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See detailSevere Prolonged Cough as Presenting Manifestation of FIP1L1-PDGFRA+ Chronic Eosinophilic Leukaemia: A Widely Ignored Association.
Roufosse, Florence; Heimann, Pierre; LAMBERT, Frédéric ULg et al

in Respiration; international review of thoracic diseases (2016)

Chronic eosinophilic leukaemia associated with the FIP1L1-PDGFRA fusion gene (F/P+ CEL) is a rare cause of marked persistent hypereosinophilia, arising almost exclusively in male patients. Clinical ... [more ▼]

Chronic eosinophilic leukaemia associated with the FIP1L1-PDGFRA fusion gene (F/P+ CEL) is a rare cause of marked persistent hypereosinophilia, arising almost exclusively in male patients. Clinical presentations are heterogeneous with a higher incidence of eosinophil-mediated cardiomyopathy than in other hypereosinophilic syndrome variants. Features of chronic myeloproliferative disease are often present, including splenomegaly and elevated serum vitamin B12 levels. The diagnosis is made by fluorescence in situ hybridization (FISH) showing the deletion of the CHIC2 locus and/or RT-PCR showing the FIP1L1-PDGFRA fusion transcript. Treatment with imatinib mesylate, a tyrosine kinase inhibitor, results in rapid and complete resolution of hypereosinophilia and associated symptoms, except for those related to sub-endocardial fibrosis that may be irreversible. We report the case of a male patient in whom isolated intractable cough remained the only clinical manifestation of F/P+ CEL for 4 years. Furthermore, eosinophil autofluorescence, an as yet unreported artefact in this setting, precluded the detection of the CHIC2 deletion and further delayed diagnosis, underlining that both FISH and RT-PCR should be performed when this disease is suspected. [less ▲]

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See detailPrise en charge actuelle du lymphome de la zone marginale
Bonnet, Christophe ULg; LEJEUNE, Marie ULg; VAN KEMSEKE, Catherine ULg et al

in Revue Médicale Suisse (2015)

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See detailImplementation of geriatric assessment-based recommendations in older patients with cancer: A multicentre prospective study
Baitar, Abdelbari; Kenis, Cindy; Moor, Ramona et al

in Journal of geriatric oncology (2015), 6(5), 401-10

PURPOSE: The main objective of this study was to describe geriatric recommendations based on a geriatric assessment (GA) and to evaluate the implementation of these recommendations. PATIENTS AND METHODS ... [more ▼]

PURPOSE: The main objective of this study was to describe geriatric recommendations based on a geriatric assessment (GA) and to evaluate the implementation of these recommendations. PATIENTS AND METHODS: A two-step approach of screening followed by a GA was implemented in nine hospitals in Belgium. Patients >/=70years were included at diagnosis or at disease progression/relapse. Concrete geriatric recommendations were systematically documented and reported to the treating physicians and consisted of referrals to professional health care workers. Patient charts were reviewed after one month to verify which geriatric recommendations have been performed. RESULTS: From August 2011 to July 2012, 1550 patients were included for analysis. The median age was 77 (range: 70-97) and 57.0% were female. A solid tumour was diagnosed in 91.4% and a haematological malignancy in 8.6%. Geriatric screening with the G8 identified 63.6% of the patients for GA (n=986). A median of two geriatric recommendations (range: 1-6) were given for 76.2% (95%CI: 73.4-78.8) of the evaluable patients (n=710). A median of one geriatric recommendation (range: 1-5) was performed in 52.1% (95%CI: 48.4-55.8) of the evaluable patients (n=689). In general, 460 or 35.3% (95%CI: 32.8-38.0) of all the geriatric recommendations were performed. Geriatric recommendations most frequently consisted of referrals to the dietician (60.4%), social worker (40.3%), and psychologist (28.9%). CONCLUSION: This implementation study provides insight into GA-based recommendations/interventions in daily oncology practice. Geriatric recommendations were given in about three-fourths of patients. About one-third of all geriatric recommendations were performed in approximately half of these patients. [less ▲]

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See detailIdentification of clinical parameters predictive of one-year survival using two geriatric tools in clinically fit older patients with hematological malignancies: Major impact of cognition
Dubruille, Stéphanie; Libert, Yves; Roos, Myriam et al

in Journal of Geriatric Oncology (2015), 6(5), 362-369

Background Little is known about the reliability of G8 screening tool and the prognostic value of clinical parameters within the Comprehensive Geriatric Assessment (CGA) in clinically fit older patients ... [more ▼]

