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Hematopoietic cell transplantation (HCT) is the curative treatment for many malignant and non-malignant blood disorders and some solid cancers. However, transplant procedures are considered tertiary level care requiring a high degree of technicality and expertise and generating very high costs for hospital structures in developing countries as well as for patients without health insurance. During the 11th annual harmonization workshops of the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC), a designated working group reviewed the literature in order to elaborate unified guidelines, for developing the transplant activity in emerging countries. Access to infrastructure must comply with international standards and therefore requires a hospital system already in place, capable of accommodating and supporting the HCT activity. In addition, the commitment of the state and the establishment for the financing of the project seems essential.

CAR-T cells are an innovative treatment for an increasing number of patients, particularly since the extension of their indication to mantle lymphoma and multiple myeloma. Several complications of CAR T-cell therapy, that were first described as exceptional, have now been reported in series of patients, since its first clinical use in 2011. Among them, cardiac complications, delayed cytopenias, acute and chronic Graft versus Host Disease, and tumoral lysis syndrome are recognized as specific potent complications following CAR T-cells infusion. During the twelfth edition of practice harmonization workshops of the Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC), a working group focused its work on the management of these complications with focuses the epidemiology, the physiopathology and the risk factors of these 4 side effects. Our recommendations apply to commercial CAR-T cells, in order to guide strategies for the management of complications associated with this new therapeutic approach.

Background There are currently few data on the outcome of acute myeloid leukemia (AML) in adolescents after allogeneic HSCT. The aim of this study is to describe the outcome and its specific risk factors for children, adolescents and young adults after a first allogeneic HSCT for AML. Methods In this retrospective study, we compared the outcome of AML patients receiving a first allogeneic HSCT between 2005 and 2017 according to their age at transplantation’s time: children (n = 564), adolescent and post-adolescent (APA) patients (15–25 years, n = 647) and young adults (26–40 years; n = 1434). Results With a median follow-up of 4.37 years (min–max 0.18–14.73 years), the probability of 2-year overall survival (OS) was 71.4% in children, 61.1% in APA patients and 62.9% in young adults (p = 0.0009 for intergroup difference). Both relapse and non-relapse mortality (NRM) Cumulative Incidence (CI) estimated at 2 years were different between the age groups (30.8% for children, 35.2% for APA patients and 29.4% for young adults—p = 0.0254, and 7.0% for children, 10.6% for APA patients and 14.2% for young adults, p p Conclusion Age is an independent risk factor for NRM and extensive chronic GVHD. This study suggests that APA patients with AML could be beneficially treated with a chemotherapy-based MAC regimen and bone marrow as a stem cells source.

Myeloid-derived suppressor cells (MDSCs) are innate immune cells that acquire the capacity to suppress adaptive immune responses. In the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT), MDSCs (in the donor graft and in the recipient, after allo-HSCT) might mediate immune suppression through multiple mechanisms. However, it remains unclear how MDSCs can be distinguished from their normal myeloid counterparts in the hematopoietic stem cell donor graft and during immune reconstitution after allo-HSCT in the recipient. Our ability to understand their exact role in allo-HSCT is limited by the absence of a specific gene signature or surface markers for identifying MDSCs among myeloid cells and by their plasticity in different microenvironments. According to various studies, MDSCs might induce transplant tolerance and control graft vs. host disease (GVHD), but their impact on the graft vs. tumor effect (GVT) is not fully understood. In fact, we know that MDSCs commonly expand in patients with cancer, and they are thought to promote hematological malignancy progression. However, little is known about whether depleting them might be an effective strategy for enhancing GVT effects. Here, we review data published over the past 40 years on allo-HSCT to delineate the different MDSC subsets, and their abilities to induce transplant tolerance and preserve the GVT effect. This review will provide a basis for determining whether one MDSC subset might be proposed as the most appropriate candidate for cellular therapies, due to its ability to modulate GVHD.

We included 255 patients from the L.E.A. French long-term follow-up cohort. All had received hematopoietic stem cell transplantation (HSCT) and/or testicular radiation for childhood acute leukemia and were older than 18 years at last L.E.A. evaluation. Total testosterone deficiency was defined as a12 nmol/l level or by substitutive therapy, partial deficiency as normal testosterone with elevated luteinizing hormone (10 UI/l). After myeloablative total body irradiation (n = 178), 55.6% had total deficiency, 15.7% partial deficiency, and 28.7% were normal. A 4-6 Gy testicular boost and a younger age at HSCT increased significantly the risk. After a Busulfan-containing myeloablative conditioning regimen (n = 53), 28.3% had total deficiency, 15.1% partial deficiency, 56.6% were normal (62.5% vs. 0% in patients without or with additional testicular radiation). A 24-Gy testicular radiation without HSCT induced total or partial deficiency in 71.4% and 28.6%, respectively (n = 21). Total testosterone deficiency increased the risk of metabolic syndrome: 25% vs. 12.1% in men with partial testosterone deficiency and 8.8% when Leydig cell function was normal (p = 0.031).

Summary Long bones from mammals host blood cell formation and contain multiple cell types, including adipocytes. Overabundance of adipocytes in bone marrow is associated with pathological conditions such as age-related osteoporosis or marrow aplasia induced by irradiation or chemotherapy. However, physiological functions of bone marrow adipocytes are poorly documented. Here, we investigated the consequence of total adipocyte deficiency on bone homeostasis in mice. By generating adipocyte-deficient mice using PPARγ deletion, we found that lipoatrophy leads to dramatic alterations of trabecular and cortical femoral bone. Cortical bone is extremely porous and poorly defined due to the excessive presence of active bone-resorbing osteoclasts. Hence, our observation demonstrates that osteoclast formation occurs in the absence of PPARγ despite its supposed role in osteoclastogenesis. We found that two independent models of lipoatrophy recapitulated this phenotype, demonstrating that hyperosteoclastogenesis is not intrinsically linked to PPARγ deficiency. We further showed that adiponectin, a cytokine produced by adipocytes and mesenchymal stromal cells, is a potent inhibitor of osteoclastogenesis in vitro and in vivo . Furthermore, pharmacological activation of adiponectin receptors by the synthetic agonist AdipoRon inhibits mature osteoclast activity both in mouse and human by blocking podosome formation. Mechanistically, adiponectin-inhibiting action on mature osteoclasts occurs though AMPK activation, thereby demonstrating that even fully differentiated and active, osteoclasts are sensitive to adipose-derived signals. Finally, we showed that AdipoRon inhibits bone erosion in vivo in a murine model of inflammatory bone loss. Collectively, these data reveal that adiponectin-producing cells are key regulators of bone homeostasis, and that preserving functional bone marrow adiponectin pathway can improve bone integrity in the context of metabolic and inflammatory disorders.

Neurological complications are common after allogeneic hematopoietic stem cell transplantation (HSCT) but it is often difficult to define the cause among infections, Graft- versus-Host Disease (GvHD), adverse effects from medications or nervous system disease (for instance autoimmune disease). We describe a rare case of ocular GvHD associated with the reduction of tacrolimus in a female patient, three months after allogeneic HSCT for acute myeloblastic leukemia in second remission. The multidisciplinary investigations led to the diagnosis of retrobulbar optic neuritis associated with the expression of auto (allo)immune markers. Quickly after rising dosage of tacrolimus to therapeutic level, the ocular symptoms disappeared without relapse thereafter.

