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Aline Tanguy-Schmidt,
Philippe Rousselot,
Yves Chalandon,
Jean-Michel Cayuela,
Sandrine Hayette,
Marie-Christiane Vekemans,
Martine Escoffre,
Françoise Huguet,
Delphine Réa,
André Delannoy,
Jean-Yves Cahn, Jean-Paul Vernant,
Norbert Ifrah,
Hervé Dombret,
Xavier Thomas
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ABSTRACT: We report here the results of the GRAAPH-2003 trial with long-term follow-up in 45 patients with de novo Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Imatinib-based strategy improved the 4-year overall survival (OS) up to 52% versus 20% in the pre-imatinib LALA-94 trial (P = .0001). Despite the selection in patients who actually underwent transplantation, these results suggest that allogeneic or autologous stem cell transplants (SCTs) still have a place in overcoming the poor prognosis of Ph+ ALL in the era of imatinib therapy. OS was 50% after allogeneic SCT (24 patients), 33% in patients without a transplantation (9 patients), and 80% after autologous SCT (10 patients without allogeneic donor or >55 years, including 7 patients in complete molecular response).
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2012; · 3.15 Impact Factor
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ABSTRACT: Preliminary clinical experience has suggested that radiation therapy (RT) may be effectively incorporated into conditioning therapy before transplant for patients with refractory/relapsed malignant lymphoma. We investigated the feasibility of debulking selective lymph node irradiation before autologous and/or allogeneic stem cell transplantation (SCT) using helical tomotherapy (HT).
Six consecutive patients with refractory malignant lymphoma were referred to our institution for salvage HT before SCT. All patients had been previously heavily treated but had bulky residual tumor despite chemotherapy (CT) intensification. Two patients had received previous radiation therapy. HT delivered 30-40 Gy in the involved fields (IF), using 6 MV photons, 2 Gy per daily fraction. Total duration of treatment was 28 to 35 days.
Using HT, doses to critical organs (heart, lungs, esophagus, and parotids) were significantly decreased and highly conformational irradiation could be delivered to all clinical target volumes. HT delivery was technically possible, even in patients with lesions extremely difficult to irradiate in other conditions or in patients with previous radiation therapy. No Grade 2 or higher toxicity occurred. Four months after the end of HT, 5 patients experienced complete clinical, radiologic, and metabolic response and were subsequently referred for SCT.
By more effectively sparing critical organs, HT may contribute to improving the tolerance of debulking irradiation before allograft. Quality of life may be preserved, and doses to the heart may be decreased. This is particularly relevant in heavily treated patients who are at risk for subsequent heart disease. These preliminary results require further prospective assessment.
International journal of radiation oncology, biology, physics 11/2011; 81(4):1184-9. · 4.59 Impact Factor
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Antoine Froissart,
Marc Buffet,
Agnès Veyradier,
Pascale Poullin,
François Provôt,
Sandrine Malot,
Michael Schwarzinger,
Lionel Galicier,
Philippe Vanhille, Jean-Paul Vernant, [......],
Eric Mariotte,
Eric Rondeau,
Jean-Paul Mira,
Alain Wynckel,
Karine Clabault,
Gabriel Choukroun,
Claire Presne,
Jacques Pourrat,
Mohamed Hamidou,
Paul Coppo
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ABSTRACT: To assess the efficacy and safety of rituximab in adults responding poorly to standard treatment for severe autoimmune thrombotic thrombocytopenic purpura.
Open-label prospective study. Outcomes in the survivors were compared to those of 53 historical survivors who were given therapeutic plasma exchange alone or with vincristine.
Hospitals belonging to the Reference Network for Thrombotic Microangiopathies in France.
Twenty-two adults with either no response or a disease exacerbation when treated with intensive therapeutic plasma exchange.
Add-on rituximab therapy, four infusions over 15 days.
One patient died despite two rituximab infusions. In the rituximab-treated patients, the time to a durable remission was significantly shortened (p = .03), although the plasma volume required to achieve a durable remission was not significantly different compared to the controls. Platelet count recovery occurred within 35 days in all 21 survivors, compared to only 78% of the historical controls (p < .02). Of the rituximab-treated patients, none had a relapse within the first year but three relapsed later on. In patients treated with rituximab, a rapid and profound peripheral B-cell depletion was produced, lasting for 9 months and correlating with higher a disintegrin and metalloproteinase with thrombospondin-13 activity and lower anti-a disintegrin and metalloproteinase with thrombospondin-13 antibody titers. These differences were no longer significant after 12 months. No severe side effects occurred.
