Impact thérapeutique de la midostaurin dans la prise en charge des mastocytoses systémiques avancées

Patients with advanced systemic mastocytosis have a poor prognosis and limited treatment options. The primary and the most common oncogenetic driver of systemic mastocytosis pathogenesis is D816V-mutated c-KIT tyrosine kinase receptor. Midostaurin bloked this cell pathway. We analyzed 46 patients, with a median age of 66 years (36 to 84 years) and an advanced systemic mastocytosis (ASM (n=17), ASM-AHD (n=25), et MCL (n=4)). 83% of patients were treated by Midostaurin in first line and 17% in second line at least. Midostaurin was given at 100 mg twice daily for at least 3 cycles of 28 days. We report an overall response rate of 80% (39% with partial remission and 41% with clinical remission). Median overall survival for the whole cohort was 69,3 months, 44,6 months for ASM, 80,4 months for ASM-AHD and 69,3 months for the 4 MCL. The most frequent grade 3/4 nonhematologic side effects were vomiting (17%), headache (11%), fatigue (9%) and constipation (9%). The most frequent grade 3/4 hematologic toxicitie was anemia (9%). These data illustrate the sustainable efficacy of Midostaurin in the therapeutic management of advanced systemic mastocytosis.Les patients atteints de mastocytoses systémiques avancées ont un pronostic sombre et les options thérapeutiques restent limitées. L’oncogénèse de ces hémopathies s’explique en partie par l’expression d’un récepteur à activité tyrosine kinase auto-activé, c-KIT, portant le plus souvent la mutation D816V. La Midostaurin assure le blocage de cette voie de signalisation. Nous avons analysé 46 patients, avec un âge médian de 66 ans (36 à 84 ans), présentant une mastocytose systémique avancée (ASM (n=17), ASM-AHD (n=25), et MCL (n=4)). 83% des patients ont été traités par Midostaurin en première ligne, 17% au moins en deuxième ligne. La Midostaurine a été donnée à 100 mg deux fois par jour pendant au moins 3 cycles de 28 jours. La durée médiane de traitement sur l'ensemble de la cohorte était de 15,6 mois (3 à 109 mois). Nous rapportons une réponse globale à 80% (rémission partielle dans 39% des cas et rémission clinique dans 41% des cas). La survie globale médiane sur l’ensemble de la population étudiée était de 69,3 mois, 44,6 mois pour les ASM, 80,4 mois pour les ASM-AHD et 69,3 mois pour les 4 patients avec MCL. Les effets indésirables non-hématologiques de grades 3/4 les plus courants étaient les vomissements (17%), les céphalées (11%), l’asthénie (9%) et la constipation (9%). L’effet indésirable hématologique de grades 3/4 le plus courant était l’anémie (9%). Ces données illustrent l’efficacité durable de la Midostaurin dans la prise en charge thérapeutique des mastocytoses systémiques avancées

Carfilzomib-Induced Thrombotic Microangiopathy Treated with Eculizumab: A Case Report and Rapid Literature Review

Background: Thrombotic microangiopathies (TMAs) can be induced by drugs. Recent works have indicated proteasome inhibitors, including carfilzomib, as a possible new causative agent. Although the physiopathology and management of carfilzomib-induced TMA are still unknown, eculizumab seems to be efficient. Results: We report a clinical case of TMA during carfilzomib treatment for multiple myeloma, possibly triggered by a concomitant influenza infection, suggesting a multi-hit process. Histologic analysis of the kidney biopsy proved renal TMA. Eculizumab allowed rapid and long-lasting renal and hematologic recovery. We enriched our work with a systemic review of published cases of carfilzomib-induced TMA treated by eculizumab. Twelve patients were included, all of whom presented acute renal failure and nine of them required hemodialysis. Eculizumab led to TMA resolution in eleven patients and complete renal recovery with hemodialysis withdrawal for seven of them within a month. One patient died from multiple myeloma progression. Two patients presented inter-current viral infection. Soluble complement fragment Bb and C5b9s were found in two patients and genetic benign variant of Factor H (CFH3–CFH1) in four. Conclusion: Our results suggest that eculizumab is effective in carfilzomib-induced TMA, which could support its inclusion as a treatment option. Further studies are required to clarify its physiopathology, complement role, and management