Introduction: Adolescents and Young Adults (AYA) represent a specific population in the Acute Lymphoblastic Leukemia (ALL) landscape, often presenting high-risk diseases and increased chemotherapy-related toxicities. Indications of Hematopoietic Stem Cell Transplantation for pediatric patients (HSCT) have been restricted to those with early poor response to chemotherapy. The same trend has led to a decrease of HSCT indications in AYAs, which are nevertheless still more frequent than in younger counterpart. Outcomes of AYAs after HSCT seemed to be worse than the ones of children in two previous studies published in 2013 and 2014. In Minneapolis, the decrease of overall survival in AYA was attributed to an excess of Treatment Related mortality (TRM) (28% versus 14%; p=0.04), but because of small numbers, factors influencing TRM were not identified. Our study aimed to compare, in a large cohort, the outcomes of children and AYA with ALL after HSCT and to determine factors influencing potential differences. Material and Methods: All patients aged between 1 and 25 years, reported in the SFGM-TC (Francophone Society of bone marrow transplantation and cellular therapy) registry, who received a first HSCT in treatment for ALL between 2005 and 2012 were included. The AYA group was defined by age range between 15 and 25 years old, according to European studies and the SFGM-TC. Data about diagnosis and transplantation procedure were prospectively collected in the registry. Before transplant procedure, patients or their parents/guardians provide a signed consent in order to be included in the registry. Results: 891 patients were included, 494 children and 397 AYA. Median time of follow up was 45.6 months (0 to 114). HSCT was performed in first CR for 56.8% of the AYAs, whereas 57.5% of children received HSCT in second CR or more advanced phase (p Five-year OS was lower in AYA 53.1% versus 64% (p = 0.0012) and we confirmed higher 5-years TRM in AYA 19% versus 13% (p=0.04). TRM incidence markedly rose after 10 years of age (from 9% before 10 years old to 20% between 10 and 15 years, and 17% after 15 years). Graft versus host disease and Relapse Free Survival probability (GRFS) was lower in AYA: 36% versus 47% (p=0.007), while Cumulative Incidence of Relapse (CIR) and acute Graft versus Host Disease (GvHD) incidence were both similar in our two groups: 32% and 61% in AYAs versus 27% and 59% in children, (p=0.19 and p=0.62), respectively. Thus, chronic GvHD, which occurred more frequently in AYA than in children (32% versus 19%, p In our multivariate analysis, two factors were associated with higher risk of cGvHD: use of PBSC as stem cell source (HR 1.41 [0.96-2.07], p=0.083), and absence of ATG use (HR associated with use of ATG: 0.62 [0.42-0.92], p=0.017) (Figure 3). Of note a subgroup analysis in patients who received a bone marrow transplant after a MAC, showed no TRM difference between AYA and children. Conclusion: AYA or patients aged more than 10 years, compared to ones aged less than 10 years have a worse outcome after HSCT for ALL. Excess of death in this specific population is mainly due cGvHD. Transplantation practices in those patients, particularly choice of stem cells source and GvHD prophylaxis, should be discussed. Their treatment adherence should also be questioned and reinforced by development of multidisciplinary teams. Figure 1 Figure 1. Disclosures Peffault De Latour: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Jazz Pharmaceuticals: Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Forcade: Novartis: Other: travel grant.

Background: Pediatric patients younger than two years of age with acute myeloid leukemia (AML) commonly receive a chemotherapy-based myeloablative conditioning regimen before allogeneic hematopoietic stem cell transplantation (HSCT). The optimal choice of cytotoxic agents is still controversial. Methods: A retrospective EBMT-registry based study was conducted to investigate the impact of different chemotherapy-based conditionings on the outcomes in young children. Children younger than two years of age receiving a first HSCT of bone marrow (BM), peripheral blood stem cells (PBSC) or cord blood (CB) from matched siblings (MSD) or unrelated donors (UD) in first complete remission (CR1) between 2000 and 2019 were included. Busulfan/Cyclophosphamide (BuCy) and BuCy/Melphalan (BuCyMel) were the most frequent combinations on which this analysis focused. The primary endpoint was leukemia-free survival (LFS). Multivariate analysis adjusting for differences between the conditioning regimens and risk factors influencing outcome was performed using the Cox's proportional hazards regression model. Results: 289 patients (56% male) transplanted at a median age of 1.2 years (IQR 0.9-1.6) after BuCy (164, 57%) or BuCyMel (125, 43%) were included. 184 (64%) patients received BM, 71 (24%) CB and 34 (12%) PBSC from UD (201, 70%) and MSD (88, 30%). In-vivo T-cell-depletion (TCD) was performed in 160 (58%, missing data 14) of the HSCTs with anti-thymocyte-globulin (ATG, 153) or alemtuzumab (7). Ex-vivo TCD was performed in 13 (5%, missing data 3) of the HSCTs. Graft-versus-host-disease (GvHD)-prophylaxis was Cyclosporin-A-based in 90% of the HSCTs. Median follow-up (FU) was 4.9 years (95% CI 3.9-5.5). After a median FU of 4 years, 4-y-LFS after BuCyMel (74.3%, 95% CI 65.1-81.4) was significantly better compared to BuCy (59.7%, 95% CI 51.2-67.2), hazard ratio (HR) 0.56 (95% CI 0.35-0.90, P=0.02). Overall survival (4-y-OS) after BuCyMel (77.2%, 95% CI 68.1-84.0) was significantly better compared to BuCy (66.6%, 95% CI 58.0-73.8), HR=0.58 (95% CI 0.35-0.97, P=0.04). No significant differences were found in the probability of relapse (4-y-RI (whole cohort) 26.2% (95% CI 21.0-31.7), HR of BuCyMel 0.59 (95% CI 0.34-1.02), P=0.06), non-relapse mortality (4-y-NRM (whole cohort) 7.8% (95% CI 5.0-11.4), HR of BuCyMel 0.49 (95% CI 0.19-1.24), P=0.13) and incidence of acute grade II-IV GvHD at day 100 (day-100-aGvHD II-IV (whole cohort) 36.8% (95% CI 31.2-42.5), HR of BuCyMel 0.59 (95% CI 0.35-1.01), P=0.06). Incidence of chronic GvHD (4-y-cGvHD (whole cohort)) was 9.8% (95%-CI 6.3-14.2). The donor type had no significant influence on the outcome. Conclusion: Bu-based conditionings of HSCT for infants with AML at high risk of relapse offer a high probability of cure. Conditioning with three alkylators (BuCyMel) resulted in better LFS and OS compared with two alkylators (BuCy) without significantly increasing the risk of both NRM and aGvHD. Future trials will evaluate the impact of the more recently introduced alkylator Treosulfan within the conditioning of HSCT in pediatric AML. Disclosures Peters: Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Moraleda: Pfizer: Other: Educational Grants, Research Funding; Sanofi: Other: Educational Grants, Research Funding; MSD: Other: Educational Grants, Research Funding; ROCHE: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Takeda: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Sandoz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Gilead: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Educational Grants, Research Funding; NovoNordisk: Other: Educational Grants, Research Funding; Janssen: Other: Educational Grants, Research Funding; Celgene: Other: Educational Grants, Research Funding; Amgen: Other: Educational Grants, Research Funding. Biffi: BlueBirdBio: Consultancy, Other: Advisory Board. Corbacioglu: Gentium/Jazz Pharmaceuticals: Consultancy, Honoraria.