Adults with severe thrombocytopenic purpura who responded poorly to therapeutic plasma exchange and who were treated with rituximab had shorter overall treatment duration and reduced 1-yr relapses than historical controls.
Critical care medicine 09/2011; 40(1):104-11. · 6.37 Impact Factor
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Roel J W van Kampen,
Carmen Canals,
Harry C Schouten,
Arnon Nagler,
Kirsty J Thomson, Jean-Paul Vernant,
Agnes Buzyn,
Marc A Boogaerts,
Jian-Jian Luan,
Sébastien Maury,
Noel J Milpied,
Jean-Pierre Jouet,
Gert J Ossenkoppele,
Anna Sureda
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ABSTRACT: To analyze the outcome, including nonrelapse mortality (NRM), relapse rate (RR), progression-free survival (PFS), and overall survival (OS), of patients with diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) relapsed after an autologous stem-cell transplantation (ASCT) and treated with an allogeneic stem-cell transplantation (allo-SCT).
The European Group for Blood and Marrow Transplantation database was scanned for a first allo-SCT in relapsed DLBCL after a previous ASCT between 1997 and 2006. Other inclusion criteria were age at allo-SCT ≥ 18 years and availability of an HLA-identical sibling or a matched unrelated donor. A total of 101 patients (57 males; median age, 46 years) were included. Median follow-up for survivors was 36 months.
Myeloablative conditioning regimen was used in 37 patients and reduced intensity conditioning (RIC) was used in 64 patients. Three-year NRM was 28.2% (95% CI, 20% to 39%), RR was 30.1% (95% CI, 22% to 41%), PFS was 41.7% (95% CI, 32% to 52%), and OS was 53.8% (95% CI, 44% to 64%). NRM was significantly increased in patients ≥ 45 years (P = .01) and in those with an early relapse (< 12 months) after ASCT (P = .01). RR was significantly higher in refractory patients (P = .03). A time interval to relapse after ASCT of < 12 months was associated with lower PFS (P = .03). The use of RIC regimens was followed by a trend to a lower NRM (P = .1) and a trend to a higher RR (P = .1), with no differences in PFS and OS. No differences were seen between HLA-identical siblings and matched unrelated donors.
Allo-SCT in relapsed DLBCL after ASCT is a promising therapeutic modality. Patients with a long remission after ASCT and with sensitive disease at allo-SCT are the best candidates for this approach.
Journal of Clinical Oncology 02/2011; 29(10):1342-8. · 18.37 Impact Factor
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Stéphanie Nguyen,
Vivien Béziat,
Françoise Norol,
Madalina Uzunov,
Hélène Trebeden-Negre,
Nabih Azar,
Ali Boudifa,
Dominique Bories,
Patrice Debré, Jean-Paul Vernant,
Vincent Vieillard,
Nathalie Dhédin
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ABSTRACT: Allogeneic donor natural killer (NK)-cell infusion (NK-DLI) is a promising immunotherapy for patients with hematologic disorders.
This report describes the case of a patient who received a single haploidentical NK-DLI for a relapse of acute myeloid leukemia (AML) after haploidentical hematopoietic stem cell transplantation. He underwent a cytoreductive, immunosuppressive regimen before NK-DLI and received high-dose interleukin-2 in vivo for 8 weeks afterward.
No major adverse effect was observed. Prospective phenotypic and functional studies of the NK cells showed major expansion of infused NK cells and, more importantly, of the alloreactive KIR2DL1+KIR2DL2/DL3-NKG2A- subset, which reached 117×10(6) cells/L on Day +14 after NK-DLI, the greatest expansion of infused alloreactive NK cells reported so far. Infused NK cells conserved their lytic capacities against K562 target cells and primary AML-mismatched blasts.
We review the literature to clarify these data and to detail the indications for allogeneic NK-DLI, the criteria for determining the most suitable donor, the types of conditioning regimens, and the procedures for selecting and activating NK cells.
