Sainte-Foy-lès-Lyon, France
Sainte-Foy-lès-Lyon, France

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PubMed | University of Cologne, Center Leon Berard, University Hospital Freiburg, University of Duisburg - Essen and 22 more.
Type: Clinical Trial, Phase III | Journal: Lancet (London, England) | Year: 2016

Mantle cell lymphoma is characterised by a poor long-term prognosis. The European Mantle Cell Lymphoma Network aimed to investigate whether the introduction of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation (ASCT) improves outcome.This randomised, open-label, parallel-group, phase 3 trial was done in 128 haemato-oncological hospital departments or private practices in Germany, France, Belgium, and Poland. Patients aged 65 years or younger with untreated stage II-IV mantle cell lymphoma were centrally randomised (1:1), with computer-assisted random block selection, to receive either six courses of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by myeloablative radiochemotherapy and ASCT (control group), or six courses of alternating R-CHOP or R-DHAP (rituximab plus dexamethasone, high-dose cytarabine, and cisplatin) followed by a high-dose cytarabine-containing conditioning regimen and ASCT (cytarabine group). Patients were stratified by study group and international prognostic index. The primary outcome was time to treatment failure from randomisation to stable disease after at least four induction cycles, progression, or death from any cause. Patients with stage II-IV mantle cell lymphoma were included in the primary analysis if treatment was started according to randomisation. For safety analyses, patients were assessed according to the treatment actually started. This study is registered with ClinicalTrials.gov, number NCT00209222.Of 497 patients (median age 55 years [IQR 49-60]) randomised from July 20, 2004, to March 18, 2010, 234 of 249 in the control group and 232 of 248 in the cytarabine group were included in the primary analysis. After a median follow-up of 6.1 years (95% CI 5.4-6.4), time to treatment failure was significantly longer in the cytarabine group (median 9.1 years [95% CI 6.3-not reached], 5 year rate 65% [95% CI 57-71]) than in the control group (3.9 years [3.2-4.4], 40% [33-46]; hazard ratio 0.56; p=0.038). During induction immunochemotherapy, patients who received high-dose cytarabine had increased grade 3 or 4 haematological toxicity (haemoglobin 71 [29%] of 241m vs 19 [8%] of 227 controls; platelets 176 [73%] of 240 vs 21 [9%] of 225), grade 3 or 4 febrile neutropenia (39 [17%] of 230 vs 19 [8%] of 224), and grade 1 or 2 renal toxicity (creatinine 102 [43%] of 236 vs 22 [10%] of 224). The number of ASCT-related deaths was similar (eight [3.4%]) in both groups.Immunochemotherapy containing high-dose cytarabine followed by ASCT should be considered standard of care in patients aged 65 years or younger with mantle cell lymphoma.European Commission, Lymphoma Research Foundation, and Roche.


PubMed | University of Houston, Dalhousie University, New York University, University of Nantes and 30 more.
Type: Journal Article | Journal: Leukemia | Year: 2016

The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.


Bridoux F.,University of Poitiers | Leung N.,Mayo Medical School | Hutchison C.A.,University of Otago | Touchard G.,University of Poitiers | And 11 more authors.
Kidney International | Year: 2015

Monoclonal gammopathy of renal significance (MGRS) regroups all renal disorders caused by a monoclonal immunoglobulin (MIg) secreted by a nonmalignant B-cell clone. By definition, patients with MGRS do not meet the criteria for overt multiple myeloma/B-cell proliferation, and the hematologic disorder is generally consistent with monoclonal gammopathy of undetermined significance (MGUS). However, MGRS is associated with high morbidity due to the severity of renal and sometimes systemic lesions induced by the MIg. Early recognition is crucial, as suppression of MIg secretion by chemotherapy often improves outcomes. The spectrum of renal diseases in MGRS is wide, including old entities such as AL amyloidosis and newly described lesions, particularly proliferative glomerulonephritis with monoclonal Ig deposits and C3 glomerulopathy with monoclonal gammopathy. Kidney biopsy is indicated in most cases to determine the exact lesion associated with MGRS and evaluate its severity. Diagnosis requires integration of morphologic alterations by light microscopy, immunofluorescence (IF), electron microscopy, and in some cases by IF staining for Ig isotypes, immunoelectron microscopy, and proteomic analysis. Complete hematologic workup with serum and urine protein electrophoresis, immunofixation, and serum-free light-chain assay is required. This review addresses the pathologic and clinical features of MGRS lesions, indications of renal biopsy, and a proposed algorithm for the hematologic workup. © 2015 International Society of Nephrology.