Hematopoietic stem cell transplantation is a well-established efficient therapy for hematological diseases, but Graft-Versus-Host Disease (GVHD) is a major and frequent complication encumbering its outcome despite the administration of calcineurin inhibitor based GvHD-prophylaxis. Corticosteroids represent the worldwide first line treatment, however in case of steroid refractory acute GVHD there is no consensus about a subsequent treatment although Ruxolitinib is subject to a phase III trial. Multiple molecules have been tried, most of them immunosuppressive, increasing the risk of deadly infections and transplantation-related mortality (TRM). Recent studies reported that mesenchymal stromal cells (MSC) infusion which have immune modulatory abilities might be effective and harmless in steroid or treatment-refractory GVHD (R-GVHD). In France, MSCs are considered as an Advanced Therapy Medicinal Product. For 4 years, its administration as a compassionate use is subject to approval by an expert committee from SFGM-TC before its validation by the French regulatory agency (ANSM). We retrospectively analyzed the demands for MSC use in France since 2011 for patients suffering from R-GVHD. We evaluated the response at day 28 (range 23-28) and at the last follow-up and its safety. Eleven demands were validated by both expert committee and ANSM, 8 patients (pts) received ex-vivo expanded MSCs, 1 pt refused the therapy, 1 infusion was postponed due to COVID-19 related sanitary crisis and the last 1 didn't receive MSCs due to relapse. Among pts who received MSCs, median age was 6 years (2-69), sex ratio was 0,6. All pts underwent their first HSCT for either malignant disease (62,5%) or non-malignant disease (37,5%). Four pts were transplanted from sibling donor, 2 pts from mismatched unrelated donors and 2 pts from haplo-identical donors. Stem cells source was bone marrow for 4 pts, peripheral blood stem cells for 3 and cord blood for 1. Donors median age was 28,8 years (0-49,5), 1 male had a female donor. Six pts got a myeloablative conditioning regimen (TBI-based for 2). All pts received a ciclosporin-based (CSA) GVHD prophylaxis (CSA alone, n=1; CSA + Mycophenolate Mofetil (MMF) or Methotrexate, n=7). Five pts had ATG. Six pts were suffering from acute GVHD, while 2 from extensive chronic GVHD (cGVHD). All 6 pts with acute GVHD presented a grade III or IV, refractory to corticosteroids and at least 2 other lines of GVHD therapy. All but one had a multipolar GVHD with at least 2 affected organs. Five pts were still taking corticosteroids, and six were taking additional immunosuppressive molecules (Tacrolimus, Ruxolitinib, Etanercetp, Inolimomab, MMF) at time of MSC infusion. Five pts received German commercialized MSCs (Obnitixâ, MEDAC, Germany; see Bader et al, 2018), 2 get mother's derived MSCs (not the initial donor), and 1 from a third-party donor. A median of 4 infusions were administered (1-4), once a week for 4 weeks. Mean single dose of MSCs was 1.23.10e6/kg (range: 0,86 - 3). No toxicity was reported except for 1 pt who experienced anaphylactic reaction within minutes, leading to the interruption of infusion (mother's derived MSCs prepared with fetal bovine serum where all other preparations were performed with platelet lysate). The median time from GVHD onset to first MSC infusion was 135 days (63-457). Overall response rate was 86% (6/7) at the first and at the last evaluation with 1 complete response (CR) and 5 partial responses (reduction of at least one grade of at least one affected organ). One pt did not respond and the last 1 was not evaluable due to anaphylactic reaction. Both were suffering from cGVHD. Among the seven pts who received complete MSC infusions, median follow-up was 1,5 months (1,1-18,5) due to premature TRM, overall survival (OS) at six months was 33,3%. Five pts died, all of them from a transplantation-related cause: GVHD n=2, severe infections n=3. Literature reported better outcomes lately, Bader and al, 2019 reported a 64% OS at 6 months and 51% of CR at last follow up. Those disparities might be explained by a delayed treatment after GVHD onset (135 days versus 28 days) and a median of 3 (2-10) therapies after receiving corticosteroids before MSC infusion due to difficulty to obtain MSCs in France. Besides, we included patient suffering from R-cGVHD. Regarding those results, MSC efficacy and safety should be confirmed in a proper clinical trial. Figure Disclosures Rubio: Neovii: Research Funding; Novartis: Honoraria; MSD: Honoraria; Gilead: Honoraria; Medac: Consultancy. Dalle:Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum: Consultancy, Honoraria; Medac: Consultancy, Honoraria; Orchard: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Relapse of acute myeloblastic leukemia (AML) after first allogenic hematopoietic stem-cell transplantation (allo-HSCT) is a fatal complication. Sixty-five children transplanted for AML were included in a prospective national study from June 2005 to July 2008 to explore the feasibility of preemptive immune modulation based on the monitoring of blood chimerism. Relapse occurred in 23 patients (35%). The median time between the last complete chimerism and relapse was 13.5 days (2-138). Prompt discontinuation of cyclosporin and the administration of donor lymphocyte infusions (DLIs) based on chimerism monitoring failed as a preemptive tool, either for detecting relapse or certifying long-term remission.

Recommendations for visits or environment restrictions, and sometimes for food are usually well described for inpatient within HSCT unit procedures where those measures are less precise and detailed for outpatient from the discharge to the immune reconstitution achievement. The present paper main objective is to define risk patient groups depending on time, immune-suppressive drugs as well as graft-versus-host disease and immune reconstitution. We define here 3 risk patient groups and propose measures about house cleaning, pets, schools, social activities, hygiene, foods, sexual life and siblings.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative procedure in patients with Shwachman–Diamond syndrome (SDS) with bone marrow abnormalities. The results of 74 patients with SDS (6 acute myeloid leukemia, 7 myelodysplastic syndrome, and 61 bone marrow failure) treated with HSCT between 1988 and 2016 are reported. The donor source was: 24% sibling, 8% parent, and 68% unrelated donor. The stem cell source was: 70% bone marrow, 19% peripheral blood stem cells, and 11% cord blood. The conditioning regimen was myeloablative in 54% and reduced intensity in 46%. Neutrophil engraftment was achieved in 84% of patients after a median time of 17.5 days. Graft failure occurred in 15% of HSCTs. Grades I–IV acute and chronic GVHD were observed in 55% and 20% of patients, respectively. After a median follow-up of 7.3 years (95% CI 4.8–10.2), 28 patients died for progression/relapse (7) or toxicity (21). The 5-year overall survival and nonrelapse mortality were 63.3% (95% CI 50.8–73.4) and 19.8% (95% CI 10.8–30.8), respectively. In conclusion, this is the largest series so far reported and confirms that HSCT is a suitable option for patients with SDS. Further efforts are needed to lower transplant-related toxicity and reduce graft failure.