Background Little is known about the reliability of G8 screening tool and the prognostic value of clinical parameters within the Comprehensive Geriatric Assessment (CGA) in clinically fit older patients with hematological malignancies. Materials and Methods This study was performed to assess the reliability of G8 as a screening tool and to determine the predictive value of CGA items in terms of 1-year overall survival (OS). G8 and CGA were proposed to 107 consecutive patients (65–89 years) with hematological malignancies assessed by their physicians as clinically fit, meaning not exhibiting geriatric syndromes and/or irreversible comorbidities significantly impairing their daily function, and thus able to receive chemotherapy. Results Out of 107 patients, 90 patients were evaluable and completed both scales; 72% and 80% were defined as “vulnerable” when evaluated with G8 (≤14.5) or CGA (≥2 impairments) respectively. The area under ROC-curve of G8 compared to CGA was 0.749 ± 0.051. Neither G8 nor CGA total scores were predictive of 1-year OS. However, age (HR = 1.105, 95% CI: 1.016–1.202; p = 0.019), diagnosis (HR = 5.208, 95% CI: 1.895–14.310; p = 0.001) and cognitive status (HR = 3.260, 95% CI: 1.043–10.194; p = 0.042) were predictive of OS. Conclusions We conclude that in our selected hematological patients: 1) the G8 score does not help selecting patients for CGA, 2) the G8 and CGA total scores do not predict OS, and 3) in addition to the age and disease itself, cognitive impairment appears to be a powerful prognostic factor. [less ▲]

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See detailIdarubicin 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)
DE WITTE, Theo; SUCIU, Stefan; MEERT, Liv et al

in Annals of Hematology (2015), 94

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 ... [more ▼]

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/m² on day 7 of the remission-induction course further consisting of a continuous infusion of cytarabine 100 mg/m²/day for 10 days and idarubicin 12 mg/m²/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 timeto recovery of neutrophils to 0.5x109/1 and of platelets to >50x109/1 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. [less ▲]

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See detailMulticenter implementation of geriatric assessment in Belgian patients with cancer: A survey on treating physicians' general experiences and expectations.
Kenis, Cindy; Heeren, Pieter; Bron, Dominique et al

in Journal of geriatric oncology (2014), 5(4), 431-438

OBJECTIVES: The aim of this study is to identify treating physicians' general experiences and expectations regarding geriatric assessment (GA) in older patients with cancer. MATERIALS AND METHODS: A ... [more ▼]

OBJECTIVES: The aim of this study is to identify treating physicians' general experiences and expectations regarding geriatric assessment (GA) in older patients with cancer. MATERIALS AND METHODS: A survey was carried out in 9 Belgian hospitals, which participated in a national GA implementation project focusing on older patients with cancer. A newly developed questionnaire was completed by their treating physicians. Data collection comprised of reviewing hospital data, general respondent data, and treating physicians' general experiences and expectations regarding GA. Descriptive statistics were calculated. RESULTS: Eighty-two physicians from 9 hospitals participated. The GA team composition can vary substantially, with a nurse as core member. Ideally, all older patients with cancer in whom a treatment decision is necessary, should benefit from the GA. Nearly all GA domains are reported as very important. Availability of GA results can be improved. Treating physicians want geriatricians to coordinate geriatric recommendations related to the identified GA problems, and expect from trained healthcare workers (THCWs) to collect GA data, to report GA results, and to follow-up the implementation of geriatric recommendations. CONCLUSION: This study identifies relevant information for improving the implementation of GA in older patients with cancer in Belgium and reveals priorities for a THCW from the treating physician's point of view. To increase the effectiveness of GA, further efforts are needed to improve the implementation of geriatric recommendations. [less ▲]

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See detailHigh-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
Willemze, Roelof; Suciu, Stefan; Meloni, Giovanna et al

in Journal of Clinical Oncology (2014), 32(3), 219-228

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/m2 for remission ... [more ▼]

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/m2 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/m2 per day by continuous infusion for 10 days) or high-dose (HD) cytarabine (3,000 mg/m2 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/m2 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. [less ▲]

