Search

Medication non-adherence (NA) after allogeneic hematopoietic cell transplantation (allo-HCT) can lead to serious complications. This study assesses NA in French adult and pediatric recipients and identifies factors associated with NA. In accordance with the EMERGE and STROBE guidelines, a cross sectional multicentric survey was conducted. We used a self-reported questionnaire that was adapted to adults and pediatrics and that could provide a picture of all three phases of medication adherence: initiation, implementation, persistence. We enrolled 242 patients, 203 adults (mean age: 51 years old, 50.7% male) and 39 children (mean age: 9 years old, 56.4% female). Reported NA was estimated at about 75% in both populations, adults and pediatrics. In adults, the univariate analysis showed that patients less than 50 years old (P = 0.041), (i) treated with cyclosporine (P = 0.02), (ii) treated with valacyclovir/acyclovir (P = 0.016), and (iii) experiencing side effects (P = 0.009), were significantly more non-adherent. In multivariate analysis, only recipient age was significantly associated to NA (P = 0.05). The limited size of the pediatric population did not allow us to draw any statistical conclusion about this population. To the best of our knowledge, this is the first study in France on NA in allo-HCT recipients. Our results highlight the age factor as the only factor related to NA. Further studies are needed to confirm our observations and refine results in pediatric populations, currently most at risk of medication NA.

Resume Les complications stomatologiques de l’allogreffe de cellules souches hematopoietiques (CSH) sont frequentes et tres inconfortables pour les patients. La reaction du greffon contre l’hote represente la principale complication. Les infections, les troubles du gout et les risques carcinologiques constituent les autres effets secondaires de la procedure. Differents traitements locaux sont utilises mais restent imparfaits. Dans le cadre de la dixieme edition des ateliers d’harmonisation des pratiques en allogreffe, organises par la Societe francophone de greffe de moelle et de therapie cellulaire (SFGM-TC) a Lille, en septembre 2019, la demarche diagnostique et les traitements des complications orales apres allogreffe de CSH ont ete revus apres analyse des resultats des etudes publiees.

International audience; Acute and chronic renal failures are very common after allogeneic HSCT. These complications have a real impact on mortality and morbidity of transplant recipients. Within the framework of the ninth workshops of practice harmonization of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held in Lille in September 2018, various causes and mechanisms of renal failure, diagnostic work-up, treatment and recommendations to limit renal failure after transplantation are reviewed. Recommendations to adjust medications to avoid renal failure are also proposed in this article.

Resume La greffe allogenique de cellules souches hematopoietiques (CSH) est une therapeutique usuelle pour de nombreuses maladies hematologiques. Au cours des dernieres decennies, des progres importants ont ete realises dans les domaines de la prise en charge des patients. La selection des donneurs, les conditionnements de greffe et les soins de support des patients ont contribue a l’amelioration de la survie des patients. La plupart des procedures en rapport avec la greffe allogenique de CSH ont ete standardisees par des recommandations nationales ou internationales amenant a des certifications telles que Joint Accreditation Committee ISCT-Europe & EBMT (JACIE). Mais tous ces standards et ces recommandations ne definissent pas de facon precise les moyens minimums humains et materiels necessaires a la realisation de telles procedures. En plus, les unites dans lesquelles sont places ces patients sont soumises a des regles architecturales et procedurales non uniformisees. Lors de cet atelier, nous avons tente de definir une trame minimale concernant le personnel, l’infrastructure architecturale et des pratiques d’hygiene generales pour les patients, le personnel et les visiteurs.

Introduction: Data regarding coronavirus disease 2019 (COVID-19) description are still limited in pediatric oncology. The French society of pediatric oncology (SFCE) has initiated a study to better describe the presentation and evolution of COVID-19 in patients followed in French pediatric oncology and hematology wards. Methods: All patients diagnosed with COVID-19 (polymerase chain reaction [PCR] positive for severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2], or positive IgM serology, or chest computed tomography scan and clinical signs typical of COVID-19) and followed in a SFCE center were enrolled. Data from medical records were analyzed for all patients enrolled up to the end of May 2020. Results: Data was available for 37 patients. Thirty-one were children under 18 years of age. Nineteen patients were female. Seventeen patients had a solid tumor, 16 had a hematological malignancy and four recently underwent hematopoietic stem cell transplantation (HSCT) for non-oncological conditions. Twenty-eight patients presented symptoms, most often with fever, cough, rhinorrhea and asthenia. Ground-glass opacities were the most frequent radiological finding with abnormalities mostly bilateral and peripherally distributed. Twenty-four patients received chemotherapy a month prior to COVID-19 diagnosis. Most patients did not require hospitalization. Three patients required oxygen at the time of diagnosis. In total, five patients were admitted in an intensive care unit because of COVID-19 and one died from the disease. Conclusion: Children and young adults infected with SARS-CoV-2 and treated for a cancer and/or with a HSCT may be at risk for severe COVID-19 and should be closely monitored. (NCT04433871)

