Patients with Hematological Malignancies Treated with T-Cell or B-Cell Immunotherapy Remain at High Risk of Severe Forms of COVID-19 in the Omicron Era.

BACKGROUND: Patients with hematological malignancies are at greater risk of severe COVID-19 and have been prioritized for COVID-19 vaccination. A significant proportion of them have an impaired vaccine response, both due to the underlying disease and to the treatments. METHODS: We conducted a prospective observational study to identify the specific risks of the outpatient population with hematological diseases. RESULT: Between 22 December 2021 to 12 February 2022, we followed 338 patients of which 16.9% (n = 57) developed SARS-CoV-2 infection despite previous vaccination (94.7%). COVID-19 patients were more likely to have received immunotherapy (85.5% vs. 41%, p < 10-4), and particularly anti-CD20 monoclonal antibodies (40% vs. 14.9%, p < 10-4) and Bruton's tyrosine kinase inhibitors (BTKi) (7.3% vs. 0.7%, p < 10-2). There was no significant difference in demographic characteristics or hematological malignancies between COVID-19-positive and non-positive patients. Patients hospitalized for COVID-19 had more frequently received immunotherapy than patients with asymptomatic or benign forms (100% vs. 77.3%, p < 0.05). Hospitalized COVID-19 patients had a higher proportion of negative or weakly positive serologies than non-hospitalized patients (92.3% vs. 61%, p < 0.05). Patients who received tixagevimab/cilgavimab prophylaxis (n = 102) were less likely to be COVID-19-positive (4.9 vs. 22%, p < 0.05) without significant difference in hospitalization rates. CONCLUSION: In the immunocompromised population of patients with hematological malignancies, the underlying treatment of blood cancer by immunotherapy appears to be a risk factor for SARS-CoV-2 infection and for developing a severe form.

The transfusion of non-prophylactically RH-KEL1 antigen-matched red blood cells is feasible in selected myelodysplastic syndrome and acute myeloid leukaemia patients.

BACKGROUND AND OBJECTIVES: Most myelodysplastic syndromes (MDS) patients become red blood cell (RBC) transfusion-dependent. Transfusing MDS patients with prophylactically RH-KEL1 antigen-matched (PAM) RBC units is recommended to avoid RBC allo-immunization. D+C-E-c+e+, D+C-E+c+e- and D+C+E-c-e+ phenotypes are infrequent among French blood donors. To preserve infrequent phenotype RBC units for patients other than MDS, and to manage frequent phenotype RBC unit stocks, we let, for 1 year, higher-risk non-immunized chronically transfused MDS and acute myeloid leukaemia (AML) patients receive RBC transfusions matched only for D. Our objectives were to evaluate the impact of non-PAM transfusions on the transfusion policy (which would be modified in case of RBC allo-immunization) for frequent and infrequent phenotypes patients and to estimate the number of infrequent phenotypes RBC units that could be redistributed to other patients. RESULTS: Ninety patients were enrolled. Thirty-five patients had infrequent phenotypes, nine received only PAM RBC (143 units) and 26 PAM and non-PAM RBC (415 and 532, respectively): none developed allo-immunization. Fifty-five patients had frequent RBC phenotypes, 34 received only PAM RBC (561 units) and three developed antibodies (2 non-RH-KEL1 and one anti-E); 21 received PAM and non-PAM RBC (436 and 109, respectively) and one developed allo-immunization (unknown specificity). Our strategy enabled us to preserve 532 infrequent phenotypes RBC units: 216 D+C-E-c+e+, 33 D+C-E+c+e- and 283 D+C+E-c-e+ units, representing 48.8% of the total number of RBC units received by infrequent phenotypes patients during the study period. CONCLUSION: Allowing the transfusion of non-PAM RBC in selected chronically transfused MDS and AML patients was feasible and enabled to redistribute infrequent phenotypes RBC units to other patients in need.

Eprenetapopt Plus Azacitidine in TP53-Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Phase II Study by the Groupe Francophone des Myélodysplasies (GFM).