Transfusion 02/2011; 51(8):1769-78. · 3.22 Impact Factor
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Michelle Rosenzwajg,
Nathalie Dhédin,
Sébastien Maury,
Gilbert Bensimon,
Dan Avi Landau,
Françoise Norol,
Hélène Trébéden-Negre,
Madalina Uzunov, Jean-Paul Vernant,
David Klatzmann,
José L Cohen
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ABSTRACT: The subpopulation of regulatory T cells (Treg) was shown to play a key role in alloreactive responses. In allogeneic hematopoietic stem cell transplantation, several groups tested whether Treg content in transplants correlates with graft-versus-host disease (GVHD) with controversial results. In a retrospective study of 49 consecutive HLA-matched sibling transplantations, we studied the relationship between Treg content in bone marrow transplants and acute GVHD (aGVHD) occurrence. We observed a large variability in Treg in bone marrow grafts. However, contrary to previous observations in peripheral blood stem cells transplantation, we report that the Treg content of allogeneic bone marrow transplantation did not predict the occurrence of aGVHD.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2011; 17(2):265-9. · 3.15 Impact Factor
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ABSTRACT: Some patients demonstrate delayed recoveries after autologous hematopoietic stem cell transplantation despite infusion of an adequate number of CD34+ cells/kg and clinically stable status. Factors considered being possible predictors of this outcome in this context were explored.
A total of 246 patients were evaluated in terms of engraftment. Delayed recovery was defined by white blood cell recovery time exceeding mean+1 SEM. Clinical factors and graft characteristics were examined. Comparisons between patients with normal or delayed engraftment were made. Proinflammatory cytokines and proteolytic enzyme quantification and CXCR4+ and CD44+ cell enumeration were performed on peripheral hematopoietic stem cells (PHSC) product samples of patients with delayed engraftment and patients with usual engraftment time.
Sixteen patients, who received at least 3 × 10(6) CD34+ cells/kg without known clinical factors likely to affect engraftment, demonstrated a delayed recovery time of over 20 days. Some graft variables were found to be significantly increased in these patients by univariate analysis. One variable was the total number of nucleated cells cryopreserved and infused. Among the nucleated cells, the absolute number of granulocytes before and after cryopreservation also differed significantly between the two groups. A multivariate analysis showed that the main predictive factor for delayed recovery was the number of nucleated cells in the graft (p=0.0044). The influence of contaminating cells might be related to the release of elastase, matrix metalloproteinase-9, interleukin (IL)-1β, and IL-6 involved in stem cell homing.
Therefore, the numeration of total nucleated cells and granulocytes should be considered as a possible quality control variable of PHSCs submitted for cryopreservation.
Transfusion 12/2010; 50(12):2649-59. · 3.22 Impact Factor
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American Journal of Hematology 11/2010; 85(11):892. · 4.67 Impact Factor
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Sébastien Maury,
François M Lemoine,
Yosr Hicheri,
Michelle Rosenzwajg,
Cécile Badoual,
Mustapha Cheraï,
Jean-Louis Beaumont,
Nabih Azar,
Nathalie Dhedin,
Anne Sirvent,
Agnès Buzyn,
Marie-Thérèse Rubio,
Stéphane Vigouroux,
Olivier Montagne,
Dominique Bories,
Françoise Roudot-Thoraval, Jean-Paul Vernant,
Catherine Cordonnier,
David Klatzmann,
José L Cohen
[show abstract]
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ABSTRACT: Donor T cells play a pivotal role in the graft-versus-tumor effect after allogeneic hematopoietic stem cell transplantation. Regulatory T cells (T(reg)s) may reduce alloreactivity, the major component of the graft-versus-tumor effect. In the setting of donor lymphocyte infusion after hematopoietic stem cell transplantation, we postulated that T(reg) depletion could improve alloreactivity and likewise the graft-versus-tumor effect of donor T cells. The safety and efficacy of T(reg)-depleted donor lymphocyte infusion was studied in 17 adult patients with malignancy relapse after hematopoietic stem cell transplantation. All but one had previously failed to respond to at least one standard donor lymphocyte infusion, and none had experienced graft-versus-host disease. Two of the 17 patients developed graft-versus-host disease after their first T(reg)-depleted donor lymphocyte infusion and experienced a long-term remission of their malignancy. Four of the 15 patients who did not respond after a first T(reg)-depleted donor lymphocyte infusion received a second T(reg)-depleted donor lymphocyte infusion combined with lymphodepleting chemotherapy aimed to also eliminate recipient T(reg)s. All four developed acute-like graft-versus-host disease that was associated with a partial or complete and durable remission. In the whole cohort, graft-versus-host disease induction through T(reg) depletion was associated with improved survival. These results suggest that T(reg)-depleted donor lymphocyte infusion is a safe, feasible approach that induces graft-versus-host or graft-versus-tumor effects in alloreactivity-resistant patients. In patients not responding to this approach, the combination of chemotherapy-induced lymphodepletion of the recipient synergizes with the effect of T(reg)-depleted donor lymphocyte infusion. These findings offer a rational therapeutic approach for cancer cellular immunotherapy.
