Efficacy of antibiotic short course for bloodstream infections in acute myeloid leukemia patients with febrile neutropenia: A retrospective comparative study

International audienceObjectives: There is no specific recommendation about antimicrobial treatment length for documented infections in chemotherapy induced febrile neutropenia (FN). Practices have changed along time in our center regarding length of antibiotic treatment. The aim of this study was to compare long versus short antibiotic course for bloodstream infection (BSI) treatment in acute myeloid leukemia (AML) patients during FN. Methods: This monocentric retrospective comparative study included all consecutive BSI episodes among AML patients with FN for 3 years (2017-2019). Episodes were classified regarding the length of antibiotic treatment, considered as short course if the treatment lasted ≤ 7 days, except for nonfermenting bacteria and Staphylococcus aureus or lugdunensis for which the threshold was ≤ 10 days and ≤ 14 days, respectively. The primary outcome was the number of BSI relapses in both groups within 30 days of antibiotic discontinuation. Results: Among 71 AML patients, 104 BSI episodes were included; 48 (46%) received short course treatment. Only 8 (7.6%) BSI episodes relapsed within 30 days of antibiotic discontinuation, 5 having received short course treatment. No association was found between risk of relapse and short course of antibiotic treatment (p = 0.37). The only risk factor significantly associated with BSI relapse was neutropenia duration (p = 0.005). Conclusion: Antibiotic short course seemed as effective as prolonged treatment for BSI in AML patients during FN, with very few relapses at day 30. These encouraging findings should be confirmed through prospective studies

Long‐term molecular remission in a patient with acute myeloid leukemia harboring a new NUP98‐LEDGF

Abstract A large variety of molecular rearrangements of the NUP98 gene have been described in the past decades (n = 72), involving fusion partners coding for different transcription factors, chromatin modifying enzymes, as well as various cytosolic proteins. Here, we report the case of an AML‐M2 patient with a variant NUP98‐LEDGF/PSIP1 gene fusion (N9‐L10). In this patient, three different NUP98-LEDGF fusion mRNAs were characterized due to alternative splicing in LEDGF exon 11. Targeted high‐throughput sequencing revealed the presence of IDH1, SRSF2, and WT1 additional pathogenic mutations. To improve the therapeutic monitoring, quantification of NUP98‐LEDGF mRNA by real‐time PCR was developed. Because of poor response to conventional chemotherapy, allogeneic stem cell transplantation was performed, followed by 20 cycles of azacitidine‐based preemptive treatment of relapse. More than 31 months after diagnosis, corresponding to 25 months post SCT and 4 months after the last cycle of azacytidine, the patient is in complete molecular remission (undetectable NUP98‐LEDGF mRNA transcripts). This study highlights the considerable variability in breakpoint location within both NUP98 and LEDGF, associated with alternative splicing affecting LEDGF. It also emphasizes the need to fully characterize the breakpoints within the two genes and the identification of all fusion mRNAs, particularly for the development of a molecular monitoring assay. All these data seem critical for the optimal management of NUP98‐LEDGF + hematological malignancies commonly associated with a poor prognosis

Outcome of human umbilical cord blood stem cell transplantation (CBT) for acute myeloid leukemia in patients achieving first complete remission after one versus two induction courses: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

We compared transplantation outcomes of adult patients with AML that underwent cord blood transplantation (CBT) in CR1 following 1 versus 2 induction courses. Study included 325 patients, 243 (75%) with 1 and 82 (25%) with 2 induction courses. Engraftment was lower for patients achieving CR1 after 1 vs. 2 induction courses: 91% vs. 99% (p = 0.02). Incidence of acute GVHD was similar, 38% and 36% (p = 0.81), as was 2-year chronic GVHD at 23.4% and 27.5%, respectively (p = 0.65). Two-year non-relapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were not statistically different between patients achieving CR1 with 1 vs. 2 induction courses with 23% vs. 24% (p = 0.87), 25% vs. 30% (p = 0.4), 52% vs. 46% (p = 0.3), 59% vs. 50% (p = 0.2), and 44% vs. 41% (p = 0.66), respectively. Results were confirmed by multivariable analysis, NRM (hazard ratio (HR) = 1.1; 95% CI, 0.6–1.8, p = 0.7), RI (HR = 1.4; 95% CI, 0.9–2.3, p = 0.1), LFS (HR = 1.3; 95% CI, 0.9–1.8, p = 0.2), OS (HR = 1.3; 95% CI, 0.9–1.9, p = 0.1), and GRFS (HR = 1.1; 95% CI, 0.8–1.5, p = 0.5). Overall, outcomes of AML patients undergoing CBT in CR1 achieved after 1 or 2 induction courses are similar