Carfilzomib-Induced Thrombotic Microangiopathy Treated with Eculizumab: A Case Report and Rapid Literature Review

Background: Thrombotic microangiopathies (TMAs) can be induced by drugs. Recent works have indicated proteasome inhibitors, including carfilzomib, as a possible new causative agent. Although the physiopathology and management of carfilzomib-induced TMA are still unknown, eculizumab seems to be efficient. Results: We report a clinical case of TMA during carfilzomib treatment for multiple myeloma, possibly triggered by a concomitant influenza infection, suggesting a multi-hit process. Histologic analysis of the kidney biopsy proved renal TMA. Eculizumab allowed rapid and long-lasting renal and hematologic recovery. We enriched our work with a systemic review of published cases of carfilzomib-induced TMA treated by eculizumab. Twelve patients were included, all of whom presented acute renal failure and nine of them required hemodialysis. Eculizumab led to TMA resolution in eleven patients and complete renal recovery with hemodialysis withdrawal for seven of them within a month. One patient died from multiple myeloma progression. Two patients presented inter-current viral infection. Soluble complement fragment Bb and C5b9s were found in two patients and genetic benign variant of Factor H (CFH3–CFH1) in four. Conclusion: Our results suggest that eculizumab is effective in carfilzomib-induced TMA, which could support its inclusion as a treatment option. Further studies are required to clarify its physiopathology, complement role, and management

Salvage therapy with brentuximab-vedotin and bendamustine for patients with R/R PTCL: a retrospective study from the LYSA.

peer reviewe

Prospective comparison of prognostic scores for prediction of outcome after out-of-hospital cardiac arrest: results of the AfterROSC1 multicentric study

International audienceBackground Out-of-hospital cardiac arrest (OHCA) is a heterogeneous entity with multiple origins and prognoses. An early, reliable assessment of the prognosis is useful to adapt therapeutic strategy, tailor intensity of care, and inform relatives. We aimed primarily to undertake a prospective multicentric study to evaluate predictive performance of the Cardiac Arrest Prognosis (CAHP) Score as compare to historical dataset systematically collected after OHCA (Utstein style criteria). Our secondary aim was to evaluate other dedicated scores for predicting outcome after OHCA and to compare them to Utstein style criteria. Methods We prospectively collected data from 24 French and Belgium Intensive Care Units (ICUs) between August 2020 and June 2022. All cases of non-traumatic OHCA (cardiac and non-cardiac causes) patients with stable return of spontaneous circulation (ROSC) and comatose at ICU admission (defined by Glasgow coma score ≤ 8) on ICU admission were included. The primary outcome was the modified Rankin scale (mRS) at day 90 after cardiac arrest, assessed by phone interviews. A wide range of developed scores (CAHP, OHCA, CREST, C-Graph, TTM, CAST, NULL-PLEASE, and MIRACLE2) were included, and their accuracies in predicting poor outcome at 90 days after OHCA (defined as mRS ≥ 4) were determined using the area under the receiving operating characteristic curve (AUROC) and the calibration belt. Results During the study period, 907 patients were screened, and 658 were included in the study. Patients were predominantly male (72%), with a mean age of 61 ± 15, most having collapsed from a supposed cardiac cause (64%). The mortality rate at day 90 was 63% and unfavorable neurological outcomes were observed in 66%. The performance (AUROC) of Utstein criteria for poor outcome prediction was moderate at 0.79 [0.76–0.83], whereas AUROCs from other scores varied from 0.79 [0.75–0.83] to 0.88 [0.86–0.91]. For each score, the proportion of patients for whom individual values could not be calculated varied from 1.4% to 17.4%. Conclusions In patients admitted to ICUs after a successfully resuscitated OHCA, most of the scores available for the evaluation of the subsequent prognosis are more efficient than the usual Utstein criteria but calibration is unacceptable for some of them. Our results show that some scores (CAHP, sCAHP, mCAHP, OHCA, rCAST) have superior performance, and that their ease and speed of determination should encourage their use. Trial registration https://clinicaltrials.gov/ct2/show/NCT0416789