Integration of Pharmacogenetics and Pharmacogenomics in Drug Development: Implications for Regulatory and Medical Decision Making in Pediatric Diseases

n/

Peripheral Blood Stem Cells versus Bone Marrow for T Cell-Replete Haploidentical Transplantation with Post-Transplant Cyclophosphamide in Hodgkin Lymphoma.

Abstract Haploidentical stem cell transplantation (haplo-SCT) with post-transplant cyclophosphamide (PT-Cy) represents a potential curative strategy for patients with Hodgkin lymphoma (HL) when a matched related or unrelated donor is not available. The role of graft source, either bone marrow (BM) or peripheral blood stem cells (PBSCs), in this setting has not been fully elucidated. We performed a retrospective study on 91 patients with HL to compare the outcome after BM (n = 53) or PBSC (n = 38) transplant. Eighty-nine patients engrafted with no difference between BM and PBSCs in terms of median time for neutrophil (20 versus 20 days, P = .405) and platelet (26 versus 26.5 days, P = .994) engraftment. With a median follow-up of 40.2 months, 100-day cumulative incidences of grades II to IV acute graft-versus host disease (GVHD) and grades II to IV acute GVHD were 24% and 4%, respectively. Graft source was not associated with a different risk of acute GVHD both by univariate and multivariate analyses. Consistently, 1-year cumulative incidence of chronic GVHD was 7% with no differences between the 2 graft types (P = .761). Two-year rates of overall survival (OS), progression-free survival (PFS), nonrelapse mortality, and GVHD/relapse-free survival (GRFS) were 67%, 58%, 20%, and 52%, respectively. By univariate analysis, pretransplant disease status was the main variable affecting all outcomes. By multivariate analysis, PBSCs resulted in a protective factor for OS (hazard ratio [HR], .29; P = .006), PFS (HR, .38; P = .001), and GRFS (HR, .44; P = .020). The other independent variables affecting the final outcome were pretransplant disease status and hematopoietic cell transplant–specific comorbidity index. In conclusion, when planning a haplo-SCT with PT-Cy for patients with poor-risk HL, graft type is an important variable to take into account when selecting the best available donor

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality

Evaluation de la maladie du greffon contre l'hôte après greffe de sang placentaire conditionnée par un régime à intensité réduite chez l'adulte

AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

Saprochaete clavata Outbreak Infecting Cancer Center through Dishwasher

International audienceS aprochaete clavata (previously Geotrichum clavatum) is a rare emerging pathogen, an ascomycetous yeast-producing arthroconidia that causes invasive fungal infections in immunocompromised patients. The species has mainly been reported in Europe, often associated with sporadic cases or small outbreaks (1,2). Unlike Magnusiomyces capitatus (3,4), which has been associated with dairy products, S. clavata has rarely been isolated from environmental samples (5,6). Patients most at risk for infections from Geotrichum spp. have hematologic diseases with severe neutropenia (7) and are undergoing chemotherapy, mainly with cytarabine (1) or caspofungin (8). They often have central venous catheters (9). In recent years, S. clavata fungemia outbreaks associated with high mortality rates in vulnerable patients with malignancies have been described throughout Europe, mainly in France (1), Italy (2,10), Czechia (11), and Spain (12). No source of contamination was identified in any of these outbreaks despite thorough investigation. During February 2016-December 2017, the Paoli-Calmettes Institute, a cancer center in Marseille, France, was faced with an outbreak of S. clavata infections involving 9 patients hospitalized in 3 different wards, suggesting a common source of contamination. We describe the findings of an outbreak investigation that recovered S. clavata in different environmental samples, including from a dishwasher in the central kitchen and another, available to patients and their families, in the stem-cell transplant ward. Whole-genome sequencing (WGS) confirmed that the environmental and clinical isolates from patients belonged to the same phylogenetic clade. Handwashing, avoiding direct skin contact, checking air quality, and sterilizing food are routine practice to prevent contamination in hematology wards; however, examining dishwashers for contamination and operability may not be done routinely. Our findings should prompt adding dishwasher inspections to guidelines for preventing infection. Materials and Methods Case Definition Criteria We defined S. clavata infection by obtaining ≥1 positive results for S. clavata blood culture from a usually sterile body site or from a bronchoalveolar lavage or tracheal aspirate of the respiratory tract. Infection was also confirmed by observing pleural fluid in a patient with pleural effusion or lung infection