Science translational medicine 07/2010; 2(41):41ra52. · 7.80 Impact Factor
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Paul Coppo,
Michael Schwarzinger,
Marc Buffet,
Alain Wynckel,
Karine Clabault,
Claire Presne,
Pascale Poullin,
Sandrine Malot,
Philippe Vanhille,
Elie Azoulay, [......],
Jacques Pourrat,
Stéphane Girault,
Dominique Bordessoule,
Samir Saheb,
Michel Ramakers,
Mohamed Hamidou, Jean-Paul Vernant,
Bertrand Guidet,
Martine Wolf,
Agnès Veyradier
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ABSTRACT: Severe ADAMTS13 deficiency occurs in 13% to 75% of thrombotic microangiopathies (TMA). In this context, the early identification of a severe, antibody-mediated, ADAMTS13 deficiency may allow to start targeted therapies such as B-lymphocytes-depleting monoclonal antibodies. To date, assays exploring ADAMTS13 activity require skill and are limited to only some specialized reference laboratories, given the very low incidence of the disease. To identify clinical features which may allow to predict rapidly an acquired ADAMTS13 deficiency, we performed a cross-sectional analysis of our national registry from 2000 to 2007. The clinical presentation of 160 patients with TMA and acquired ADAMTS13 deficiency was compared with that of 54 patients with detectable ADAMTS13 activity. ADAMTS13 deficiency was associated with more relapses during treatment and with a good renal prognosis. Patients with acquired ADAMTS13 deficiency had platelet count < 30 x 10(9)/L (adjusted odds ratio [OR] 9.1, 95% confidence interval [CI] 3.4-24.2, P<.001), serum creatinine level < or =200 micromol/L (OR 23.4, 95% CI 8.8-62.5, P<.001), and detectable antinuclear antibodies (OR 2.8, 95% CI 1.0-8.0, P<.05). When at least 1 criteria was met, patients with a severe acquired ADAMTS13 deficiency were identified with positive predictive value of 85%, negative predictive value of 93.3%, sensitivity of 98.8%, and specificity of 48.1%. Our criteria should be useful to identify rapidly newly diagnosed patients with an acquired ADAMTS13 deficiency to better tailor treatment for different pathophysiological groups.
PLoS ONE 01/2010; 5(4):e10208. · 4.09 Impact Factor
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Sébastien Maury,
Françoise Huguet,
Thibaut Leguay,
Francis Lacombe,
Marc Maynadié,
Sandrine Girard,
Adrienne de Labarthe,
Emilienne Kuhlein,
Emmanuel Raffoux,
Xavier Thomas,
Patrice Chevallier,
Agnès Buzyn,
André Delannoy,
Yves Chalandon, Jean-Paul Vernant,
Philippe Rousselot,
Elizabeth Macintyre,
Norbert Ifrah,
Hervé Dombret,
Marie-Christine Béné
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ABSTRACT: The prognostic significance of CD20 expression in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has been mostly studied in children and yielded conflicting results. In 143 adults with Philadelphia chromosome-negative BCP-ALL treated in the multicentric GRAALL 2003 trial, CD20 positivity over 20% was observed in 32% of patients. While not influencing complete remission achievement, CD20 expression was associated with a higher cumulative incidence of relapse (CIR) at 42 months (P=0.04), independently of the ALL high-risk subset (P=0.025). Notably, the negative impact of CD20 expression on CIR was only observed in patients with a white blood cell count (WBC) over 30x10(9)/L (P=0.006), while not in those with a lower WBC. In the former subgroup, this impact translated into lower event-free survival (15% vs. 59% at 42 months, P=0.003). CD20 expression thus appears to be associated with a worse outcome, which reinforces the interest of evaluating rituximab combined to chemotherapy in CD20-positive adult BCP-ALL. ClinicalTrials.gov ID, NCT00222027.
