patients aged 60 years or over with newly diagnosed myelodysplastic syndromes/acute myeloid leukemia and impairments in activities of daily living, Karnofsky Index below 80%, quality of life/'fatigue' of 50 or over, are likely to have poor outcomes.
- Published
- 2013
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31. Intensive consolidation therapy compared with standard consolidation and maintenance therapy for adults with acute myeloid leukaemia aged between 46 and 60 years: final results of the randomized phase III study (AML 8B) of the European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups.
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Hengeveld M, Suciu S, Karrasch M, Specchia G, Marie JP, Muus P, Petti MC, Rotoli B, Amadori S, Fioritoni G, Leoni P, Morra E, Thaler J, Resegotti L, Fazi P, Vignetti M, Mandelli F, Zittoun R, and de Witte T
- Subjects
- Adolescent, Adult, Age Factors, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Consolidation Chemotherapy standards, Europe, Female, Hematology methods, Hematology organization & administration, Humans, Induction Chemotherapy methods, International Cooperation, Italy, Maintenance Chemotherapy standards, Male, Medical Oncology methods, Medical Oncology organization & administration, Middle Aged, Societies, Medical organization & administration, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Consolidation Chemotherapy methods, Leukemia, Myeloid, Acute drug therapy, Maintenance Chemotherapy methods
- Abstract
The most effective post-remission treatment to maintain complete remission (CR) in adults aged between 46 and 60 years with acute myeloid leukaemia (AML) is uncertain. Previously untreated patients with AML in CR after induction chemotherapy with daunorubicin and cytarabine were randomized between two intensive courses of consolidation therapy containing high-dose cytarabine, combined with amsacrine or daunorubicin and a standard consolidation and maintenance therapy containing standard dose cytarabine and daunorubicin. One hundred fifty-eight CR patients were assigned to the intensive group and 157 patients to the standard group. After a median follow-up of 7.5 years, the 4-year survival rate was 32 % in the intensive group versus 34 % in the standard group (P = 0.29). In the intensive group, the 4-year relapse incidence was lower than in the standard group: 55 and 75 %, respectively (P = 0.0003), whereas treatment-related mortality incidence was higher: 22 versus 3 % (P < 0.0001). Two intensive consolidation courses containing high-dose cytarabine as post-remission treatment in patients with AML aged between 46 and 60 years old did not translate in better long-term outcome despite a 20 % lower relapse incidence. Better supportive care and prevention of treatment-related complications may improve the overall survival after intensified post-remission therapy in this age group.
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- 2012
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32. Unrelated cord blood transplantation in adults with myelodysplasia or secondary acute myeloblastic leukemia: a survey on behalf of Eurocord and CLWP of EBMT.
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Robin M, Sanz GF, Ionescu I, Rio B, Sirvent A, Renaud M, Carreras E, Milpied N, Mohty M, Beguin Y, Bordigoni P, de Witte T, Picardi A, Purtill D, Gluckman E, Kroger N, and Rocha V
- Subjects
- Adolescent, Adult, Aged, Disease-Free Survival, Female, Graft vs Host Disease etiology, Humans, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Myelodysplastic Syndromes mortality, Recurrence, Cord Blood Stem Cell Transplantation, Leukemia, Myeloid, Acute therapy, Myelodysplastic Syndromes therapy, Neoplasms, Second Primary therapy
- Abstract
The aim of our study was to evaluate, through the Eurocord and European Group for Blood and Marrow Transplantation (EBMT) registries, outcomes and risk factors for outcomes in adult patients who underwent single or double unrelated cord blood transplantation (UCBT) for myelodysplastic syndrome (MDS) or secondary acute myeloblastic leukemia (sAML). A total of 180 adults with MDS (n=39) or sAML (n=69) were analyzed. Risk factors for outcomes were analyzed using the Fine and Gray method and the Cox model. Median age was 43 (18-72) years. In all, 77 patients (71%) received a single UCBT. Myeloablative conditioning regimen (MAC) was given to 57 (53%) patients. Median numbers of nucleated and CD34(+) cells at freezing were 3.6 × 10(7) and 1.1 × 10(5) kg. At 60 days, cumulative incidence of neutrophil recovery was 78±4% and was independently associated with the number of CD34(+) cells per kg (>1.1 × 10(5); P=0.005) and advanced disease status (blasts <5% at time of UCBT, P=0.016). A 2-year non-relapse mortality (NRM) was significantly higher after MAC (62 vs 34%; P=0.009). A 2-year disease-free-survival (DFS) and overall survival (OS) were 30 and 34%, respectively. In multivariate analysis, patients with high-risk disease (blasts >5% and International Prognostic scoring system (IPSS) intermediate-2 or high in MDS) had significant poorer DFS (hazard ratio (HR): 1.76; P=0.047). In spite of high NRM, these data indicate that UCBT is an acceptable alternative option to treat adults with high-risk MDS or sAML, without a suitable human leukocyte antigen (HLA)-matched donor.