Human-Derived α1-Antitrypsin is Still Efficacious in Heavily Pretreated Patients with Steroid-Resistant Gastrointestinal Graft-versus-Host Disease

International audienceAlmost one-half of patients developing graft-versus-host disease (GVHD) will not respond to standard first-line steroid treatment. Alpha-1 antitrypsin (AAT) is able to induce tolerance in preclinical models of GVHD. AAT alters the cytokine milieu, promotes a tolerogenic shift of dendritic cells, and skews effector T cells toward regulatory T cells. Gastrointestinal steroid-refractory (SR)-GVHD is a protein-losing enteropathy that might represent the optimal setting in which to use AAT. Here we analyze the outcomes of 16 patients treated with human-derived AAT in advanced-stage gut SR-GVHD, with two-thirds of the patients having failed at least 1 treatment for SR-GVHD. The overall response rate (ORR) was 44%, with a complete response (CR) rate of 27%. Gastrointestinal response was observed in 61% of patients. The median time to best response was 21 days (range, 6 to 26 days). At day 56 after AAT treatment, all CRs were maintained, and the ORR was 39%. The 1-year overall survival was 48% (95% confidence interval, 26% to 74%). Ancillary studies showed that AAT serum levels were in the normal range at the beginning of treatment, whereas fecal loss was elevated. AAT levels consistently rose after exogenous administration, but no correlation was found between serum levels and response. REG3α and IL-33 levels were associated with response while, in contrast to previous reports, regulatory T cells decreased during AAT treatment. This retrospective analysis supports a previous report of AAT as a promising agent in the management of gut SR-GVHD and should prompt its evaluation at an earlier stage

Pooled Fecal Allogenic Microbiotherapy for Refractory Gastrointestinal Acute Graft-Versus-Host Disease: Results from the Early Access Program in France

International audienceIntroduction Acute graft-versus-host disease (aGvHD) is a major source of mortality following allogeneic hematopoietic cell transplantation (allo-HCT). Standard 1st line therapy for the treatment of aGvHD involves corticosteroids (CS). However, more than 50% of patients are refractory to CS (SR-aGvHD) and the associated mortality rate is of up to 80%. Recently, Ruxolitinib has been approved as 2nd line treatment for SR-aGvHD. However, patients with severe gastrointestinal (GI) aGvHD seem less likely to respond to Ruxolitinib and have poor outcomes with limited therapeutic options.In this context, fecal microbiotherapy has shown promising results in several pilot studies in patients with refractory GI-aGvHD. Here we report clinical outcomes from 81 patients diagnosed with SR or dependent (SD) GI-aGvHD treated with the pooled allogeneic microbiotherapy MaaT013 as part of the Early Access Program (EAP) in France.Methods 81 patients with SR/SD GI-aGvHD (Classical n=62, late onset n=12, overlap syndrome n=7) were treated with MaaT013 as part of an EAP in France. These patients had failed 1 to 6 prior systemic GvHD treatment lines (median 2; 66/81 received Ruxolitinib). Most patients had grade III-IV aGvHD (11% grade II, 51% grade III, 38% grade IV).For each patient, a total of 3 MaaT013 administrations were planned every 7 +/- 2 days. Each dose comprised 30g of feces in 150 mL of diluent, from 4 to 8 healthy donors, administered by enema (except for 1 patient by nasogastric tube).Treatment response was calculated among all treated patients based on aGvHD staging and grading at day 28 (D28) at the time of the EAP request.Results At D28, the GI-overall response rate (ORR) was 56%: 30 complete response (CR, 37%), 11 very good response rate (VGPR, 14%), 4 partial response (PR, 5%). The GI-ORR was higher in patients with lower grade aGvHD (89% in grade II, 66% in grade III, 32% in grade IV) and higher in SD versus SR patients (92% versus 49%). Including skin and liver symptoms (n=78), response rate was 49%, including 24 CR, 11 VGPR and 3 PR and inversely correlated with aGvHD initial grade (88% in grade II, 55% in grade III, 30% in grade IV).Overall survival (OS) was 51% at 6 months (M6) and 39% at M12. The median follow-up among surviving patients was 355 days (range, 53-731). OS was significantly higher in patients achieving at least GI-PR at D28 (Responder, R; n=45) compared to patients in treatment failure (Non-responder, NR; n=35): 69% versus 28% at M6, 59% versus 14% at M12, respectively. Median survival duration in R was 451 days versus 32 days in NR.Interestingly, aGvHD response was improved in the subgroup of 31 patients previously treated with Ruxolitinib as 2nd line and MaaT013 as 3rd line (65% D28 GI-ORR, OS M6 55% and 49% M12 and 74% versus 15% at M6 and 74% versus 0% at M12 for R and NR respectively).MaaT013 displayed a good overall safety profile in the EAP population: 20 pharmacovigilance cases were reported in 18 patients: sepsis in 11 patients, C. difficile colitis in 2, E. coli osteoarthritis in 1, G. silvicola in stools from 1, P. aeruginosa sinusitis in 1, appearance of air bubbles in the mesorectum in 1, respiratory distress in 1. No pathogen transmission was reported. In 2 patients, non-pathogenic commensal bacteria isolated following infectious events were detected in the administered MaaT013 batch. Causality could not be formally excluded in these cases.The overall incidence of bacteremia (14%) remains low, compared to an incidence of 31% to 74% in bloodstream infections reported in patients with GI-aGvHD. This suggests that fecal microbiotherapy may have a protective effect on bacterial translocation, but this needs to be confirmed in further clinical trials.47 deaths have been reported; the cause of which was GvHD in 21 patients, severe infection in 13, relapse of underlying malignancy in 6, COVID-19 in 3, hemorrhage during surgery in 1, neurological complications post allo-HCT in 1, and cardiac arrest in 2 patients. No causality link with MaaT013 administration has been identified.Conclusion Overall, EAP clinical data showed that MaaT013 was safe and effective for the treatment of SR/SD-GI-aGvHD especially in patients having previously received ruxolitinib. Interestingly, GI-response to aGvHD correlates with increased OS, suggesting a strong favorable benefit-risk profile for MaaT013. A Phase 3 trial is currently ongoing to confirm these results in ruxolitinib-refractory patients (NCT04769895)

