Abstract
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.
Abstract
Background
Nocardiosis is rare after hematopoietic cell transplantation (HCT). Little is known regarding its presentation, management, and outcome in this population.
Methods
This ...retrospective international study reviewed nocardiosis episodes in HCT recipients (1/1/2000–31/12/2018; 135 transplant centers; 33 countries) and described their clinical, microbiological, radiological, and outcome characteristics.
Results
We identified 81 nocardiosis episodes in 74 allo- and 7 auto-HCT recipients. Nocardiosis occurred a median of 8 (IQR: 4–18) months post-HCT. The most frequently involved organs were lungs (70/81; 86%) and brain (30/81; 37%); 29 (36%) patients were afebrile; 46/81 (57%) had disseminated infections. The most common lung imaging findings were consolidations (33/68; 49%) or nodules (32/68; 47%); brain imaging findings were multiple brain abscesses (19/30; 63%). Ten of 30 (33%) patients with brain involvement lacked neurological symptoms. Fourteen of 48 (29%) patients were bacteremic. Nocardia farcinica was the most common among molecularly identified species (27%; 12/44). Highest susceptibility rates were reported to linezolid (45/45; 100%), amikacin (56/57; 98%), trimethoprim-sulfamethoxazole (57/63; 90%), and imipenem (49/57; 86%). One-year and last follow-up (IQR: 4–42.5 months) all-cause mortality were 40% (32/81) and 52% (42/81), respectively. In the multivariable analysis, underlying disease not in complete remission (HR: 2.81; 95% CI: 1.32–5.95) and prior bacterial infection (HR: 3.42; 95% CI: 1.62–7.22) were associated with higher 1-year all-cause mortality.
Conclusions
Nocardiosis is a late post-HCT infection usually manifesting as a pulmonary disease with frequent dissemination, brain infection, and bacteremia. Brain imaging should be performed in HCT recipients with nocardiosis regardless of neurological symptoms. Overall mortality is high.
Nocardiosis is a late post–hematopoietic cell transplantation (-HCT) infection usually manifesting as pulmonary disease with frequent dissemination, brain infection, and bacteremia. Brain imaging should be performed in HCT recipients with nocardiosis regardless of neurological symptoms. Overall mortality is high.
Purpose
Physicochemical incompatibility (PCI) between drugs infused together is frequent, but under-recognized. PCI can lead to drug inactivity, catheter occlusion, embolism or inflammatory ...reactions. The aims of this work were to identify most frequent and relevant drug incompatibilities and to review and develop strategies for their prevention.
Method
This was an observational prospective survey conducted between January and March 2015 in an intensive care unit (ICU) and in September 2014 in a hematology sterile unit (HSU). Drugs administered to patients were recorded and their compatibility assessed based on published compatibility data.
Results
Drug incompatibilities accounted for 12% (23/189) and 17% (116/686) of drug pairs infused in the ICU and the HSU, respectively. Pantoprazole was the most frequent drug implied in PCI. Regarding drug classes, anti-infective agents and gastrointestinal drugs were the most frequently implied. Among the incompatible pairs, 78% and 61% implicated a drug with extreme pH in the ICU and HSU, respectively. The tools proposed to reduce the frequency of PCI included: compatibility cross-tables, labeling of drugs with extreme pH and optimized administration schedules.
Conclusions
Given the frequency and the potential for severe consequences of PCI, pharmacists have a role to play in raising awareness of nurses and practitioners, and proposing adequate tools and solutions to reduce their incidence.
Minimal residual disease (MRD) is now a powerful surrogate marker to assess the response to chemotherapy in acute myeloid leukemia (AML).
mutation has been associated with adverse outcomes. In this ...study, we aimed to investigate the impact of
status on NPM1 MRD predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for
-mutated AML in two French institutions were analyzed retrospectively.
status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. Only 20.4% of
patients reached ≥ 4log MRD1 reduction compared to 47.5% in
wt cases. A 4log reduction of
MRD was associated with a better outcome, even in
mutated patients, independent of the allelic ratio.
negative patients who reached a 4log reduction had a superior outcome to those who did not (HR = 0.23;
< 0.001). However, postinduction
MRD1 reduction was not predictive of OS and LFS in
mut patients. These results confirm that post-induction
MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of
also identifies a subgroup of patients at high risk of relapse.
COVID-19 has been associated with high morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HCT) recipients.
This study reports on 986 patients reported to the EBMT registry ...during the first 29 months of the pandemic.
