PD-1 blockade and allogeneic hematopoietic stem cell transplantation in Hodgkin lymphoma, a matter of time: a national study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire

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Late relapse after hematopoietic stem cell transplantation for acute leukemia: a retrospective study by SFGM-TC.

peer reviewedLate relapse (LR) after allogeneic hematopoietic stem cell transplantation (AHSCT) for acute leukemia is a rare event (nearly 4.5%) and raises the questions of prognosis and outcome after salvage therapy. We performed a retrospective multicentric study between January 1, 2010, and December 31, 2016, using data from the French national retrospective register ProMISe provided by the SFGM-TC (French Society for Bone Marrow Transplantation and Cellular Therapy). We included patients presenting with LR, defined as a relapse occurring at least 2 years after AHSCT. We used the Cox model to identify prognosis factors associated with LR. During the study period, a total of 7582 AHSCTs were performed in 29 centers, and 33.8% of patients relapsed. Among them, 319 (12.4%) were considered to have LR, representing an incidence of 4.2% for the entire cohort. The full dataset was available for 290 patients, including 250 (86.2%) with acute myeloid leukemia and 40 (13.8%) with acute lymphoid leukemia. The median interval from AHSCT to LR was 38.2 months (interquartile range [IQR], 29.2 to 49.7 months), and 27.2% of the patients had extramedullary involvement at LR (17.2% exclusively and 10% associated with medullary involvement). One-third of the patients had persistent full donor chimerism at LR. Median overall survival (OS) after LR was 19.9 months (IQR, 5.6 to 46.4 months). The most common salvage therapy was induction regimen (55.5%), with complete remission (CR) obtained in 50.7% of cases. Ninety-four patients (38.5%) underwent a second AHSCT, with a median OS of 20.4 months (IQR, 7.1 to 49.1 months). Nonrelapse mortality after second AHSCT was 18.2%. The Cox model identified the following factors as associated with delay of LR: disease status not in first CR at first HSCT (odds ratio [OR], 1.31; 95% confidence interval [CI], 1.04 to 1.64; P = .02) and the use of post-transplantation cyclophosphamide (OR, 2.23; 95% CI, 1.21 to 4.14; P = .01). Chronic GVHD appeared to be a protective factor (OR, .64; 95% CI, .42 to .96; P = .04). The prognosis of LR is better than in early relapse, with a median OS after LR of 19.9 months. Salvage therapy associated with a second AHSCT improves outcome and is feasible, without creating excess toxicity

Etude rétrospective du suivi de chimérisme dans l'allogreffe de cellules souches hématopoïétiques (vers une optimisation de la procédure de surveillance)

L'impact du chimérisme sur le devenir après allogreffe de cellules souches hématopoïétiques reste encore discuté, ainsi que la surveillance qui en découle. 123 greffes réalisées dans le service d'hématologie adulte du Centre Henri Becquerel à Rouen ont été sélectionnées à partir de critères techniques : suivi de chimérisme sur sang total et/ou dans les sous-populations myéloïde et lymphoïde T par méthode VNTR ou PCR quantitative, avec minimum de 2 analyses dont une dans les 3 premiers mois. La présence d'un chimérisme mixte ou complet a été confrontée aux paramètres de devenir post-greffe. L'incidence de chimérisme mixte initial sur sang total est de 23.5% dans les greffes à conditionnement standard (n=93) et de 51.7% dans les greffes à conditionnement atténué (n=30). Les échecs de greffe présentent ou non un chimérisme mixte en fonction du mécanisme sous-jacent. La survenue d'une GVH aiguë et sa sévérité sont associées à un chimérisme complet à 1 mois dans la lignée T(p=0.00042 et p=0.0016). Une réponse complète à 3 mois est corrélée à l'existence d'un chimérisme complet à 1 mois sur sang total seulement dans les greffes à conditionnement standard (p=0.021), mais pas dans la lignée T, même dans les greffes à conditionnement atténué. Lors de la rechute, un chimérisme mixte correspond à la détection de cellules anormales dans le sang en cas d'hémopathies avec leucémisation , et éventuellement, à la présence de lymphocytes T de l'hôte pouvant témoigner d'un défaut d'alloréactivité préalable. L'analyse du chimérisme peut aider à guider des stratégies préventives de rejet ou de rechute, notamment dans le cadre des greffes à conditionnement atténué, et à guider le traitement des rechutes. La synthèse des données de cette base interne rapprochée de celle de la littérature a permis de proposer une procédure de suivi du chimérisme optimisée en terme de choix de technique, d'indication de l'analyse de sous-populations et de rythme de surveillance.ROUEN-BU Médecine-Pharmacie (765402102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Intronic BCL-6 mutations are preferentially targeted to the translocated allele in t(3;14)(q27;q32) non-Hodgkin B-cell lymphoma

