Banet A.

Battipaglia G.

Bonnin A.

Brissot E.

Dulery R.

Gaugler B.

Malard F.

Mohty M.

Ricard L.

Siblany L.

Stocker N.

van de Wyngaert Z.

English

Archivio della ricerca - Università degli studi di Napoli Federico II

CORRESPONDENCEMicrobiota dysbiosis after high-dose melphalan and autologoushematopoietic cell transplantation in multiple myeloma© The Author(s), under exclusive licence to Springer Nature Limited 2023Bone Marrow Transplantation (2023) 58:1275–1278; https://doi.org/10.1038/s41409-023-02078-1TO THE EDITOR:The impact of gut microbiota composition on patients’ outcomesafter allogeneic hematopoietic cell transplantation (alloHCT) isnow well established. In particular, a large study including patientstreated in four centers across three continents confirms that lossof gut microbiota diversity at engraftment is associated with alower overall survival (OS) [1]. Similarly, the role of the gutmicrobiota on patients’ outcomes after autologous (auto) HCT wasrecently investigated in a cohort of 534 patients with lymphoma,multiple myeloma (MM) and amyloidosis [2]. They found that anabove median fecal intestinal diversity in the peri-engraftmentperiod was associated with decreased risk of death or progression,adjusting for disease and disease status. Nevertheless, little dataare available regarding the durability of microbiota changes afterautoHCT. It was recently shown that after induction chemotherapyfor acute myeloid leukemia and despite major reductions inantibiotic pressure after hospital discharge, the trajectory ofmicrobiota recovery yielded new communities that were highlydissimilar to baseline [3]. Whether the microbiota follows a similarpattern after autoHCT remains to be confirmed. With thisbackground we performed a study to evaluate gut microbiotacomposition up to day 90 (D90) after high- dose melphalan (HDM)and autoHCT for MM.This retrospective analysis included 23 adult patients whounderwent HDM and autoHCT for MM between May 2016 andOctober 2018 in our institution (Saint-Antoine University Hospital,Paris, France) and who had at least two evaluable fecal samples,one collected before HDM and the second after autoHCT. Fecalsample collection was planned before HDM (D-2 sample, D0 beingthe day of autoHCT) and then at day 7 (D7 sample), at neutrophilrecovery (D14 sample), at day 60 (D60), and at D90. Infectionprophylaxis, monitoring, and supportive care, stool collection,DNA extraction, 16S DNA sequencing, 16S sequence analysis, andstatistical analyses are described in the Supplementary Methods.Patient and transplant characteristics are detailed in Table 1.Written informed consent was obtained from each patient. Thestudy was approved by the local institutional review board.Antibiotic exposure was high in our cohort with a median of 2antibiotics administered (range, 0–6). Nineteen patients received abroad-spectrum antibiotic with a large anti-anaerobic coverage(either piperacillin-tazobactam, imipenem-cilastatin and/or mer-openem) for a median duration of 8 days (range, 3–16) (Fig. 1a).Antibiotics were discontinued at a median of 15 days afterautoHCT (range 11–24) and at a median of 3 days (range 1–13)after neutrophil recovery. Similar to a previous report [2], afterTable 1. Study population and transplant characteristics.Patients 23Median age, years (Range) 62 (49–70)Male/female 15/8Multiple myeloma subtypeIgG kappa 12IgG lambda 3IgA kappa 1IgA lambda 1Free light chain kappa 5Free light chain lambda 1ISS at diagnosisStage I 12Stage II 8Stage III 3High-risk cytogenetics: t(4 ;14) or del17p 7Time from diagnosis to autoHCT, median (range) 6.1 (3.5–44.3) monthsLine of treatment, median (range) 1 (1–2)Induction chemotherapyVTDa 14VCD 4Dara-VTD 3RD 2Number of induction course, median (range) 4 (range, 4–6)Response before autoHCTPR 11VGPR 6CR 6Melphalan140mg/m2 5200mg/m2 18Length of stay for autoHCT, median (range) 18 (15–26) daysNumber of antibiotics used in patient, median(range)2 (0–6)Use of antibioticsP-I-M 