BACKGROUND Busulfan (Bu) is the cornerstone of conditioning regimens prior to hematopoietic stem cell transplantation, widely used in both adults and children for the treatment of malignant and nonmalignant diseases. Despite an intravenous formulation, interindividual variability (IIV) remains high and optimal exposure difficult to achieve, especially in neonates and infants. PROCEDURE To ensure both efficacy and safety, we set up in 2005 an observational study designed for children not fully assessed during the drug registration procedure. From a large cohort of 540 patients, we developed a Bu population pharmacokinetic model based on body weight (BW) and maturation concepts to reduce IIV and optimize exposure. A new dosing nomogram was evaluated to better fit the population pharmacokinetic model. RESULTS Bu clearance IIV was significantly decreased from 61.3% (covariate-free model) to 28.6% when combining BW and maturation function. Median Bu area under the curve (AUC) was 1179 µmol/L × min compared to 1025 with the EMA dosing nomogram for children

Antithymocyte globulin is a major drug in transplantation. rATG has been successfully used to prevent graft-versus-host disease in allogeneic HSCT. However, its first infusion is associated with reactions ranging from simple fevers to distributive shocks and may interfere with the transplant conditioning. To evaluate the impact of rATG infusion rate on clinical tolerability, we conducted a retrospective study of all pediatric allogeneic HSCT patients who received rATG (Thymoglobulin®) as part of their conditioning at Lille University Hospital from 2003 to 2018. Until 2012, patients received rATG with a theoretical infusion time of 12 hours (12H group, n = 33). From 2012, they had a theoretical infusion time of 4 hours (4H group, n = 43). Patients from the 12H arm presented more ≥ grade 3 infusion-related reactions at first dose (70% versus 44%, P = .027), had significantly higher fever (median of 39.6°C versus 39.2°C, P = .002), and needed a greater use of symptomatic treatments. However, they received a slightly higher first dose of rATG (median of 2.7 versus 2.3 mg/kg, P = .042). In view of these results, a rATG infusion time of 4 hours can be a relevant option for pediatric transplant centers to avoid interference with the conditioning regimen and facilitate medical surveillance.

Osteopetrosis (OP) is a rare skeletal disease, which can affect the skull base and calvaria. A multidisciplinary approach is mandatory and patient may need neurosurgical care. Few observations have been published, and optimal management of OP is not established yet. We report a case of an infant with OP diagnosed at 5 months, who presented signs of intracranial hypertension associated with unilateral blindness. Bone marrow allograft was performed at 6 months of age. At neurosurgical first examination at 11 months, the child was hypotonic, with severe amblyopia; features of bicoronal synostosis were appreciated, with tense anterior fontanel bulging indicating synostotic oxycephaly. Head circumference had decreased from +3 SD to +1SD. Cerebral CT scan showed reduction of intracranial volume, inward thickening of the calvaria, bilateral stenosis of optic canal, ventricular dilatation, enlarged arachnoid spaces, and tonsillar herniation. We performed cranial vault expansion with frontal advancement and bi parietal decompression, thinning of the inner table, unroofing of the left orbit and optic canal in order to obtain optic nerve decompression. Postoperative course was uneventful, and the patient was discharged on day 8. Vision was unchanged but rapid improvement of axial tonus was noted. The CT scan showed satisfactory calvarial expansion with regression of tonsillar herniation. Neurosurgical evaluation and care are necessary in the context of a multidisciplinary approach to the patient affected by osteopetrosis. Cranial vault remodeling and expansion should be considered in patients with sign of intracranial hypertension. Timing of optic canal decompression is to be defined.