Myeloablative conditioning before allogeneic HSCT during childhood exposes to serious long-term complications, especially gonadal dysfunction. Pubertal issues are less described than other post-HSCT sequelae in childhood.Pubertal development and biological gonadal parameters were assessed in a retrospective monocentric cohort of prepubertal patients who underwent HSCT after myeloablative conditioning with TBI or busulfan between 1981 and 2017.Seventy-four patients (28 girls and 46 boys) were included. No spontaneous pubertal development was found in 50% of girls and 10% of boys (P .001), and delayed puberty or no spontaneous pubertal development was found in 57% of girls and 24% of boys (P = .009). HRT was used in 82% of girls and 24% of boys (P .001). In univariate analysis, TBI conditioning (P = .05), female sex (P .001), acute GVHD (P = .05), extensive chronic GVHD (P = .021), steroid treatment6 months (P = .016), and malignant diseases (P = .016) were associated with no spontaneous pubertal development, whereas TBI conditioning (P = .003) and extensive chronic GVHD (P = .005) were associated with delayed puberty. In multivariate analysis, factors independently associated with no spontaneous puberty onset were female sex (P = .001) and age10 years (P = .033). Factors independently associated with delayed puberty were extensive chronic GVHD (P = .041) and age10 years (P = .031).This study highlighted the toxicity of MAC in prepubescent children: TBI did worse, but this was especially true for the most susceptible patients (girls, leukemic patients, and patients older than 10 years). It suggests a possible role of GVHD in delayed puberty.

Graft failure occurs in 3-5% of hematopoietic stem cell transplantations (HSCT) and raises up to 10% for mismatched HSCT. It is a severe complication leading to lethal infections or bleedings. Several studies reported that engraftment could be improved by mesenchymal stromal cells (MSCs) infusion. Those cells are multipotent cells capable of differentiation in at least 3 lineages (adipocytes, chondrocytes and osteocytes) and of supportive effects on hematopoiesis. This treatment is considered as an Advanced Therapy Medicinal Product in France and there is currently no authorization for its use outside of clinical trials. We retrospectively analyzed the demands from HSCT French centers to the expert committee of the SFGMTC and the French regulatory agency (ANSM), since 2014, in order to ask for MSCs exceptional recourse for patients with graft failure. Nine requests for MSCs were made. One patient did not receive any MSCs because MSCs bag was contaminated, another one had an haploidentical transplantation without MSCs instead. Finally, 7 patients received 1 or 2 infusions of MSCs (Table). Median age was of 6 years (4-23), sex ratio was of 2,5. Two patients (29%) had an acute lymphoblastic leukemia (ALL) and 5 patients (71%) had an aplastic anemia (idiopathic n=4, congenital n=1). Five patients had received one transplantation, and 2 patients had received two transplantations, followed by a primary graft failure (n=6) and a secondary graft failure (n=1). Only 2 patients had received a myeloablative conditioning regimen (MAC) for the first procedure, one chemo- and one TBI- based. The other 5 patients had received a reduced-intensity conditioning (RIC) regimen, 4 of them with 2 grays TBI. Two patients had received a cord blood unit and 5 bone marrows from 1 sibling, 3 haploidentical and 1 mismatched donors. Only 2 patients had received antithymoglobulins in their previous regimen. Engraftments failed despite a median richness of 5,14.106 CD34 cells/kg/bone marrow graft (1,84-9,5) and of 1,25.105CD34 cells/kg/cord blood unit (1,2-1,3). Median delay between first HSCT with graft failure and MSCs infusion was of 2 months (1-32). To prepare last HSCT,six patients received a reduced intensity conditioning regimen with 2 grays TBI (Baltimore), and one patient received a myeloablative, chemo-based, regimen, with antithymoglobulins. Three patients received a graft from the same previous donor. Six patients received a haploidentical graft (5 bone marrows, 1 peripheral blood stem cells), and 1 received bone marrow from a mismatched donor. Median number of CD34+ cells was of 9,02.106/kg (1,61-12,43). All MSCs were from 8 pooled donors (OBNITIX®) except for one patient who received MSCs from a relative donor (which was different from the HSCT donor). All infusions were well tolerated and made on the same day as HSCT, apart from one patient who received MSCs for a secondary graft failure on day 228 post-transplantation, followed by an infusion of CD34+ cells on day 231, and a second infusion of MSCs on day 259. Mean dose of MSCs was of 1,72.106/kg (1,25-3,1). Median time for neutrophil recovery (neutrophils over 0.5 G/L) and platelet recovery (platelets over 50 G/L) on 3 consecutive days was respectively of 23 days (10-34) and 35 days (26-238). At day 30, 5 patients (71%) had a full donor chimerism. Only one patient presented a graft failure leading to a third HSCT. No secondary graft failure occurred after a median follow-up of 13 months (4-104). At last follow-up, none of the patients who achieved platelet and neutrophil recovery required neither blood or platelets transfusion nor thrombopoietin receptor analogs. Infusion of MSCs at the time of HSCT to prevent graft failure was safe and effective for 6/7 patients. Larger prospective trials are necessary to confirm MSCs impact on engraftment and graft function. Table Disclosures Dalle: AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Orchard: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Medac: Consultancy, Honoraria; Bellicum: Consultancy, Honoraria; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rubio:Medac: Consultancy; Gilead: Honoraria; MSD: Honoraria; Novartis: Honoraria; Neovii: Research Funding.

Objective Adenovirus (AdV) infections are potentially life‐threatening for allogeneic hematopoietic stem cell transplant (allo‐HCT) recipients. The AdVance study aimed to evaluate the incidence, management, and outcomes of AdV infections in European allo‐HCT recipients. Methods As part of the study, physician surveys were conducted to determine current AdV screening and treatment practices at their center. Results All of the 28 respondents who treat pediatric patients reported routine AdV screening practices, with 93% screening all allo‐HCT recipients and others screening those with transplant‐related risk factors. Nearly all centers take a pre‐emptive approach to AdV treatment in both high‐ (89%) and low‐risk patients (75%). Among the 14 respondents who treat adult patients, 5 (36%) reported routine screening practices and few (21%) screen all allo‐HCT recipients unless risk factors are present. In adults, pre‐emptive AdV treatment is uncommon and quantitative AdV thresholds are rare. Typical treatment for all patients with symptomatic AdV infection is off‐label intravenous cidofovir. Conclusions Our findings confirm that screening for AdV is more common in pediatric patients. Antiviral treatment is employed in both pediatric and adult patients, although adults are generally treated when AdV disease is diagnosed. The approach to AdV screening and treatment is risk‐based and consistent with clinical guidelines.

