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

Focal adhesion kinase (FAK), une protéine aux fonctions multiples

FAK (focal adhesion kinase) est une protéine cytoplasmique ubiquitaire retrouvée au sein du complexe d’adhérence. Son activation par les intégrines mais aussi par différents facteurs de croissance, cytokines ou hormones se traduit par l’autophosphorylation d’un résidu tyrosine (397) libérant un site de liaison pour la protéine Src. Cette liaison va permettre l’activation des protéines du complexe d’adhérence, aboutissant à la transmission de signaux régulateurs pour la migration, la survie et la prolifération cellulaires. Un dérèglement de ce système peut limiter ainsi plusieurs fonctions cellulaires, voire entraîner l’apoptose, et pourrait participer aux processus de cancérogenèse. Cet article présente les mécanismes par lesquels FAK contribue à la régulation cellulaire.Focal adhesion kinase (FAK) is a cytoplasmic protein tyrosine kinase localized to regions called focal adhesions. Many stimuli can induce tyrosine phosphorylation and activation of FAK, including integrins and growth factors. The major site of autophosphorylation, tyrosine 397, is a docking site for the SH2 domains of Src family proteins. The other sites of phosphorylation are phosphorylated by Src kinases. Phosphorylated FAK binds proteins of focal adhesion and can activate them directly or indirectly by phosphorylation. These activated proteins forming the FAK complex facilitate the generation of downstream signals necessary to regulate cell functions, like motility, survival and proliferation. Dysregulation of FAK could participate in the development of cancer. This review will focus upon the mechanisms by which FAK transmits biochemical signals and elicits biological effects

Impact d'une prophylaxie par Fluconazole versus Posaconazole sur l'incidence des infections fongiques invasives chez des patients recevant une chimiothérapie d'induction pour une leucémie aiguë myéloïde

Les infections fongiques invasives (IFI) restent des complications préoccupantes chez les patients atteints d'hémopathie maligne et notamment de leucémie aiguë myéloïde (LAM), de part leur incidence et leur taux de mortalité attribuable élevés. Compte tenu de ces risques, la prophylaxie antifungique a toujours été discutée. Méthode : Nous avons réalisé une étude rétrospective monocentrique de deux prophylaxies antifongiques (Fluconazole/Posconazole) chez 91 patients consécutifs suivis entre 2005 et 2009 ayant reçu une chimiothérapie d'induction pour une LAM, afin d'évaluer leur impact sur l'incidence des IFI et l'écologie mycologique des patients. Le coût global des antifongiques a par ailleurs été estimé. Résultats : 39 patients ont reçu une prophylaxie par Fluconazole contre 52 pour Posaconazole. Les caractéristiques cliniques des patients sont comparables. 17 patients ont présenté une IFI, sans différence entre les 2 groupes. L'utilisation d'un traitement empirique ou préemptif est similaire quelque soit la prophylaxie occasionnant in fine des coûts identiques entre les groupes. Enfin, l'étude mycologique des selles montre une augmentation de la colonisation par Candida non-albicans dans le groupe Fluconazole au cours du séjour et l'apparition d'une colonisation par Saccharomyces cerevisiae pour les patients sous Posaconazole. Conclusion : II nous semble préférable de privilégier le Posaconazole compte tenu de son AMM, de son large spectre et de sa relative innocuité. Cependant, il nous parait indispensable d'intégrer des dosages systématiques afin d'assurer un contrôle optimal. Le traitement empirique doit être rediscuté compte tenu de son absence d'influence sur l'incidence des IFI et de son coût au profit d'un traitement par Voriconazole dès le diagnostic d'IFI possible. L'amphotéricine B liposomale ou la caspofungine devraient être réservées quand l'administration de posaconazole n'est plus possible ou en cas suspicion d'une IFI non aspergillaire.ST ETIENNE-BU Médecine (422182102) / SudocSudocFranceF

Fulminant hepatitis due to very severe sinusoidal obstruction syndrome (SOS/VOD) after autologous peripheral stem cell transplantation: a case report