The median age was 50.3 years (min - max; 1.0 - 80.7). The median time from most recent HCT to diagnosis of COVID-19 was 20 months (min - max; 0.0 - 383.9). The median time was 19.3 (0.0 - 287.6) months during 2020, 21.2 (0.1 - 324.5) months during 2021, and 19.7 (0.1 - 383.9) months during 2022 (p = NS). 145/986 (14.7%) patients died; 124 (12.6%) due to COVID-19 and 21 of other causes. Only 2/204 (1%) fully vaccinated patients died from COVID-19. There was a successive improvement in overall survival over time. In multivariate analysis, increasing age (p<.0001), worse performance status (p<.0001), contracting COVID-19 within the first 30 days (p<.0001) or 30 - 100 days after HCT (p=.003), ongoing immunosuppression (p=.004), pre-existing lung disease (p=.003), and recipient CMV seropositivity (p=.004) had negative impact on overall survival while patients contracting COVID-19 in 2020 (p<.0001) or 2021 (p=.027) had worse overall survival than patients with COVID-19 diagnosed in 2022.
Although the outcome of COVID-19 has improved, patients having risk factors were still at risk for severe COVID-19 including death.
Key pointsDara post-alloHCT does not appear to increase the incidence of GVHDSuperior PFS was seen in those with prior cGvHDInfections are commonExtra-medullary disease progression is common
Nocardiosis is a rare but life-threatening infection after hematopoietic cell transplantation (HCT). We aimed at identifying risk factors for nocardiosis after allogeneic HCT and clarifying the ...effect of trimethoprim-sulfamethoxazole prophylaxis on its occurrence.
We performed a retrospective multicenter case-control study of patients diagnosed with nocardiosis after allogeneic HCT between January 2000 and December 2018. For each case, two controls were matched by center, transplant date, and age group. Multivariable analysis was conducted using conditional logistic regression to identify potential risk factors for nocardiosis. Kaplan-Meier survival curves of cases and controls were compared using log-rank tests.
Sixty-four cases and 128 controls were included. Nocardiosis occurred at a median of 9 months after allogeneic HCT (interquartile range: 5–18). After adjustment for potential confounders in a multivariable model, Nocardia infection was associated with tacrolimus use (adjusted odds ratio aOR 9.9, 95 % confidence interval 95 % CI: 1.6–62.7), lymphocyte count < 500/µL (aOR 8.9, 95 % CI: 2.3–34.7), male sex (aOR 8.1, 95 % CI: 2.1–31.5), recent use of systemic corticosteroids (aOR 7.9, 95 % CI: 2.2–28.2), and recent CMV infection (aOR 4.3, 95 % CI: 1.2–15.9). Conversely, use of trimethoprim-sulfamethoxazole prophylaxis was associated with a significantly decreased risk of nocardiosis (aOR 0.2, 95 % CI: 0.1–0.8). HCT recipients who developed nocardiosis had a significantly decreased survival, as compared with controls (12-month survival: 58 % and 90 %, respectively; p < 0.0001).
We identified six factors independently associated with the occurrence of nocardiosis among allogeneic HCT recipients. In particular, trimethoprim-sulfamethoxazole prophylaxis was found to protect against nocardiosis.
•Nocardiosis after allogeneic hematopoietic cell transplantation is a rare but severe infection.•Tacrolimus use, lymphopenia, recent corticosteroids, recent CMV infection and male sex were associated with Nocardiosis.•Trimethoprim-sulfamethoxazole prophylaxis was found to protect against nocardiosis.•Patients with nocardiosis had a significantly increased risk of death compared to controls.
Although the outcome in younger adults with acute myeloid leukemia (AML) has improved, the benefit associated with standard intensive chemotherapy in older patients remains debatable. In this study, ...we investigated the incidence and the prognostic significance of genetic characteristics according to treatment intensity in patients aged 60 years or older. On the 495 patients of our cohort,
(25.2%),
(23.7%) and
(16.8%) were the most frequent molecular mutations found at diagnosis. In this elderly population, intensive chemotherapy seemed to be a suitable option in terms of early death and survival, except for normal karyotype (NK)
patients and those aged over 70 within the adverse cytogenetic/molecular risk group. The
mutation was systematically associated with an unfavorable outcome, independently of the ratio. NK
genotype tends to confer a good prognosis in patients treated intensively. Regarding minimal residual disease prognostic value, overall survival was significantly better for patients achieving a 4 log
reduction (median OS: 24.4 vs. 12.8 months,
= 0.013) but did not reach statistical significance for progression free survival. This retrospective study highlights that intensive chemotherapy may not be the most appropriate option for each elderly patient and that molecular markers may help treatment intensity decision-making.
