Bénédicte Bruno

Better outcome of patients undergoing enteral tube feeding after myeloablative conditioning for allogeneic stem cell transplantation.

Background Parenteral nutrition (PN) is still widely preferred to enteral nutrition (EN) in malnourished patients undergoing allogeneic stem-cell transplantation (allo-SCT) after myeloablative conditioning (MAC). The purpose was to determine whether EN improves early outcome after MAC allo-SCT. Methods Early outcome was prospectively assessed in patients undergoing MAC allo-SCT. A total of 121 consecutive patients undergoing a first MAC allo-SCT for acute leukemia, myelodysplastic syndrome, or myeloproliferative syndrome were included. Patients who received cord blood were excluded. Enteral nutrition was systematically offered, although PN was provided when EN had been refused or was poorly tolerated. Among the patients, 94 received EN (EN group) and 27 did not (non-EN group). Overall survival (OS), cumulative incidence of engraftment and acute graft-versus-host disease (aGVHD) within the first 100 days after transplantation were studied. Because EN and PN treatment assignments were not random, propensity score adjustments were performed on patient outcomes. Results Outcome was better in the EN group than in the non-EN group for OS (hazard ratio [HR], 0.12; 95% confidence interval [CI], 0.04–0.42; P=0.0008), neutrophil (HR, 2.07; 95% CI, 1.26–3.39; P=0.004), and platelet (HR, 1.93; 95% CI, 1.004–3.70; P=0.049) engraftments and aGVHD development (HR, 0.12; 95% CI, 0.04–0.39; P=0.0004). In Cox model analysis, EN demonstrated a protective effect (HR, 0.20; 95% CI, 0.05–0.77; P=0.019) on OS, whereas demonstrated a detrimental impact (HR, 4.18; 95% CI, 1.02–17.12; P=0.047). Enteral nutrition was found to be an independent factor in neutrophil engraftment (HR, 2.17; 95% CI, 1.24–3.81; P=0.007), whereas PN delayed platelet engraftment (HR, 0.57; 95% CI, 0.33–0.99; P=0.046). Enteral nutrition was the only factor that was protective against grades 3 to 4 aGVHD development (HR, 0.19; 95% CI, 0.05–0.72; P=0.01). Conclusions Routine use of EN is preferable to upfront PN in these patients.

Efficacy of fractionated gemtuzumab ozogamicin combined with cytarabine in advanced childhood myeloid leukaemia

Gemtuzumab ozogamicin (GO) monotherapy is reported to yield a 20–30% response rate in advanced acute myeloid leukaemia (AML). This study examined the efficacy and tolerability of GO combined with cytarabine (GOCYT) in children with refractory/relapsed CD33+ AML. Seventeen children received GO 3 mg/m2 on days 1, 4 and 7 plus cytarabine 100 mg/m2/d for 7 d on a compassionate‐use basis. Seven patients then received GO‐based consolidation. At the outset of GOCYT, two patients were refractory; eight patients were in refractory first relapse; six patients had relapsed after stem cell transplantation (SCT); and one patient [del(5q) therapy‐related AML (t‐AML)] had not yet been treated. Mean follow‐up was 17 months (8–33 months). Ten responses were obtained after GOCYT induction, including complete remission (CR) or CR without complete recovery of platelets (CRp) in six patients (35%). The responses improved in three children who received GOCYT consolidation, increasing the CR + CRp rate to 53%. SCT was subsequently performed in eight responders. Grade 3–4 adverse events consisted of haematological disorders (n = 17, 100%) and documented infections (n = 5, 29%). No cases of sinusoidal obstructive syndrome occurred. Three patients were alive at the cut‐off date for this analysis, all of whom had responded to GOCYT. GOCYT combination therapy yielded a high response rate (53%) and showed acceptable toxicity in heavily pretreated children with refractory/relapsed AML. These results warrant a larger prospective study.

Is there still a place for myeloablative regimen to transplant young adults with sickle cell disease

To the editor: We have read with great interest the comprehensive and detailed review on hematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD) published by Hsieh et al in a recent issue of the journal.[1][1] As emphasized by the authors, allogeneic HSCT is currently the only

A landscape of germline mutations in a cohort of inherited bone marrow failure patients

Bone marrow (BM) failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented ≥5% BM blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged ≤2 years and 36.9% were ≥18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germ line mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (GATA2, RUNX1), telomeropathies (TERC, TERT, RTEL1), ribosome disorders (SBDS, DNAJC21, RPL5), and DNA repair deficiency (LIG4). Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in inherited BMF (IBMF), such as SAMD9 and SAMD9L (N = 16 of the 86 patients, 18.6%), MECOM/EVI1 (N = 6, 7.0%), and ERCC6L2 (N = 7, 8.1%), each of which was associated with a distinct natural history; SAMD9 and SAMD9L patients often experienced transient aplasia and monosomy 7, whereas MECOM patients presented early-onset severe aplastic anemia, and ERCC6L2 patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly recognized disease entities. Using a high-throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling.

T-cell therapy using a bank of EBV-specific cytotoxic T cells: lessons from a phase I/II feasibility and safety study.

We report herein the results we obtained and the limitations we experienced during the production and use of a bank of Epstein-Barr virus (EBV)-transformed human cytotoxic T lymphocytes (EBV-CTLs). To assess the feasibility and toxicity of this strategy, we selected and stored, in liquid nitrogen, 4 billion EBV-CTLs from each of the 13 selected donors. Subsequently, in a multicenter phase I/II study, 11 patients with EBV-associated lymphoma resistant to conventional treatments received 1–3 doses of 5 million EBV-CTLs/kg with 1–3 and 0–4 compatibilities for human leukocyte antigen (HLA)-I and HLA-II, respectively. Except for one event of fever after injection, no immediate or delayed toxicity, no graft versus host disease, and no graft rejection attributable to CTL infusion were observed. Three patients presented complete remission and 1 partial remission after treatment. Considering the clinical options currently available, and the constrains associated with CTL preparation and implementation, we conclude that CTL banks should consist of a reasonably small number of cell lines with documented specificities. This objective could be more easily achieved if the few homozygous donors for the most frequent HLA alleles of the targeted population could be made available for such a project.