Resume Dans le cadre du suivi a long terme des patients traites dans l’enfance ou adolescence pour un cancer, nous presentons plus specifiquement dans cet article le suivi a long terme et donc les sequelles possibles des patients ayant eu une allogreffe de cellules souches hematopoietiques. Cet article est base sur un travail collaboratif organise par la Societe francaise de greffe de moelle et therapie cellulaire (SFGM-TC) qui a eu lieu au cours des 4 es journees d’harmonisation des pratiques en allogreffe. Les patients concernes sont les enfants et jeunes adultes (0–25 ans). Nous avons defini le suivi des sequelles au-dela de 1 an post-greffe. Nos recommandations sont basees sur une revue de la litterature, en coherence avec l’etude Leucemie Enfant Adulte (LEA), cohorte de suivi a long terme des patients traites pour une hemopathie maligne dans l’enfance, greffes ou non. Il est apparu important de determiner la nature des troubles rencontres, leurs facteurs de risque, leur frequence et le suivi necessaire a mettre en place pour leur detection. Nous n’aborderons pas la prise en charge therapeutique des sequelles.

Resume Dans une demarche qui vise a uniformiser les procedures d’allogreffe de cellules souches hematopoietiques, la Societe francophone de greffe de moelle et de therapie cellulaire (SFGM-TC) a organise les sixiemes ateliers d’harmonisation des pratiques en allogreffe en septembre 2015 a Lille. Le but de ces ateliers annuels est de trouver un terrain d’entente entre des centres qui le souhaitent dans les domaines ou la litterature ne fournit pas de reponses incontestables et consensuelles. Dans cet atelier nous faisons la mise a jour du carnet de suivi nationale.

Allogeneic hematopoietic stem cell transplantation is mainly indicated in bone marrow dysfunction related to blood diseases, but also in some rare diseases (adrenoleucodystrophy, mitochondrial neurogastrointestinal encephalomyopathy or MNGIE...). After decades, this treatment has proven to be efficient at the cost of numerous early and delayed side effects such as infection, graft-versus-host disease, cardiovascular complications and secondary malignancies. These complications are mainly related to the conditioning, which requires a powerful chemotherapy associated to total body irradiation (myelo-ablation) or immunosuppression (non myelo-ablation). Among side effects, the endocrine complications may be classified as 1) hormonal endocrine deficiencies (particularly gonado- and somatotropic) related to delayed consequences of chemo- and above all radiotherapy, with their consequences on growth, puberty, bone and fertility); 2) auto-immune diseases, particularly dysthyroidism; 3) secondary tumors involving either endocrine glands (thyroid carcinoma) or dependent on hormonal status (breast cancer, meningioma), favored by immune dysregulation and radiotherapy; 4) metabolic complications, especially steroid-induced diabetes and dyslipidemia with their increased cardio-vascular risk. These complications are intricate. Moreover, hormone replacement therapy can modulate the cardio-vascular or the tumoral risk of patients, already increased by radiotherapy and chemotherapy, especially steroids and anthracyclins... Therefore, patients and families should be informed of these side effects and of the importance of a long-term follow-up requiring a multidisciplinary approach.

Background The prognosis of febrile neutropenia (FN) in childhood cancer has been considerably improved by the intensification of treatment, including systematic hospitalization and broad-spectrum antibiotics. As only few children present with a severe bacterial infection (SBI), clinical decision rules have been developed to distinguish those at risk for SBI. The aim of this study was to evaluate the reproducibility of six clinical decision rules proposed in the literature and to compare their performance. Methods This retrospective two-center cohort study included all episodes of chemotherapy-induced FN in children admitted between January 2005 and December 2006. Each rule was applied to our patients. Their sensitivity (Se) and specificity (Sp) were calculated and compared with the authors' results, to assess reproducibility. The most predictive rule was defined in advance as that yielding 100% Se, the highest Sp, and the greatest simplicity for bedside application. Results Three hundred seventy-seven episodes of FN in 167 patients were collected; 64 episodes were associated with SBI, including 36 with bacteremia. Four of the six rules were reproducible, but none were able to be validated. The most predictive rule for bacteremia had 96% Se (95% confidence interval (CI): 79–99%) and 25% Sp (95% CI: 19–33%), and the most predictive rule for SBI had 95% Se (95% CI: 87–98%), but no power of discrimination (Sp = 5%, 95% CI: 3–8%). Conclusion This study emphasizes the difficulty in identifying standardized decision rules in the management of a condition with numerous clinical variables like FN. Pediatr Blood Cancer. 2010;55:662–667. © 2010 Wiley-Liss, Inc.

