Prophylactic versus restrictive platelet transfusion strategy in patients with haematological malignancies in the ICU setting, a propensity-score analysis.

PURPOSE: Prophylactic platelet transfusions (PT) aim to reduce bleeding. We assessed whether restrictive PT compared to prophylactic strategy could apply in ICU. MATERIAL AND METHODS: We conducted a retrospective monocentric study including patients >18 yo with haematological malignancy admitted to the ICU with thrombocytopenia <20 G/L between 2018 and 2021. Patients were classified in 2 groups according transfusion strategy applied during the first 3 days: prophylactic or restrictive transfusion. RESULTS: 180 patients were included, 87 and 93 in the restrictive and prophylactic groups respectively. After propensity-score analysis, 2 groups of 54 matched patients were analyzed. Restrictive strategy led to a significant reduction in PT with incidence rate for 100-ICU-patients-days of 34.9 and 49.9, incidence rate ratio = 0.699 [0.5-0.9], p = 0.006, representing a 31% decrease. Decreased PT persisted until day 28 with platelet concentrates transfusions-free days at day 28 of 21 [13-25] and 16.5 [10.2-21] in the 2 groups (p = 0.04). Restrictive strategy did not result in higher grade ≥ 2 bleeding. Transfusion efficiency was low with similar number of days with platelet <10 or < 20 G/L regardless of strategy. Platelet transfusion strategy was not associated with 28-day mortality. Platelet nadir <5G/L was associated with day-28 mortality with HR = 1.882 [1.011-3.055], p = 0.046. CONCLUSION: A restrictive PT strategy appears feasible in the ICU.

Poor prognosis of SRSF2 gene mutations in patients treated with VEN-AZA for newly diagnosed acute myeloid leukemia.

Mutations in spliceosome genes (SRSF2, SF3B1, U2AF1, ZRSR2) correlate with inferior outcomes in patients treated with intensive chemotherapy for Acute Myeloid Leukemia. However, their prognostic impact in patients treated with less intensive protocols is not well known. This study aimed to evaluate the impact of Spliceosome mutations in patients treated with Venetoclax and Azacitidine for newly diagnosed AML. 117 patients treated in 3 different hospitals were included in the analysis. 34 harbored a mutation in at least one of the spliceosome genes (splice-mut cohort). K/NRAS mutations were more frequent in the splice-mut cohort (47% vs 19%, p=0.0022). Response rates did not differ between splice-mut and splice-wt cohorts. With a median follow-up of 15 months, splice mutations were associated with a lower 18-month LFS (p=0.0045). When analyzing splice mutations separately, we found SRSF2 mutations to be associated with poorer outcomes (p=0.034 and p=0.037 for OS and LFS respectively). This negative prognostic impact remained true in our multivariate analysis. We believe this finding should warrant further studies aimed at overcoming this negative impact.

Tripartite prehabilitation of patients with acute myeloid leukaemia and high-risk myelodysplastic syndromes during intensive chemotherapy before allogeneic haematopoietic stem cell transplantation (COHABILIT): protocol for an innovating prospective multicentre study.

OBJECTIVES: Acute myeloid leukaemia (AML) and high-risk myelodysplastic syndromes (MDS) are often treated with intensive chemotherapy followed by allogeneic haematopoietic stem cell transplantation (allo-HSCT). The pretransplant treatment results in a general deterioration of the patient's health and quality of life. Furthermore, allo-HSCT can be responsible for significant toxicity with risks of graft-versus-host disease (GvHD). Developing strategies to prevent physical deconditioning, undernutrition and psychological distress could help maintain a satisfactory general state of health before transplantation and thus limit these deleterious effects. This protocol evaluates the feasibility and adherence to a personalised prehabilitation programme, which can be modulated and assisted by connected objects, provided from the diagnosis to the allo-HSCT. METHODS AND ANALYSIS: This multicentre interventional study will include 50 patients treated for AML or high-risk MDS with intensive chemotherapy and eligible for allo-HSCT. The intervention consists of a coached, supervised or self-directed physical activity programme, organised during the hospitalisation phases and periods at home. At the same time, patients will receive a weekly dietary follow-up. The whole intervention is controlled and modulated through the use of a dedicated application and connected objects allowing adaptation and individualisation. The rate of participation in the prescribed physical activity sessions will assess the feasibility of this study. In addition, the evolution of physical capacities (Short Physical Performance Battery, grip and quadriceps strengths), psychosocial parameters (Functional Assessment of Cancer Therapy - Leukaemia, Functional Assessment of Cancer Therapy - Fatigue, subjective well-being, Hospital Anxiety and Depression Scale, self-efficacy, Coach-Athlete Relationship Questionnaire, interviews) and clinical status (weight, lean body mass, survival rate, number of infections, days of hospitalisation, GvHD) will be evaluated. ETHICS AND DISSEMINATION: The study procedures have been approved by the National Ethics Committee (21.00223.000003). Consent is given in person by each participant. The information collected on the participants contains only a non-identifiable study identifier. The results of this protocol will be published in a scientific paper and communicated to the medical staff of the medical centre. TRIAL REGISTRATION NUMBER: NCT03595787.