Highly immunocompromised pediatric and adult hematopoietic cell transplant (HCT) recipients frequently experience respiratory infections caused by viruses that are less virulent in immunocompetent individuals. Most of these infections, with the exception of rhinovirus as well as adenovirus and parainfluenza virus in tropical areas, are seasonal variable and occur before and after HCT. Infectious disease management includes sampling of respiratory specimens from nasopharyngeal washes or swabs as well as sputum and tracheal or tracheobronchial lavages. These are subjected to improved diagnostic tools including multiplex PCR assays that are routinely used allowing for expedient detection of all respiratory viruses. Disease progression along with high mortality is frequently associated with respiratory syncytial virus, parainfluenza virus, influenza virus, and metapneumovirus infections. In this review, we discuss clinical findings and the appropriate use of diagnostic measures. Additionally, we also discuss treatment options and suggest new drug formulations that might prove useful in treating respiratory viral infections. Finally, we shed light on the role of the state of immune reconstitution and on the use of immunosuppressive drugs on the outcome of infection.

Background Several studies showed that cancer therapies during tooth development are associated with dental abnormalities, including enamel defects, arrested tooth development, microdontic teeth, and agenesis. Study design We describe the case of a nine-year-old boy treated for acute myeloid leukemia at 15 months of age, who presents several dental abnormalities resulting from anticancer treatment. Results The patient was included and treated according to the ELAM 02 French protocol. Six years after allogenic hematopoietic stem cell transplantation, the intraoral and radiographic examination highlighted the agenesis of the second permanent molars and three of the four second premolars, microdontia of the first premolars, root stunting of the central incisors and first premolars, rootlessness of the first permanent molars, and enamel defects localized at the permanent incisors and canines. As a first step to reduce enamel defects, restorations with resin composite (Tetric EvoCeram® A2, Ivoclar Vivadent) were performed under a dental dam. Orthodontic treatment was contraindicated due to arrested tooth development, short roots, and a risk of resorption is considered too important. Conclusion The young age at diagnosis (

Allogeneic hematopoietic stem cell transplantation is a curative treatment for many hematological diseases. However, this procedure causes the patient to be susceptible to infection. Prophylactic treatments are administered in clinical practice even thought the level of evidence of their effectiveness is not always high. In addition, changes in the transplantation procedures - use of reduced intensity conditioning, development of alternative graft sources - must lead to a rethinking of attitudes towards prophylaxis. Our working group based its recommendations on a review of referential articles and publications on the subject found in the literature. These recommendations concern the prophylaxis of infections caused by HSV1, HSV2, varicella zoster, and hepatitis B, as well as anti-bacterial and digestive decontamination prophylaxis, prevention of pneumocystis, toxoplasmosis, tuberculosis, as well as prophylaxis of fungal infections. Other infectious agents usually involved in infections post-allotransplant have been the subject of another set of recommendations from the French Society of Bone Marrow Transplantation and Cellular Therapy.

Cyril Schweitzer (CS) : A 1.5-year-old girl was referred to the Paediatric Pneumology Department of the University Hospital of Nancy, France, for progressive tachypnoea and hypoxia. She suffered from intrauterine growth retardation, and was born prematurely at 31 weeks’ gestation; birth weight: 1.160 kg (≤2 SD); birth length: 37 cm (≤2 SD). The patient presented with acute respiratory distress syndrome at birth, requiring treatment with a dose of surfactant, 9 days of mechanical ventilation and 8 weeks of oxygen therapy. On arrival to our centre, she was dyspnoeic on exertion and oxygen saturations were between 91% and 94%. Further investigations included a high-resolution CT scan and a bronchoalveolar lavage (BAL). Laureline Berteloot (LB) and Julie Bruneau (JB) : CT imaging of the chest revealed a ‘crazy paving’ pattern whereas analysis of BAL fluid failed to identify any underlying disease. CS : Hypoxia transiently improved after initiation of inhaled corticosteroids and antireflux therapy but relapsed after a few months, so that a second BAL was performed. JB : The second BAL fluid revealed the presence of extracellular lipid and protein deposits and foamy alveolar macrophages. CS and Cecile Bonnet (CeB) : These abnormalities led to a diagnosis of pulmonary alveolar proteinosis (PAP) at the age of 2.6 years, which was confirmed by genetic testing; complex chromosome abnormalities were detected, with (1) deletion of CSF2RA and CRLF2 on the X chromosome inherited from the mother, and (2) a de novo rearrangement of the paternal X chromosome, resulting in loss of both CSF2RA alleles.1 CS, Christophe Delacourt (CD) and Jacques De Blic (JDB) : Recessive mutations in the α or β subunits of the granulocyte macrophage colony-stimulating factor receptor (GM-CSF-R, encoded respectively by CSF2RA and CSF2RB ) cause two subtypes of hereditary PAP.2 Impairment of GM-CSF-dependent surfactant clearance by alveolar macrophages leads to the progressive accumulation of surfactant in the alveolar space …

International audience; The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 7th allogeneic hematopoietic stem cell transplantation clinical practices harmonization workshop series in September 2016 in Lille, France. The objective of our workshop is to provide a discussion on the conservation and congelation of hematopoietic stem cells in a pediatric setting as well as our recommendations for this technique.

Background Allogeneic hematopoietic stem cell transplantation (HSCT), the most widely used potentially curable cellular immunotherapeutic approach in the treatment of hematological malignancies, is limited by life-threatening complications: graft versus host disease (GVHD) and infections especially viral infections refractory to antiviral drugs. Adoptive transfer of virus-specific T cells is becoming an alternative treatment for infections following HSCT. We report here the results of a phase I/II multicenter study which includes a series of adenovirus-specific T cell (ADV-VST) infusion either from the HSCT donor or from a third party haploidentical donor for patients transplanted with umbilical cord blood (UCB). Methods Fourteen patients were eligible and 11 patients received infusions of ADV-VST generated by interferon (IFN)-γ-based immunomagnetic isolation from a leukapheresis from their original donor (42.9%) or a third party haploidentical donor (57.1%). One patient resolved ADV infection before infusion, and ADV-VST could not reach release or infusion criteria for two patients. Two patients received cellular immunotherapy alone without antiviral drugs as a pre-emptive treatment. Results One patient with adenovirus infection and ten with adenovirus disease were infused with ADV-VST (mean 5.83 ± 8.23 × 103 CD3+IFN-γ+ cells/kg) up to 9 months after transplantation. The 11 patients showed in vivo expansion of specific T cells up to 60 days post-infusion, associated with adenovirus load clearance in ten of the patients (91%). Neither de novo GVHD nor side effects were observed during the first month post-infusion, but GVHD reactivations occurred in three patients, irrespective of the type of leukapheresis donor. For two of these patients, GVHD reactivation was controlled by immunosuppressive treatment. Four patients died during follow-up, one due to refractory ADV disease. Conclusions Adoptive transfer of rapidly isolated ADV-VST is an effective therapeutic option for achieving in vivo expansion of specific T cells and clearance of viral load, even as a pre-emptive treatment. Our study highlights that third party haploidentical donors are of great interest for ADV-VST generation in the context of UCB transplantation. (N° Clinical trial.gov: NCT02851576, retrospectively registered). Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0469-0) contains supplementary material, which is available to authorized users.

