Acute respiratory failure in immunocompromised patients : outcome and clinical features according to neutropenia status

Abstract Background The impact of neutropenia in critically ill immunocompromised patients admitted in a context of acute respiratory failure (ARF) remains uncertain. The primary objective was to assess the prognostic impact of neutropenia on outcomes of these patients. Secondary objective was to assess etiology of ARF according to neutropenia. Methods We performed a post hoc analysis of a prospective multicenter multinational study from 23 ICUs belonging to the Nine-I network. Between November 2015 and July 2016, all adult immunocompromised patients with ARF admitted to the ICU were included in the study. Adjusted analyses included: (1) a hierarchical model with center as random effect; (2) propensity score (PS) matched cohort; and (3) adjusted analysis in the matched cohort. Results Overall, 1481 patients were included in this study of which 165 had neutropenia at ICU admission (11%). ARF etiologies distribution was significantly different between neutropenic and non-neutropenic patients, main etiologies being bacterial pneumonia (48% vs 27% in neutropenic and non-neutropenic patients, respectively). Initial oxygenation strategy was standard supplemental oxygen in 755 patients (51%), high-flow nasal oxygen in 165 (11%), non-invasive ventilation in 202 (14%) and invasive mechanical ventilation in 359 (24%). Before adjustment, hospital mortality was significantly higher in neutropenic patients (54% vs 42%; p = 0.006). After adjustment for confounder and center effect, neutropenia was no longer associated with outcome (OR 1.40, 95% CI 0.93–2.11). Similar results were observed after matching (52% vs 46%, respectively; p = 0.35) and after adjustment in the matched cohort (OR 1.04; 95% CI 0.63–1.72). Conclusion Neutropenia at ICU admission is not associated with hospital mortality in this cohort of critically ill immunocompromised patients admitted for ARF. In neutropenic patients, main ARF etiologies are bacterial and fungal infections

Acute respiratory failure in immunocompromised patients:outcome and clinical features according to neutropenia status

Background: The impact of neutropenia in critically ill immunocompromised patients admitted in a context of acute respiratory failure (ARF) remains uncertain. The primary objective was to assess the prognostic impact of neutropenia on outcomes of these patients. Secondary objective was to assess etiology of ARF according to neutropenia. Methods: We performed a post hoc analysis of a prospective multicenter multinational study from 23 ICUs belonging to the Nine-I network. Between November 2015 and July 2016, all adult immunocompromised patients with ARF admitted to the ICU were included in the study. Adjusted analyses included: (1) a hierarchical model with center as random effect; (2) propensity score (PS) matched cohort; and (3) adjusted analysis in the matched cohort. Results: Overall, 1481 patients were included in this study of which 165 had neutropenia at ICU admission (11%). ARF etiologies distribution was significantly different between neutropenic and non-neutropenic patients, main etiologies being bacterial pneumonia (48% vs 27% in neutropenic and non-neutropenic patients, respectively). Initial oxygenation strategy was standard supplemental oxygen in 755 patients (51%), high-flow nasal oxygen in 165 (11%), non-invasive ventilation in 202 (14%) and invasive mechanical ventilation in 359 (24%). Before adjustment, hospital mortality was significantly higher in neutropenic patients (54% vs 42%; p = 0.006). After adjustment for confounder and center effect, neutropenia was no longer associated with outcome (OR 1.40, 95% CI 0.93–2.11). Similar results were observed after matching (52% vs 46%, respectively; p = 0.35) and after adjustment in the matched cohort (OR 1.04; 95% CI 0.63–1.72). Conclusion: Neutropenia at ICU admission is not associated with hospital mortality in this cohort of critically ill immunocompromised patients admitted for ARF. In neutropenic patients, main ARF etiologies are bacterial and fungal infections.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Venetoclax in Acute Myeloid Leukemia: Molecular Basis, Evidences for Preclinical and Clinical Efficacy and Strategies to Target Resistance