Characteristics and outcomes of patients with acute myeloid leukemia admitted to intensive care unit with acute respiratory failure: a post-hoc analysis of a prospective multicenter study.

BACKGROUND: Acute respiratory failure (ARF) is the leading cause of intensive care unit (ICU) admission in patients with Acute Myeloid Leukemia (AML) and data on prognostic factors affecting short-term outcome are needed. METHODS: This is a post-hoc analysis of a multicenter, international prospective cohort study on immunocompromised patients with ARF admitted to ICU. We evaluated hospital mortality and associated risk factors in patients with AML and ARF; secondly, we aimed to define specific subgroups within our study population through a cluster analysis. RESULTS: Overall, 201 of 1611 immunocompromised patients with ARF had AML and were included in the analysis. Hospital mortality was 46.8%. Variables independently associated with mortality were ECOG performance status ≥ 2 (OR = 2.79, p = 0.04), cough (OR = 2.94, p = 0.034), use of vasopressors (OR = 2.79, p = 0.044), leukemia-specific pulmonary involvement [namely leukostasis, pulmonary infiltration by blasts or acute lysis pneumopathy (OR = 4.76, p = 0.011)] and liver SOFA score (OR = 1.85, p = 0.014). Focal alveolar chest X-ray pattern was associated with survival (OR = 0.13, p = 0.001). We identified 3 clusters, that we named on the basis of the most frequently clinical, biological and radiological features found in each cluster: a "leukemic cluster", with high-risk AML patients with isolated, milder ARF; a "pulmonary cluster", consisting of symptomatic, highly oxygen-requiring, severe ARF with diffuse radiological findings in heavily immunocompromised patients; a clinical "inflammatory cluster", including patients with multi-organ failures in addition to ARF. When included in the multivariate analysis, cluster 2 and 3 were independently associated with hospital mortality. CONCLUSIONS: Among AML patients with ARF, factors associated with a worse outcome are related to patient's background (performance status, leukemic pulmonary involvement), symptoms, radiological findings, the need for vasopressors and the liver SOFA score. We identified three specific ARF syndromes in AML patients, which showed a prognostic significance and could guide clinicians to optimize management strategies.

Feasibility of Cyclosporine Prophylaxis Withdrawal in Critically Ill Allogenic Hematopoietic Stem Cell Transplant Patients Admitted to the Intensive Care Unit With No GVHD.

Twenty percent of allogenic hematopoietic stem cell transplantation (allo-HSCT) patients require intensive care unit (ICU) admission. Feasibility and long-term consequences of cyclosporine graft-versus-host disease (GVHD) prophylaxis withdrawal in the ICU are unknown. To assess the impact of cyclosporine prophylaxis withdrawal in critically ill allo-HSCT patients admitted to the ICU on GVHD incidence and to evaluate 6-month overall survival according to cyclosporine withdrawal and GVHD occurrence. From 2010 to 2020, 101 critically ill allo-HSCT patients admitted to the ICU in our institution were included. All received cyclosporine as GVHD prophylaxis. None of them had GVHD at ICU admission. Patients were admitted in the ICU after a median time of 11 days (5.5-18) after allo-HSCT. ICU, hospital mortality, and 6-month mortality were 43.6%, 56.4%, and 59.4%, respectively. Cyclosporine was withdrawn for 52 and continued for 49 patients in the ICU. A total of 38.6% (n = 39) developed secondarily acute GVHD (aGVHD) after a median of 28 days (15-40) after cyclosporine was discontinued. In 74.4% (n = 29) of cases, patients in the hematology ward developed aGVHD after ICU discharge. Cyclosporine dosages were similar in both groups. Factors independently associated with aGVHD occurrence in multivariate analysis were cyclosporine withdrawal in the ICU (subdistribution hazard ratios [sHR] = 2.04, 95% confidence interval [CI] = 1.02-4.1, P = .044), renal replacement therapy (RRT) (sHR = 0.43, 95% CI = 0.19-0.9, P = .03) and fungal prophylaxis (sHR = 2.62, 95% CI = 1.35-5.07, P = .004). Cyclosporine withdrawal in the ICU was associated with poorer 6-month overall survival (OS) (HR = 1.96, 95% CI = 1.16-3.33, P = .012), but after adjusting on severity (simplified acute physiology score, vasopressors, mechanical ventilation and RRT requirement), 6-month OS did not differ (HR = 1.35, 95% CI = 0.76-2.42, P = .30). GVHD occurrence after ICU stay was significantly associated with better 6-month OS in unadjusted (HR = 0.53, 95% CI = 0.31-0.90, P = .02) and severity-adjusted analysis (HR = 0.54, 95% CI = 0.31-0.93, P = .028). Cyclosporine prophylaxis withdrawal in critically ill allo-HSCT patients in the ICU appears to be feasible and did not impair long-term outcome.