Nous rapportons le cas d’un jeune garcon de 7 ans, sans antecedents personnels particuliers, admis en hematologie pediatrique en janvier 2015 pour suspicion de leucemie aigue. Son hemogramme montrait une hyperleucocytose a 44,7 G/L, 17 % de blastes, une hemoglobine a 8,2 g/dL ainsi qu’un taux de plaquettes a 32 G/L. Le myelogramme realise posait le diagnostic de leucemie aigue myeloide de type LAM4 selon FAB mais montrait egalement la presence d’assez nombreux mastocytes d’aspect fusiforme. L’immunophenotypage des blastes mettait en evidence l’expression aberrante du CD7 et du CD56, permettant le suivi en maladie residuelle par cytometrie en flux. Le caryotype revelait une monosomie 7 dans la totalite des mitoses et le bilan de biologie moleculaire montrait une surexpression d’EVI1, une mutation de c-Kit (exon 8), une mutation de NRAS ainsi qu’une mutation de RUNX1. Le patient a ete traite selon le protocole ELAM02, avec de la cytarabine et de la mitoxantrone en phase d’induction. La reevaluation hematologique realisee a j51, devant l’absence de sortie d’aplasie, retrouvait la presence de 39 % de blastes ainsi que de nombreux mastocytes parfois morphologiquement anormaux. La cure de consolidation (cytarabine-amsacrine) etait debutee le lendemain mais le patient presenta rapidement une allergie a l’amsacrine (eruption cutanee urticarienne). En parallele, cet enfant presentait plusieurs arguments cliniques (lesions cutanees) et para-cliniques (presence de mastocytes au myelogramme, mutation de c-kit) en faveur d’une mastocytose systemique, probablement indolente et acutisee du fait des facteurs de stress actuels. Le patient presentait egalement plusieurs arguments moleculaires, cytologiques et cytogenetiques evoquant une leucemie myelomonocytaire juvenile (ayant evolue en LAM) : mutation de NRAS, monocytose, basophilie, eosinophilie au diagnostic ainsi que la presence d’une monosomie 7 au caryotype. Au meme titre qu’avec la mastocytose, priorite etait donnee au traitement de la leucemie aigue. Devant une blastose medullaire persistante a 32 % et maladie residuelle a 16 % apres consolidation, cet enfant a recu une cure de rattrapage par FLAG-Daunoxome®. Malgre un exces de blastes (12 %) en pre-greffe, ainsi qu’une maladie residuelle positive (1,5 %) en cytometrie en flux, il a beneficie en mai 2015 d’une greffe de moelle osseuse pheno-identique 10/10 apres conditionnement myeloablatif par busulfan (15,2 mg/kg), cyclophosphamide (200 mg/kg) et serum anti-lymphocytaire (7,5 mg/kg). La prevention de la GVH etait assuree par methotrexate (j1, j3, j6) et ciclosporine a partir de j1. A j61 de la greffe, un myelogramme a ete realise afin d’adapter l’immunosuppression post-greffe. Il montrait la presence d’un exces de blastes estime a 9 % ; une maladie residuelle en cytometrie etait egalement positive (1,75 %). Devant cette inefficacite de l’allogreffe, un arret rapide, des j61, des immunosuppresseurs et l’introduction d’un inhibiteur de tyrosine kinase ont ete decides avant d’envisager des infusions de lymphocytes du donneur (DLI). Ce patient a presente un episode infectieux severe avec septicemie a E. coli. Dans les suites de cet episode, il a presente une aplasie a 3 semaines de l’introduction de l’imatinib. Ce traitement a ete arrete. Un premier myelogramme a ete realise 10 jours apres cet arret. La moelle etait aplasique, sans exces de blaste, la maladie residuelle irrealisable, le chimerisme sur sang a 94,5 % donneur puis 98,1 %. Un controle du bilan medullaire sera realise apres sortie d’aplasie. L’indication de realiser des DLI sera rediscutee apres evaluation medullaire devant l’evolution, semblant finalement favorable, en deux temps du fait de l’adaptation de l’immunosuppression post-greffe.

Selenium deficiency is observed in patients with poor intake. We report the first case of a child with lymphangiomatosis who presented a myopathy associated with severe cardiomyopathy secondary to selenium deficiency due to selenium loss in chylous fluid.