Haematologica 09/2009; 95(2):324-8. · 6.42 Impact Factor
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Irit Avivi,
Silvia Montoto,
Carme Canals,
John Maertens,
Haifa Al-Ali,
Ghulam J Mufti,
Jürgen Finke,
Anton Schattenberg,
Renato Fanin,
Jan J Cornelissen, Jean-Paul Vernant,
Nigell Russell,
Yves Beguin,
Kirsty Thomson,
Leo F Verdonck,
Guido Kobbe,
Herve Tilly,
Gerard Socié,
Anna Sureda
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ABSTRACT: Matched unrelated donor stem cell transplantation (MUD-SCT) provides the only curative option for patients with follicular lymphoma (FL) who fail conventional therapies and do not have a sibling donor. The purpose of this study was to analyse the outcome of patients with FL treated with MUD-SCT included in the European Group for Blood and Marrow Transplantation registry. 131 patients treated with reduced-intensity conditioning (RIC, n = 87) or conventional myeloablative (CONV, n = 44) MUD-SCT between 2000 and 2005 were included. Median time from diagnosis to MUD-SCT was 47 months and the median number of previous therapeutic regimens was 4 (previous autograft: 47%). RIC recipients were significantly older, with a longer interval from diagnosis to MUD-SCT and had failed a previous autograft more frequently than CONV recipients. Non-relapse mortality (NRM) was 24% and 30% at 100-d and 1-year, respectively. After a median follow-up of 36 months, 17% of the patients developed disease progression, the 3-year progression-free survival (PFS) being 47%. Three-year overall survival (OS) for the whole series was 51%. On multivariate analysis, RIC regimens were associated with at lower NRM and a significantly longer PFS and OS. This retrospective study demonstrated that MUD-SCT results, even in heavily pre-treated populations, in a meaningful PFS and OS.
British Journal of Haematology 09/2009; 147(5):719-28. · 4.94 Impact Factor
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Evelyne Racadot,
Catherine Sebban,
Claude Boucheix,
Bernard David,
Michel Attal,
Josy Reiffers,
Christian Gisselbrecht, Jean-Paul Vernant,
Xavier Troussard,
Patrick Hervé,
Denis Fiere
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ABSTRACT: Among patients included in the multicentric trial ALL87, 95 patients were randomly allocated to purged ABMT arm for post-remission therapy. Immunological phenotyping performed in patients at diagnosis allowed to assigned 51 patients (54%) to the B lineage and 34 patients (36%) to the T lineage. Only 64 patients (67%) actually received ABMT mainly because of early relapses. Fifty-two patients were depleted according to the protocol: 25 B-ALL were depleted with CD10+CD19 mAbs, 19 T-ALL with CD2+CD5+CD7 mAbs and 8 patients received an Asta-Z purged BMT. Among the 12 remaining patients, 4 received Asta-Z purged BMT and 8 an unpurged one. Using an intention to treat analysis, overall survival and event free survival were similar to results observed in chemotherapy group. This study emphasizes the importance of a precise phenotyping at ALL diagnosis which allows specific immunologic bone marrow purging for ABMT.
06/2009; 13(s1):95-98.
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ABSTRACT: In transplant recipients, cytomegalovirus (CMV) resistance to antivirals causes an increasing problem. Here we report the clinical, therapeutic, and virological characteristics of 11 cases of CMV resistance among transplant recipients at high-risk for CMV infection and receiving valganciclovir as a prophylactic, preemptive or maintenance therapy. Active CMV infection was monitored by viral DNA quantification in whole blood, and CMV resistance was assessed by UL97 and UL54 viral gene sequencing. For 10 patients, ganciclovir resistance detected after valganciclovir therapy was associated with one mutation within UL97 phosphotransferase located at codons 460 and 592-603, which constitutes a similar pattern of resistance to what has been reported previously in AIDS patients treated with valganciclovir. For the last patient, two mutations in UL97 and UL54 genes were identified. The start of valganciclovir maintenance treatment after an intravenous curative treatment while CMV DNA is still detectable in peripheral blood might represent a risk factor for the emergence of CMV resistance. The possible emergence of CMV resistance in transplant recipients at high-risk for CMV infection who receive valganciclovir therapy should be taken into account. Among those patients, CMV infection has to be closely monitored in order to detect promptly the emergence of drug-resistance.