Hepatic haemophagocytosis in haematology patients with hepatic dysfunction: prognostic impact and contribution of liver biopsy combined with the haemophagocytic syndrome diagnostic score (HScore).

Hepatic dysfunction (HD) is common in patients with haematological malignancies. Hepatic haemophagocytosis (HH) was detected in >50% of liver biopsies taken when HD remained unresolved after standard examination. We aimed to explore the contribution of liver biopsy in patients with both haematological malignancies and HD, describe the population of patients with HH, assess the prognostic impact of HH, and investigate haemophagocytic syndrome diagnostic score (HScore) utility in patients with HH. Between 2016 and 2019, 116 consecutive liver biopsies (76 transjugular, 40 percutaneous) were taken in 110 patients with haematological malignancy and HD (hyperbilirubinaemia, elevated transaminases, and/or cholestasis) and without a clear diagnosis. Liver biopsies were safe and diagnostically efficient. Predominant diagnoses included: HH (56%), graft-versus-host disease (55%), associated infections (24%), sinusoidal obstruction syndrome (15%), and tumoral infiltration (8%). Of patients, 35% were critically ill and 74% were allogeneic haematopoietic stem cell transplantation recipients, while 1-year overall survival (OS) was 35% with HH versus 58% without HH (p = 0.026). The 1-year OS was 24% with a HScore of ≥169 versus 50% with a HScore of <169 (p = 0.019). Liver biopsies are feasible in and contribute significantly to haematology patients with HD. HH occurred frequently and was associated with a poor prognosis. Combined with liver biopsy, the HScore may be helpful in refining haemophagocytic syndrome diagnosis.

High-flow nasal cannula failure in critically ill cancer patients with acute respiratory failure: Moving from avoiding intubation to avoiding delayed intubation.

BACKGROUND: High-flow nasal cannula (HFNC) is increasingly used in critically ill cancer patients with acute respiratory failure (ARF) to avoid mechanical ventilation (MV). The objective was to assess prognostic factors associated with mortality in ICU cancer patients requiring MV after HFNC failure, and to identify predictive factors of intubation. METHODS: We conducted a retrospective study from 2012-2016 in a cancer referral center. All consecutive onco-hematology adult patients admitted to the ICU treated with HFNC were included. HFNC failure was defined by intubation requirement. RESULTS: 202 patients were included, 104 successfully treated with HFNC and 98 requiring intubation. ICU and hospital mortality rates were 26.2% (n = 53) and 42.1% (n = 85) respectively, and 53.1% (n = 52) and 68.4% (n = 67) in patients requiring MV. Multivariate analysis identified 4 prognostic factors of hospital mortality after HFNC failure: complete/partial remission (OR = 0.2, 95%CI = 0.04-0.98, p<0.001) compared to patients with refractory/relapse disease (OR = 3.73, 95%CI = 1.08-12.86), intubation after day 3 (OR = 7.78, 95%CI = 1.44-41.96), number of pulmonary quadrants involved on chest X-ray (OR = 1.93, 95%CI = 1.14-3.26, p = 0.01) and SAPSII at ICU admission (OR = 1.06, 95%CI = 1-1.12, p = 0.019). Predictive factors of intubation were the absence of sepsis (sHR = 0.32, 95%CI = 0.12-0.74, p = 0.0087), Sp02<95% 15 minutes after HFNC initiation (sHR = 2.05, 95%CI = 1.32-3.18, p = 0.0014), number of quadrants on X-ray (sHR = 1.73, 95%CI = 1.46-2.06, p<0.001), Fi02>60% at HFNC initiation (sHR = 3.12, 95%CI = 2.06-4.74, p<0.001) and SAPSII at ICU admission (sHR = 1.03, 95%CI = 1.02-1.05, p<0.01). CONCLUSION: Duration of HFNC may be predictive of an excess mortality in ARF cancer patients. Early warning scores to predict HFNC failure are needed to identify patients who would benefit from early intubation.