Venetoclax is a BH3-mimetics agent specifically interacting with the antiapoptotic protein BCL-2, facilitating cytochrome c release from mitochondria, subsequent caspases activation, and cell death. Utilization of venetoclax has profoundly changed the landscape of treatment for the poor-prognosis category of AML patients unfit for intensive chemotherapy. In the phase III VIALE-A study, Venetoclax, in combination with the hypomethylating agent azacitidine, showed a 65% overall response rate and 14.7-month overall survival, in comparison with 22% and 8 months in the control arm. These results led to the widespread use of venetoclax in this indication. Other combination regimens, consisting of low-intensity, intensive, or targeted therapies are currently under evaluation. Despite promising results, preventing relapses or resistance to venetoclax is still an unmet clinical need. Numerous studies have been conducted to identify and overcome venetoclax resistance in preclinical models or in clinical trials, including the inhibition of other antiapoptotic proteins, the induction of proapoptotic BH3-only proteins, and/or the targeting of the mitochondrial metabolism and machinery

Non-invasive ventilation indication for critically ill cancer patients admitted to the intensive care unit for acute respiratory failure (ARF) with associated cardiac dysfunction: Results from an observational study.

BackgroundAcute respiratory failure (ARF) is a life-threatening complication in onco-hematology patients. Optimal ventilation strategy in immunocompromised patients has been highly controversial over the last decade. Data are lacking on patients presenting with ARF associating isolated cardiac dysfunction or in combination with another etiology. The aim of this study was to assess prognostic impact of initial ventilation strategy in onco-hematology patients presenting ARF with associated cardiac dysfunction.MethodsWe conducted an observational retrospective study in Institut Paoli-Calmettes, a cancer-referral center, assessing all critically ill cancer patients admitted to the ICU for a ARF with cardiac dysfunction.ResultsBetween 2010-2017, 127 patients were admitted. ICU and hospital mortality were 29% and 57%. Initial ventilation strategy was invasive mechanical ventilation (MV) in 21%. Others ventilation strategies were noninvasive ventilation (NIV) in 50%, associated with oxygen in 21% and high flow nasal oxygen (HFNO) in 29%, HFNO alone in 6% and standard oxygen in 23%. During ICU stay, 48% of patients required intubation. Multivariate analysis identified 3 independent factors associated with ICU mortality: SAPSII at admission (OR = 1.07/point, 95%CI = 1.03-1.11, pConclusionIn onco-hematology patients admitted for ARF with associated cardiac dysfunction, severity at ICU admission, invasive fungal infections and initial ventilation strategy were independently associated with ICU mortality. NIV was a protective factor on ICU mortality

Impact of gene mutations on treatment response and prognosis of acute myeloid leukemia secondary to myeloproliferative neoplasms

International audienceAcute myeloid leukemias secondary (sAML) to myeloproliferative neoplasms (MPN) have variable clinical courses and outcomes, but remain almost always fatal. Large cohorts of sAML to MPN are difficult to obtain and there is very little scientific literature or prospective trials for determining robust prog-nostic markers and efficient treatments. We analyzed event-free survival (EFS) and overall survival (OS) of 73 patients with MPN who progressed to sAML, based on their epidemiological characteristics , the preexisting MPN, the different treatments received, the different prognostic groups and the responses achieved according to the ELN, and their mutational status determined by next-generation DNA sequencing (NGS). For 24 patients, we were able to do a comparative NGS analysis at both MPN and sAML phase. After acute transformation EFS and OS were respectively of 2.9 months (range: 0-48.1) and 4.7 months (range: 0.1-58.8). No difference in EFS or OS regarding the previous MPN, the ELN2017 prognostic classification, the first-line therapy or the response was found. After univariate analysis, three genes, TP53, SRSF2 and TET2, impacted pejoratively sAML prognosis at sAML time. In multivariate analysis, TP53 (P 5 .0001), TET2 (P 5 .011) and SRSF2 (P 5 .018) remained independent prognostic factors. Time to sAML transformation was shorter in SRSF2-mutated patients (51.2 months, range: 14.7-98) than in SRSF2-unmutated patients (133.8 months, range: 12.6-411.2) (P < .001). Conventional clinical factors (age, karyotype, ELN2017 prognostic classification, treatments received, treatments response, Allo-SCT.. .) failed to predict the patients' outcome. Only the mutational status appeared relevant to predict patients' prognosis at sAML phase

National Institutes of Health classification for chronic graft-versus-host disease predicts outcome of allo-hematopoietic stem cell transplant after fludarabine-busulfan-antithymocyte globulin conditioning regimen