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- 2011
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33. Higher incidence of relapse in patients with acute myelocytic leukemia infused with higher doses of CD34+ cells from leukapheresis products autografted during the first remission.
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Gorin NC, Labopin M, Reiffers J, Milpied N, Blaise D, Witz F, de Witte T, Meloni G, Attal M, Bernal T, and Rocha V
- Subjects
- Adolescent, Adult, Aged, Disease-Free Survival, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy, Middle Aged, Multivariate Analysis, Prognosis, Recurrence, Remission Induction, Transplantation, Autologous, Young Adult, Antigens, CD34 adverse effects, Leukapheresis, Leukemia, Myeloid, Acute prevention & control, Leukemia, Myeloid, Acute therapy
- Abstract
The stem cell source for autologous transplantation has shifted from bone marrow to peripheral blood (PB). We previously showed that relapse incidence in patients with acute myelocytic leukemia autografted in first remission (CR1) was greater with PB than bone marrow, and a poorer outcome was associated with a shorter CR1 to PB transplantation interval (≤ 80 days). Leukemic and normal progenitors are CD34(+) and can be concomitantly mobilized; we assessed whether an association exists between the infused CD34(+) cell dose and outcome. The infused CD34(+) cell doses were available for 772 patients autografted more than 80 days after CR1 and were categorized by percentiles. We selected the highest quintile (> 7.16 × 10(6)/kg) as the cutoff point. By multivariate analysis, relapse was more probable in patients who received the highest dose (hazard ratio = 1.48; 95% confidence interval, 1.12-1.95; P = .005), and leukemia-free survival was worse (hazard ratio = 0.72; 95% confidence interval, 0.55-0.93; P = .01). In conclusion, in patients autografted in first remission, relapse was higher and leukemia-free survival lower for those who received the highest CD34(+) PB doses.
- Published
- 2010
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34. 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.
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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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35. Randomized trial of two schedules of low-dose gemtuzumab ozogamicin as induction monotherapy for newly diagnosed acute myeloid leukaemia in older patients not considered candidates for intensive chemotherapy. A phase II study of the EORTC and GIMEMA leukaemia groups (AML-19).
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Amadori S, Suciu S, Selleslag D, Stasi R, Alimena G, Baila L, Rizzoli V, Borlenghi E, Gaidano G, Magro D, Torelli G, Muus P, Venditti A, Cacciola E, Lauria F, Vignetti M, and de Witte T
- Subjects
- Aged, Aminoglycosides adverse effects, Aminoglycosides therapeutic use, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized, Antineoplastic Agents adverse effects, Antineoplastic Agents therapeutic use, Disease Progression, Drug Administration Schedule, Feasibility Studies, Female, Gemtuzumab, Humans, Male, Middle Aged, Treatment Outcome, Aminoglycosides administration & dosage, Antibodies, Monoclonal administration & dosage, Antineoplastic Agents administration & dosage, Leukemia, Myeloid, Acute drug therapy
- Abstract
This study compared two schedules of low-dose gemtuzumab ozogamicin (GO) as induction monotherapy for untreated acute myeloid leukaemia in older patients unfit for intensive chemotherapy, to identify the more promising regimen for further study. Patients were randomized to receive either best supportive care or a course of GO according to one of two schedules: 3 mg/m(2) on days 1, 3 and 5 (arm A), or GO 6 mg/m(2) on day 1 and 3 mg/m(2) on day 8 (arm B). Primary endpoint was the rate of disease non-progression (DnP), defined as the proportion of patients either achieving a response or maintaining a stable disease following GO induction in each arm. Fifty-six patients were randomized in the two GO arms (A, n = 29; B, n = 27). The rate of DnP was 38% [90% confidence interval (CI), 23-55] in arm A, and 63% (90% CI, 45-78) in arm B. Peripheral cytopenias were the most common adverse events for both regimens. The all-cause early mortality rate was 14% in arm A and 11% in arm B. The day 1 + 8 schedule, which was associated with the highest rate of DnP, met the statistical criteria to be selected as the preferred regimen for phase III comparison with best supportive care.