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

Venetoclax (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.

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.

Gut microbiota diversity after autologous fecal microbiota transfer in acute myeloid leukemia patients.

Acute myeloid leukemia (AML) intensive chemotherapy combined with broad-spectrum antibiotics, leads to gut microbiota dysbiosis promoting pathological conditions and an increased incidence of complications. Here we report findings from a phase II single-arm, multicenter study evaluating autologous fecal microbiota transfer (AFMT) in 25 AML patients treated with intensive chemotherapy and antibiotics (ClinicalTrials.gov number: NCT02928523). The co-primary outcomes of the study are to evaluate the efficacy of AFMT in dysbiosis correction and multidrug-resistant bacteria eradication. The main secondary outcomes are to define a dysbiosis biosignature, to evaluate the effect of dysbiosis correction on patient clinical status, to assess the short and mid-term safety of AFMT in this immunocompromised population, and to evaluate the feasibility of the AFMT procedure and acceptability by the patient. Intensive induction chemotherapy induces a dramatic decrease of α-diversity indices, and a microbial dysbiosis with a significant shift of the microbial communities and domination of pro-inflammatory families. After AFMT treatment, α-diversity indices return to their initial mean levels and the similarity index shows the restoration of microbial communities. The trial meets pre-specified endpoints. AFMT appears to be safe and may be effective for gut microbiota restoration in AML patients receiving intensive chemotherapy and antibiotics, with an excellent gut microbiota reconstruction based on both richness and diversity indices at the species level.

Characteristics and outcome of patients with low-/intermediate-risk acute promyelocytic leukemia treated with arsenic trioxide: an international collaborative study.

The aim of this study was to characterize a large series of 154 patients with acute promyelocytic leukemia (median age, 53 years; range, 18-90 years) and evaluate real-life outcome after up-front treatment with arsenic trioxide and all-trans retinoic acid. All patients were included in the prospective NAPOLEON registry (NCT02192619) between 2013 and 2019. The acute promyelocytic leukemia was de novo in 91% (n=140) and therapy-related in 9% (n=14); 13% (n=20) of the patients were older than 70 years. At diagnosis bleeding/hemorrhage was present in 38% and thrombosis in 3%. Complete remission was achieved in 152 patients (99%), whereas two patients (1%) experienced induction death within 18 days after starting therapy. With a median follow-up of 1.99 years (95% confidence interval: 1.61-2.30 years) 1-year and 2-year overall survival rates were 97% (95% confidence interval: 94-100%) and 95% (95% confidence interval: 91-99%), respectively. Age above 70 years was associated with a significantly shorter overall survival (P<0.001) compared to that of younger patients. So far no relapses have been observed. Six patients (4%) died in complete remission at a median of 0.95 years after diagnosis (range, 0.18-2.38 years). Our data confirm the efficiency and durability of arsenic trioxide and all-trans retinoic acid therapy in the primary management of adults with low-/intermediate-risk acute promyelocytic leukemia in the real-life setting, irrespective of age.

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 < 0.0001). Prognostic factors independently associated with hospital mortality in HD group were, performance status >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.

Blinatumomab + ponatinib for relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia in adults.

We retrospectively examined the results of a new chemo-free approach combining blinatumomab with ponatinib (blina/pona) in 26 relapsed/refractory Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) patients. All but one achieved complete morphologic remission, and 23 achieved a complete molecular response. With a median follow-up of 34.4 months, the median overall (OS) and event-free (EFS) survivals were 20 and 15.3 months, respectively. After blina/pona, 8 patients underwent an allotransplant (allo), while among the 18 non-transplanted cases, 15 received ponatinib in maintenance. Fifteen relapse/progressions occurred with a significant difference between allo and non allo cases (12.5% vs 82.3%, p = 0.003). However, OS and EFS were similar between both groups. Finally, blina/pona was well tolerated with eight reversible neurologic events and three cytokine release syndromes. Prospective studies are needed to properly assess the safety, tolerability and efficacy of the combination therapy.

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.

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.

