Center Regional Of Cancerologie Et Therapie Cellulaire Pediatrique

Clermont-Ferrand, France

Center Regional Of Cancerologie Et Therapie Cellulaire Pediatrique

Clermont-Ferrand, France
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Marabelle A.,Institute dHematologie et dOncologie Pediatrique | Marabelle A.,Center Regional Of Cancerologie Et Therapie Cellulaire Pediatrique | Merlin E.,Center Regional Of Cancerologie Et Therapie Cellulaire Pediatrique | Merlin E.,French Institute of Health and Medical Research | And 20 more authors.
Pediatric Blood and Cancer | Year: 2011

Background: Graft contamination has been blamed for causing relapse in children with high-risk neuroblastoma (HRNB) after autologous hematopoietic stem cell transplantation (HSCT). Procedure: We report the long-term results of hematopoietic reconstitution, post-transplant complications, and clinical outcome of 44 children with HRNB treated with busulfan/melphalan high-dose chemotherapy followed by transplantation of purged CD34+ immunoselected autologous peripheral HSCT. Minimal residual disease (MRD) of grafts was evaluated by anti-GD2 immunofluorescence or tyrosine hydroxylase reverse transcriptase-polymerase chain reaction (RT-PCR). Results: Contaminating neuroblasts were found in 19/38 grafts (50%) before CD34+ positive selection, and none after (technique sensitivity of one cell in 10 5). A median of 6.5 × 10 6 CD34+ cells/kg (range 0.8-23.7) were transplanted with only 2% of TRM. Neutrophils and platelet recovery occurred within a median of 12 days (range 9-47) and 44 days (range 12-259), respectively, without any secondary graft failure. Twenty-three percents of patients experienced a sepsis (10/44) and 14% a pyelonephritis (6/44). Recurrence of varicella zoster virus occurred in 21% of patients (9/44). Negative RT-PCR MRD within the leukapheresis product and cis-retinoic acid therapy were significantly and independently associated to a better survival (P < 0.05). Overall and event-free survivals at 5 years post-transplant were at 59.3% and 48.3% respectively. Conclusions: Besides high rates of manageable infections due to late immune recovery, transplantation with CD34+ immunoselected grafts in HRNB children was feasible and did not affect long-term hematopoiesis. © 2010 Wiley-Liss, Inc.


Paillard C.,Center Regional Of Cancerologie Et Therapie Cellulaire Pediatrique | Rochette E.,Center Regional Of Cancerologie Et Therapie Cellulaire Pediatrique | Rochette E.,French Institute of Health and Medical Research | Lutz P.,Service de Pediatrie i | And 23 more authors.
Bone Marrow Transplantation | Year: 2013

We report French prospective experience with reduced-intensity conditioning-allo-SCT in 46 patients (median age: 15.5 years, 4.8-20.2) presenting high-risk AL (n=11), Hodgkin's lymphoma (n=15) or solid tumors (n=20). Graft sources were BM (n=21), PBSC (n=20) and cord blood (CB; n=5) from related (n=20) or unrelated (n=26) donors. For CB grafts, only one patient out of five achieved sustained engraftment. For PBSC/BM grafts, engraftment rate was 95%, hematopoietic recovery times were not significantly different between BM, PBSC, sibling or unrelated grafts, day+100. Full donor chimerism was achieved in 94% of patients, and incidences of primary acute GVHD and chronic GVHD were 49% and 14%, respectively. Underlying disease was fatal in 39% of patients. TRM was 6.9%. Three-year OS was 49.15%. OS and EFS were not significantly different between patients transplanted with different grafts and with or without primary GVHD. Patients with solid tumor or measurable disease at transplant had poorer outcomes. Three-year EFS: 33.3% for ALL, 75.0% for AML, 51.8% for Hodgkin's lymphoma, 28.6% for neuroblastoma and 22.2% for sarcoma patients. This multicentre study concluded that Bu/fludarabine/anti-thymocyte globulin conditioning with PB or BM, related or unrelated grafts in patients with various malignancies at high-risk for transplantation toxicity results in high engraftment rates, low TRM and acceptable survival.