- Published
- 2010
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36. The NDE1 gene is disrupted by the inv(16) in 90% of cases with CBFB-MYH11-positive acute myeloid leukemia.
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Van der Reijden BA, Massop M, Simons A, de Witte T, Breuning M, and Jansen JH
- Subjects
- Humans, Leukemia, Myeloid, Acute pathology, RNA, Messenger genetics, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Chromosome Inversion, Chromosomes, Human, Pair 16 genetics, Leukemia, Myeloid, Acute genetics, Microtubule-Associated Proteins genetics, Oncogene Proteins, Fusion genetics
- Published
- 2010
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37. 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.
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- 2009
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38. Exclusion of ABCB8 and ABCB10 as cancer candidate genes in acute myeloid leukemia.
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Tang L, Bergevoet SM, Franssen LE, de Witte T, Jansen JH, Raymakers RA, and van der Reijden BA
- Subjects
- ATP Binding Cassette Transporter 1, Case-Control Studies, Cohort Studies, Humans, Leukemia, Myeloid, Acute pathology, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, ATP-Binding Cassette Transporters genetics, Leukemia, Myeloid, Acute genetics, Mutation genetics
- Published
- 2009
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39. Risk factors for therapy-related myelodysplastic syndrome and acute myeloid leukemia treated with allogeneic stem cell transplantation.
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Kröger N, Brand R, van Biezen A, Zander A, Dierlamm J, Niederwieser D, Devergie A, Ruutu T, Cornish J, Ljungman P, Gratwohl A, Cordonnier C, Beelen D, Deconinck E, Symeonidis A, and de Witte T
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Humans, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Middle Aged, Myelodysplastic Syndromes mortality, Myelodysplastic Syndromes therapy, Neoplasms, Second Primary epidemiology, Neoplasms, Second Primary mortality, Prognosis, Retrospective Studies, Risk Factors, Transplantation, Homologous, Treatment Outcome, Young Adult, Hematopoietic Stem Cell Transplantation mortality, Leukemia, Myeloid, Acute chemically induced, Myelodysplastic Syndromes chemically induced, Neoplasms, Second Primary therapy
- Abstract
Background: After successful treatment of malignant diseases, therapy-related myelodysplastic syndrome and acute myeloid leukemia have emerged as significant problems., Design and Methods: The aim of this study was to investigate outcome and risk factors in patients with therapy-related myelodysplastic syndrome or acute myeloid leukemia who underwent allogeneic stem cell transplantation. Between 1981 and 2006, 461 patients with therapy-related myelodysplastic syndrome or acute myeloid, a median age of 40 years and a history of solid tumor (n=163), malignant lymphoma (n=133), or other hematologic diseases (n=57) underwent stem cell transplantation and their data were reported to the European Group for Blood and Marrow Transplantation., Results: The cumulative incidence of non-relapse mortality and relapse at 3 years was 37% and 31%, respectively. In a multivariate analysis significant factors for relapse were not being in complete remission at the time of transplantation (p=0.002), abnormal cytogenetics (p=0.005), higher patients' age (p=0.03) and therapy-related myelodysplastic syndrome (p=0.04), while higher non-relapse mortality was influenced by higher patients' age. Furthermore, there was a marked reduction in non-relapse mortality per calendar year during the study period (p<0.001). The 3-year relapse-free and overall survival rates were 33% and 35%, respectively. In a multivariate analysis significant higher overall survival rates were seen per calendar year (p<0.001), for younger age (<40 years) and normal cytogenetics (p=0.05). Using age (<40 years), abnormal cytogenetics and not being in complete remission at the time of transplantation as risk factors, three different risk groups with overall survival rates of 62%, 33% and 24% could be easily distinguished., Conclusions: Allogeneic stem cell transplantation can cure patients with therapy-related myelodysplastic syndrome and acute myeloid leukemia and has markedly improved over time. Non-complete remission, abnormal cytogenetics and higher patients' age are the most significant factors predicting survival.
