Mesenchymal stromal cells confer chemoresistance to myeloid leukemia blasts through Side Population functionality and ABC transporter activation

Targeting chemoresistant malignant cells is one of the current major challenges in oncology. Therefore, it is mandatory to refine the characteristics of these cells to monitor their survival and develop adapted therapies. This is of particular interest in acute myeloid leukemia (AML), for which the 5-year survival rate only reaches 30%, regardless of the prognosis. The role of the microenvironment is increasingly reported to be a key regulator for blast survival. In this context, we demonstrate that contact with mesenchymal stromal cells promotes a better survival of blasts in culture in the presence of anthracycline through the activation of ABC transporters. Stroma-dependent ABC transporter activation leads to the induction of a Side Population (SP) phenotype in a subpopulation of primary leukemia blasts through alpha (α)4 engagement. The stroma-promoting effect is reversible and is observed with stromal cells isolated from either healthy donors or leukemia patients. Blasts expressing an SP phenotype are mostly quiescent and are chemoresistant in vitro and in vivo in patient-derived xenograft mouse models. At the transcriptomic level, blasts from the SP are specifically enriched in the drug metabolism program. This detoxification signature engaged in contact with mesenchymal stromal cells represents promising ways to target stroma-induced chemoresistance of AML cells

Real-world study of the efficacy and safety of belantamab mafodotin (GSK2857916) in relapsed or refractory multiple myeloma based on data from the nominative ATU in France: the IFM 2020-04 study

Belantamab mafodotin (BM) is an anti-BCMA antibody-drug conjugate (GSK2857916) that represents an alternative option in multiple myeloma. We sought to assess the efficacy and safety of BM in a real-world setting in patients who benefited from an early access program. We conducted an observational, retrospective, multicenter study. Eligibility criteria were treatment of relapsed or refractory multiple myeloma (RRMM) in monotherapy in adult patients who have received at least three lines of therapy previously, including at least one immunomodulatory agent (IMiD), a proteasome inhibitor (PI) and an anti-CD38 monoclonal antibody, and whose disease progressed during the last treatment period. The primary endpoint of the study is to assess the overall survival (OS). Between November 2019 and December 2020, 106 patients were treated with BM; 97 were eligible for the efficacy evaluation and 104 for safety. The median age was 66 (range, 37–82) years. High-risk cytogenetics were identified in 40.9% of patients. Fifty-five (56.7%) patients were triple-class refractory and 11 (11.3%) were penta-class refractory. The median number of prior lines of treatment was five (range, 3–12). The median number of BM cycles administered was three (range, 1–22). The overall response rate at best response was 38.1% (37/97). The median OS was 9.3 months (95% confidence interval [CI]: 5.9-15.3), and median progression-free survival was 3.5 months (95% CI: 1.9-4.7). The median duration of response was 9 months (range, 4.65-10.4). Treatment was delayed for 55 (52.9%) patients including 36.5% for treatment-related toxicity. Ophthalmic adverse events, mainly grade ≤2, were the most common toxicity (48%). The occurrence of keratopathy was 37.5%. Overall, our data are concordant with the results from DREAMM-2 in terms of efficacy and safety on a non-biased population

La maladie osseuse de Paget (étude paléopathologique)

Après un rappel des principaux aspects de la maladie osseuse de Paget chez le vivant, les 148 cas anciens de cette affection publiés dans la littérature paléoanthropologique sont analysés et critiqués. L'étude de trois cas personnels et la révision du premier cas publié (Pales, 1929) fournissent les éléments d'une description précise des lésions de la maladie de Paget sur l'os sec ; pour la reconnaître, nous proposons une liste de critères, avec une cotation pour chacun d'entre eux, permettant d'envisager ce diagnostic. La maladie apparaît d'abord au Néolithique, sur le rivage nord de la Méditerranée ; elle se répand ensuite lentement en Europe, au nord et à l'ouest de l'Empire romain, avant de devenir beaucoup plus fréquente dans l'Angleterre médiévale. Sa dissémination dans le monde contemporain semble liée à l'émigration anglo-saxonne. Sa présence dans l'Amérique préhistorique est contestée. Le rôle du chien, en tant que vecteur d'un éventuel agent pathogène, est discuté.BORDEAUX1-BU Sciences-Talence (335222101) / SudocSudocFranceF

Autoimmune hypoglycemia expands the biological spectrum of HHV8+ multicentric Castleman disease

Key Points Autoimmune hypoglycemia belongs to the clinical spectrum of HHV8+ MCD and rituximab is an effective treatment of this condition. This rare complication is related to autoantibodies directed toward the insulin receptor and activating the insulin signaling pathway.</jats:p

Treatments and Outcomes of Adult Patients with AML in the Real-Life - First Report of the French Observational ALFA-PPP Study