Antiviral research 01/2009; 81(2):174-9. · 3.61 Impact Factor
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Vahid Asnafi,
Agnès Buzyn,
Sandrine Le Noir,
Frédéric Baleydier,
Arnauld Simon,
Kheira Beldjord,
Oumedaly Reman,
Francis Witz,
Thierry Fagot,
Emmanuelle Tavernier,
Pascal Turlure,
Thibaut Leguay,
Françoise Huguet, Jean-Paul Vernant,
Francis Daniel,
Marie-Christine Béné,
Norbert Ifrah,
Xavier Thomas,
Hervé Dombret,
Elizabeth Macintyre
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ABSTRACT: Many somatic genetic abnormalities have been identified in T-cell acute lymphoblastic leukemia (T-ALL) but each individual abnormality accounts for a small proportion of cases; therapeutic stratification consequently still relies on classical clinical markers. NOTCH1 and/or FBXW7 mutations both lead to activation of the NOTCH1 pathway and are among the most frequent mutations in T-ALL. We screened 141 adult diagnostic T-ALL samples from patients treated on either the Lymphoblastic Acute Leukemia in Adults (LALA)-94 (n = 87) or the GRAALL-2003 (n = 54) trials. In 88 cases (62%) there were demonstrated NOTCH1 mutations (42% heterodimerization [HD], 10% HD+proline glutamate serine threonine [PEST], 6% PEST, 2% juxtamembrane mutations, 2% transactivation domain [TAD]) and 34 cases (24%) had FBXW7 mutations (21 cases had both NOTCH1 and FBXW7 mutations); 40 cases (28%) were wild type for both. There was no significant correlation between NOTCH1 and/or FBXW7 mutations and clinico-biologic features. Median event-free survival (EFS) and overall survival (OS) were 36 versus 17 months (P = .01) and not reached versus 32 months (P = .004) in patients with NOTCH1 and/or FBXW7 mutations versus other patients, respectively. Multivariate analysis showed that the presence of NOTCH1/FBXW7 mutations was an independent good prognostic factor for EFS and OS (P = .02 and P = .01, respectively). These data demonstrate that NOTCH1 pathway activation by either NOTCH1 or FBXW7 mutation identifies a large group of patients with a favorable outcome that could justify individual therapeutic stratification for T-ALL.
Blood 01/2009; 113(17):3918-24. · 9.90 Impact Factor
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Françoise Huguet,
Thibaut Leguay,
Emmanuel Raffoux,
Xavier Thomas,
Kheira Beldjord,
Eric Delabesse,
Patrice Chevallier,
Agnes Buzyn,
André Delannoy,
Yves Chalandon, Jean-Paul Vernant,
Marina Lafage-Pochitaloff,
Agnès Chassevent,
Véronique Lhéritier,
Elizabeth Macintyre,
Marie-Christine Béné,
Norbert Ifrah,
Hervé Dombret
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ABSTRACT: Retrospective comparisons have suggested that adolescents or teenagers with acute lymphoblastic leukemia (ALL) benefit from pediatric rather than adult chemotherapy regimens. Thus, the aim of the present phase II study was to test a pediatric-inspired treatment, including intensified doses of nonmyelotoxic drugs, such as prednisone, vincristine, or L-asparaginase, in adult patients with ALL up to the age of 60 years.