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- 2009
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40. DNA hypermethylation and epigenetic silencing of the tumor suppressor gene, SLC5A8, in acute myeloid leukemia with the MLL partial tandem duplication.
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Whitman SP, Hackanson B, Liyanarachchi S, Liu S, Rush LJ, Maharry K, Margeson D, Davuluri R, Wen J, Witte T, Yu L, Liu C, Bloomfield CD, Marcucci G, Plass C, and Caligiuri MA
- Subjects
- Adult, Chromatin Assembly and Disassembly, DNA Methylation, DNA, Neoplasm genetics, DNA, Neoplasm metabolism, Epigenesis, Genetic, Gene Expression, Gene Silencing, Histone Deacetylase Inhibitors, Histone Deacetylases genetics, Histone Deacetylases metabolism, Histone-Lysine N-Methyltransferase, Histones metabolism, Humans, Leukemia, Myeloid, Acute metabolism, Monocarboxylic Acid Transporters, Neoplasm Proteins metabolism, Promoter Regions, Genetic, Valproic Acid pharmacology, Cation Transport Proteins genetics, Genes, Tumor Suppressor, Leukemia, Myeloid, Acute genetics, Myeloid-Lymphoid Leukemia Protein genetics
- Abstract
Posttranslationally modified histones and DNA hypermethylation frequently interplay to deregulate gene expression in cancer. We report that acute myeloid leukemia (AML) with an aberrant histone methyltransferase, the mixed lineage leukemia partial tandem duplication (MLL-PTD), exhibits increased global DNA methylation versus AML with MLL-wildtype (MLL-WT; P = .02). Among the differentially methylated genes, the SLC5A8 tumor suppressor gene (TSG) was more frequently hypermethylated (P = .003). In MLL-PTD(+) cell lines having SLC5A8 promoter hypermethylation, incubation with decitabine activated SLC5A8 expression. Ectopic SLC5A8 expression enhanced histones H3 and H4 acetylation in response to the histone deacetylase inhibitor, valproate, consistent with the encoded protein-SMCT1-short-chain fatty acid transport function. In addition, enhanced cell death was observed in SMCT1-expressing MLL-PTD(+) AML cells treated with valproate. Within the majority of MLL-PTD AML is a mechanism in which DNA hypermethylation silences a TSG that, together with MLL-PTD, can contribute further to aberrant chromatin remodeling and altered gene expression.
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- 2008
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41. Treatment decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches.
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Deschler B, de Witte T, Mertelsmann R, and Lübbert M
- Subjects
- Age Factors, Aged, Humans, Leukemia, Myeloid, Acute epidemiology, Myelodysplastic Syndromes epidemiology, Risk Factors, Treatment Outcome, Decision Making, Leukemia, Myeloid, Acute therapy, Myelodysplastic Syndromes therapy, Problem Solving
- Abstract
Background and Objectives: High-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are mainly diseases of patients over the age of 60 years. In these patients, intensive chemotherapy and/or allogeneic blood stem cell transplantation are the only curative treatment approaches, while non-curative options include low-dose chemotherapy or best supportive care alone. The basis for treatment decision-making in this clinically and biologically heterogeneous group is not well defined., Design and Methods: In order to investigate treatment stratification patterns and outcomes in this population, we performed a systematic literature search in MedLine for relevant clinical reports published between 1989 and 2006. Only large population-based investigations and publications of clinical trials with more than 40 patients were analyzed., Results: In 36 AML studies involving a total of 12,370 patients (median age 70 years) median overall survival approached 30 weeks for intensively treated patients. In patients receiving best supportive care alone, or best supportive care plus non-intensive treatment, median overall survival was 7.5 and 12 weeks, respectively. The complete remission rate after induction was 44%, and in those patients who achieved complete remission age no longer influenced prognosis. In 18 large studies approximately 50% of AML patients received induction therapy, 30% non-intensive chemotherapy and 20% supportive care only., Interpretation and Conclusions: Due to the scarcity of randomized AML/MDS trials in which older patients are assigned to either induction or less intense therapy, predictors to identify older patients most likely to benefit from intensive therapy and novel tools to optimize (or even standardize) recommendations are needed. We propose that in this patient population in the future, geriatric assessment instruments and comorbidity scoring are implemented in treatment decision-making.