19Anti-staphylococcus 8Cephalosoporins 2Metronidazole 2Amikacine 3Ig immunoglobulin, ISS International Staging System, VTD is for bortezo-mib, thalidomide and dexamethasone, VCD bortezomib, cyclophospha-mide and dexamethasone, Dara-VTD daratumumab, bortezomib,thalidomide and dexamethasone, RD lenalidomide and dexamethasone,autoHCT autologous hematopoietic cell transplantation, PR partialresponse, VGPR very good partial response, CR complete response, P-I-Mpiperacillin-tazobactam, imipenem-cilastatin and/or meropenem.aIn one patient, thalidomide was substituted by lenalidomide.Received: 15 May 2023 Revised: 7 July 2023 Accepted: 27 July 2023Published online: 22 August 2023www.nature.com/bmt1234567890();,:HDM and autoHCT, we observed a dramatic and significantdecrease of richness based on α-diversity indices, which reflect thenumber of unique bacteria taxa present and their relativeabundances (Fig. 1b, c). Median Shannon index at the OTU(operational taxonomic unit) level, was lowest around neutrophilrecovery (D14), being 1.65, versus 3.42 before HDM (p < .0001) anddespite it increased thereafter, it remained significantly lower upto D90 after autoHCT compared to baseline (2.87 p= 0.03).Similarly, observed OTUs significantly decreased after HDM andautoHCT, from 212 at baseline to 80.5 at neutrophil recovery(p < 0.0001) and while it went up thereafter, up to D90 afterautoHCT, it remained significantly lower compared to baseline(122.5, p= 0.03). The measure of β-diversity with the Bray–Curtis(BC) similarity index, which allows a comparative assessment ofbacterial diversity between samples for each participant, demon-strated the induction of a microbial dysbiosis with a significant150.50.50.0-0.5-0.5 0.50.0Axis 1Axis 2AMJ14J60J90J70.40.30.0Incidence Prevalence0.10.20.50.60.70.80.90.40.300 50 100 0 50 100100%NoneAcinetobacterClostridium sensu stricto 1RaoultellaRoseburiaIntestinibacterKlebsiellaAlistipesStreptoococcusEnterococcusEscherichia-shigellaFlavonifractoBifidobacteriumEubacterium rectale groupRuminococcus gnavus group90%80%70%60%50%40%30%20%10%0%0.10.20.50.60.70.80.90.40.300.10.22500.03 0.030.00380.220.0001 0.0001200500D-2 D7 D60 D90200.40.20.00.6134D14 D-2 D7 D60 D90D14D-2 D7 D60 D90D14D-2 D7 D60 D90D14150100adfgeb cDays exposedBray curtis index (median)Richness (OTU level)Butycore (median)Shannon index (OTU level)1050Anti-staphylococcusP-I-MD-2 - D7D-2 - D14D-2 - D60D-2 - D90AmikacineMetronidazoleCephalosoporinsFig. 1 Gut microbiota diversity during transplantation period. a Antibiotic exposure. b Richness measured at the OTU level. c Shannonindex measured at the OTU level. d Beta-diversity measured at the OTU level with the Bray–Curtis index comparison between visits andPrincipal Coordinates Analysis based on Bray–Curtis similarity at each visit. e Butyrate producing bacteria (Butycore, a group of 15 butyrateproducing bacterial genera: Blautia, Faecalibacterium, Alistipes, Eubacterium, Bifidobacterium, Ruminococcus, Clostridium, Coprococcus, Odoribacter,Roseburia, Anaerostipes, Oscillibacter, Subdoligranulum, Butyrivibrio, Holdenmanella). f Cumulative incidence and prevalence of patients whoexperienced at least one instance of bacterial domination of the gut microbiota (domination defined as a genus relative abundance of ≥0.3(on a unitless scale from 0 to 1) over the course of autoHCT (day −2 to +100). g Taxa contributing to domination events. Domination wasdefined at the level of OTU; color-coding of taxa is defined in the color legend. (P-value were determined by two-sided Wilcoxon matched-pairs signed-rank test, no adjustments were made for multiple comparisons, error bars indicate median and interquartile range). Abbreviation:P-I-M piperacillin-tazobactam, imipenem-cilastatin and/or meropenem.Correspondence1276Bone Marrow Transplantation (2023) 58:1275 – 1278shift of the microbial communities after HDM and autoHCT(median BC D-2 – D14: 0.13) (Fig. 1d). Furthermore, long-termsamples remained dissimilar to baseline, median