International audienceIntroduction. AML treatment options have been recently enriched. New agents like gemtuzumab ozogamicin (GO), FLT3 or IDH inhibitors, or CPX-351 have been approved for some patient subsets. Less-intensive options, like the AZA-VEN combination, are used in older/unfit patients. However, while treatments and indications are standardized, their choice is not, depending on often-subjective factors. This makes observational studies so important to describe the real-life management and outcomes of AML patients. Methods. In 2022, the ALFA group initiated a 2-cohort (newly diagnosed, relapsed/refractory) prospective observational study (ALFA-PPP, NCT04777916) aiming to collect clinical data and bio-samples in all AML patients aged ≥18y referred to 27 ALFA centers. Data/sample collection was structured by approved therapies including best supportive care (BSC). Patients treated on a compassionate basis or included in a clinical trial are also registered. Treatment decision-making criteria are prospectively collected. All patients should have a centralized genomic diagnosis (50-gene NGS panel) and molecular/flow MRD follow-up. We report here the initial observations made in the first 648 patients included between April 2022 and September 2023 in the newly diagnosed cohort. The current patient recruitment rate is around 650 new patients per year. Results. There were 340 males and 308 females (median age, 65y [range, 18-100]; ECOG-PS 0/1/2/3/4/NA, 195/295/97/33/8/19; HCT-CI comorbidity index 0/1/2/3+/NA, 54/269/106/216/3; median WBC, 6.9 G/L [IQR, 2.4-26]; median marrow blast percentage, 53% [IQR, 29-79]). The numbers of patients with de novo, post-MDS, post-MPN and therapy-related AML (tAML) were 467 (72%), 54 (8%), 58 (9%) and 69 (11%), respectively. ELN-2022 risk was favorable in 136 (21%), intermediate in 129 (20%), adverse in 340 (52.5%), and not available in 43 (6.5%) patients. In the 595 patients tested, incidences of NPM1, FLT3-ITD, IDH1/2, TP53 and secondary AML (sAML)-like gene mutations were 27%, 19%, 22%, 12% and 48%, respectively. A minority of 172 (26.5%) patients were included into a clinical trial frontline (investigator/company-sponsored trial, 140/32 patients; intensive/less intensive/two-option trial, 142/20/10 patients). They were significantly younger than the 476 (73.5%) patients treated outside any clinical trial (median age, 55 vs 69y, p &lt;.001). In these 476 patients, treatment decision was intensive in 266 (median age, 62y [18-79]; 210 7+3 ± GO or midostaurin, 54 CPX-351, 2 others), less intensive in 185 (median age, 76y [36-100]; 149 AZA-VEN, 18 AZA or low-dose cytarabine alone, 13 AZA-ivosidenib, 5 others), and BSC in 21 patients, while the 4 remaining patients early died before any treatment decision. By investigator declaration, the main reason for selecting a less intensive treatment was advanced age (n=138), AML characteristics/risk (n=19), concomitant diseases (n=16), patient's choice (n=1), or other (n=11), with good statistical correlations with objective data. The objective factors independently associated with the choice of a less intensive option were age ≥65y (p&lt;.001), higher ECOG-PS (p&lt;.001) or comorbidity index (p=.001), but also post-MDS (p=.001) or post-MPN (p&lt;.001) AML, lower WBC (p=.022), poor cytogenetics (p=0.046), and TP53 (p=.003) or IDH1/2 (p=.003) mutation. A total of 89/476 (18.5%) patients received an allogeneic SCT during the first 6 months of follow-up, including 81 intensively and only 8 less-intensively treated patients. In the 185 less-intensively treated patients with a median follow-up of 15 months, median overall survival (OS) was 10.3 months (95% CI, 7.2-12.9) with a 12-month estimate at 45.3% (95% CI, 37.7-52.5). In these patients, multivariate stepwise Cox model evidenced higher ECOG-PS (p=.038), concomitant diseases (p=.003), tAML (p=.046), higher marrow blast percentage (p=.024), sAML-like (p=.048) and TP53 (p&lt;.001) mutation as bad-prognosis factors for OS, while IDH1/2 mutations (p=.001) were associated with longer OS. Conclusions. Awaiting the ELN-2024 recommendations for less-intensive AML therapies, this prospective real-life study confirms their rising place in a European context. Rather than age by itself, survival after less-intensive treatment is governed by multiple independent clinical and genomic factors. Future reports will update these observations on an annual basis

Low incidence of SARS-CoV-2, risk factors of mortality and the course of illness in the French national cohort of dialysis patients

International audienceThe aim of this study was to estimate the incidence of COVID-19 disease in the French national population of dialysis patients, their course of illness and to identify the risk factors associated with mortality. Our study included all patients on dialysis recorded in the French REIN Registry in April 2020. Clinical characteristics at last follow-up and the evolution of COVID-19 illness severity over time were recorded for diagnosed cases (either suspicious clinical symptoms, characteristic signs on the chest scan or a positive reverse transcription polymerase chain reaction) for SARS-CoV-2. A total of 1,621 infected patients were reported on the REIN registry from March 16th, 2020 to May 4th, 2020. Of these, 344 died. The prevalence of COVID-19 patients varied from less than 1% to 10% between regions. The probability of being a case was higher in males, patients with diabetes, those in need of assistance for transfer or treated at a self-care unit. Dialysis at home was associated with a lower probability of being infected as was being a smoker, a former smoker, having an active malignancy, or peripheral vascular disease. Mortality in diagnosed cases (21%) was associated with the same causes as in the general population. Higher age, hypoalbuminemia and the presence of an ischemic heart disease were statistically independently associated with a higher risk of death. Being treated at a selfcare unit was associated with a lower risk. Thus, our study showed a relatively low frequency of COVID-19 among dialysis patients contrary to what might have been assumed