Minimal residual disease is now a powerfull surrogate marker to assess response to chemotherapy in acute myeloid leukemia (AML). In younger adults, NPM1 MRD has recently demonstrated to be a ...favorable predictive marker for EFS and OS independently of fms-like tyrosine kinase-3 internal tandem duplications (FLT3-ITD) status. However, there is very few datas regarding predictive value of NPM1 MRD in elderly patients treated with intensive chemotherapy. Moreover, numerous studies have suggested the negative impact of DNMT3a mutation in NPM1 AML patients, especially in those with concurrent FLT3-ITD mutation. In this study, we aimed to investigate the impact of DNMT3a status on post induction NPM1 MRD1 predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively.
A total of 138 patients treated for NPM1 mutated AML in two French institutions (Lyon, Lille) were analyzed retrospectively. Median age of the entire cohort was 66.1 years old (range 60-78.2). An FLT3-ITD mutation was evidenced in 52 of 138 patients (37.6%) with a median FLT3-ITD AR of 0.53 (range, 0.05-3). With a median follow-up of 19.61 months (0.07-128.4), the overall CR rate was 89.9% with no influence of DNMT3a or FLT3 mutational status on the probability of CR. In this elderly cohort of NPM1mut patients, a 4log reduction of NPM1 bone marrow (BM) MRD1 was associated with better outcome (median OS: NR vs 13.4 months, HR=0.35, p<0.01)(Figure A). Overall, DNMT3 status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. However, only 9/44 (20.4%) FLT3-ITD patients reached ≥ 4log MRD1 reduction whereas 38/80 FLT3wt (47.5%) were good molecular responders (p<0.001). FLT3-ITD mutated patients who achieved a 4log reduction had a superior outcome compared to those who did not (HR=0.34; 95% CI, 0.16 to 0.70; P <0.001). Similarly, NPM1mut FLT3wt patients with a 4log reduction in NPM1 BM-MRD1 had a longer OS (3-year OS, 68.1%; 95% CI, 48.8 to 82.9) than those without good molecular response (3-year OS, 46.5%; 95% CI, 30.2 to 61.7)(Figure B). DNMT3a negative patients who achieved a 4log reduction had a superior outcome to those who did not reached at least a 4log reduction (HR=0.23; 95% CI, 0.07 to 0.72; P <0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and leukemia free survival (LFS) in DNMT3amut patients. DNMT3amut patients has a very poor LFS which was even worst in poor NPM1 MRD1 responders compared to those who reached at least 4log reduction (median LFS: 8.3 months vs 17.4 months, HR = 0.48, 95% CI, 0.25-0.91, p=0.023)(Figure C). In multivariate analysis, only DNMT3a mutational status and a 4-log reduction in NPM1 BM-MRD were significantly associated with survival. Based on these results, we identified among NPM1 positive patients 3 groups with distinct prognosis, based on FLT3-ITD, DNMT3a status and NPM1 BM-MRD post induction response (NPM1 scoring system)(Figure D). When compared to ELN 2017 intermediate risk group (AUC=0.695), NPM1 scoring system (NPM1 SS) was more accurate for OS prediction in patients within intermediate (AUC=0.833) and unfavorable (AUC=0.863) NPM1 SS risk group. However, there was no significant difference in AUC between NPM1 SS favorable and ELN 2017 favorable risk group.
These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3a also identify a subgroup of patients at very high risk of relapase, despite good molecular responses. As hematopoietic stem cell transplantation (HSCT) might improve OS in elderly patients, DNMT3a positive AML elderly patients should be considered for HSCT or post induction maintenance strategies, even within the favorable ELN risk group.
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Sujobert:Gilead/Kyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding.
Class I Human Leukocyte Antigen (HLA) evolutionary divergence (HED) is a metric which reflects immunopeptidome diversity and has been associated with immune checkpoint inhibitor responses in solid ...tumors. Its impact and interest in allogeneic hematopoietic stem cell transplantation (HCT) have not yet been thoroughly studied. This study analyzed the clinical and immune impact of class I and II HED in 492 acute myeloid leukemia (AML) recipients undergoing HCT. The overall cohort was divided into a training (n=338) and a testing (n=132) set. Univariate cox screening found a positive impact of a high class I HED and a negative impact of a high class II HED on both disease-free (DFS) and overall survival (OS). These results were combined in a unique marker, class I/class II HED ratio, and assessed in the testing cohort. The final multivariate cox model confirmed the positive impact of a high
low class I/class II HED ratio on both DFS (Hazard Ratio (HR) 0.41 95% CI 0.2-0.83; p=0.01) and OS (HR 0.34 0.19-0.59; p<0.001), independently of HLA matching and other HCT parameters. No significant association was found between the ratio and graft-versus-host disease (GvHD) nor with neutrophil and platelet recovery. A high class I HED was associated with a tendency for an increase in NK, CD8 T-cell, and B cell recovery at 12 months. These results introduce HED as an original and independent prognosis marker reflecting immunopeptidome diversity and alloreactivity after HCT.
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