- Published
- 2006
42. Autologous stem cell transplantation for therapy-related acute myeloid leukemia and myelodysplastic syndrome.
- Author
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Kröger N, Brand R, van Biezen A, Cahn JY, Slavin S, Blaise D, Sierra J, Zander A, Niederwieser D, and de Witte T
- Subjects
- Adolescent, Adult, Age Factors, Aged, Child, Child, Preschool, Disease-Free Survival, Female, Graft Survival, Humans, Incidence, Leukemia, Myeloid, Acute etiology, Male, Middle Aged, Myelodysplastic Syndromes etiology, Neoplasms, Second Primary etiology, Recurrence, Remission Induction, Survival Rate, Transplantation, Autologous, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Myelodysplastic Syndromes mortality, Myelodysplastic Syndromes therapy, Neoplasms, Second Primary mortality, Neoplasms, Second Primary therapy, Stem Cell Transplantation mortality
- Abstract
We report the results of 65 patients with treatment-related myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) who were transplanted from an autograft and reported to the EBMT. The median age was 39 years (range, 3-69), and stem cell source was bone marrow (n = 31), or peripheral blood progenitor cells (n = 30), or the combination of both (n = 4). The primary disease was solid tumors (n = 37), Hodgkin's disease (n = 13), non-Hodgkin's lymphoma (n = 10), acute lymphoblastic leukemia (n = 2) or myeloproliferative syndromes (n = 3). The types of MDS were as follows: RAEB (n = 1; 2%), RAEB-t (n = 3; 5%), or AML (n = 56; 87%). The median time between diagnosis and transplantation was 5 months (range, 3-86). The Kaplan-Meier estimates of the probability of 3-year overall and disease-free survival were 35% (95% CI: 21-49%) and 32% (95% CI: 18-45%), respectively. The median leukocyte engraftment was faster after transplantation with peripheral blood stem cells than with bone marrow: 12 (range, 9-26) vs 29 (range, 11-67) days (P<0.001). The cumulative incidence of relapse was 58% (95% CI: 44-72%) and of treatment-related mortality 12% (95% CI: 6-38%). Lower relapse rate was seen in patients transplanted in first complete remission (CR1 vs non-CR1: 3 years: 48 vs 89%; P = 0.05). Furthermore, age beyond 40 years resulted in a higher treatment-related mortality (47 vs 7%; P = 0.01). In a multivariate analysis, transplantation in CR1 age as well as their interaction influenced overall survival significantly. Autologous transplantation may cure a substantial number of patients with treatment-related MDS/AML, especially if they are in CR1 and of younger age.
- Published
- 2006
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43. Systematic screening at diagnosis of -5/del(5)(q31), -7, or chromosome 8 aneuploidy by interphase fluorescence in situ hybridization in 110 acute myelocytic leukemia and high-risk myelodysplastic syndrome patients: concordances and discrepancies with conventional cytogenetics.
- Author
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Beyer V, Castagné C, Mühlematter D, Parlier V, Gmür J, Hess U, Kovacsovics T, Meyer-Monard S, Tichelli A, Tobler A, Jacky E, Schanz U, Bargetzi M, Hagemeijer A, de Witte T, van Melle G, and Jotterand M
- Subjects
- Adolescent, Adult, Aged, Cytogenetic Analysis, Female, Humans, In Situ Hybridization, Fluorescence, Interphase, Leukemia, Myeloid, Acute diagnosis, Male, Middle Aged, Myelodysplastic Syndromes diagnosis, Trisomy, Aneuploidy, Chromosome Deletion, Chromosomes, Human, Pair 5 genetics, Chromosomes, Human, Pair 7 genetics, Chromosomes, Human, Pair 8 genetics, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes genetics
- Abstract
To assess the contribution of interphase fluorescence in situ hybridization (I-FISH) toward the detection of recurring unbalanced chromosomal anomalies at diagnosis, a systematic screening of -5/del(5)(q31), -7, and chromosome 8 aneuploidy was performed on 110 patients with acute myelocytic leukemia or high-risk myelodysplastic syndrome. We searched for monosomy 5/del(5q) by one-color I-FISH with a probe specific for the 5q31 region and for -7/8 by dual-color I-FISH with centromeric probes for chromosomes 7 and 8. Discrepancies between conventional cytogenetics (CC) and I-FISH were observed in 8 of the 110 patients (7.3%). For -5/del(5)(q31), a discordance was observed in two patients with complex abnormalities involving chromosome 5. Whereas no discordance was observed for -7, I-FISH detected a trisomy 7 unnoticed by CC in two cases. In six patients, I-FISH revealed a chromosome 8 aneuploidy not detected by CC. Our results illustrate that, when using this specific set of probes, I-FISH is of special interest for the detection of minor clones with chromosome 8 aneuploidy, breakpoint assessment, and sequence identification (markers). Also, to avoid misinterpretations, I-FISH should not be used alone at disease presentation, particularly in cases complex changes that have clearly established prognostic significance.