Impact of allele-level HLA matching on outcomes after double cord blood transplantation in adults with malignancies

In single unrelated cord blood transplantation (UCBT), an increasing number of HLA allele mismatches (MM) has been associated with inferior overall survival (OS) and attributed to higher transplant-related mortality (TRM). Previous studies on the role of allele-level HLA matching after double UCBT (dUCBT) showed conflicting results. In this study, we report the impact of allele-level HLA matching on the outcomes of a large dUCBT cohort. We included 963 adults with hematologic malignancies, with available allele-level HLA matching at HLA-A, -B, -C, and -DRB1, receiving dUCBT between 2006 to 2019. Assignment of donor-recipient HLA match was performed considering the unit with the highest disparity with the recipient. Three hundred ninety-two patients received dUCBT with 0 to 3 MM and 571 with ≥4 allele MM. For recipients of dUCBT with 0 to 3 MM, day-100 and 4-year TRM were 10% and 23%, respectively, compared with 16% and 36% for those with ≥4 MM. A higher degree of allele MM was also associated with the worse neutrophil recovery and lower incidence of relapse; no significant effect on graft-versus-host disease was observed. Patients receiving units with 0 to 3 MM had a 4-year OS of 54% compared with 43% for those receiving units with ≥4 MM. The inferior OS associated with higher HLA disparity was only partially mitigated by increased total nucleated cell doses. Our results confirm that allele-level HLA typing is a significant factor for OS after dUCBT, and units with ≥4 MM (≤4/8 HLA-matched) should be avoided if possible.</p

Once-weekly liposomal amphotericin B for prophylaxis of invasive fungal infection after graft-versus-host disease in allogeneic hematopoietic stem cell transplantation: a comparative retrospective single-center study

BACKGROUND AND OBJECTIVES: The liposomal formulation of amphotericin B (LAmB) has been shown to cause few and mild infusion-related reactions, while achieving high plasma and tissue concentrations compared with conventional amphotericin B. We investigated the efficacy and safety of high-dose LAmB (7.5 mg/kg once weekly) prophylaxis of fungal infections in allogeneic stem-cell transplanted (allo-SCT) patients with graft-versus-host disease (GvHD). DESIGN AND SETTING: Retrospective, comparative, single-center. METHODS: Forty-two patients receiving high-dose prednisone for GvHD after allo-SCT had LAmB prophylaxis; 83 patients in the control group received other antifungal prophylaxis. RESULTS: In the LAmB prophylaxis group, the median duration of treatment was 7 weeks. The cumulative incidence of invasive fungal infection was 8% at 1 year after transplantation, 8% at 2 years and 16% at 3 years in the LAmB group vs. 36% at 1 year, 44% at 2 years and 49% at 3 years in the other prophylaxis group (P=.008). Fungal infection-related mortality after transplantation was observed in none of the patients in the LAmB prophylaxis group vs. 12 patients (14%) at 1 year, 14 patients (17%) at 2 years and 16 patients (19%) at 3 years in the control group (P=.005). The tolerance of the treatment was good with only 5 patients (12%) having a reversible nephrotoxicity leading to temporary treatment discontinuation. CONCLUSIONS: High-dose LAmB prophylaxis seems effective and well tolerated in this short series of allo-SCT patients with GvHD. Prospective clinical studies are required to confirm these results

A study of elite sport-inspired coaching for patients after allogeneic hematopoietic stem cell transplantation

International audienceA need for social support is often expressed after hospitalization post HSCT. Emotional support and positive psychological constructs play an important role in post-HSCT recovery. Interventions generating positive affect can influence the health and well-being of transplant patients. It has been established that coaching in elite sport area leads to performance by playing a decisive role in maintaining the athlete's feelings of hope and autonomy in order to enable him or her to achieve their goals. In this single-center, prospective, one-arm study, we evaluated, in 32 post-HSCT patients, the acceptability of a coaching program inspired by elite sport coaching. Benefits were evaluated by questionnaires and semi-structured interviews. The coaching program was accepted by 97% of the patients. Analysis of the scores on the "Means" sub-dimension of Hope showed a significant increase over time (p = 0.0249 < 0.05) for every patient. Qualitative analysis of patient's satisfaction pointed out that this support facilitated the transition to a life without illness in particular in the non-hospital context of coaching sessions. Our results show that a "sport-inspired coaching" may offer an innovative approach supporting psychological and social recovery after HSCT and helping to start and/or maintain the processes leading to psychological well-being