Casasnovas R.-O.,Hematologie Clinique | Meignan M.,Hopital Henri Mondor | Berriolo-Riedinger A.,Center Georges Francois Leclerc | Bardet S.,Center Francois Baclesse | And 9 more authors.
Blood | Year: 2011

The prognostic value of interim positron emission tomography (PET) interpreted according to visual criteria is a matter of debate in diffuse large B-cell lymphoma (DLBCL). Maximal standardized uptake value reduction (ΔSUVmax) may better predict outcome. To compare the prognostic value of both methods, we analyzed PET done at baseline (PET0) and after 2 (PET2) and 4 (PET4) cycles in 85 patients with high-risk DLBCL enrolled on a prospective multicenter trial. All images were centrally reviewed and interpreted visually according to the International Harmonization Project criteria and by computing ΔSUVmax between PET0 and PET2 (ΔSUVmaxPET0-2) or PET4 (ΔSUVmaxPET0-4). Optimal cutoff to predict progression or death was 66% for ΔSUVmaxPET0-2 and 70% for ΔSUVmaxPET0-4. Outcomes did not differ significantly whether PET2 and PET4 were visually positive or negative. Inversely, ΔSUVmaxPET0-2 analysis (> 66% vs ≤ 66%) identified patients with significantly different 2-year progression-free survival (77% vs 57%; P = .0282) and overall survival (93% vs 60%; P < .0001). ΔSUVmaxPET0-4 analysis (> 70% vs ≤ 70%) seemed even more predictive for 2-year progression-free survival (83 vs 40%; P < .0001) and overall survival (94% vs 50%; P < .0001). ΔSUVmax analysis of sequential interim PET is feasible for highrisk DLBCL and better predicts outcome than visual analysis. The trial was registered at http://clinicaltrials.gov as NCT00498043. © 2011 by The American Society of Hematology.


Kanoun S.,Center Gf Leclerc | Rossi C.,Hematologie Clinique | Berriolo-Riedinger A.,Center Gf Leclerc | Dygai-Cochet I.,Center Gf Leclerc | And 7 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2014