- Published
- 2004
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44. 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.
- Author
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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.
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- 2003
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45. Rapid identification of CBFB-MYH11-positive acute myeloid leukemia (AML) cases by one single MYH11 real-time RT-PCR.
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van der Reijden BA, Massop M, Tönnissen E, van de Locht L, Muus P, de Witte T, and Jansen JH
- Subjects
- Humans, RNA, Messenger analysis, Leukemia, Myeloid, Acute genetics, Oncogene Proteins, Fusion genetics, Reverse Transcriptase Polymerase Chain Reaction
- Published
- 2003
- Full Text
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46. Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS.
- Author
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de Witte T, Suciu S, Verhoef G, Labar B, Archimbaud E, Aul C, Selleslag D, Ferrant A, Wijermans P, Mandelli F, Amadori S, Jehn U, Muus P, Boogaerts M, Zittoun R, Gratwohl A, Zwierzina H, Hagemeijer A, and Willemze R
- Subjects
- Adult, Combined Modality Therapy, Cytarabine administration & dosage, Disease-Free Survival, Etoposide administration & dosage, Follow-Up Studies, Humans, Idarubicin administration & dosage, Leukemia, Myeloid, Acute mortality, Middle Aged, Mitoxantrone administration & dosage, Myelodysplastic Syndromes mortality, Remission Induction, Survival Rate, Time Factors, Transplantation, Autologous, Transplantation, Homologous, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute therapy, Myelodysplastic Syndromes therapy
- Abstract
This study investigated the feasibility of allogeneic (alloSCT) and autologous stem cell transplantation (ASCT) as postconsolidation therapy for patients with myelodysplastic syndromes (MDSs) or acute myeloid leukemia after MDS. Patients with a histocompatible sibling were candidates for alloSCT and the remaining patients for ASCT. Remission-induction therapy consisted of 1 or 2 courses with idarubicin, cytarabine, and etoposide, followed by one intensive consolidation course with cytarabine and mitoxantrone. Initially, bone marrow cells were used for ASCT. Subsequently, mobilized blood stem cells were used in an attempt to shorten posttransplantation hypoplasia. With a median follow-up of 3.6 years the 184 evaluable patients showed a 4-year survival rate of 26% and a median survival of 13 months. The remission-induction chemotherapy induced complete remission (CR) in 100 patients (54%). The 4-year disease-free survival (DFS) rate was 29% and the median DFS was 12 months. Twenty-eight of 39 patients (72%) with a donor were allografted in CR-1, including 2 patients who underwent transplantation in CR-1 without a consolidation course. Thirty-six of 59 patients (61%) without a donor received ASCT in CR-1. The 4-year DFS rates in the group of patients with or without a donor were 31% and 27%, respectively. The 4-year survival rates from CR were 36% and 33%, respectively. This large prospective study shows the feasibility of both alloSCT and ASCT. This treatment approach leads to a relatively high remission rate, and the majority of patients in remission received the SCT in CR-1. The ongoing study investigates whether this approach is better than treatment with chemotherapy only.
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- 2001
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47. No impact of high-dose cytarabine on the outcome of patients transplanted for acute myeloblastic leukaemia in first remission. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).