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See detailGuidelines of the Belgian Hematological Society for newly diagnosed and relapsed follicular lymphoma 2012
Debussche, S.; Van Hoof, A.; Sonet, Anne et al

in Belgian Journal of Hematology (2012), 3(2), 41-50

Follicular lymphoma is an indolent lymphoma that has occurred more frequently over the last decades. In this article we present an overview of the diagnosis and initial work-up, prognostic scoring system ... [more ▼]

Follicular lymphoma is an indolent lymphoma that has occurred more frequently over the last decades. In this article we present an overview of the diagnosis and initial work-up, prognostic scoring system and choice of therapy. For limited stage disease radiotherapy is the treatment of choice, and may have a curative potential. For advanced stages treatment should be initiated upon certain criteria, and is essentially based on immunochemotherapy, rituximab plus chemotherapy. The choice of chemotherapy depends on age, frailty, and specific toxicities of chemotherapy. Maintenance therapy with rituximab after induction has become standard practice. Since virtually all patients relapse eventually, an overview of the treatment in the relapsed setting is given. The treatment is then again based on immunochemotherapy but there is also a place for radio-immunotherapy, or immunotherapy alone. For young patients, high dose chemotherapy with autologous stem cell rescue should be considered. A brief overview on novel agents, and agents that are in the pipeline, is given. We conclude with some recommendations for follow-up. [less ▲]

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See detailEORTC Leukemia Group achievements
Willemze, Roel; Suciu, Stefan; Marie, Jean-Pierre et al

in EJC Supplements (2012), I

The EORTC Leukemia Group (LG) has a long history of promoting the study of leukemias and related malignancies and reports here on three of their most significant achievements. In acute myelogenous ... [more ▼]

The EORTC Leukemia Group (LG) has a long history of promoting the study of leukemias and related malignancies and reports here on three of their most significant achievements. In acute myelogenous leukemia (AML), the LG and Italian group GIMEMA started their fruitful collaboration in 1986 with the AML-8 trial with 1519 inclusions. In the AML-8A trial, in patients who reached complete remission, without a HLA identical sibling, autograft provided longer disease-free survival than a second course of consolidation, whereas the best outcome was observed in patients with a donor, who had to be allografted. The AML-10 trial set a new standard of treatment for induction/consolidation with replacement of daunorubicin by either idarubicin or mitoxantrone. The AML-12 trial tested the effect of high-dose cytosinearabinoside during induction (2109 inclusions, data base locked in August 2011 for final analysis). Development of intergroup trials focusing on subgroups of AML bearing specific genetic abnormalities is now mandatory to validate the “targeted approach” of driving molecular events. In high-risk myelodysplastic syndrome (MDS), the phase III trial conducted by the LG in collaboration with the German MDS Study Group showed that the response rate of decitabine versus best supportive care was higher (complete or partial remissions, 19% versus 0%, and hematologic improvement, 15% versus 2%), progression-free survival was significantly prolonged (median 6.6 versus 3 months), cumulative incidence of AML was significantly decreased (22% versus 33% at one year), but the impact on OS was less evident (median 10.1 versus 8.5 months; hazard ratio 0.88). Quality of life had improved significantly in patients in the decitabine arm. The assessment of HDAC inhibitors, such as vorinostat, will probably be tested in the next trial. Also in MDS, relevant genetic lesions involved in the pathogenesis of this disease were identified using single nucleotide polymorphisms array-based genomic profiling and genomic sequencing in 102 patients with MDS. Acquired abnormalities of the TET2 gene were identified in 26% of the cases and in the EZH2 gene in 5−10% of the patients. TET2 mutations were detected in 96% of the bone marrow cells, including CD34+ progenitor cells, suggesting that TET2 mutations could be an early event during disease evolution. In normal bone marrow, TET2 expression was elevated in granulocytes, suggesting a role in myelopoiesis. Conclusion: during the last 25 years the EORTC LG in cooperation with GIMEMA made a considerable contribution to the improvement of treatment results of patients with acute leukemia or MDS. [less ▲]