BC D-2 – D90being 0.30. Furthermore, we looked at Butycore, a group of 15butyrate producing bacterial genera : Blautia, Faecalibacterium,Alistipes, Eubacterium, Bifidobacterium, Ruminococcus, Clostridium,Coprococcus, Odoribacter, Roseburia, Anaerostipes, Oscillibacter,Subdoligranulum, Butyrivibrio, Holdenmanella (“Butycore”). Wefound that these bacteria decreased after HDM and HCT, from0.41 at baseline to 0.03 at neutrophil recovery (p= 0.0038). At D90after autoHCT, the Butycore remained lower, being 0.26, althoughnot statistically different compared to baseline (p= 0.22) (Fig. 1e).Finally, in order to evaluate microbiome disruption, we looked atbacterial domination during autoHCT, defined as a relativeabundance of any OTU ≥ 30%. Bacterial domination prevalencepeaked at 76% at D14 after autoHCT (Fig. 1f), with Escherichia-Shigella being the most common genera contributing toposttransplant domination in our patients, followed by Strepto-coccus and Enterococcus (Fig. 1g).In this study we confirmed that patients that underwentautoHCT after HDM experienced an important gut bacterialmicrobiota injury. Furthermore, we found that similar to what wasreported in acute myeloid leukemia [3], gut bacterial microbiotadysbiosis persists at least up to D90 after autoHCT, indicating thatuse of high-dose chemotherapy, along with nutritional alterationand use of broad spectrum antibiotics [4], inherent to thistreatment, have a prolonged impact on the gut bacterialmicrobiota, despite patients being discharged from hospital anddiscontinuation of broad-spectrum antibiotics. In particular, wefound that gut microbiota α-diversity remained significantlydecreased at D90 after autoHCT, with a lower level (althoughnot statistically significant) of butyrate producing bacteria. This isparticularly important since it was recently reported that inpatients on lenalidomide maintenance, higher stool butyrateconcentration (p= 0.037), butyrate producers (p= 0.025), and α-diversity (p= 0.0035) are associated with sustained minimalresidual disease negativity [5]. Furthermore, the authors foundthat healthier dietary protein correlated with butyrate andsustained minimal residual disease negativity [5]. A previousstudy also found that gut microbiota composition was associatedwith minimal residual disease in MM [6]. This suggests that earlyintervention after autoHCT is important in improving gutmicrobiota diversity before initiation of lenalidomide mainte-nance therapy. Such intervention could rely on dietary recom-mendation, reduced exposition to antibiotics, and the use ofprebiotics, probiotics with rationally selected strains or fecalmicrobiota transplantation [7]. We have previously shown thatadministration of autologous fecal microbiota transplantationafter intensive chemotherapy in acute myeloid leukemia is safe,increases α-diversity indices to their initial mean levels, andrestores the microbial communities [8]. Similarly, it was shownthat autologous fecal microbiota transplantation boosted micro-bial diversity and reestablished the intestinal microbiota compo-sition that the patient had before antibiotic treatment andalloHCT [9].We acknowledge that given the limited number of patientsincluded in our study we were not able to evaluate the impact ofthe microbiota on patients’ outcomes and that assessment ofminimal residual disease was not performed routinely at that timepreventing us from analyzing the interplay between themicrobiota and minimal residual disease in our cohort. Never-theless, we shed some light on the interplay between the use ofHDM followed by autoHCT, broad-spectrum antibiotics, andprolonged microbiota injury. Such studies are important for thedevelopment of new approaches to reduce treatment burden ongut microbiota composition and improve outcomes for MMpatients.Florent Malard 1,2✉, Giorgia Battipaglia 1,2,Béatrice Gaugler 2, Lama Siblany2, Zoe van de Wyngaert1,2,Agnes Bonnin1,2, Rémy Duléry 1,2, Anne Banet1,2,Nicolas Stocker1,2, Laure