- Author
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Cahn JY, Labopin M, Sierra J, Blaise D, Reiffers J, Ferrant A, Bergmann L, Visani G, Cornelissen J, De Witte T, Bosi A, Frassoni F, and Gorin NC
- Subjects
- Adolescent, Adult, Age Factors, Aged, Child, Child, Preschool, Disease-Free Survival, Female, Humans, Infant, Infant, Newborn, Leukemia, Myeloid, Acute blood, Leukocyte Count, Male, Middle Aged, Neoplasm Recurrence, Local etiology, Prognosis, Regression Analysis, Retrospective Studies, Transplantation, Autologous, Transplantation, Homologous, Treatment Outcome, Antimetabolites, Antineoplastic therapeutic use, Bone Marrow Transplantation methods, Cytarabine therapeutic use, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute therapy
- Abstract
High-dose cytarabine is currently used in combination with anthracycline in the treatment of acute myeloblastic leukaemia (AML). Moreover, high-dose cytarabine has been reported to produce long-term disease-free survival in a proportion of patients, especially in certain subtypes of AML. However, it remains unknown whether the outcome of patients undergoing allogeneic or autologous stem cell transplantation is influenced by previous treatment with high-dose cytarabine. To this end, 1672 patients with AML in first remission who were reported to the Acute Leukaemia Working Party registry of the European Group for Blood and Marrow Transplantation (EBMT) and who were transplanted between 1980 and 1995 were analysed according to the dose intensity of cytarabine given at induction and/or consolidation. Autologous stem cell transplantation (ABMT) was performed in 846 patients and allogeneic bone marrow transplantation (BMT) in 826 patients. This study shows that the dose of cytarabine (Ara-C) given at induction and/or consolidation did not influence the relapse incidence in patients subsequently allografted or autografted. In addition, it did not give any advantage in terms of overall outcome. Therefore, high-dose (HD) Ara-C may not be needed for patients who have a planned stem cell transplantation (SCT) as post-remission therapy. Nevertheless, HD Ara-C may be utilized in certain subtypes of AML that are believed to be curable by chemotherapy alone.
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- 2000
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48. Outcome of T cell-depleted transplantation after conditioning with an intensified regimen in patients aged 50 years or more is comparable with that in younger patients.
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Schattenberg A, Schaap N, Preijers F, van der Maazen R, and de Witte T
- Subjects
- Adolescent, Adult, Age Factors, Bone Marrow Transplantation immunology, Bone Marrow Transplantation mortality, Female, Graft vs Host Disease epidemiology, Humans, Idarubicin therapeutic use, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Retrospective Studies, Survival Rate, Bone Marrow Transplantation physiology, Cyclophosphamide therapeutic use, Immunosuppressive Agents therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Leukemia, Myeloid, Acute therapy, Lymphocyte Depletion, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, T-Lymphocytes immunology
- Abstract
One hundred and thirty-one patients were transplanted for AML-CR1, ALL-CR1 or CML-CP1 after conditioning with 120 mg/kg body weight cyclophosphamide and 2 x 4.5 Gy TBI. Conditioning was intensified with the addition of 42 mg/m2 idarubicin. Grafts were T cell-depleted using counterflow centrifugation. Donors were HLA-identical siblings. We compared outcome of BMT in 109 patients aged less than 50 (median, 35) years with that of 22 patients with an age of 50 years or more (median, 53 years). For the patients aged <50 years, 2-year probabilities of treatment-related mortality, relapse, survival and leukemia-free survival were 26% (95% CI, 17% to 35%), 26% (95% CI, 17% to 35%), 64% (95% CI, 55% to 73%), and 56% (95% CI, 47% to 65%). For the patients aged > or =50 years, these figures were 13% (95% CI, 0% to 30%), 24% (95% CI, 6% to 42%), 66% (95% CI, 46% to 86%), and 67% (95% CI, 47% to 87%), respectively. Outcome did not differ significantly between the two age groups. TRM was within the range of that reported in the literature for recipients of T cell-depleted grafts. We conclude that T cell-depleted transplantation after a conditioning regimen that was intensified with the addition of idarubicin is feasible in patients aged > or =50 years. For this age group of patients, results of nonmyeloablative regimens should be compared with that obtained with T cell-depleted grafts.
- Published
- 2000
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49. Roquinimex (Linomide) vs placebo in AML after autologous bone marrow transplantation.
