CNS Involvement at Initial Diagnosis and Risk of Relapse After Allogeneic HCT for Acute Lymphoblastic Leukemia in First Complete Remission

Outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) for adult acute lymphoblastic leukemia (ALL) have improved over time. Studies have shown that total body irradiation (TBI) is the preferable type of myeloablative conditioning (MAC). However, outcomes based on central nervous system (CNS) involvement, namely CNS-positive versus CNS-negative, have not been compared. Here, we evaluated outcomes of 547 patients (CNS-positive = 96, CNS-negative = 451) who were allografted in the first complete remission (CR1) between 2009 and 2019. Primary endpoint was leukemia-free survival (LFS). Median follow-up was not different between the CNS-positive and CNS-negative groups (79 versus 67.2 months, P = 0.58). The CNS-positive group were younger (median age 31.3 versus 39.7 years, P = 0.004) and were allografted more recently (median year 2012 versus 2010, P = 0.003). In both groups, MAC was the preferred approach (82.3% versus 85.6%, P = 0.41). On multivariate analysis, the CNS-positive group had higher incidence of relapse (RI) (hazard ratio [HR] = 1.58 [95% confidence interval (CI) = 1.06-2.35], P = 0.025), but no adverse effect on LFS (HR = 1.38 [95% CI = 0.99-1.92], P = 0.057) or overall survival (OS) (HR = 1.28 [95% CI = 0.89-1.85], P = 0.18). A subgroup multivariate analysis limited to CNS-positive patients showed that a TBI-based MAC regimen resulted in better LFS (HR = 0.43 [95% CI = 0.22-0.83], P = 0.01) and OS (HR = 0.44 [95% CI = 0.21-0.92], P = 0.03) and lower RI (HR = 0.35 [95% CI = 0.15-0.79], P = 0.01). Another subgroup analysis in CNS-negative patients showed that MAC-TBI preparative regimens also showed a lower RI without a benefit in LFS or OS. While a MAC-TBI allo-HCT regimen may not be suitable to all, particularly for older patients with comorbidities, this approach should be considered for patients who are deemed fit and able to tolerate.Peer reviewe

Outcome after allogeneic stem cell transplantation with haploidentical versus HLA-matched donors in patients with higher-risk MDS.

peer reviewedAllogeneic hematopoietic stem cell transplantation remains the best curative option for higher-risk myelodysplastic syndrome. The presence of monosomal karyotype and/or complex karyotype abnormalities predicts inferior survival after allo-SCT in MDS patients. Haploidentical allo-SCT has been increasingly used in acute leukemia (AL) and has similar results as using HLA-matched donors, but data on higher-risk MDS is sparse. We compared outcomes in 266 patients with higher-risk MDS after HLA-matched sibling donor (MSD, n = 79), HLA-matched unrelated donor (MUD, n = 139) and HLA haploidentical donor (HID, n = 48) from 2010 to 2019. Median donor age differed between the three groups (p < 0.001). The overall survival was significantly different between the three groups with a better OS observed in the MUD group (p = 0.014). This observation could be explained by a higher progression-free survival with MUD (p = 0.014). The cumulative incidence of grade 2-4 acute GvHD was significantly higher in the HID group (p = 0.051). However, in multivariable analysis, patients transplanted using an HID had comparable mortality to patients transplanted using a MUD (subdistribution hazard ratio [sHR]: 0.58 [0.32-1.07]; p = 0.080) and a MSD ([sHR]: 0.56 [0.28-1.11]; p = 0.094). MUD do not remain a significant positive predictor of survival, suggesting that beyond the donor-recipient HLA matching, the donor age might impact recipient outcome

K-Stacker: an algorithm to hack the orbital parameters of planets hidden in high-contrast imaging. First applications to VLT/SPHERE multi-epoch observations