Merlin E.,Center Regional Of Cancerologie Et Therapie Cellulaire Pediatrique | Merlin E.,French Institute of Health and Medical Research | Kanold J.,Center Regional Of Cancerologie Et Therapie Cellulaire Pediatrique | Kanold J.,French Institute of Health and Medical Research | And 2 more authors.
Expert Opinion on Biological Therapy | Year: 2012

Extracorporeal photochemotherapy has been used for almost three decades for the treatment of several T-cell-mediated diseases, and its efficacy has been proven in few well-designed controlled randomized trials. However, to date, there are no reliable data on a hypothetic dose-effect, optimal rhythm of administration, drug interactions, or the "pharmacokinetics" and "pharmacodynamics" of this cell therapy. In particular, it is not clear whether ECP gains to be used in combination with immunosuppressive or immunomodulative drugs. In the future, clinical trials may address these issues in order to clarify the most beneficial use of a cell therapy which absence of toxicity is uniformly recognized. © 2012 Informa UK, Ltd.


Merlin E.,Center Regional Of Cancerologie Et Therapie Cellulaire Pediatrique | Merlin E.,French Institute of Health and Medical Research | Goncalves-Mendes N.,Center Regional Of Cancerologie Et Therapie Cellulaire Pediatrique | Hannani D.,French Institute of Health and Medical Research | And 9 more authors.
Transplant Immunology | Year: 2011

The benefits of extracorporeal photochemotherapy (ECP; psoralen and UVA exposure of blood mononuclear cells) in graft-versus-host-disease (GVHD) are well-recognized, but the mechanisms of action remain elusive. As the metabolism of l-arginine in immune cells is known to play a role in immune tolerance, we investigated the effect of ECP on arginine metabolism, and the influence of extracellular l -arginine concentration on the response to ECP in cells from patients on therapy by ECP for a GVHD and healthy donors cultured before and after ECP in the presence of different concentrations of arginine (0, 50, 100, 200 and 1000 μmol/l). At baseline arginine was not metabolized through the same pathway in patients and donors. When cells were exposed to ECP, the production of ornithine but not NO° was enhanced, while mRNA of arginase 1 was up-regulated but not INOS. In GVHD patients, increasing arginine concentration resulted in down-regulation of IFNγ and TNFα mRNA expression, whereas IL10 was up-regulated especially at physiological plasma levels (between 0 and 100 μM). Overall, our study shows that ECP orients the metabolism of arginine toward the arginase pathway together with shifting the cytokine profile toward IL-10, providing new insights into the enigmatic mechanism of action of ECP. © 2010 Elsevier B.V.


Desvignes F.,Pole de Gynecologie obstetrique reproduction Humaine | Pouly J.L.,Pole de Gynecologie obstetrique reproduction Humaine | Janny L.,Laboratoire AMP | Canis M.,Pole de Gynecologie obstetrique reproduction Humaine | And 4 more authors.
Gynecologie Obstetrique Fertilite | Year: 2014