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See detailValproate synergizes with purine nucleoside analogues to induce apoptosis of B-chronic lymphocytic leukaemia cells.
Bouzar, Amel ULg; Boxus, Mathieu ULg; Defoiche, Julien et al

in British journal of haematology (2009), 144(1),

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See detailReduction of B cell turnover in chronic lymphocytic leukaemia.
Defoiche, Julien; Debacq, Christophe; Asquith, Becca et al

in British Journal of Haematology (2008), 143(2), 240-7

Whether chronic lymphocytic leukaemia (CLL) is a latent or a proliferating disease has been intensively debated. Whilst the dogma that CLL results from accumulation of dormant lymphocytes is supported by ... [more ▼]

Whether chronic lymphocytic leukaemia (CLL) is a latent or a proliferating disease has been intensively debated. Whilst the dogma that CLL results from accumulation of dormant lymphocytes is supported by the unresponsiveness of leukaemic cells to antigens and polyclonal activators, recent in vivo kinetic measurements indicate that B lymphocytes do divide at significant rates in CLL. However, an important and still unanswered question is whether CLL cells proliferate faster or slower compared with their normal counterparts. This report addressed directly this point and compared B-cell kinetics in CLL subjects and healthy controls, using a pulse-chase approach based on incorporation of deuterium from 6,6-(2)H(2)-glucose into DNA. We confirmed that B cells proliferated at significant levels in CLL but found that the proliferation rates were reduced compared with healthy subjects (mean 0.47 vs. 1.31%/d respectively, P = 0.007), equivalent to an extended doubling time of circulating B cells (147 d vs. 53 d). In conclusion, CLL B cells proliferate at reduced levels compared with healthy controls. CLL is thus characterized by an aberrant B-cell kinetics with a decrease in cell turnover, an observation that may impact on elaboration of efficient therapeutic strategies. [less ▲]

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See detailValproic acid induces apoptosis in chronic lymphocytic leukemia cells through activation of the death receptor pathway and potentiates TRAIL response.
Lagneaux, Laurence; Gillet, Nicolas ULg; Stamatopoulos, Basile et al

in Experimental hematology (2007), 35(10), 1527-37

OBJECTIVE: Chronic lymphocytic leukemia (CLL) cells develop chemoresistance over time associated with defects in apoptosis pathway. Novel treatment strategies are required to overcome resistance of cells ... [more ▼]

OBJECTIVE: Chronic lymphocytic leukemia (CLL) cells develop chemoresistance over time associated with defects in apoptosis pathway. Novel treatment strategies are required to overcome resistance of cells to commonly used agents. The effects of valproic acid (VPA), an antiepileptic drug with histone deacetylase inhibitory activity, on mononuclear cells isolated from 40 CLL patients were evaluated. METHODS: CLL cells were treated with increasing doses of VPA (0.5, 1, 2, and 5 mM). The mode of cytotoxic drug action was determined by annexin binding, DNA fragmentation, and caspase activation. RESULTS: Exposure of CLL cells to VPA resulted in dose-dependent cytotoxicity and apoptosis in the 40 CLL patients. VPA treatment induced apoptotic changes in CLL cells including phosphatidylserine externalization and DNA fragmentation. The mean apoptotic rates were similar between IgV(H) mutated and unmutated patients, the latter presenting a more aggressive clinical course. VPA induced apoptosis via the extrinsic pathway involving engagement of the caspase-8-dependent cascade. Although CLL cells are commonly resistant to death receptor-induced apoptosis, VPA significantly increased sensitivity of leukemic cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and led to downregulation of c-FLIP (L) expression. VPA caused no potentialization of TRAIL-induced apoptosis on normal B cells. In addition, VPA overcame the prosurvival effects of bone marrow stromal cells. CONCLUSION: These findings point out that the combination of TRAIL and VPA, at clinically relevant concentration, may be valuable in the treatment of CLL. [less ▲]

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See detailPhase III randomized study comparing 5 or 10 microg per kg per day of filgrastim for mobilization of peripheral blood progenitor cells with chemotherapy, followed by intensification and autologous transplantation in patients with nonmyeloid malignancies.
Andre, Marc; Baudoux, Etienne ULg; Bron, Dominique et al

in Transfusion (2003), 43(1), 50-7

BACKGROUND: It is not known whether increasing the dose of filgrastim after mobilizing chemotherapy improves collection of peripheral blood progenitor cells (PBPC) and leads to faster hematopoietic ... [more ▼]