Between 2003 and 2005, 225 adult patients (median age, 31 years; range, 15 to 60 years) with Philadelphia chromosome-negative ALL were enrolled onto the Group for Research on Adult Acute Lymphoblastic Leukemia 2003 protocol, which included several pediatric options. Some adult options, such as allogeneic stem-cell transplantation for patients with high-risk ALL, were nevertheless retained.
were retrospectively compared with the historical France-Belgium Group for Lymphoblastic Acute Leukemia in Adults 94 (LALA-94) trial experience in 712 patients age 15 to 55 years. Results Complete remission rate was 93.5%. At 42 months, event-free survival (EFS) and overall survival (OS) rates were 55% (95% CI, 48% to 52%) and 60% (95% CI, 53% to 66%), respectively. Age remained an important bad prognostic factor, with 45 years of age as best cutoff. In older versus younger patients, there was a higher cumulative incidence of chemotherapy-related deaths (23% v 5%, respectively; P < .001) and deaths in first CR (22% v 5%, respectively; P < .001), whereas the incidence of relapse remained stable (30% v 32%, respectively). Complete remission rate (P = .02), EFS (P < .001), and OS (P < .001) compared favorably with the previous LALA-94 experience.
These results suggest that pediatric-inspired therapy markedly improves the outcome of adult patients with ALL, at least until the age of 45 years.
Journal of Clinical Oncology 01/2009; 27(6):911-8. · 18.37 Impact Factor
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ABSTRACT: Recovery of human cytomegalovirus (HCMV)-specific T immunity is critical for protection against HCMV disease in the early phase after allogeneic stem cell transplantation (SCT). Using an enzyme-linked immunospot assay with overlapping 15-mer peptides spanning pp65 and immediate-early 1 HCMV proteins, we investigated which HCMV-specific CD8(+) gamma interferon-positive (IFN-gamma(+)) T-cell responses against pp65 and IE-1 were associated with control of HCMV replication in 48 recipients of unmanipulated HLA-matched allografts at 3 months (M3) and 6 months (M6) after SCT and in 23 donors. At M3 after SCT, the magnitude of the pp65-specific IFN-gamma-producing CD8(+) T-cell response was greater in recipients than in donors, regardless of HCMV status. In contrast, expansion of IE-1-specific CD8(+) T cells at M3 was associated with protection against HCMV, and no patient with this expansion had HCMV replication at M3. At M6, the number of HCMV-specific CD8(+) T cells against both pp65 and IE-1 had expanded in all recipients, regardless of their previous levels of HCMV replication. The recipients' HCMV-specific CD8(+) T cells already detectable in related donors were predominantly targeting pp65. In contrast, in 40% of the cases, the HCMV-specific CD8(+) T cells in recipients involved new CD8(+) T-cell specificities undetectable in their related donors and preferentially targeting IE-1. Taken together, these results showed that the delay in reconstituting IE-1-specific CD8(+) T cells is correlated with the lack of protection against HCMV in the first 3 months after SCT. They also show that IE-1 is a major antigenic determinant of the early restoration of protective immunity to HCMV after SCT.
Journal of Virology 09/2008; 82(20):10143-52. · 5.40 Impact Factor
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Philippe Guardiola,
Mathieu Kuentz,
Frédéric Garban,
Didier Blaise,
Josy Reiffers,
Michel Attal,
Agnès Buzyn,
Bruno Lioure,
Pierre Bordigoni,
Nathalie Fegueux,
Marie-Laure Tanguy, Jean-Paul Vernant,
Eliane Gluckman,
Gérard Socié,
French Society of Bone Marrow Transplantation
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ABSTRACT: In this retrospective multicentre study, we analysed the results of 82 consecutive second early allogeneic transplants for primary (n = 28) or secondary (n = 54) graft failures performed between 1985 and 1997 in patients with acute leukaemia (n = 33), aplastic anaemia (n = 29) or chronic myeloid leukaemia (n = 20). HLA-matched siblings were used in 64 cases. The same donors were used for both transplants in 56 cases and the first transplant was T-cell depleted in 30 cases. The median age at transplant was 25 years and the median intertransplant time interval was 2 months. Estimates of the 3-year overall survival and day 100 transplant-related mortality were 30% and 53% respectively. A recipient age < 34 years at transplant, an intertransplant time interval ≥ 80 d and a positive recipient cytomegalovirus serology were predictors of a better outcome. The use of cyclosporin A (CsA) after second transplant had a dramatic impact on outcome, the best results being observed with CsA alone. The day 40 probability of neutrophil recovery was 73%. The use of peripheral blood progenitor cells (PBPCs) was associated with a higher and faster neutrophil recovery. Other factors associated with neutrophil recovery were an intertransplant time interval ≥ 80 d and a positive recipient cytomegalovirus serology. Therefore, second early allogeneic transplantation for graft failure is an effective treatment, especially if patients can receive CsA for graft-versus-host disease prevention and are retransplanted more than 80 d from first transplant.