Abstract Background Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (SOS/VOD), is a potentially fatal complication of allogeneic or autologous hematopoietic stem cell transplantation. A plethora of transplant and patient-related risk factors predispose to SOS/VOD and should be taken into account for prognosis assessment as well as for adequate therapeutic intervention. Case presentation We describe the case of a mantle cell lymphoma patient who developed a fulminant hepatitis following oxaliplatin-containing intensive chemotherapy and autologous transplantation. This clinical manifestation was secondary to a very severe SOS/VOD. The patient did not exhibit the usual risk factors and presented a non-classical form with major cytolysis, thus puzzling SOS/VOD diagnosis in this context. Conclusion SOS has been previously reported after oxaliplatin-based chemotherapy regimens for colorectal cancers, in particular in patients with colorectal liver metastases. We therefore suspected a potential relationship with oxaliplatin-based regimen as a driver of SOS/VOD in a non-susceptible lymphoma patient. With regards to this case, clinicians and especially intensivists should be aware of this atypical presentation

Impact of fluconazole versus posaconazole prophylaxis on the incidence of fungal infections in patients receiving induction chemotherapy for acute myeloid leukemia

Background: Invasive fungal infections (IFIs) remain one of the worrying complications in patients with acute myeloid leukemia (AML) due to their incidence and high level of attributable mortality. In light of these risks, antifungal prophylaxis has always been debated. We conducted a single-center retrospective study of two prophylactic antifungal agents (fluconazole/posaconazole) in 91 consecutive patients receiving induction chemotherapy for AML between 2005 and 2009, in order to evaluate the impact on the incidence of IFI and on the mycological flora of the patients. Methods: In total, 39 patients received prophylactic fluconazole versus 52 who received posaconazole. The baseline characteristics of the two groups were comparable. Results: Overall, 17 patients developed an IFI, with no difference in frequency between the two groups. Utilization of empirical or pre-emptive therapy was similar irrespective of the type of prophylaxis used. Mycological examination of stools revealed an increase in non-albicans Candida colonization in the fluconazole group during hospitalization and the appearance of Saccharomyces cerevisiae colonization in patients receiving posaconazole. Conclusion: The present study does not distinguish between fluconazole and posaconazole as a primary effective prevention against fungal infections. More prospective studies and meta-analyses are warranted

Upfront allogeneic stem cell transplantation after reduced-intensity/nonmyeloablative conditioning for patients with myelodysplastic syndrome : a study by the Société Française de Greffe de Moelle et de Thérapie Cellulaire

Cytoreduction before allogeneic stem cell transplantation (allo-SCT) for patients with myelodysplastic syndromes remains a debatable issue. After excluding patients who had received preconditioning induction chemotherapy, we analyzed 128 consecutive patients with myelodysplastic syndrome who received reducedintensity or nonmyeloablative conditioning (RIC/NMA) allo-SCT. Among them, 40 received azacitidine (AZA) before transplant (AZA group) and 88 were transplanted up front (best supportive care [BSC] group). At diagnosis, 55 patients had intermediate 2 or high-risk scores per the International Prognostic Scoring System and 33 had a high cytogenetic risk score. Progression to a more advanced disease before allo-SCT was recorded in 22 patients. Source of stem cells were blood (n ¼ 112) or marrow (n ¼ 16) from sibling (n ¼ 78) or HLA-matched unrelated (n ¼ 50) donors. With a median follow-up of 60 months, 3-year overall survival, relapse-free survival, cumulative incidence of relapse, and nonrelapse mortality were, respectively, 53% versus 53% (P ¼ .69), 37% versus 42% (P ¼ .78), 35% versus 36% (P ¼ .99), and 20% versus 23% (P ¼ .74), for the AZA group and BSC group, respectively. Multivariate analysis confirmed the absence of statistical differences in outcome between the AZA and BSC groups, after adjusting for potential confounders using the propensity score approach. The absence of cytoreduction before RIC/NMA allo-SCT did not seem to alter the outcome. However, our results emphasize the need to perform prospective protocols to delineate the role of debulking strategy and to identify subsets of patients who may benefit from this approach