Abstract 1251 Allogeneic stem cell transplantation (allo-SCT) following reduced-intensity conditioning (RIC) represents a concrete alternative to standard myeloablative conditioning. Even though, immune reactions observed after RIC (i.e. GVHD, GVL.), tend to be similar to those observed after myeloablative regimens, there are many differences in their clinical features, timing of onset, and their impact on patient's outcome. The homeostatic cytokines, IL-7 and IL-15 are essential driving forces for homeostatic peripheral expansion of T lymphocytes that are responsible, not only for GVL effect but also for GVHD which is a major complication post-transplant. Almost all mature T-cells express the specific IL-7 receptor alpha chain (IL-7Rα). Memory CD8+ T cells and natural killer (NK) cells express the highest levels of IL-2/15Rβ chain, making these cells particularly responsive to IL-15. Few studies have associated GVHD with systemic levels of either IL-7 or IL-15 but only one concerned patients undergoing RIC. However, patients reported in the latter study, had received prior induction chemotherapy and experienced profound lymphopenia after conditioning, leading to levels of IL-7 and IL-15 comparable to those usually observed after myeloablative regimens. In addition, the issue of IL-7R and IL-2/15Rβ expression has not been addressed yet in allo-SCT patients. This prompted us to prospectively investigate plasma levels of IL-7 and IL-15, T-cell recovery, and the expression levels of IL-7Rα and IL-2/15Rβ chains in patients undergoing RIC. Forty-five consecutive patients who underwent fully HLA-matched allo-SCT after RIC were included. Plasma levels of IL-7 and IL-15 were determined by ELISA at enrolment, on day 0 before grafting, every three days during the first month, and then on days 60 and 90. CD3+, CD4+, CD8+ T-cells and NK cells counts at day 30, 60 and 90 post-graft were obtained by flow-cytometry-based technique. Expression of IL-7Rα and IL-2/15Rβ (% and MFI) was evaluated on each subsets of naïve and memory T-cells, categorized according to their expression of CD45RA and CCR7 markers. Kinetic courses of plasma IL-7 levels, evolved inversely to lymphocyte counts up to day 30 (R= -.529; P= .001). The higher plasma IL-7 levels were associated with the lower MFI of IL-7Rα on CD4+ naïve, CD8+ naïve, CD4+ central memory, and CD8+ central memory T-cells (p=.005, .01, A total of 16 (35%) recipients developed grades 2–4 acute GVHD (aGVHD) at a median time of 42 days post graft. By day +30, IL-7 and IL-15 levels were slightly correlated with aGVHD grades (R=.30; P=.05 and R=.31; P = .048, respectively) and inversely correlated with the time to onset (IL-7: R= -.334; P= .031 and IL-15: R= -.367; P= .018). In those patients, there was a diminished surface densities of IL-7Rα chain in both the naïve (P= .029) and the central memory (P= .043) CD4+ T-cells. In multivariate analysis, IL-7 level measured on day +30 was the foremost predictive factor for grade 2–4 aGVHD (P= .002). Collectively, this study indicates that the level of IL-7 depends rather on the level of lymphopenia whereas IL-15 is more sensitive to the inflammatory context. A high level of IL-7 induces a downregulation of IL-7Rα on naïve and central memory CD4+ T cells, already known to contain alloreactive T cells. The determination of plasma level of IL-7 by day+30 would help predict aGVHD. This predictive time is less precocious than those observed after myeloablative conditioning in agreement with the later development of aGVHD observed with RIC regimens. Disclosures: No relevant conflicts of interest to declare.