Objectives Ovarian Tissue Cryopreservation (OTC) is a very promising approach of fertility preservation for women and young patients who have to follow gonadotoxic treatments (chemotherapy, radiotherapy...). The aim of this study was to analyse the indications and the outcomes of the patients who had OTC in our center during the last 17 years. Patients and methods The study is retrospective. Forty-six patients, who underwent OTC in the Laboratory of Reproductive Biology of the University Hospital of Clermont-Ferrand, between January 1997 and December 2009, were included. Results The average age on the day of ovarian tissue harvesting was 19.5 years. Fifty-two percent of the patients were minor. In order of decreasing frequency, the diseases for which OTC has been proposed were hematologic, ovarian tumors, sarcoma ou PNET and breast neoplasia. In 93.5 %, the harvesting of ovarian cortex was performed by laparoscopy. After OTC, 82.6 % of the patients were treated by chemotherapy. A bone marrow transplant was performed for 48 % of the study patients. At the time of data collection, 57 % of the patients who had evaluation of their ovarian function presented premature ovarian failure. Eight patients had one or more pregnancies after treatment. It was a natural pregnancy for five of them. The three others were obtained by medically assisted procreation (in vitro fertilization and oocyte donation). Discussion and conclusion We report a long-term follow-up of patients treated in our center for OTC. The originality of our study is to evaluate all aspects of OTC from the decision to propose the patients an OTC to their outcomes several years after the ovarian tissue harvesting. It is therefore a multidisciplinary approach both oncology, gynecological and pediatric whereas OTC is often considered restrictively in the literature. Finally, it seems to be essential to establish a specific medical care for these patients. This monitoring will allow an adequate assessment of pubertal development and ovarian function, management of estrogen deficiency and secondary infertility, supporting patients in their desire for motherhood. © 2014 Elsevier Masson SAS. All rights reserved.


Hannani D.,French Institute of Health and Medical Research | Hannani D.,Joseph Fourier University | Merlin E.,Center Regional Of Cancerologie Et Therapie Cellulaire Pediatrique | Gabert F.,French Institute of Health and Medical Research | And 11 more authors.
Transplantation | Year: 2010

Background. Graft versus host disease (GvHD) is the main complication after hematopoietic stem-cell transplantation. Extracorporeal photochemotherapy (ECP) is a cell therapy currently used for the treatment of T-cell-mediated diseases and seems as a valuable second-line therapy for patients suffering from steroid-refractory acute or chronic GvHD. ECP induces the apoptosis of treated cells and is believed to elicit a specific immune regulation of alloreactive T cells through repeated apoptotic T-cell infusions. However, its mechanisms of action have not yet been elucidated. In GvHD, alloreactive but not nonalloreactive T cells are continuously activated by their environment. We hypothesized that ECP has a differential apoptotic effect on activated compared with resting T cells. METHOD.: The ECP-induced apoptosis of resting and activated T cells from patients with chronic GvHD was assessed. The kinetic of apoptosis was also evaluated using several triggers of T-cell activation such as mitogenic or antigen-specific activation. The influence of survival cytokines (interleukin-2, -7, and -15) was also evaluated. Results. Activated T cells from patients with chronic GvHD underwent apoptosis faster than resting T cells. This phenomenon was confirmed using mitogenic and antigen-specific activated T cells from healthy donors and cannot be delayed by protective cytokines. Conclusions. ECP induces a faster apoptosis of alloreactive activated T cells than of nonalloreactive resting T cells in GvHD and more generally of activated T cells than of resting T cells. These novel findings provide new insights about the ECP-induced specific control of pathogenic T cells in GvHD. © 2010 Lippincott Williams & Wilkins.


PubMed | Center Regional Of Cancerologie Et Therapie Cellulaire Pediatrique
Type: Journal Article | Journal: Cytotherapy | Year: 2011

The clinical benefits of extracorporeal photochemotherapy (ECP) are well recognized, but its clinical use is limited by logistical difficulties, especially because of the need to perform repeated aphereses. The cryopreservation of mononuclear cells could allow maintenance of the ECP schedule while reducing the number of aphereses. The aim of this work was to assess whether previous cryopreservation impairs the immunomodulatory function of ECP-treated peripheral blood mononuclear cells (PBMC).Fresh or previously cryopreserved PBMC were exposed to ECP and added on day 0 into a mixed leukocyte reaction. Proliferation of alloreactive lymphocytes was measured by carboxyfluorescein succinimidyl ester (CFSE) dye dilution. Apoptosis was quantified by annexin-7AAD staining.ECP-induced apoptosis was slightly increased in cryopreserved cells but the kinetics of apoptosis were similar to fresh cells. Lymphocytes stimulated in the presence of ECP-treated PBMC displayed a significant decrease in proliferation. The suppression was enforced when ECP-treated cells had been activated previously by allogeneic stimulation. Cryopreservation before ECP exposure did not impact apoptosis triggering or anti-proliferative properties of ECP-treated cells.Cryopreservation before ECP does not impair the immunomodulatory effects of treated cells. These data warrant investigation of the clinical use of cryopreserved PBMC for ECP.