BACKGROUND: Acute 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. METHODS: We 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. RESULTS: Between 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, p<0.001), invasive fungal infection (OR = 7.65, 95%CI = 1.7-34.6, p = 0.008) and initial ventilation strategy (p = 0.015). Compared to NIV, HFNO alone and standard oxygen alone were associated with an increased ICU mortality, with respective OR of 19.56 (p = 0.01) and 10.72 (p = 0.01). We realized a propensity score analysis including 40 matched patients, 20 in the NIV arm and 20 receiving others ventilation strategies, excluding initial MV patients. ICU mortality was lower in patients treated with NIV (10%), versus 50% in the other arm (p = 0.037). CONCLUSION: In 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.

Alternative Effective and Safe Induction Regimens for Newly Diagnosed Acute Myeloid Leukemia in Patients With Cardiac Contraindication to Anthracyclines.

INTRODUCTION: The standard first-line treatment for acute myeloid leukemia (AML) is a combination of cytarabine and anthracyclines. To date, there is no commonly agreed-on regimen for patients who are ineligible for this therapy because of cardiac comorbidities or prior exposure to anthracyclines. We compared 3 anthracycline-free regimens currently used in France. PATIENTS AND METHODS: Two patients with newly diagnosed or relapsed/refractory AML were treated intensively in 3 French centers. All patients had at least one contraindication to the receipt of anthracyclines. Three regimen types were used: fludarabine, cytarabine, and granulocyte-colony stimulating factor (FLAG); clofarabine and cytarabine (CLARA); and topotecan plus cytarabine (TA). RESULTS: Thirty patients (58%) had de novo AML. The European LeukemiaNet 2013 risk categories were favorable, intermediate, and adverse in 4 (8%), 27 (52%), and 20 (39%) patients, respectively. Twenty-four patients received TA and 28 FLAG/CLARA regimens. Fifty percent of patients had cardiac dysfunction, and 50% had prior anthracycline exposure above the maximum tolerated dose. The rate of cardiac events was similar after TA (17%) and FLAG/CLARA (25%) (P = .78). The 5-year nonrelapse mortality was 17.9% and 12.5% in the TA and FLAG/CLARA groups, respectively (P = .59). In patients with previously untreated AML, complete response occurred in 18 (72%) of 25, but median overall survival was only 9.7 months. CONCLUSION: TA, FLAG, and CLARA regimens are efficient and are associated with acceptable toxicity in AML patients ineligible for the 3 + 7 regimen as a result of cardiac comorbidities. However, long-term outcome remains disappointing, thereby highlighting the need for the development of less toxic regimens.

Thiotepa, Fludarabine, and Busulfan Conditioning Regimen before T Cell-Replete Haploidentical Transplantation with Post-Transplant Cyclophosphamide for Acute Myeloid Leukemia: A Bicentric Experience of 100 Patients.

Haploidentical stem cell transplantation (haplo-SCT) with post-transplant cyclophosphamide (PT-Cy) is an alternative treatment for acute myeloid leukemia (AML) patients who lack HLA-matched donors. Relapse after haplo-SCT remains a major concern, especially after nonmyeloablative conditioning regimens. Promising results were reported for TBF-based conditioning regimens (thiotepa, busulfan, and fludarabine) in patients transplanted from different categories of donors and for various disease types but not specifically in PT-Cy haplo-SCT for AML. Here we evaluate the outcome of 100 AML patients who received haplo-SCT with PT-Cy after TBF conditioning regimens (reduced-intensity conditioning, n = 77; myeloablative conditioning, n = 23) in 2 transplant programs. Cumulative incidences of grades III to IV acute and moderate or severe chronic graft-versus-host disease (GVHD) were 7% and 14%, respectively. NRM at 2 years was 28%, significantly influenced by disease status at haplo-SCT (first complete response [CR1] versus advanced AML: 16% versus 38%, P = .016) but not by conditioning intensity or age. The cumulative incidences of relapse at 2 years were 17% and 24% in CR1 and advanced AML, respectively (not significant). Progression-free survival, overall survival, and GVHD and relapse-free survival at 2 years were 67%, 71%, and 49% in CR1 patients, respectively, whereas comparative values in patients with advanced disease were 37%, 41%, and 32%. Our study suggests that TBF conditioning for PT-Cy haplo-SCT is safe and effective for AML patients in CR1. In patients with more advanced disease, the relatively low incidence of relapse seems counterbalanced by a high nonrelapse mortality, underlining the need for alternative strategies to decrease relapse risk, without increasing the intensity of conditioning regimen.