Pooled allogeneic faecal microbiota MaaT013 for steroid-resistant gastrointestinal acute graft-versus-host disease: a single-arm, multicentre phase 2 trialResearch in context

Summary: Background: Failure of gastrointestinal acute graft-versus-host disease (GI-aGvHD) to respond to steroid therapy is associated with limited further therapeutic options. We aimed to assess the safety and efficacy of the first-in-human use of the pooled allogeneic faecal microbiota, MaaT013, for the treatment of steroid-refractory GI-aGvHD. Methods: This prospective, international, single-arm, phase 2a study reports clinical outcomes from a 24-patient cohort with grade III-IV, steroid refractory GI-aGvHD treated with the pooled allogeneic faecal microbiota MaaT013. MaaT013 involved pooling faecal matter from 3 to 8 screened donors then transplanting the pooled batches into patients to treat GI-aGVHD. The 24 patients were treated in the HERACLES study (Aug 2018 to Nov 2020) at 26 sites in Europe and an additional 52 patients were treated in a compassionate use/expanded access program (EAP) in France (July 2018 to April 2021). The primary endpoint was GI response at day 28, defined as the proportion of patients with GI-aGvHD who had a complete response (CR) or very good partial response (VGPR). GvHD grading and staging were assessed according to the revised Glucksberg criteria. Adverse events and severe adverse events were monitored for 6 months and 12 months, respectively. The HERACLES study was registered with ClinicalTrials.gov (NCT03359980). Findings: Compared with single donors, MaaT013 is characterised by higher microbial richness and reduced variability across batches. At day 28 (D28), the GI-overall response rate (ORR) was 38% in the prospective population, including 5 complete responses (CR), 2 very good partial responses (VGPR) and 2 partial responses (PR). In the EAP, the GI-ORR was 58% (17 CR, 9 VGPR and 4 PR). The 12-month overall survival (OS) was 25% in the prospective study and 38% in the EAP. Regarding safety, five infectious complications, including 3 sepsis, could not be excluded from being related to the study procedure in HERACLES. Shotgun sequencing analyses of the identified strains suggest that none were found in MaaT013. In the EAP, 18 pharmacovigilance cases were reported among 52 treated patients, including 11 bacteraemia/sepsis. In HERACLES, we observed in stools from responding patients at D28 a higher microbiota richness and increased levels of beneficial bacteria, in particular butyrate producers, along with increased levels of short-chain fatty acid and bile acids. In contrast, stools from non-responding (NR) patients displayed increased levels of pathogenic pro-inflammatory bacteria along with increased systemic inflammatory parameters. Interpretation: Overall, MaaT013 was safe in this population of highly immunocompromised patients and was associated with responses in some patients with GI-aGvHD and deserves further investigation. Funding: MaaT Pharma