British Journal of Haematology 08/2008; 111(1):292 - 302. · 4.94 Impact Factor
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Patrice Chevallier,
Mohamad Mohty,
Bruno Lioure,
Gerard Michel,
Nathalie Contentin,
Eric Deconinck,
Pierre Bordigoni, Jean-Paul Vernant,
Mathilde Hunault,
Stéphane Vigouroux,
Didier Blaise,
Reza Tabrizi,
Agnes Buzyn,
Gerard Socie,
Mauricette Michallet,
Christelle Volteau,
Jean-Luc Harousseau
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ABSTRACT: This retrospective multicenter study assessed the outcome of 51 patients with myeloid sarcoma (MS) who underwent allogeneic hematopoietic stem-cell transplantation (alloHSCT).
Most patients had MS presenting in conjunction with acute myeloid leukemia (AML) or after AML. Six patients had isolated MS. The median time between diagnosis and alloHSCT was 8 months (range, 2.8 to 67). Forty patients were in complete remission (CR) at time of alloHSCT.
With a median follow-up of 33 (range, 1 to 182) months, the Kaplan-Meier estimates of overall survival (OS) and disease-free survival were 47% (95% CI, 33% to 61%) and 36% (95% CI, 24% to 50%) at 5 years. Twenty patients (39%) relapsed at a median of 204 (range, 35 to 1151) days after alloHSCT, with relapse being the major cause of death. In a Cox multivariate analysis, age > or = 15 years and remission status at time of alloHSCT (CR v other) were associated with improved OS (hazard ratio [HR], 0.27; 95% CI, 0.12 to 0.65; P = .003; and HR, 0.22; 95% CI, 0.08 to 0.57; P = .002, respectively).
We conclude that first-line alloHSCT performed early in the course of MS is a valid therapeutic option.
Journal of Clinical Oncology 08/2008; 26(30):4940-3. · 18.37 Impact Factor
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Oumedaly Reman,
Arnaud Pigneux,
Françoise Huguet,
Norbert Vey,
André Delannoy,
Nathalie Fegueux,
Stéphane de Botton,
Aspasia Stamatoullas,
Olivier Tournilhac,
Agnès Buzyn,
Christiane Charrin,
Claude Boucheix,
Jean Gabert,
Véronique Lhéritier, Jean-Paul Vernant,
Denis Fière,
Hervé Dombret,
Xavier Thomas
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ABSTRACT: Outcome of adult acute lymphoblastic leukemia (ALL) with central nervous system (CNS) involvement is not clearly defined. We studied 104 patients presenting with CNS involvement at diagnosis among 1493 patients (7%) included into the LALA trials, and 109 patients presenting CNS disease at the time of first relapse among the 709 relapsing patients (15%). Eighty-seven patients (84%) with CNS leukemia at diagnosis achieved complete remission (CR). Fifty-three patients underwent stem cell transplantation (SCT): 25 allogeneic SCT, 28 autologous SCT, while 34 continued with chemotherapy alone. Seven-year overall survival (OS) and disease-free survival (DFS) were 34% and 35%, respectively. There were no significant differences in terms of CR, OS and DFS among patients with CNS involvement at diagnosis and those without CNS disease. There were also no differences among the two groups regarding T lineage ALL, B lineage ALL, and among those who underwent SCT. After a first relapse, 38 patients with CNS recurrence (35%) achieved a second CR. The median OS was 6.3 months. Outcome was similar to that of relapsing patients without CNS disease. CNS leukemia in adult ALL is uncommon at diagnosis as well as at the time of first relapse. With intensification therapy, patients with CNS leukemia at diagnosis have a similar outcome than those who did not present with CNS involvement. CNS leukemia at first relapse remains of similar poor prognosis than all other adult ALL in first relapse.
Leukemia Research 06/2008; 32(11):1741-50. · 2.92 Impact Factor