PURPOSE: TP53-mutated (TP53m) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) have very poor outcome irrespective of the treatment received, including 40% responses (20% complete remission [CR]) with azacitidine (AZA) alone, short response duration, and a median overall survival (OS) of approximately 6 months. Eprenetapopt (APR-246), a novel first-in-class drug, leads to p53 protein reconformation and reactivates its proapoptotic and cell-cycle arrest functions. PATIENTS AND METHODS: This phase II study assessed the safety and efficacy of eprenetapopt in combination with AZA in untreated high or very high International Prognostic Scoring System-R TP53m MDS and AML patients. RESULTS: Fifty-two TP53m patients (34 MDS, 18 AML [including seven with more than 30% blasts]) were enrolled. In MDS, we observed an overall response rate (ORR) of 62%, including 47% CR, with a median duration of response at 10.4 months. In AML, the ORR was 33% including 17% CR (27% and 0% CR in AML with less than and more than 30% marrow blasts, respectively). Seventy-three percent of responders achieved TP53 next-generation sequencing negativity (ie, variant allele frequency < 5%). The main treatment-related adverse events were febrile neutropenia (36%) and neurologic adverse events (40%), the latter correlating with a lower glomerular filtration rate at treatment onset (P < .01) and higher age (P = .05), and resolving with temporary drug interruption without recurrence after adequate eprenetapopt dose reduction. With a median follow-up of 9.7 months, median OS was 12.1 months in MDS, and 13.9 and 3.0 months in AML with less than and more than 30% marrow blasts, respectively. CONCLUSION: In this very high-risk population of TP53m MDS and AML patients, eprenetapopt combined with AZA was safe and showed potentially higher ORR and CR rate, and longer OS than reported with AZA alone.

Synergistic effects of PRIMA-1Met (APR-246) and 5-azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia.

Myelodysplastic syndromes and acute myeloid leukemia with TP53 mutations are characterized by frequent relapses, poor or short responses, and poor survival with the currently available therapies including chemotherapy and 5-azacitidine (AZA). PRIMA-1Met(APR-246,APR) is a methylated derivative of PRIMA-1, which induces apoptosis in human tumor cells through restoration of the transcriptional transactivation function of mutant p53. Here we show that low doses of APR on its own or in combination with AZA reactivate the p53 pathway and induce an apoptosis program. Functionally, we demonstrate that APR exerts these activities on its own and that it synergizes with AZA in TP53-mutated myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) cell lines and in TP53-mutated primary cells from MDS/AML patients. Low doses of APR on its own or in combination with AZA also show significant efficacy in vivo Lastly, using transcriptomic analysis, we found that the APR + AZA synergy was mediated by downregulation of the FLT3 pathway in drug-treated cells. Activation of the FLT3 pathway by FLT3 ligand reversed the inhibition of cell proliferation by APR + AZA. These data suggest that TP53-mutated MDS/AML may be better targeted by the addition of APR-246 to conventional treatments.

Respective roles of migration and social deprivation for virological non-suppression in HIV-infected adults on antiretroviral therapy in France.

Barriers to achieve sustained HIV virological suppression on antiretroviral therapy (ART) jeopardize the success of the 90:90:90 UNAIDS initiative which aims to end the HIV/AIDS epidemic. In France, where access to ART is free and universally available, we analyze the way in which social determinants of health (i.e. cultural, environmental) and economic factors might influence virological outcomes. A cross-sectional study was performed in two hospitals located in Paris area. All consecutive people living with HIV (PLHIV) on ART for at least 6 months attending the outpatient clinics between 01/05/2013 and 31/10/2014 answered an individual score of deprivation, EPICES, retrieving information on health insurance status, economic status, family support and leisure activity. This score varies from 0 to 100 with deprivation state defined above 30.17. Factors associated with HIV viral load >50 copies/ml were assessed by logistic regression modeling with a backward stepwise selection to select the final multivariable model. Sensitivity analyses were performed using two other thresholds for virological non-suppression (100 or 200 copies/ml). Overall, 475 PLHIV were included (53% male, median age 47 years, 66% not born in France mainly in a sub-Saharan African country). Half of French natives and 85% of migrants were classified as deprived. Median duration on ART was 9.7 years with virological suppression in 95.2% of non-deprived participants and in 83.5% of deprived ones (p = 0.001). The final multivariable model retained ART tiredness, younger age, a previous AIDS event and social deprivation (adjusted Odds Ratio, 2.9; 95%CI, 1.2-7.0) as determinants of virological non-suppression but not migration in itself. When using separate components of EPICES score, reporting economic difficulties and non-homeownership were associated with virological non-suppression. In addition to interventions focusing on cultural aspects of migration, social interventions are needed to help people with social vulnerability to obtain sustained responses on ART.