Translocations and somatic mutations are common genetic alterations of the BCL-6 gene on chromosome 3q27 in B-cell lymphoma, with implications for lymphomagenesis. The 2 events may have linked origins and can influence juxtaposed loci. To evaluate this further, we compared mutations occurring within the major mutation cluster region of the translocated and untranslocated BCL-6 alleles in 7 t(3;14)(q27;14q32) lymphomas. In 6 of 7 cases, the translocated allele revealed significantly higher mutations (mean, 5.8 x 10–2 bp–1) than did the untranslocated allele (mean, 5.3 x 10–3 bp–1; P < .01). The increase mapped to der(14q32), which retains the BCL-6 promoter and is transcriptionally active, as revealed by fusion transcripts and ongoing somatic mutations, absent in the der(3q27) region. These results indicate that enhanced mutational activity at the translocated allele may be a consequence of loss of cis regulatory elements or gain of IgH enhancer elements. Junctional sequences indicate translocation origins from earlier BCL-6 mutations and switch recombinase events

Sample size estimation in clinical trials using ventilator-free days as the primary outcome: a systematic review

Abstract Background Ventilator-free days (VFDs) are a composite endpoint increasingly used as the primary outcome in critical care trials. However, because of the skewed distribution and competitive risk between components, sample size estimation remains challenging. This systematic review was conducted to systematically assess whether the sample size was congruent, as calculated to evaluate VFDs in trials, with VFDs’ distribution and the impact of alternative methods on sample size estimation. Methods A systematic literature search was conducted within the PubMed and Embase databases for randomized clinical trials in adults with VFDs as the primary outcome until December 2021. We focused on peer-reviewed journals with 2021 impact factors greater than five. After reviewing definitions of VFDs, we extracted the sample size and methods used for its estimation. The data were collected by two independent investigators and recorded in a standardized, pilot-tested forms tool. Sample sizes were calculated using alternative statistical approaches, and risks of bias were assessed with the Cochrane risk-of-bias tool. Results Of the 26 clinical trials included, 19 (73%) raised “some concerns” when assessing risks of bias. Twenty-four (92%) trials were two-arm superiority trials, and 23 (89%) were conducted at multiple sites. Almost all the trials (96%) were unable to consider the unique distribution of VFDs and death as a competitive risk. Moreover, significant heterogeneity was found in the definitions of VFDs, especially regarding varying start time and type of respiratory support. Methods for sample size estimation were also heterogeneous, and simple models, such as the Mann–Whitney–Wilcoxon rank-sum test, were used in 14 (54%) trials. Finally, the sample sizes calculated varied by a factor of 1.6 to 17.4. Conclusions A standardized definition and methodology for VFDs, including the use of a core outcome set, seems to be required. Indeed, this could facilitate the interpretation of findings in clinical trials, as well as their construction, especially the sample size estimation which is a trade-off between cost, ethics, and statistical power. Systematic review registration PROSPERO ID: CRD42021282304. Registered 15 December 2021 ( https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021282304 )

Allogeneic hematopoietic stem cell transplantation for T-prolymphocytic leukemia: a report from the French society for stem cell transplantation (SFGM-TC)

T-prolymphocytic leukemia (T-PLL), a rare aggressive mature T-cell disorder, remains frequently resistant to conventional chemotherapy. Studies have suggested that allogeneic hematopoietic stem cell transplantation (HSCT) might possibly serve to consolidate the response to initial chemotherapy. The current report summarizes the outcome of 27 T-PLL cases identified in the registry in French Society for stem cell transplantation (SFGM-TC). Prior to HSCT, 14 patients were in complete remission (CR), 10 in partial response, three refractory, or in progression. Following HSCT, 21 patients achieved CR as best response. With a median follow-up for surviving patients of 33 (range, 6–103) months, 10 patients are still alive in continuous CR. Overall survival and progression-free survival estimates at 3 yr were 36% (95% CI: 17–54%) and 26% (95% CI: 14–45%), respectively. The relapse incidence after HSCT was 47% occurring at a median of 11.7 (range, 2–24) months. Overall cumulative incidence of transplant-related mortality was 31% at 3 yr. These results suggest that HSCT may allow long-term survival in patients with T-PLL following induction treatment; however, it is associated with a significant rate of toxicity

Germline JAK2 E846D Substitution as the Cause of Erythrocytosis?

International audienceThe discovery in 2005 of the JAK2 V617F gain-of-function mutation in myeloproliferative neoplasms and more particularly in polycythemia vera has deeply changed the diagnostic and therapeutic approaches to polycythemia. More recently, the use of NGS in routine practice has revealed a large number of variants, although it is not always possible to classify them as pathogenic. This is notably the case for the JAK2 E846D variant for which for which questions remain unanswered. In a large French national cohort of 650 patients with well-characterized erythrocytosis, an isolated germline heterozygous JAK2 E846D substitution was observed in only two cases. For one of the patients, a family study could be performed, without segregation of the variant with the erythrocytosis phenotype. On the other hand, based on the large UK Biobank resource cohort including more than half a million UK participants, the JAK2 E846D variant was found in 760 individuals, associated with a moderate increase in hemoglobin and hematocrit values, but with no significant difference to the mean values of the rest of the studied population. Altogether, our data as well as UK Biobank cohort analyses suggest that the occurrence of an absolute polycythemia cannot be attributed to the sole demonstration of an isolated JAK2 E846D variant. However, it must be accompanied by other stimuli or favoring factors in order to generate absolute erythrocytosis