We analyzed the impact of cytogenetics on 193 children enrolled in two successive French trials (LAME89/91 and ELAM02), who received hematopoietic stem cell transplantation during CR1. Detailed karyotype was available for 66/74 (89%) in LAME89/91 and 118/119 (99%) in ELAM02. Several karyotype and transplant characteristics differed according to therapeutic protocol: unfavorable karyotypes were more frequent in ELAM02 (36% vs 18%), pretransplant chemotherapy included high-dose cytarabine in ELAM02 and not in LAME89/91, IV replaced oral busulfan in the conditioning regimen, methotrexate was removed from post-transplant immunosuppression, and matched unrelated donor and cord blood transplantation were introduced. Five-year overall survival (OS) was 78.2% in LAME89 and 81.4% in ELAM02. OS was significantly lower for the unfavorable cytogenetic risk group in LAME89/91 when compared with intermediate and favorable groups (50% vs 90.6 and 86.4%, P=0.001). This difference was no longer apparent in ELAM02 (80.9% vs 71.3% and 5/5, respectively). Survival improvement for children with unfavorable karyotype was statistically significant (P=0.026) and was due to decrease in relapse risk. Five-year transplantation-related mortality was 6.75% in LAME89/91. In ELAM02, it was 3.2% for patients with a sibling donor and 10.9% with an unrelated donor or cord blood. We conclude that the outcome of children with unfavorable karyotype transplanted in CR1 has improved.

International audience; We compared the long-term impact of donor type (sibling donor [SD] versus matched unrelated donor [MUD] or umbilical cord blood [UCB]) on late side effects and quality of life (QoL) in childhood acute leukemia survivors treated with hematopoietic stem cell transplantation. We included 314 patients who underwent transplantation from 1997 to 2012 and were enrolled in the multicenter French Leucemie de l'Enfant et de L'Adolescent ("Leukemia in Children and Adolescents") cohort. More than one-third of the patients were adults at last visit; mean follow-up duration was 6.2 years. At least 1 late effect was observed in 284 of 314 patients (90.4%). The average number of adverse late effects was 2.1 +/- 1, 2.4 +/- 2, and 2.4 +/- 2 after SD, MUD, and UCB transplantation, respectively. In a multivariate analysis, considering the SD group as the reference, we did not detect an impact of donor type for most sequelae, with the exception of increased risk of major growth failure after MUD transplantation (odds ratio [OR], 2.42) and elevated risk of osteonecrosis after UCB transplantation (OR, 4.15). The adults and children's parents reported comparable QoL among the 3 groups. Adult patient QoL scores were lower than age- and sex-matched French reference scores for almost all dimensions. We conclude that although these patients are heavily burdened by long-term complications, donor type had a very limited impact on their long-term health status and QoL.

Cryopreservation as a way to maintain extracorporeal photopheresis regimen for GvHD treatment while circumventing patient temporary inability to undergo apheresis

The introduction of tyrosine kinase inhibitors (TKIs) to treat chronic myelogenous leukemia (CML), has largely replaced curative strategies based on allogeneic hematopoietic stem cell transplantation (HSCT). Allogeneic HSCT continue to be recommended for patients progressing to a more advanced phase of the disease and those in first chronic phase (CP1) failing second and third generation TKIs. Although the role of allogeneic HSCT using matched related or unrelated donor remains well established in the post-TKI era, controversies exist in transplant using alternative donors, and data in this setting is scarce. Umbilical cord blood (UCB) can be used as an alternative stem cell source for patients in whom allogeneic HSCT is indicated, but lack an appropriate human leucocyte antigen (HLA)-matched adult donor. The advantages of UCBT include rapid availability, absence of donor risk, and the relatively lower risk of GVHD with preserved graft versus leukemia effect. Because of the lack of large studies on the outcome of UCBT for CML patients in the TKI era, we performed a retrospective analysis to identify risk factors for outcomes after unrelated cord blood transplants in adults with CML. Through the EBMT database, 150 CML patients were identified as UCBT recipients. Median year of UCBT was 2008 (range, 2000 to 2015) with a median follow up of 62.2 months (range, 3 to 203.1 months). Median age at the time of transplant was 40.4 years (range, 18.8 to 66.5) with a male to female ratio of 92/58. The median time from CML diagnosis to UCBT was 29.9 months (range, 3.4 to 273.6) with first (Q1) and third (Q3) quartile at 12.4 and 57.3 months respectively. Eleven patients received an UCBT as a second allogeneic HSCT. Conditioning regimen was of reduced intensity (RIC) in 44 patients while 92 received a myeloablative conditioning (MAC), and 61 out of 128 evaluable patients received T-cell depletion. Disease status at the time of transplant was first chronic phase (CP1, n=45), second or third chronic phase (CP2 and CP3, n=48) or advanced phase (accelerated phase or blastic phase, AP/BP, n=55). Overall survival (OS) at 12, 24 and 36 months were 52.1% (95% CI 44.0 to 60.1%), 44.5% (95% CI 36.3 to 52.6 %) and 41.2% (95% CI 33.0% to 49.4%) respectively. Median time to neutrophil and platelet engraftment were 23 and 47 days respectively in 119 patients who engrafted, while 24 and 7 patients experienced primary (16%) or secondary (4.6%) graft failure respectively. At 24 months, the cumulative incidence of non-relapse mortality (NRM) and relapse were 38.9% (95% CI 31.0 to 46.9%) and 25.3% (95% CI 18.2% to 32.3%), while cumulative incidence of grade 2-4 acute GvHD was 34.3% (95% CI 26.1 to 42.5%) and 24 months cumulative incidence of chronic GvHD was 24.8% (95% CI 15.6 to 34.0%). OS and disease-free survival (DFS) were significantly reduced for patients in AP/BP at the time of transplant compared to patients in CP1 or CP2/CP3 (24 months OS, 27.1% vs 55.3% and 53.7%, p=0.0026; 24 months DFS, 21.5% vs 39.4% and 47.1% respectively, p=0.0059, Figure 1). Cumulative incidence of relapse was significantly increased in patients in AP/BP at the time of HSCT compared to patient in CP1 or CP2/3 (24 months relapse incidence of 37.6% vs 20.6% and 17.1% respectively, p=0.0178). There was no significant difference in OS and DFS in patients receiving RIC compared to MAC (24 months OS 47.1 and 48.1% respectively, p=0.8; 24 months DFS 33% vs 40.6%, p=0.36). Cumulative incidence of relapse at 24 months was 34.7% in RIC and 24.6% in MAC, although this was not statistically significant (p=0.14). In conclusion, UCBT is more effective in CML patients who are in first CP but also in those who are in second or third CP at the time of transplant. NRM remains high, possibly related to differences in practices of UCBT over time and between centers. Comparison with alternative graft source such as haploidentical HSCT is needed, although little data is available in this setting. Patients who are in advanced phase disease at the time of transplant have a dismal prognosis comparable to those who receive an allogeneic HSCT from HLA-matched adult donors, although pre and post-transplant intervention with 3rd generation TKI may help improve outcome of these patients. Finally the use of RIC regimen for UCBT is an alternative for patients who cannot tolerate a MAC regimen; further analysis will help identify patients who would benefit from this approach. Figure 1. Figure 1. Disclosures De Lavallade: Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Angelucci:Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Roche Italy: Other: Local (national) advisory board; Celgene: Honoraria, Other: Chair DMC; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs.