Abstract In 2005, the National Institutes of Health (NIH) proposed standard criteria for diagnosis, organ scoring and global assessment of chronic graft-versus-host disease (cGvHD) severity. We retrospectively reclassified cGvHD with NIH criteria in a monocentric cohort of 130 consecutive adult patients with hematological malignancies presenting cGvHD after receiving allo-hematopoietic stem cell transplant (HSCT) with a fludarabine-busulfan-antithymocyte globulin (ATG) conditioning regimen, among 313 consecutive HSCT recipients. We compared NIH and Seattle classifications to correlate severity and outcome. The follow up range was effectively 2-120 months. Forty-four percent developed Seattle-defined cGvHD (22% limited, 78% extensive forms). Using NIH criteria, there were 23%, 40% and 37% mild, moderate and severe forms, respectively, and 58%, 32% and 8% classic cGvHD, late acute GvHD and overlap syndrome. Five-year overall survival was 55% (49-61), and cumulative incidences of non-relapse mortality (NRM) and relapse/progression at 2 years were 19% (14-23) and 19% (14-24). NIH mild and moderate forms were associated with better survival compared to severe cGvHD (hazard ratio [HR] = 3.28, 95% confidence interval [CI]: 1.38-7.82, p = 0.007), due to higher NRM among patients with severe cGvHD (HR = 3.04, 95% CI: 1.05-8.78, p = 0.04) but comparable relapse risk (p = NS). In conclusion, the NIH classification appears to be more accurate in predicting outcome mostly by the reclassification of old-defined extensive forms into NIH-defined moderate or severe

The prognostic impact of abdominal surgery in cancer patients with neutropenic enterocolitis: a systematic review and meta-analysis, on behalf the Groupe de Recherche en Réanimation Respiratoire du patient d’Onco-Hématologie (GRRR-OH)

Abstract Neutropenic enterocolitis (NE) is a diagnostic and therapeutic challenge associated with high mortality rates, with controversial opinions on its optimal management. Physicians are usually reluctant to select surgery as the first-choice treatment, concerns being raised regarding the potential risks associated with abdominal surgery during neutropenia. Nevertheless, no published studies comforted this idea, literature is scarce and surgery has never been compared to medical treatment. This review and meta-analysis aimed to determine the prognostic impact of abdominal surgery on outcome of neutropenic cancer patients presenting with NE, versus medical conservative treatment. This meta-analysis included studies analyzing cancer patients presenting with NE, treated with surgical or medical treatment, searched by PubMed and Cochrane databases (1983–2016), according to PRISMA recommendations. The endpoint was hospital mortality. Fixed-effects models were used. The meta-analysis included 20 studies (385 patients). Overall estimated mortality was 42.2% (95% CI = 40.2–44.2). Abdominal surgery was associated with a favorable outcome with an OR of 0.41 (95% CI = 0.23–0.74; p = 0.003). Pre-defined subgroups analysis showed that neither period of admission, underlying malignancy nor neutropenia during the surgical procedure, influenced this result. Surgery was not associated with an excess risk of mortality compared to medical treatment. Defining the optimal indications of surgical treatment is needed. Trial registration PROSPERO CRD4201604895

Azacitidine Plus Venetoclax for the Treatment of Relapsed and Newly Diagnosed Acute Myeloid Leukemia Patients

International audienceVenetoclax (VEN) belongs the BH3-mimetic class that selectively targets BCL-2, activating apoptosis. The combination of VEN and azacitidine (AZA) has changed the paradigm of treatment of newly diagnosed (ND) acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy. There is scarce evidence for the use of VEN–AZA for relapsed or refractory (R/R) AML. We compared the outcome of 39 R/R AML and 38 ND AML patients treated between 01/20 and 12/21. The median age was 69 (22–86) and 73 (61–81) in the R/R and ND groups, respectively. Adverse cytogenetics were found in 36% of patients in the R/R group and 59% of patients in the ND group. Overall response rate was 37% in R/R AML, including 13% CR, 8% CRi, 3% PR and 13% MLFS, and 58% in the ND AML, including 32% CR, 13% CRi and 13% MLFS. Adverse cytogenetics was associated with treatment failure in the R/R group (Relative Risk = 0.13, p = 0.005). Median overall survival (OS) was 5.9 months in the R/R group and 9.4 months in the ND group. Median OS was 2.2 months in the adverse cytogenetics group versus 8.7 months in the intermediate cytogenetics group in the R/R group (p = 0.02). Median leukemia-free survival was not different between the two groups (9.4 months and 10.3 months), indicating that VEN–AZA can be an efficient salvage treatment for selected R/R AML patients. In conclusion, VEN–AZA is a promising treatment for ND AML and for selected R/R AML patients