- Author
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Simonsson B, Tötterman T, Hokland P, Lauria F, Carella AM, Fernandez MN, Rozman C, Ferrant A, de Witte T, Zander AR, Meier K, Hansson F, and Nilsson BI
- Subjects
- Adolescent, Adult, Aged, Angiogenesis Inhibitors adverse effects, Bone Marrow Purging, Child, Combined Modality Therapy, Disease-Free Survival, Female, Follow-Up Studies, Humans, Hydroxyquinolines adverse effects, Killer Cells, Natural immunology, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Placebos, Recurrence, Survival Rate, Time Factors, Transplantation, Autologous, Angiogenesis Inhibitors therapeutic use, Bone Marrow Transplantation adverse effects, Hydroxyquinolines therapeutic use, Leukemia, Myeloid, Acute therapy
- Abstract
Roquinimex, Linomide, a quinoline derivative with pleiotropic immunomodulatory activity, has previously been shown to enhance natural killer (NK) cell number and activity after ABMT in patients with AML. In this study 278 AML patients in remission were randomized to receive Roquinimex 0.2 mg/kg body weight or placebo twice weekly for 2 years following ABMT. Out of 139 patients in each group, 109 Roquinimex patients and 108 placebo patients were in their first CR. Median age at inclusion was 41 years for Roquinimex patients and 39 years for placebo patients. Twelve patients in each group had their marrow purged prior to reinfusion. Relapse and death were study endpoints. Surviving patients were followed for 2.6 to 6. 9 years. The total number of relapses was 60 in the Roquinimex group and 63 in the placebo group (not significant). Leukemia-free and overall survivals were similar in the two groups. Recovery of platelet counts was significantly delayed in the Roquinimex group as compared to placebo. No other significant differences regarding toxicity parameters were recorded. In conclusion, previous findings on NK cells could not be confirmed and the study showed no benefit for Roquinimex over placebo regarding relapse or survival following ABMT for AML in remission.
- Published
- 2000
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50. Effect of centre on outcome of bone-marrow transplantation for acute myeloid leukaemia. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation.
- Author
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Frassoni F, Labopin M, Powles R, Mary JY, Arcese W, Bacigalupo A, Bunjes D, Gluckman E, Ruutu T, Schaefer UW, Sierra J, Vernant JP, Willemze R, de Witte T, and Gorin NC
- Subjects
- Adolescent, Adult, Age Factors, Bone Marrow Transplantation adverse effects, Disease-Free Survival, Europe, Female, Humans, Incidence, Leukemia, Myeloid, Acute complications, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Multivariate Analysis, Prognosis, Proportional Hazards Models, Recurrence, Remission Induction methods, Risk Factors, Bone Marrow Transplantation methods, Bone Marrow Transplantation mortality, Leukemia, Myeloid, Acute therapy
- Abstract
Background: There is increasing pressure for the recognition and replication of good clinical practice. We undertook a study to assess the variability in outcome of allogeneic bone-marrow transplantation among major European centres., Methods: We studied 13 centres, including 522 patients (aged 16-55 years), which had undertaken more than 30 bone-marrow transplantations between Jan 1, 1987, and Dec 31, 1995, for acute myeloid leukaemia in first complete remission. We undertook a (global) multivariate analysis of all factors known previously to influence outcome and a stratified analysis that initially defined, by multivariate analysis, significant variables in this study and then used a proportional-hazard model including centres., Findings: The overall results at 3 years were 57% (95% CI 53-61) for leukaemia-free survival (LFS), 23% (19-27) for relapse incidence (RI), and 26% (22-30) for treatment-related mortality (TRM) with a range for centres of 36-75%, 10-37%, and 8-54%, respectively. Both methods of analysis showed the centre effect to be highly significant for LFS and TRM, but not for RI. Variables associated with a significantly poor outcome were age over 43 years (p=0.01), time from diagnosis to first complete remission longer than 65 days (p=0.02), and centre (p=0.013) for LFS, and age over 43 years (p=0.023), time from first complete remission to transplantation of longer than 93 days (p=0.03), and centre (p=0.001) for TRM. Moreover, different centres had different prognostic criteria for good-risk or bad-risk patients indicating that risk factors do not have the same impact in each individual centre., Interpretation: The outcome of bone-marrow transplantation for acute myeloid leukaemia in first complete remission is influenced by the centre in which the procedure is done, even with adjustment for known prognostic risk factors. Significant prognostic factors vary among centres, which means that the relative risk is not the same in each individual centre. However, centres may treat populations with different risks of as yet unidentified prognostic factors. Experience may partly account for the difference in outcome among centres.
- Published
- 2000
- Full Text
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