The two first authors contributed equally. Introduction There is currently little data on the outcome of AML in adolescents and young adults (AyAs) after allogeneic HSCT. In this retrospective study from the SFGM-TC registry, we analyzed the outcome of AML patients classified in 3 groups according to the age at transplantation: children ( Patients and Method This study included 2240 patients from 43 centers among France, Belgium, Switzerland, Lebanon and Algeria, of whom 481 children (21.5%), 545 AyAs (24.3%) and 1214 adults (54.2%). All patients received a first allogeneic HSCT for AML between 2005 and 2015. Five-years OS, NRM, GRFS and EFS and cumulative incidence of relapse were compared between the three groups of patients. Results The median follow-up of the study was 7 years (range, 4-9.6). According to the 2016 WHO classification, children had the highest rate (31.8%) of adverse risk disease, followed by AyAs (25.2%) and adults (21.3%) (p=0.0001). Extramedullary disease was observed in 42.8%, 24% and 21.4 % of children, AyAs and adults (p=0.0001). Among patients in complete remission (CR), younger age was associated more frequently with advanced disease (29.9% ≥ CR2 for children, 23% for AyAs and 18.2% for adults) (p=0.0001). Donors were matched siblings in 36.4% of children, 36.7% of AyAs and 40.3% of adults, and matched unrelated in 29.1%, 33.4% and 35.7% respectively. Children had more mismatched unrelated donors (31.6%), compared to AyAs (25.3%), and adults (19.5%) (p=0.0001). Stem cell source was different between the 3 groups (p=0.0001): bone marrow (BM) was the main source for children (60.9 % of grafts) followed by cord blood (CB) (28.9%), whereas peripheral blood stem cells (PBSC) was the main source for adults (60 %), followed by BM (29.7%) and CB (10.2%). AyAs were transplanted with BM in 44.4% of cases, PBSC in 40.4% or CB in 15.2%. The intensity of the conditioning was myeloablative (MAC) in 93% of children, 79% of AYAs and 77.7% of adults, while a reduced-intensity regimen was used in 4% of children, 12.3% of AyAs and 14.1 % of adults (p=0.0001). The 5y-overall survival (OS) was higher in children (64%), compared to AyAs (54%) and adults (52%) (p=0.001) (figure). One-year cumulative incidence (CI) of relapse was comparable in the 3 groups: 27 % for children, 33% for AYAs and 28% for adults (p=0.19) (figure). The 5y-CI of EFS and the 5y-CI of NRM were better for children (56%) compared to AyAs (49%) and adults (47%) (p=0.017) respectively and 11%, 18% and 27% for NRM in each group respectively (p=0.0001). Regarding causes of deaths, GvHD related mortality was significantly higher in AyAs and adults with 3.1%, 5.1% and 7.7% in each group respectively. There was no difference in the CI of grade II-IV acute GvHD at day +100 between the 3 groups: 37.7%, 35.8% and 35% respectively (p=0.58) while the one-year CI of chronic GvHD was higher in adults (37%) and AyAs (31%) compared to children (17%) (p=0.0001) (Figure). AyAs had a significantly lower 5y-OS and 5y-EFS than children and AyAs had a greater risk of NRM than children in this study. Moreover the GRFS is significantly better in children with 5y-survival 26% for children, 18% for AyAs and 17% for adults (p=0.011) (figure). In univariate and multivariate analysis, independent factors associated with OS were age, TBI, cytogenetics and status of disease, HLA matching and donor age. Conclusion AyAs patients seem to have greater risk of NRM and cGvHD after HSCT than children. This study suggests that AyAs should be treated more like children and that donor age and HLA compatibility should be considered in the treatment strategy. Figure. Figure. Disclosures Chalandon: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs. Beguin:Kiadis Pharma: Consultancy. Peffault De Latour:Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.

Introduction: Thrombopoietin receptor agonist eltrombopag (ELT) provides hematologic improvement in up to 50% of adults with acquired aplastic anemia (AAA) refractory to immunosuppressive therapy (IST). However, current data for ELT efficacy and tolerance in childhood AAA is very limited. Methods: We conducted a multicenter nationwide retrospective study on behalf of the French Reference Center for Aplastic Anemia. Patients under 18 treated with ELT after IST for AAA were included. Lineage responses were defined as follows: red cells transfusion independency or hemoglobin increase of 1.5 g/dL, platelets transfusion independency or a 20 G/L increase in platelets counts, doubling of the neutrophil count or an increase above 0.5 G / L. Results: We identified 12 children (2-17 years old, mean 9.5±5.9 years) treated for severe (7) /very severe (5) AAA with horse ATG and cyclosporine as first-line treatment between 2014 and 2018 in five different centers. Minor PNH clone was identified at diagnosis in two patients. All patients had a normal bone-marrow karyotype and FISH. None had a matched related donor. Median time between IST onset and eltrombopag initiation was 3.5 months [1-46]. All patients still met severe aplastic anemia criteria and needed RBC and platelet transfusions at ELT initiation. Mean hemoglobin, reticulocytes, platelets and neutrophils values were 7.3±0.8 g/dL, 24.5±24 G/L, 11±5.9 G/L and 0.8±0.7 G/L. Seven patients had received IST for more than 3 months and were therefore considered refractory to this treatment. ELT was indicated for an uncontrolled bacterial infection in 2 patients one and two months after IST initiation. One patient received an excessive dose of 12.5 mg/kg/day. Average ELT dosage for the other patients was 2±0.6 mg/kg/d. The median duration of treatment with ELT was 5.5 months [1-10]. After ELT initiation, nine patients (75%) reached hematological response for at least one cell line with no additional treatment. In these patients, hemoglobin increased on average by 3±1.3 g/dL, neutrophils by 2.5±3.5 G/L and platelets by 89.8±39.7 G/L. Seven patients (58%) achieved a trilineage response and were both RBC and platelets transfusions independent after 1 month (1), 3 months (3) and six months (7). Five patients (41.6%) reached a robust response (platelets > 50 G/L, hemoglobin > 10 g/dL, neutrophils > 1 G/L). All these trilineage responders were still on cyclosporine at the time of last assessment. ELT was withdrawn in 4 trilineage responders. Two of them still fulfilled robust response criteria 3 and 43 months after ELT withdrawal while the 2 others required occasional transfusions. The 3 others trilineage responders who were still receiving ELT remained transfusion independent 6 (2) and 11 (1) months after ELT initiation. Two patients (16.6%) had a unique lineage response: one was lost of view and one developed a myelodysplasia with RUNX1 mutation 3 months after ELT initiation. He is alive 8 months after HSCT. No clonal evolution was reported in the 5 other patients for whom cytogenetics follow-up was available. No response was achieved in 3 patients (25%), all of whom were treated for less than 3 months: ELT was withdrawn for deemed inefficiency in 2 patients (16.6%) after 1 and 2 months respectively and for toxicity (disseminated intravascular coagulation) in another patient after 2 months. These patients underwent HSCT. One patient died of graft failure 3 months after HSCT. Overall, eleven patients (91%) were alive 13.4±5.6 months after eltrombopag onset. Disseminated intravascular coagulation occurred in a 2 years patient who received a large ELT dosage (12.5 mg/Kg). No other grade III-IV toxicity was reported. Discussion/Conclusion: This is the first report of ELT for childhood severe AAA after IST. Eltrombopag was overall well tolerated. We observed a high rate of sustained trilineage response as reported in adult patients and only 1 case of clonal evolution which is a known complication in non-responsive AAA. Onset of the trilinear hematologic responses is progressive and achieved 3-6 months after ELT initiation. A longer follow-up of this cohort is mandatory to assess response durability and clonal evolution final risk. Nevertheless, we propose that ELT should be considered for severe AAA non-responsive to IST after 3 months of treatment especially if only an alternative donor is available. Disclosures No relevant conflicts of interest to declare.