Hepatic dysfunction impairs prognosis in critically ill patients with hematological malignancies: A post-hoc analysis of a prospective multicenter multinational dataset

Purpose: Hyperbilirubinemia is frequent in patients with hematological malignancies admitted to the intensive care unit (ICU). Literature about hepatic dysfunction (HD) in this context is scarce. Methods: We investigated the prognostic impact of HD analyzing a prospective multicenter cohort of 893 critically ill hematology patients. Two groups were defined: patients with HD (total bilirubin ≥33 μmol/L at ICU admission) and patients without HD. Results: Twenty one percent of patients were found to have HD at ICU admission. Cyclosporine, antimicrobials before ICU admission, abdominal symptoms, ascites, history of liver disease, neutropenia, increased serum creatinine and myeloma were independently associated with HD. Etiology remained undetermined in 73% of patients. Hospital mortality was 56.3% and 36.3% respectively in patients with and without HD (p 1 (OR = 2.07, 95% CI = 1.49–2.87, p < 0.0001), invasive mechanical ventilation (OR = 3.92, 95% CI = 2.69–5.71, p < 0.0001), renal replacement therapy (OR = 1.74, 95% CI = 1.22–2.47, p = 0.002), vasoactive drug (OR = 1.81, 95% CI = 1.21–2.71, p = 0.004) and SOFA score without bilirubin level at ICU admission (OR = 1.09, 95% CI = 1.04–1.14, p < 0.0001). Conclusions: HD is common, underestimated, infrequently investigated, and is associated with impaired outcome in critically ill hematology patients. HD should be considered upon ICU admission and managed as other organ dysfunctions.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

HLA-Matched Sibling versus Unrelated versus Haploidentical Related Donor Allogeneic Hematopoietic Stem Cell Transplantation for Patients Aged Over 60 Years with Acute Myeloid Leukemia: A Single-Center Donor Comparison

Haploidentical related donor (HRD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) was developed as a valid option for the treatment of acute myeloid leukemia (AML) in the absence of a matched donor. However, many investigators are reluctant to consider the use of this alternative in elderly patients, anticipating high morbidity. Here, we report a single-center comparison of HRD versus matched sibling donor (MSD) and unrelated donor (UD) allo-HSCT for patients with AML aged >= 60 years. Ninety-four patients (MSD: n = 31; UD: n = 30; HRD: n = 33) were analyzed. The median age was 65 (range, 60 to 73) years. We observed a higher cumulative incidence of grade 3 to 4 acute graft-versus-host disease (GVHD) after UD allo-HSCT (MSD versus UD versus HRD: 3% versus 33% versus 6%, respectively; P = .006). Two-year cumulative incidence of moderate or severe chronic GVHD was 17%, 27%, and 16% in the MSD, UD, and HRD groups, respectively (P = .487). No difference was observed in the 2-year cumulative incidence of relapse or nonrelapse mortality (NRM) (relapse: MSD versus UD versus HRD: 32% versus 25% versus 25%, respectively; P = .411; NRM: MSD versus UD versus HRD: 19% versus 27% versus 24%, respectively; P = .709). At 2 years, progression-free survival, overall survival, and GVHD- and relapse-free survival were 48%, 50%, and 39%, respectively, in the MSD group; 48%, 51%, and 23%, respectively, in the UD group; and 50%, 52%, and 32%, respectively, in the HRD group, without statistically significant differences between the groups. We conclude that HRD allo-HSCT is highly feasible and no less efficient than MSD or UD allo-HSCT in patients with AML aged >= 60 years. Thus, the absence of a HLA-identical donor should not limit the consideration of allo-HSCT for the treatment of AML. (C) 2018 American Society for Blood and Marrow Transplantation