Purpose: The presence of a bulky tumour at staging in Hodgkin lymphoma (HL) is a predictor of a poor outcome. The total metabolic tumour volume at baseline (TMTV0) computed on PET may improve the evaluation of tumour burden. To explore the clinical usefulness of TMTV0, we compared the prognostic value of TMTV0, tumour bulk and interim PET response in a retrospective single-centre study. Methods: From 2007 to 2010, 59 consecutive patients with a first diagnosis of HL were treated in our institution. PET was done at baseline (PET0) and after two cycles of chemotherapy (PET2), and treatment was not modified according to the PET2 result. TMTV0 was measured with a semiautomatic method using a 41 % SUVmax threshold. SUVmax reduction between PET0 and PET2 (ΔSUVmaxPET0-2) was also computed. Based on ROC analysis, patients with a ΔSUVmaxPET0-2 >71 % were considered good responders and a TMTV0 >225 ml was considered to represent hypermetabolic bulky disease. Results: Median TMTV0 was 117 ml and 17 patients (29 %) had a TMTV0 >225 ml. TMTV0 (>225 ml vs. ≤225 ml) and tumour bulk (<10 cm vs. ≥10 cm) were predictive of 4-year PFS: 42 % vs. 85 % (p=0.001) and 44 % vs. 79 % (p < 0.03), respectively. In multivariate analysis, using ΔSUVmaxPET0-2, TMTV0 and bulky tumour as covariates, only ΔSUVmaxPET0-2 (p=0.0005, RR 6.3) and TMTV0 (p < 0.006, RR 4.4) remained independent predictors of PFS. Three prognosis groups were thus identified: ΔSUVmaxPET0-2 >71 % and TMTV0 ≤225 ml (n=37, 63 %), ΔSUVmaxPET0-2=<71 % or TMTV0 >225 ml (n=17, 29 %), and ΔSUVmaxPET0-2=<71 % and TMTV0 >225 ml (n=5, 8 %). In these three groups the 4-year PFS rates were 92 %, 49 %, and 20 % (p < 0.0001), respectively. Conclusion: TMTV0 is more relevant than tumour bulk for predicting the outcome in patients with HL, and adds a significant prognostic insight to interim PET response assessment. The combination of TMTV0 and ΔSUVmaxPET0-2 made it possible to identify three subsets of HL patients with different outcomes. This may guide clinicians in their choice of therapeutic strategy. © 2014 Springer-Verlag.


PubMed | Hannover Medical School, University of Leipzig, University of Munster, Hematologie Clinique and 15 more.
Type: Journal Article | Journal: Bone marrow transplantation | Year: 2016

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a therapeutic option for adult patients with T-cell ALL (T-ALL). Meanwhile, few allo-SCT data specific to adult T-ALL have been described thus far. Specifically, the optimal myeloablative conditioning regimen is unknown. In this retrospective study, 601 patients were included. Patients received allo-SCT in CR1, CR2, CR >2 or in advanced disease in 69%, 15%, 2% and 14% of cases, respectively. With an overall follow-up of 58 months, 523 patients received a TBI-based regimen, whereas 78 patients received a chemotherapy-based regimen including IV busulfan-cyclophosphamide (IV Bu-Cy) (n=46). Unlike patients aged 35 years, patients aged <35 years who received a TBI-based regimen displayed an improved outcome compared with patients who received a chemotherapy-based regimen (5-year leukemia-free survival (LFS) of 50% for TBI versus 18% for chemo-only regimen or IV Bu-Cy regimens, P=10(-5) and 10(-4), respectively). In multivariate analysis, use of TBI was associated with an improved LFS (hazard ratio (HR)=0.55 (0.34-0.86), P=0.01) and overall survival (HR=0.54 (0.34-0.87), P=0.01) in patients aged <35 years. In conclusion, younger adult patients with T-ALL entitled to receive a myeloablative allo-SCT may benefit from TBI-based regimens.


Soverini S.,University of Bologna | Hochhaus A.,Universitatsklinikum Jena | Nicolini F.E.,Hematologie Clinique | Gruber F.,University of Tromsø | And 11 more authors.
Blood | Year: 2011

Mutations in the Bcr-Abl kinase domain may cause, or contribute to, resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia patients. Recommendations aimed to rationalize the use of BCR-ABL mutation testing in chronic myeloid leukemia have been compiled by a panel of experts appointed by the European LeukemiaNet (ELN) and European Treatment and Outcome Study and are here reported. Based on a critical review of the literature and, whenever necessary, on panelists' experience, key issues were identified and discussed concerning: (1) when to perform mutation analysis, (2) how to perform it, and (3) how to translate results into clinical practice. In chronic phase patients receiving imatinib first-line, mutation analysis is recommended only in case of failure or suboptimal response according to the ELN criteria. In imatinib-resistant patients receiving an alternative TKI, mutation analysis is recommended in case of hematologic or cytogenetic failure as provisionally defined by the ELN. The recommended methodology is direct sequencing, although it may be preceded by screening with other techniques, such as denaturing-high performance liquid chromatography. In all the cases outlined within this abstract, a positive result is an indication for therapeutic change. Some specific mutations weigh on TKI selection. © 2011 by The American Society of Hematology.