BACKGROUND: It is not known whether increasing the dose of filgrastim after mobilizing chemotherapy improves collection of peripheral blood progenitor cells (PBPC) and leads to faster hematopoietic engraftment after autologous transplantation. STUDY DESIGN AND METHODS: A randomized, open-label, multicenter trial was carried out in patients with breast cancer, multiple myeloma, and lymphoma, in which patients were randomized to receive 5 or 10 microg per kg per day of filgrastim after standard chemotherapy to mobilize PBPCs. After high-dose chemotherapy, the components from the first two leukapheresis procedures were returned, and all patients received 5 microg per kg day of filgrastim after transplantation. RESULTS: A total of 131 patients were randomized, of whom 128 were mobilized (Group A, 5 microg/kg, n = 66; Group B, 10 microg/kg, n = 62) and 112 were transplanted. Only six patients were not transplanted because of insufficient CD34+ cell numbers. The median number of CD34+ cells collected in the first two leukapheresis procedures tended to be higher in Group B than in Group A (12.0 vs. 7.2 x 10(6)/kg, NS), but after transplantation there was no significant difference in median times to platelet (9 days in both groups) or neutrophil (8 days in both groups) engraftment or the number of platelet transfusions (three in both groups). A subsequent subgroup analysis separating patients transplanted after first- or second-line chemotherapy also showed no measurable impact of filgrastim dose on the median CD34+ cell yield or on platelet engraftment in either subgroup. CONCLUSION: PBPC mobilization with chemotherapy and 5 microg per kg of filgrastim is very efficient, and 10 microg per kg of filgrastim does not provide additional clinical benefit. [less ▲]

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See detailThe belgian experience in unrelated donor bone marrow transplantation: identification of center experience as an important prognostic factor.
Dresse, Marie-Françoise ULg; Boogaerts, Marc; Vermylen, Christiane et al

in Haematologica (1999), 84(7), 637-42

BACKGROUND AND OBJECTIVE: We reviewed all unrelated donor bone marrow transplants (UDBMT) performed in Belgium up to December 1995 to identify prognostic factors for relapse, transplant-related mortality ... [more ▼]

BACKGROUND AND OBJECTIVE: We reviewed all unrelated donor bone marrow transplants (UDBMT) performed in Belgium up to December 1995 to identify prognostic factors for relapse, transplant-related mortality and survival. DESIGN AND METHODS: A total of 163 UDBMT were performed in 92 males and 71 females aged 1-55 (median 26) years. Patients were transplanted for ALL (n=35), AML (n=34), CML (n=51), other myeloid malignancies (n=14), SAA (n=21) or miscellaneous other diseases (n=8). Most patients had advanced disease; a few patients were in CR1 (n=10) or early chronic phase (CP) of CML (n=5). RESULTS: Overall survival at 5 yrs was 17% (95% confidence interval: 8-32%), but survival was significantly better for patients with non-malignant disorders (55% at 4 yrs). The relapse rate +/-SE was projected to be 40 (28-54)% at 5 yrs, 36 (20-56)% for standard-risk and 68 (43-85)% for high-risk malignancies (p=0.0029). There was no relapse in CML patients transplanted in 1st CP compared to 68% at 4 yrs with more advanced CML (p=0.0033). Grade II-IV acute graft-versus-host disease (aGVHD) occurred in 55% by day 100 and was strongly modulated by age, ranging from 41% in <20-yr-old to 80% in >40-yr-old patients (p=0. 0021). Transplant-related mortality (TRM) was projected to be 72 (52-87)% at 5 yrs including 2 very late deaths from lung fibrosis and secondary cancer. Main causes of death were original disease in 27, secondary malignancy in 2, GVHD in 28, interstitial pneumonia in 21, other infections in 19, and miscellaneous toxic causes in 21 patients. In multivariate analysis, the relapse rate was strongly dependent on the disease status (p=0.0029), TRM being significantly worse with older age (p=0.0049), and overall survival being significantly worse in more advanced disease (p=0.0006), after a second transplant (p=0.0166), in centers of smaller size (p=0.0316) and in older patients (NS). INTERPRETATION AND CONCLUSIONS: Although results have improved somewhat in recent years, UDBMT remains a procedure with a high TRM. UDBMT should be performed in patients with less advanced diseases and in centers with more experience, particularly in the treatment of adult patients. [less ▲]

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