Transplantation of 2 unrelated cord blood (UCB) units instead of 1 has a been proposed to increase the cell dose. We report a prospective a randomized study, designed to compare single-vs double-UCB a transplantation in children and young adults with acute leukemia in a remission or myelodysplasia. Eligible patients had at least two 4-6 a HLA-identical UCBs with >3x10(7) nucleated cells/kg for the first and a >1.5x10(7) for the second. The primary end point was the 2-year a cumulative incidence of transplantation strategy failure, a composite a end point including transplant-related mortality (TRM), engraftment a failure, and autologous recovery. Randomized patients who did not a proceed to transplantation due to refractory disease were considered a transplantation failures. A total of 151 patients were randomized and a included in the intent-to-treat analysis; 137 were transplanted. a Double-UCB transplantation did not decrease transplantation strategy a failure (23.4% 6 4.9% vs 14.9% +/- 4.2%). Two-year posttransplant a survival, disease-free survival, and TRM were 68.8% +/- 6.0%, 67.6% a +/- 6.0%, and 5.9% +/- 2.9% after single-unit transplantation a compared with 74.8% +/- 5.5%, 68.1% +/- 6.0%, and 11.6% +/- 3.9% a after double-unit transplantation. The final relapse risk did not a significantly differ, but relapses were delayed after double-unit a transplantation. Overall incidences of graft-versus-host disease (GVHD) a were similar, but chronic GVHD was more frequently extensive after a double-UCB transplantation (31.9% +/- 5.7% vs 14.7% +/- 4.3%, a P=.02). In an exploratory subgroup analysis, we found a significantly a lower relapse risk after double-unit transplantation in patients a receiving total body irradiation without antithymocyte globulin (ATG), a whereas the relapse risk was similar in the group treated with busulfan, a cyclophosphamide, and ATG. Single-UCB transplantation with adequate cell a dose remains the standard of care and leads to low TRM. Double-unit a transplantation should be reserved for patients who lack such units. a This trial was registered at www. clinicaltrials. gov as #NCT01067300.

International audience; Relapse after transplantation is a major cause of treatment failure in paediatric acute lymphoblastic leukaemia (ALL). Here, we report the findings of a prospective national study designed to investigate the feasibility of immune intervention in children in first or subsequent remission following myeloablative conditioning. This study included 133 children who received a transplant for ALL between 2005 and 2008. Minimal Residual Disease (MRD) based on T cell receptor/immunoglobulin gene rearrangements was measured on days -30, 30, 90 and 150 post-transplantation. Ciclosporin treatment was rapidly discontinued and donor lymphocyte infusions (DLI) were programmed for patients with a pre- or post-transplant MRD status ≥10(-3) . Only nine patients received DLI. Pre- and post-transplant MRD status, and the duration of ciclosporin were independently associated with 5-year overall survival (OS), which was 62·07% for the whole cohort. OS was substantially higher in patients cleared of MRD than in those with persistent MRD (52·3% vs. 14·3%, respectively). Only pre-transplant MRD status (Hazard Ratio 2·57, P = 0·04) and duration of ciclosporin treatment (P < 0·001) were independently associated with relapse. The kinetics of chimerism were not useful for predicting relapse, whereas MRD monitoring up to 90 d post-transplantation was a valuable prognostic tool to guide therapeutic intervention.

We describe herein the first reported case of a drug–drug interaction between dasatinib and esomeprazole in a patient with Philadelphia-positive acute lymphoblastic leukemia leading to a decrease in dasatinib oral absorption.

Cytarabine (cytosine arabinoside) is one of the most effective drugs for the treatment of patients diagnosed with acute myeloid leukemia (AML). Despite its efficiency against AML cells, the emergence of drug resistance due to prolonged chemotherapy in most patients is still a major obstacle. Several studies have shown that drug resistance mechanisms alter the sensitivity of leukemia cells to immune system effector cells. To investigate this phenomenon, parental acute myeloid cell lines, HL-60 and KG-1, were continuously exposed to increasing doses of cytarabine in order to establish equivalent resistant cell lines, HL-60(R) and KG-1(R). Our data indicate that cytarabine-resistant cells are more susceptible to natural killer (NK)-mediated cell lysis as compared with parental cytarabine-sensitive cells. The increased susceptibility correlates with the induction of UL-16 binding proteins (ULBP) 1/2/3 and NK group 2, member D (NKG2D) ligands on target cells by a mechanism involving c-Myc induction. More importantly, chromatin immunoprecipitation assay revealed that ULBP1/3 are direct targets of c-Myc. Using drug-resistant primary AML blasts as target cells, inhibition of c-Myc resulted in decreased expression of NKG2D ligands and the subsequent impairment of NK cell lysis. This study provides for the first time, the c-Myc dependent regulation of NKG2D ligands in AML.

International audience; Minimal residual disease (MRD) is a major predictive factor of the cure rate of acute lymphoblastic leukaemia (ALL). Haematopoietic cell transplantation is a treatment option for patients at high risk of relapse. Between 2005 and 2008, we conducted a prospective study evaluating the feasibility and efficacy of the reduction of immunosuppressive medication shortly after a non-ex vivo T depleted myeloablative transplantation. Immunoglobulin (Ig)H/T-cell receptor MRD 30 d before transplant could be obtained in 122 of the 133 cases of high-risk paediatric ALL enrolled. There were no significant demographic differences except remission status (first or second complete remission) between the 95 children with MRD \textless10(-3) and the 27 with MRD ≥10(-3) . Multivariate analysis identified sex match and MRD as being significantly associated with 5-year survival. MRD ≥10(-3) compromised the 5-year cumulative incidence of relapse (43*6 vs. 16*7%). Complete remission status and stem cell source did not modify the relationship between MRD and prognosis. Thus, pre-transplant MRD is still a major predictor of outcome for ALL. The MRD-guided strategy resulted in survival for 72*3% of patients with MRD\textless10(-3) and 40*4% of those with MRD ≥10(-3).