Abstract 2329 The mainstay of treatment for Chronic Graft Versus Host Disease (cGVHD) is steroids, but there are limited treatment options for steroid refractory cGVHD particularly in its sclerotic and fibrotic form (ScGVHD). We initially reported the efficacy and safety of imatinib mesylate (IM), a first generation tyrosine kinas' inhibitor, as a salvage therapy for ScGVHD patients (Magro L, et al. Blood, 2009). However, about 50% of the patients (Pts) became refractory or intolerant to IM. Nilotinib, a second generation tyrosine kinas' inhibitor, is labelled for IM resistant and advanced Chronic Myeloid leukemia and could be an attractive alternative to IM especially in refractory and intolerant patients. We studied the clinical outcomes of 7 Pts who developed extensive ScGVHD at our institution. Among them, 5 had received prior IM. Patients' characteristics and transplantation modalities are summarised in table 1. Acute and cGVHD was scored according to standard criteria. All pts but one failed at least 3 lines of prior systemic immunosuppressive therapy. CGVHD features, responses to nilotinib and patients' outcomes are described in table 2. To our knowledge, this is the first report relating the impact of nilotinib on cGVHD setting. Although, tolerance to nilotinib has not been as good as we could expect, this drug appeared to be effective with manageable side-effects in some patients. One of the limitations of this study, is that nilotinib was used in patients with advanced cGVHD. Prospective studies are, therefore, warranted to investigate the efficacy and the tolerance of nilotinib in patients with less advanced disease. Table 1. Patients and transplantation characteristics Case N Age, y Sex, R/D diagnosis Conditioning/Stem cell source GVHD prophylaxis cGVHD sites Immunosuppression before nilotinib 1 30.5 M/F ALL MAC/BM CSA-MTX Mouth, skin eyes,liver CS-CSA-MMF-RTX-EVE 2 31 F/M AA MAC/PBSC CSA-CS-MMF Skin, mouth, eyes,bronchiolitis,joint contacture CS-TAC-MMF-EVE-IM 3 51.6 M/M HODG RIC/PBSC CSA-MTX Skin, mouth CS-CSA-MMF-IM 4 45.3 M/M AML MAC/BM CSA-MTX Skin, mouth, bronchiolitis, joint contracture CS-CSA-MMF-INO-ECP-RTX-AZA-IM 5 57.5 M/M MDS MAC/BM CSA-MTX Skin, bronchiolitis, joint contracture CS-CSA-MMF-RTX-ECP-IM 6 50.3 M/F CML MAC/BM CSA-MTX Skin, mouth, eyes, liver, joint contracture CS-CSA-MMF-ECP-IM 7 53.3 M/M AML MAC/BM CSA-MTX Skin none R/D: recipient/donor; aGVHD: acute graft versus host disease; cGVHD: chronic graft versus host disease; CML: chronic myeloid leukemia; MAC: myeloablative conditioning; BM: bone marrow; PBSC: peripheral blood stem cells; CSA: ciclosporine A; CS: corticosteroids, RIC: reduced intensity conditioning; MMF: mycophenolate mofetyl; AZA: azathioprine; MDS: myelodysplastic syndrome; MTX: metothrexate; RTX: rituximab; ECP: extracorporal photophere-sis; INO: inolimomab; HODG, hodgkin; AA: aplastic anemia; TAC: tacrolimus, ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia.; EVE: everolimus and IM: imatinib mesylate. Table 2. Outcome after nilotinib therapy Case N° Maximal tolerate dose of nilotinib, mg Nilotinb therapy duration at last follow up, mo Side effects/nilotinib discontinuation at last follow up cGVHD status at 2 mo of nilotinib cGVHD response in other organs at last follow up cGVHD status at last follow up Overall follow-up, mo Status at last follow up 1 800 3 None/yes failure – PR 69 alive 2 400 0.5 Pain swallowing, diarrhea/yes failure – progressive 46.8 Died of infection 3 800 2.5 Nausea, diarrhea/yes PR Mouth PR (>90%) 73.1 alive 4 800 7.5 None/yes MR Mouth progressive 72 alive 5 800 1 Cough, dyspnea, muscle cramps/yes PR bronchiolitis PR 59 alive 6 800 0.5 Headache, diarrhea/yes failure – PR 60.3 alive 7 800 7.5 None/no PR – PR 32 alive cGVHD indicates chronic graft versus host disease; PR, partial response and MR, minor response. Disclosures: No relevant conflicts of interest to declare.