Alchalby H.,University of Hamburg | Zabelina T.,University of Hamburg | Stubig T.,University of Hamburg | van Biezen A.,Leiden University | And 9 more authors.
Biology of Blood and Marrow Transplantation | Year: 2014

Transformed acute myeloid leukemia in myelofibrosis results in a median survival of less than 5months. 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 1year was 28% (95% confidence interval, 14 to 42) and of relapse at 3years 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. © 2014 American Society for Blood and Marrow Transplantation.


Nicolini F.E.,Hematologie Clinique | Turkina A.,Hematology Research Center | Shen Z.-X.,Shanghai Ruijin Hospital | Gallagher N.,Novartis | And 6 more authors.
Cancer | Year: 2012

BACKGROUND: Nilotinib is a selective, potent BCR-ABL inhibitor. Previous studies demonstrated the efficacy and safety of nilotinib in Philadelphia chromosome-positive chronic myeloid leukemia patients in chronic phase (CML-CP) or accelerated phase who failed prior imatinib. METHODS: This expanded access trial further characterized the safety of nilotinib 400 mg twice daily in patients with CML-CP (N = 1422). RESULTS: In this large, heavily pretreated population, nilotinib demonstrated significant efficacy, with complete hematologic response and complete cytogenetic response achieved in 43% and 34% of patients, respectively. Responses were rapid, mostly occurring within 6 months, and were higher in patients with suboptimal response to imatinib, with 75% and 50% achieving major cytogenetic response and complete cytogenetic response, respectively. At 18 months, the progression-free survival rate was 80%. Most patients achieved planned dosing of 400 mg twice daily and maintained the dose >12 months. Nonhematologic adverse events (AEs) were mostly mild to moderate and included rash (28%), headache (25%), and nausea (17%). Grade 3 or 4 thrombocytopenia (22%), neutropenia (14%), and anemia (3%) were low and managed by dose reduction or brief interruption. Grade 3 or 4 elevations in serum bilirubin and lipase occurred in 4% and 7% of patients, respectively. The incidence of newly occurring AEs decreased over time. Of patients who experienced a dose reduction because of AEs and attempted a re-escalation, 87% successfully achieved re-escalation to the full dose. CONCLUSIONS: This large study confirms that nilotinib was well tolerated and that grade 3 or 4 AEs occurred infrequently and were manageable through transient dose interruptions. Copyright © 2011 American Cancer Society.


Casasnovas R.-O.,Hematologie Clinique | Meignan M.,Hopital Henri Mondor | Berriolo-Riedinger A.,Center Georges Francois Leclerc | Itti E.,Hopital Henri Mondor | And 3 more authors.
Current Hematologic Malignancy Reports | Year: 2012

The prognosis value of interim positron emission tomography (PET) remains controversial in diffuse large Bcell lymphoma (DLBCL) patients because of the absence of consensus on criteria able to early identify good and bad responders to treatment. Visual interpretation using the International Harmonization Project (IHP) criteria, primarily established for end of treatment evaluation, was related to a low positive predictive value of treatment failure. The 5- point scale (5PS) that refers the residual uptake to the liver as background tissue was shown to slightly reduce falsepositive interim PET interpretations compared to IHP criteria. Semiquantification of fluorodeoxyglucose (FDG) uptake using standardized uptake value (SUV) and assessment of reduction of maximum SUV (SUVmax) between baseline and interim PET drastically improves both the interpretation accuracy and the interobserver reproducibility, and better predicts patient outcome than visual analysis. This latter approach is feasible in a multicenter setting and allows clinicians to design a risk-adapted therapeutic strategy based on early PET response assessment. © Springer Science+Business Media, LLC 2012.

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