Impact on long-term OS of conditioning regimen in allogeneic BMT for children with AML in first CR: TBI + CY versus BU + CY: a report from the Société Française de Greffe de Moelle et de Thérapie Cellulaire

Allogeneic hematopoietic SCT (HSCT) appears to be an efficient tool to cure high-risk AML in first CR but the choice between BU-based or TBI-based conditioning regimens still remains controversial. In order to analyze the impact of conditioning regimen on long-term survival, we conducted a retrospective analysis from French registry data including all consecutive patients under 18 years old (n=226) from 1980 to 2004 transplanted for AML in CR1 from sibling (n=142) or matched unrelated donors and given either TBI-1200 cGy and CY 120 mg/kg (TBI-Cy, n=84) or BU 16 mg/kg and CY 200 mg/kg (BuCy200, n=142). Patient subgroups were comparable for all criteria except for median age at diagnosis and HSCT and for donor type. Both 5-year OS and disease-free survival (DFS) were significantly better in BuCy200 group (P=0.02 and 0.005, respectively). In multivariate analysis, both HLA matching and BuCy200 appeared as good prognostic factors for treatment-related mortality and DFS. Grade 2–4 acute GvHD and chronic GvHD rates were statistically higher in TBI-Cy group than in Bu-Cy200 one with a RR at 2 (P=0.002). In total, Bu-Cy200 conditioning regimen gives better outcome compared with TBI-Cy irrespective of the stem cell source and the donor type.

Immune reconstitution following myeloablative allogeneic hematopoietic stem cell transplantation: the impact of expanding CD28negative CD8+ T cells on relapse.

Allogeneic stem cell transplantation has become standard therapy for hematologic malignancies through the positive immunologic graft-versus-leukemia effect. Initial immune recovery relies on peripheral expansion of infused T cells, which switch to a memory-like phenotype. This study prospectively investigated whether changes in subset composition precedes complications after myeloablative HLA-matched transplantation for hematologic malignancies. Of 80 allograft recipients, 18 were still free of clinical complication throughout 395 to 1564 days of follow-up. Compared with this complication-free subgroup, patients who developed chronic graft-versus-host disease (cGVHD) without relapsing recovered similar numbers of circulating T cells with predominance of CD8+ T cells lacking CC-chemokine receptor-7 and CD28 expression throughout the first year after transplantation. Conversely, poor CD8+ T cell recovery with diminished numbers of CD28neg CD8+ T cells (approximately 1/4th of that of relapse-free patients) preceded occurrence of malignant relapse. In multivariate analysis, lower CD28neg CD8+ T cell counts by day 60 postallograft were associated with a greater risk of subsequent relapse (hazard ratio [HR] 0.33; 95% confidence interval [CI]: 0.14-0.76; P = .01). Enumeration of CD28neg CD8+ T cells in patients could assist in predicting risk of relapse and help build an algorithm for accelerating the immune recovery by reducing the immunosuppressive treatment and considering the introduction of preemptive donor lymphocyte infusions.

NUP214-ABL1 fusion defines a rare subtype of B-cell precursor acute lymphoblastic leukemia that could benefit from tyrosine kinase inhibitors

Acute lymphoblastic leukemia (ALL) comprises multiple entities with distinct clinico-biological features and treatment response. Among prognostic factors, cytogenetics remains one of the most discriminating parameters and is currently used to determine risk and treatment stratification. However,

Immunosuppresseurs dans la prévention de la réaction du greffon contre l'hôte : rapport de la SFGM-TC

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the fourth annual series of workshops which brought together practitioners from all member centers and took place in September 2013 in Lille. Here we report our recommendations regarding the use of immunosuppressive treatment in the prevention of graft versus host disease: report by the SFGM-TC.

Natural history of GATA2 deficiency in a survey of 79 French and Belgian patients

Heterozygous germline GATA2 mutations strongly predispose to leukemia, immunodeficiency, and/or lymphoedema. We describe a series of 79 patients (53 families) diagnosed since 2011, made up of all patients in France and Belgium, with a follow up of 2249 patients/years. Median age at first clinical symptoms was 18.6 years (range, 0-61 years). Severe infectious diseases (mycobacteria, fungus, and human papilloma virus) and hematologic malignancies were the most common first manifestations. The probability of remaining symptom-free was 8% at 40 years old. Among the 53 probands, 24 had missense mutations including 4 recurrent alleles, 21 had nonsense or frameshift mutations, 4 had a whole-gene deletion, 2 had splice defects, and 2 patients had complex mutations. There were significantly more cases of leukemia in patients with missense mutations (n=14 of 34) than in patients with nonsense or frameshift mutations (n=2 of 28). We also identify new features of the disease: acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, fatal progressive multifocal leukoencephalopathy related to the JC virus, and immune/inflammatory diseases. A revised International Prognostic Scoring System (IPSS) score allowed a distinction to be made between a stable disease and hematologic transformation. Chemotherapy is of limited efficacy, and has a high toxicity with severe infectious complications. As the mortality rate is high in our cohort (up to 35% at the age of 40), hematopoietic stem cell transplantation (HSCT) remains the best choice of treatment to avoid severe infectious and/or hematologic complications. The timing of HSCT remains difficult to determine, but the earlier it is performed, the better the outcome.