Abstract 2380 Nonmyeloablative, or reduced-intensity conditioning (RIC), regimens before allo-SCT have emerged as an attractive modality to decrease transplant-related toxicity while preserving the graft-versus-tumor effect. However, as for standard myeloablative allo-CST, only one third of patients have an HLA-identical sibling donor. Indeed, with the increase in the number of single-child families, stem cell grafts from unrelated donors are being increasingly used. We have previously reported, that in patients with standard-risk malignancy undergoing allo-SCT with CPM and TBI as conditioning treatment, unmodified marrow as a source of graft, and Cs-A plus short-course MTX as GVHD prophylaxis, there were no significant differences between the outcomes of patients receiving graft from siblings and those from unrelated fully HLA-matched donors (Yakoub-Agha et al, JCO 2006). However, no conclusions can be drawn with certainty concerning patients with more advanced disease, those who received a peripheral blood graft or especially those with a non-myeloablative conditioning regimen. Here we report a retrospective study of 58 consecutive patients who received RIC allo-CST. Donors were HLA-identical sibling (n=35) and unrelated molecularly HLA-identical donor. All donor/recipient pairs were typed at the allelic level. They were first typed at 2-digit level for HLA class I (HLA-A, B and Cw) and class II (HLA-DRB1 and DQB1) using published HLA class I PCR-SSO and/or SSP typing protocols. For unrelated donors, HLA-A, B, Cw, DRB1, B3, B4, B5 and DQB1 subtyping was performed using different PCR-SSP kits. HLA typing was performed according to the current use of the EFI Histocompatibility Laboratory standards. Only donor/recipient unrelated pairs matched for both alleles were included in this study. Diagnosis were AML (n=27), ALL (n=3), myelodysplastic syndrome (n=13), and myeloproliferative syndrome (n=15). Of the 32 (55%) males patients, 14 (43%) received graft from female donor (classical sex-mismatch). Medians age of recipients and donors at transplantation were 58 years (41.3-65.5) and 47.1 years (22.2-67.5), respectively. Patients received either low-dose TBI (2Gy) (n=46) or Busulfan-based (n=12) conditioning regimen. Antithymoglobulin was given to 12 patients. As usual in RIC setting, Peripheral Blood Stem Cells was the main source of graft (n=38; 65%), otherwise marrow graft (n=20). Results: with the median of follow-up of 27.2 months (range, 8.1–79.4), 24 patients died including 9 from TRM. Relapse was recorded in 21 patients. Eighteen patients experienced acute GVHD (aGVHD) including 12 with II-IV grades and 7 with III-IV grades. Contrary to what we have previously reported in myeloablative allo-CST sittings, patients who underwent RIC and received graft from unrelated HLA-matched (10/10) donor, experienced worse outcomes compared to those transplanted with an HLA-identical sibling. Indeed, in multivariate analyses, donor type (unrelated HLA-matched 10/10 vs HLA-identical sibling) was the most important risk factors negatively influenced the overall survival and EFS [p=.01; HR=3.068; [95%CI: 1.312–7.174]) and (p=.050; HR=2.081; [95%CI: 1.001–4.347]), respectively. To our knowledge, this is the first study which compares results of sibling transplantation to HLA-allellically-matched (10/10) unrelated transplantation. Even though, results of the latter did not compare favorably to those obtained with an HLA-identical sibling donors, grafts from HLA-matched unrelated donors, are still an attractive option especially for patients with high-risk malignancy. Our data emphasis the need of prospective studies evaluating factors influencing outcomes of HLA-allellically-matched (10/10) unrelated transplantations. Disclosures: No relevant conflicts of interest to declare.

Background: Busulfan (Bu) is the corner stone of hematopoietic stem-cell transplantation (HSCT) regimens with a narrow therapeutic window (TW). Graft rejection or toxicities are reported according to plasmatic exposure. In very young children, Bu exhibits large pharmacokinetic (PK) variability. Bu clearance was demonstrated to be non-linearly related to body weight (BW) and thus BW is used to optimally define the Bu dosage in children [Vassal et al., CCP 2006]. Search for additional data to confirm the TW and to describe clinical outcomes is still a topical question to better understand Pk/Pd relationship and to safely use Bu in young children and infants. Objective: To study the Pk/Pd relationship of Bu in pediatric recipients of bone marrow transplantation (BMT) receiving Bu-based conditioning regimens (CR). To correlate early toxicities (mainly hepatic veno-occlusive disease (VOD), non infectious pulmonary disease (niPD) and outcome i.e. overall survival (OS) at last follow up with type of CR, the underlying diseases, age at transplantation and Pk of busulfan Patients and Method: This multicenter prospective observational study included 307 pts transplanted between 2006 and 2013 from 14 French Pediatric BMT units; median age at transplantation was 18.4 months [1.3-289], with a median BW of 11.3 kg [3.4-82]. 100 pts were younger than 1 year, 71 pts < 9 kg and 171 pts < 16 kg. Patients were mostly affected by non-malignant diseases (primary immune deficiency (n=143), inherited metabolic disorders (n=50), hemoglobinopathies (n=20) while 78 patients suffered from malignant disease. 257 patients received allogenic HSCT (genoidentical donor n=79, matched unrelated donor n=33, mismatch unrelated donor n=18, haploidentical intra-familial donor n=59, other mismatched intra familial donor n=8 or unrelated cord blood n=51) and 41 autologous BMT. All patients received Bu-based conditioning regimen in combination with cyclophosphamide (BuCy n=119), fludarabine (BuFlu n=88), melphalan (BuMel n=36) or thiotepa (BuTTP n=3). 40 patients received BuFlu associated with a second alkylating agent (Mel, TTP or Cy), 12 patients received BuCy associated with a third agent (Mel or VP16). Serotherapy was given in 70% of the patients. Starting doses of Bu were given according to the European SmPC or EBMT-ESID recommendations. The median posology was 1 mg/kg 4x/day for 4 days [0.6-1.3 mg/kg]. PK was assessed on plasma samples with area under the curve (AUC) evaluation from the 1st(D1), 9th (D9) and 13th (D13) dose in 150 patients, D1 and D9 in 40 patients, D1 and D13 in 46 patients while 62 patients were monitored on D1 only (684 PK datasets). PK analysis was performed using Non linear Mixed Effect Modelling. A one-compartment PK model suitably fitted the concentrations vs time data. Median follow up is 27 months (0.33 to 96 months post BMT). Results: At D1, 67% of patients were within the therapeutic window (TW) [900-1500 µM.min] and 66% of patients reached the cumulative TW [14400-24000 µM.min]. Incidence of VOD and niPD were respectively 35% and 14%. Both toxicities correlated with type of CR and age 900 µM.min. OS was 69.1% at last follow up and was not significantly associated with CR and age at transplantation. Conclusion: In this large series of pediatric BMT recipients, we found that toxicities as VOD and niPD correlated with type of CR and age at transplantation in univariate analysis. Combination of 2 alkylating agents with Bu or BuFlu and transplantation < 1 year of age were associated with the highest incidence of toxicites. The TW targeting performance was improved in this cohort compared to previous reported data (Paci et al. TDM 2012). Specific TW for each group of pathologies will be proposed. Disclosures No relevant conflicts of interest to declare.