PubMed | Center Regional Of Cancerologie Et Therapie Cellulaire Pediatrique
Type: Journal Article | Journal: Transplant immunology | Year: 2010

The benefits of extracorporeal photochemotherapy (ECP; psoralen and UVA exposure of blood mononuclear cells) in graft-versus-host-disease (GVHD) are well-recognized, but the mechanisms of action remain elusive. As the metabolism of l-arginine in immune cells is known to play a role in immune tolerance, we investigated the effect of ECP on arginine metabolism, and the influence of extracellular l-arginine concentration on the response to ECP in cells from patients on therapy by ECP for a GVHD and healthy donors cultured before and after ECP in the presence of different concentrations of arginine (0, 50, 100, 200 and 1000 mol/l). At baseline arginine was not metabolized through the same pathway in patients and donors. When cells were exposed to ECP, the production of ornithine but not NO was enhanced, while mRNA of arginase 1 was up-regulated but not INOS. In GVHD patients, increasing arginine concentration resulted in down-regulation of IFN and TNF mRNA expression, whereas IL10 was up-regulated especially at physiological plasma levels (between 0 and 100 M). Overall, our study shows that ECP orients the metabolism of arginine toward the arginase pathway together with shifting the cytokine profile toward IL-10, providing new insights into the enigmatic mechanism of action of ECP.


We report French prospective experience with reduced-intensity conditioning-allo-SCT in 46 patients (median age: 15.5 years, 4.8-20.2) presenting high-risk AL (n=11), Hodgkins lymphoma (n=15) or solid tumors (n=20). Graft sources were BM (n=21), PBSC (n=20) and cord blood (CB; n=5) from related (n=20) or unrelated (n=26) donors. For CB grafts, only one patient out of five achieved sustained engraftment. For PBSC/BM grafts, engraftment rate was 95%, hematopoietic recovery times were not significantly different between BM, PBSC, sibling or unrelated grafts, day+100. Full donor chimerism was achieved in 94% of patients, and incidences of primary acute GVHD and chronic GVHD were 49% and 14%, respectively. Underlying disease was fatal in 39% of patients. TRM was 6.9%. Three-year OS was 49.15%. OS and EFS were not significantly different between patients transplanted with different grafts and with or without primary GVHD. Patients with solid tumor or measurable disease at transplant had poorer outcomes. Three-year EFS: 33.3% for ALL, 75.0% for AML, 51.8% for Hodgkins lymphoma, 28.6% for neuroblastoma and 22.2% for sarcoma patients. This multicentre study concluded that Bu/fludarabine/anti-thymocyte globulin conditioning with PB or BM, related or unrelated grafts in patients with various malignancies at high-risk for transplantation toxicity results in high engraftment rates, low TRM and acceptable survival.


PubMed | Center Regional Of Cancerologie Et Therapie Cellulaire Pediatrique
Type: | Journal: Journal of inherited metabolic disease | Year: 2012

To date, little is known about the fertility of women suffering from mucopolysaccharidosis type I (MPS I). We report on a female patient with MPS I treated by allogeneic bone marrow transplantation (BMT) at the age of 4 years (after a conditioning regimen containing busulfan 16 mg/kg and cyclophosphamide 100 mg/kg) who had four successful pregnancies without any reproductive assistance. Clinical and biological examinations of the children were normal. On the basis of this case, we discuss the fertility counselling of female MPS I patients at the time of BMT.

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