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International audience; Data regarding the safety and efficacy of reduced-toxicity conditioning regimen (RTC) prior to allogeneic stem cell transplantation (allo-SCT) to treat hematological malignancies in pediatric patients are limited. This prospective multicenter, phase 2 trial investigated a RTC regimen based on the combination of intravenous busulfan (3.2 mg/kg/d x 4 days), fludarabine (30 mg/m2/d x 5 days) and antithymocyte globulin (Thymoglobulin®, Genzyme; 5 mg/kg total dose) with the aim of delivering high dose myeloablation that would allow optimal disease control while minimizing toxicity, in a subgroup of children at very high risk of non-relapse mortality (NRM). The primary endpoint was NRM at 1 year after allo-SCT. A total of 48 high risk patients were included (median age, 13 years; range, 3-24). At 1 year, the cumulative incidence of recurrence/disease progression and NRM were 33% and 8%, respectively. With a median follow-up of 23 months, the Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) at 1 year were 69% and 58%, respectively. We conclude that the RTC regimen used in this prospective trial is safe, with a

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.

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT) conditioning. The DEFIFrance post-marketing registry study evaluated effectiveness and safety in patients who received defibrotide. It collected retrospective/prospective patient data from 53 French HCT centres from July 2014 to March 2020. Primary endpoints were survival and complete response (CR; total serum bilirubin

International audience; Purpose: In the acute lymphoblastic leukemia (ALL) landscape, adolescents and young adults (AYA) often present high-risk diseases and increased chemotherapy-related toxicity. Studies analyzing the outcomes of AYA after hematopoietic stem cell transplantation (HSCT) are scarce. Our study aimed to compare the outcomes of children and AYA with ALL after HSCT and to determine the factors influencing potential differences.Method: 891 patients, from the SFGM-TC registry, aged between 1 and 25 years who received HSCT between 2005 and 2012 were included. The outcomes of AYA were compared to the ones of their younger counterparts.Results: Five-year OS and GRFS were lower in AYA: 53.1% versus 64% and 36% versus 47% (p = 0.0012 and p = 0.007, respectively). WhileCIR was similar in both groups, 5 year-treatment related mortality was higher in AYA: 19% versus 13% (p = 0.04). The lower GRFS in AYA was mainly explained by a higher chronic graft versus host disease (cGvHD) incidence: 32% versus 19% (p < 0.001). Use of peripheral blood stem cells and use of anti-thymoglobulin appeared to be the main factors impacting cGvHD occurrence in AYA.Conclusion: AYA have worse outcomes than children after HSCT for ALL because of a greater risk of TRM due to cGvHD. HSCT practices should be questioned in this population.Keywords: Acute lymphoblastic leukemia; Adolescents and young adults; Graft versus host disease; Hematopoietic stem cell transplantation.

International audience; Texte de l'atelier Rappel du titre de l'atelier : Complications des cellules CAR T autres que les infections, CRS et ICANS: recommandations de la Société Francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC) Résumé en Français : Les cellules CART sont un traitement innovant, qui s'adresse à un nombre croissant de patients, en particulier depuis l'élargissement des indications au lymphome du manteau et au myélome multiple. Certaines complications, jugées rares, ont cependant été décrites de façon itérative pour des petites séries de patients, du fait de l'augmentation du nombre de patients traités dans le monde depuis les premiers essais cliniques en 2011. Parmi elles, le syndrome de lyse tumorale, les complications cardiaques, les cytopénies différées ou prolongées, la maladie du greffon contre l'hôte aiguë ou chronique, et font actuellement l'objet d'une reconnaissance en tant que complications potentielles et spécifiques du traitement par cellules CART. Nous détaillons ici l'épidémiologie, la physiopathologie connue ou suspectée, les facteurs de risque de ces complications, et proposons des recommandations pratiques de leur prévention et de leur prise en charge. Ces recommandations s'adressent aux cellules CART commerciales. Mots clés : CART cells, syndrome de lyse tumorale, complications cardio-vasculaires, cytopénies retardées, GVHD, Résumé en anglais : 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 CART cells, in order to guide strategies for the management of complications associated with this new therapeutic approach.

The immune effector cell-associated syndrome (ICANS) has been described as the second most frequent specific complication following CAR-T cell therapy. The median time to the onset of neurological symptoms is five days after CAR-T infusion. ICANS can be concomitant to cytokine release syndrome but often follows the resolution of the latter. However, 10 % of patients experience delayed onset after 3 weeks of CAR-T cell infusion. The duration of symptoms is usually short, around five days if an early appropriate treatment is given. Symptoms are heterogeneous, ranging from mild symptoms quickly reversible (alterations of consciousness, deterioration in handwriting) to more serious forms with seizures or even a coma. The ICANS severity is currently based on the ASTCT score. The diagnosis of ICANS is clinical but EEG, MRI and lumbar punction can help ruling out alternative diagnoses. The first line treatment consists of high-dose corticosteroids. 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 updating the SFGM-TC recommendations on the management of ICANS. In this review we discuss the management of ICANS and other neurological toxicities in patients undergoing of CAR-T cell therapy. These recommendations apply to commercial CAR-T cells, in order to guide strategies for the management neurological complications associated with this new therapeutic approach.

Infections occurring after CAR T-cells are a common complication. At the acute phase of treatment following CAR T-cell infusion, the exact incidence of infections is unknown given the overlapping symptoms with cytokine release syndrome. The risk factors for infection include the malignant underlying disease and its multiple treatments, and an immunosuppressive state induced by CAR-T cells themselves and the treatment of their complications. 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 post-CAR infectious complications. In this review we discuss anti-infection prophylaxis and vaccination of patients undergoing CAR T-cell therapy as well as a special chapter for the specific case of COVID-19. These recommendations apply to commercial CAR-T cells, in order to guide strategies for the management and prevention of infectious complications associated with this new therapeutic approach.

Background: There are currently few data on the outcome of acute myeloid leukemia (AML) in adolescents and young adults (AYAs) after allogeneic HSCT. The aim of this study is to describe the outcome and its specific risk factors for children, AYAs and 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 (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 AYAs and 62.9% in 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 AYAs and 29.4% for adults - p=0.0254, and 7.0% for children, 10.6% for AYAs and 14.2% for adults, pConclusion: Age is an independent risk factor for NRM and extensive chronic GVHD. This study suggests that AYAs AML patients should be treated with chemotherapy-based MAC regimen and bone marrow as stem cells source.

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.

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.

International audience

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.

Resume Une allogreffe de cellules souches hematopoietiques depend de l’eradication de la pathologie traitee et d’une reconstitution satisfaisante de l’hematopoiese (et de la lymphopoiese) issues des cellules du donneur. Cependant, des retards de reconstitution, l’apparition secondaire ou la persistance de cytopenies sont regulierement observees et constituent des causes possibles d’echec d’une allogreffe. Ces dysfonctions du greffon sont a distinguer des problemes de non-prise du greffon. Bien que ces situations soient relativement frequentes, il n’existe pas de conduite a tenir bien codifiee ou de recommandations emises par les differentes societes savantes de greffe. Le groupe de travail a base ses recommandations a partir d’une analyse d’articles originaux et revues publies references dans la litterature.

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.

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.

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.

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 …

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.

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.

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.

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.