Abstract 2378 Allogeneic stem cell transplantation (allo-SCT) offers potential curative treatment of for a wide range of otherwise fatal hematological diseases. However, only one third of patients have an HLA-identical sibling donor. We have previously reported that in patients with standard risk malignancy, transplantation from unrelated HLA-allellically matched donors (10/10) led to outcomes similar to those from HLA-identical sibling donors (Yakoub-Agha et al, JCO 2006). Indeed, with the increase in the number of single-child families, stem cell grafts from unrelated donors are being increasingly used and more than 30% of patients eligible for allo-CST, are still lacking a well-matched donor. In the attempt to investigate the impact of unrelated one-antigen HLA-mismatched graft, we report a single center retrospective study on 209 patients who underwent allo-CST from identical HLA-sibling donor (n=123), unrelated HLA-matched donor (10/10) (n=73) and unrelated one-antigen-HLA-mismatched donor (9/10) (n=13) over the last 5 years. In order to homogenize our cohort, patients with CML, aplastic anemia or lymphoproliferative disorder were excluded from the study. Therefore, underlying diseases were AML (n=104), ALL (n=54), myelodysplastic syndrome (n=30), and myeloproliferative syndrome (n=21). Of the 117 (56%) males patients, 49 (23%) received graft from female donor (classical sex-mismatch). Medians age of recipients and donors at transplantation were 45.2 years (4.4-65.5) and 40.8 years (2.0-67.5), respectively. Patients received conditioning regimens using either myeloablative (n=149) including 81 who received High-dose TBI (12Gy) or nonmyeloablative (n=60) including 48 who received low-dose TBI (2Gy). Antithymoglobulin was given to 25 pts. Bone marrow was the main source of stem cells (n=150; 72%). Results: with the median of follow-up of 37.9 months, 78 patients died including 25 from TRM. Relapse was recorded in 70 patients. Seventy-two patients experienced acute GVHD (aGVHD) including 47 with II-IV grades and 30 with III-IV grades. In multivariate analyses, donor type (unrelated regardless the degree of HLA-matching vs related) and conditioning (nonmyeloablative vs myeloablative) were the most important risk factors negatively influencing the overall survival [p=.002; HR=2.038 and p=.016; HR=1.81, respectively) and event-free survival (p=.005; HR=1.783 and p=.015; HR=1.728, respectively). As expected, the only factor that influenced the risk of relapse was the conditioning type (nonmyeloablative vs myeloablative) (p=.048; HR=1.699) while donor type was found to influence TRM (p=.030; HR=2.428). Graft from unrelated one-antigen HLA-mismatched donor (9/10) was the foremost risk factor for acute grade II-IV GVHD (p=.019; HR=2.663; [95%CI: 1.178–6.019]). In conclusion, except for acute II-IV GHVD, allo-CST from unrelated one-antigen HLA-mismatched donor (9/10), seemed to led to outcomes similar to those from HLA-identical unrelated donor (10/10) and may be considered as an alternative option for patients without a full-matched donor. Prospective studies are warranted, however, to confirm our data in larger cohort of patients. Disclosures: No relevant conflicts of interest to declare.