Context. Recent high-contrast imaging surveys, using the Spectro- Polarimetic High contrast imager for Exoplanets REsearch (SPHERE) or the Gemini Planet Imager in search of planets in young, nearby systems, have shown evidence of a small number of giant planets at relatively large separation beyond 10-30 au, where those surveys are the most sensitive. Access to smaller physical separations between 5 and 30 au is the next step for future planet imagers on 10 m telescopes and the next generation of extremely large telescopes in order to bridge the gap with indirect techniques such as radial velocity, transit, and soon astrometry with Gaia. In addition to new technologies and instruments, the development of innovative observing strategies combined with optimized data processing tools is participating in the improvement of detection capabilities at very close angular separation. In that context, we recently proposed a new algorithm, Keplerian-Stacker, which combines multiple observations acquired at different epochs and takes into account the orbital motion of a potential planet present in the images to boost the ultimate detection limit. We showed that this algorithm is able to find planets in time series of simulated images of the SPHERE InfraRed Dual-band Imager and Spectrograph (IRDIS) even when a planet remains undetected at one epoch. Aims: Our goal is to test and validate the K-Stacker algorithm performances on real SPHERE datasets to demonstrate the resilience of this algorithm to instrumental speckles and the gain offered in terms of true detection. This will motivate future dedicated multi-epoch observation campaigns of well- chosen, young, nearby systems and very nearby stars carefully selected to search for planets in emitted and reflected light, respectively, to open a new path concerning the observing strategy used with current and future planet imagers. Methods: To test K-Stacker, we injected fake planets and scanned the low signal-to-noise ratio (S/N) regime in a series of raw observations obtained by the SPHERE/IRDIS instrument in the course of the SPHERE High-contrast ImagiNg survey for Exoplanets. We also considered the cases of two specific targets intensively monitored during this campaign: β Pictoris and HD 95086. For each target and epoch, the data were reduced using standard angular differential imaging processing techniques and then recombined with K-Stacker to recover the fake planetary signals. In addition, the known exoplanets β Pictoris b and HD 95086 b previously identified at lower S/N in single epochs have also been recovered by K-Stacker. Results: We show that K-Stacker achieves a high success rate of ≈100% when the S/N of the planet in the stacked image reaches ≈9. The improvement of the S/N is given as the square root of the total exposure time contained in the data being combined. At S/N Based on observations collected at the European Southern Observatory under programs: 095.C-0298, 096.C-0241, 097.C-0865, 198.C-0209, 099.C-0127

Cyberlindnera jadinii (teleomorph Candida utilis) candidaemia in a patient with aplastic anaemia: a case report

International audienceIntroduction. We present what is believed to be the first report of candidaemia caused by Cyberlindnera (Pichia) jadinii (teleomorph of Candida utilis) in a patient with an aplastic anaemia.Case presentation. The patient, a 21-year-old male, presented with hepatic cytolysis, cutaneous and pulmonary involvement, and septic shock. Cyberlindnera jadinii was identified by aerobic blood culture and MS. The patient initially received multiple and combined antifungal therapy, but continued to have persistent skin lesions and fever. He was successfully treated by emergency haploidentical haematopoietic stem cell transplantation, combined with triple antifungal therapy and supportive care.Conclusion. Cyberlindnera jadinii, teleomorph of Candida utilis, which is not usually invasive, can lead to an opportunistic invasive infection in unhealthy adult patients. For treatment of the invasive candida infection, it is necessary to combine antifungal therapy and supportive care

Early-Onset Schizophrenia in a paediatric population of French psychiatric and medico-social care centres: A cross sectional study.

BackgroundEarly-Onset Schizophrenia (EOS) is rare but severe mental health disorder in children and adolescents. Diagnosis of schizophrenia before the age of 18 years remains complex and challenging, especially in young children. In France, there are no recent reliable epidemiological data about the prevalence of EOS. The present study evaluates the EOS rate in a target clinical population of children and adolescents in psychiatric and medico-social care centres in the South-East of France.MethodsPsychiatric and medico-social centres for children and adolescent in the geographical area have been contacted, and after receiving their agreement to participate in the study, eligible patients corresponding to inclusion criteria were selected based on patients' medical records. Main inclusion criteria were age 7 to 17 years and intelligence quotient > 35. EOS categorical diagnosis was assessed by Kiddie-SADS Present and Lifetime psychosis section.Results37 centres participated and 302 subjects have been included in the study. The main result was the categorical diagnosis of EOS in 27 subjects, corresponding to a rate of 8.9% in the study population. Half of the patients presented mild to moderate intellectual deficiency. Interestingly, only 2.3% had a diagnosis of schizophrenia spectrum disorder noted in their medical records before standardized assessment.ConclusionsThe results of the study highlight the importance of using a standardized diagnostic tool for the diagnosis of schizophrenia in the paediatric population. In fact, EOS might be underdiagnosed in children and adolescents with neurodevelopmental disorders and subnormal cognitive functioning.Trial registrationNCT01512641. Registered 19 January 2012; https://clinicaltrials.gov/ct2/show/NCT01512641

Stratégies préventives et thérapeutiques de la rechute après allogreffe de cellules souches hématopoïétiques : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

International audienc

Post-transplant cyclophosphamide versus anti-thymocyte globulin after reduced intensity peripheral blood allogeneic cell transplantation in recipients of matched sibling or 10/10 HLA matched unrelated donors: final analysis of a randomized, open-label, multicenter, phase 2 trial

Abstract The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is not established after reduced intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) from fully matched donors. This was a randomized, open-label, multicenter, phase 2 trial. All patients received a RIC regimen with fludarabine, intravenous busulfan for 2 days (Flu-Bu2), and a peripheral blood stem cell (PBSC) graft from a matched related or 10/10 HLA-matched unrelated donor. Patients were randomly assigned to receive anti-thymocyte globulin (ATG) 5 mg/kg plus standard GVHD prophylaxis or PTCy 50 mg/kg/d at days +3 and +4 plus standard GVHD prophylaxis. The primary endpoint was the composite endpoint of GVHD- and relapse-free survival (GRFS) at 12 months after HSCT. Eighty-nine patients were randomly assigned to receive either PTCy or control prophylaxis with ATG. At 12 months, disease-free survival was 65.9% in the PTCy group and 67.6% in the ATG group (P = 0.99). Cumulative incidence of relapse, non-relapse mortality, and overall survival were also comparable in the two groups. GRFS at 12 months was 54.5% in the PTCy group versus 43.2% in the ATG group (P = 0.27). The median time to neutrophil and platelet count recovery was significantly longer in the PTCy group compared to the ATG group. Except for day +30, where EORTC QLQ-C30 scores were significantly lower in the PTCy compared to the ATG group, the evolution with time was not different between the two groups. Although the primary objective was not met, PTCy is effective for GVHD prophylaxis in patients receiving Flu-Bu2 conditioning with a PBSC graft from a fully matched donor and was well tolerated in term of adverse events and quality of life. This trial was registered at clinicaltrials.gov: NCT02876679

Efficacy and safety of defibrotide in the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome following hematopoietic stem cell transplantation: Interim results from the defifrance study

45th Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation (EBMT), Frankfurt, GERMANY, MAR 24-27, 2019International audienc

Atgam Efficacy and Safety in Moderate-to-Very Severe Acquired Aplastic Anemia: Outcome of a Large Multicenter Cohort of 634 Children and Adults from the French Authorization for Temporary Use Surveillance Program

International audienceIntroduction Acquired aplastic anemia (AA) is a rare immunological disease leading to bone marrow failure. First-line treatment in patients aged &gt;40 years or without a matched related donor is immunosuppressive therapy (IST) based on anti-human T lymphocyte immunoglobulin (ATG) plus cyclosporine. This ATGAM Temporary Use Authorization program was a retrospective, multicenter study to report safety and efficacy surveillance data on ATGAM use in patients with AA. Methods This study collected surveillance data from the ATGAM Named Patients Program for French authorities ahead of ATGAM registration. Patients were treated with ATGAM 40 mg/kg for 4 days in addition to cyclosporine. Safety and efficacy data were collected from patients treated from September 2011 to August 2022 and reported to the French authority every 6 months. Patients were classified as severe AA if they had 2 of the following criteria: neutrophil count &lt;0.5x10 9/L, platelet count &lt;20x10 9/L, or reticulocyte count &lt;60x10 9/L. Very severe AA: same as severe except neutrophil count &lt;0.2x10 9/L. Patients not meeting criteria for very severe/severe AA were classified as moderate. Patient response was evaluated using the RACE study criteria (Peffault de Latour, et al [2022]), for severe AA: complete response was defined as: hemoglobin &gt;100g/L, neutrophil count &gt;1.0x10 9/L, and platelet count &gt;100x10 9/L; partial response: no longer meeting criteria for severe disease; no response: still severe AA and/or transfusion dependent. For moderate AA (Marsh, et al [1999]), complete response was defined as: neutrophil count &gt;2.0x10 9/L and platelet count &gt;100x10 9/L; partial response: neutrophil count &gt;1.0x10 9/L and platelet count &gt;30x10 9/L; no response: transfusion dependent. Patients were classified as receiving first-line treatment (never received ATG), refractory (failed to respond to previous IST with ATG within 12 months before initial ATGAM), or relapse (recurrence of AA after a positive response to IST with ATG), regardless of AA severity. Results In total, 634 patients with moderate-to-very severe AA were treated with ATGAM (n=537 first-line; n=68 refractory/relapse; n=29 not classified) in addition to cyclosporine (40 first-line patients also received eltrombopag) from January 2012 to August 2022. By severity, n=124 were moderate, n=317 severe, n=133 very severe, and n=60 severity unknown. Patient demographics are shown in Table 1. Overall response (partial+complete) in patients on first-line therapy at 3, 6, and 12 months was 22.5% (n=78), 50.6% (n=156), and 79.2% (n=164), respectively. By severity, overall response rates in first-line therapy for moderate and severe/very severe cohorts, respectively, were: 25.0% (n=20) and 21.7% (n=58) at 3 months; 56.8% (n=42) and 48.7% (n=114) at 6 months; and 74.1% (n=40) and 81.0% (n=124) at 12 months. Overall response at 6 and 12 months by age and AA severity in patients on first-line treatment is shown in Table 2. Median duration of follow-up was 12.4 months. Overall survival (95% confidence interval) at 12 months for all patients was 91.5% (88.8-93.6). The treatment was well tolerated, and no new safety signals were observed with ATGAM. Cumulatively, 1,087 adverse events were reported in 364 patients over the entire program period, the majority of which were disease related. Conclusion This real-world, retrospective study utilizing surveillance data showed response rates in line with the recent RACE study (Peffault de Latour, et al [2022]) for patients with first-line severe AA treated with a combination of ATGAM and cyclosporine. No new safety risks were identified in this large cohort of patients. Treatment with ATGAM remains of benefit in patients with moderate-to-very severe AA