Ricard1,2, Eolia Brissot 1,2 andMohamad Mohty1,21Sorbonne Université, APHP, Hôpital Saint Antoine, Serviced’Hématologie Clinique et de Thérapie cellulaire, Paris, France.2INSERM, Centre de Recherche Saint-Antoine (CRSA), F-75012 Paris,France. ✉email: florent.malard@inserm.frREFERENCES1. Peled JU, Gomes ALC, Devlin SM, Littmann ER, Taur Y, Sung AD, et al. Microbiota aspredictor of mortality in allogeneic hematopoietic-cell transplantation. N Engl JMed. 2020;382:822–34. https://doi.org/10.1056/NEJMoa1900623.2. Khan N, Lindner S, Gomes ALC, Devlin SM, Shah G, Sung AD, et al. Fecal microbiotadiversity disruption and clinical outcomes after auto-HCT: a multicenter observa-tional study. Blood. 2020. https://doi.org/10.1182/blood.2020006923.3. Rashidi A, Ebadi M, Rehman TU, Elhusseini H, Halaweish HF, Kaiser T, et al. Lastingshift in the gut microbiota in patients with acute myeloid leukemia. Blood Adv.2022;6:3451–7. https://doi.org/10.1182/bloodadvances.2021006783.4. Garzón Herazo JR, Muñoz Velandia OM, Solano JC, Molina Pimienta L, FigueroaLemus WJ. The nutrition risk index is associated with bacteremia within 30 daysafter autologous stem cell transplantation in patients with multiple myeloma.Transpl Infect Dis. 2020;22:e13302 https://doi.org/10.1111/tid.13302.5. Shah UA, Maclachlan KH, Derkach A, Salcedo M, Barnett K, Caple J, et al. Sustainedminimal residual disease negativity in multiple myeloma is associated with stoolbutyrate and healthier plant-based diets. Clin Cancer Res. 2022;28:5149–55.https://doi.org/10.1158/1078-0432.Ccr-22-0723.6. Pianko MJ, Devlin SM, Littmann ER, Chansakul A, Mastey D, Salcedo M, et al.Minimal residual disease negativity in multiple myeloma is associated withintestinal microbiota composition. Blood Adv. 2019;3:2040–4. https://doi.org/10.1182/bloodadvances.2019032276.7. Malard F, Gaugler B, Mohty M. Faecal microbiota transplantation in patients withhaematological malignancies undergoing cellular therapies: from translationalresearch to routine clinical practice. Lancet Haematol. 2022;9:e776–e785. https://doi.org/10.1016/s2352-3026(22)00223-x.8. Malard F, Vekhoff A, Lapusan S, Isnard F, D’incan-Corda E, Rey J, et al. Gutmicrobiota diversity after autologous fecal microbiota transfer in acute myeloidleukemia patients. Nat Commun. 2021;12:3084 https://doi.org/10.1038/s41467-021-23376-6.9. Taur Y, Coyte K, Schluter J, Robilotti E, Figueroa C, Gjonbalaj M, et al. Reconstitutionof the gut microbiota of antibiotic-treated patients by autologous fecal microbiotatransplant. Sci Transl Med. 2018;10. https://doi.org/10.1126/scitranslmed.aap9489.ACKNOWLEDGEMENTSThe authors acknowledge the « af3m, Association Française des Malades du MyélomeMultiple » and the « IFM, Intergroupe Francophone du Myélome » for their support.The authors acknowledge the “Tumorothèque” of the Clinical HaematologyDepartment at Saint-Antoine hospital for logistical support for handling of samples.The authors acknowledge the Association for Training, Education and Research inHematology, Immunology and Transplantation for the generous and continuoussupport of the research work. We thank our nursing staff for offering the best care toour patients.AUTHOR CONTRIBUTIONSFM designed the study, recruited patients, performed experimental work, collected,assembled and analyzed data, and wrote and revised the manuscript. GB recruitedpatients, collected and assembled data, and helped write the manuscript. BG, LS, NSand LR, performed experimental work, collected, assembled, analyzed data, andhelped write the manuscript. ZW, ABo, RD, ABa and EB recruited patients, collecteddata and helped write the manuscript. MM designed the study, supervised research,analyzed data and helped write the manuscript.COMPETING INTERESTSFM reports lecture honoraria from, Therakos/Mallinckrodt, Janssen, Sanofi, JAZZPharmaceuticals, Gilead, Novartis, and Bristol Myers Squibb, all outside the submittedwork. MM reports grants and lecture honoraria from Janssen, Sanofi, Maat PharmaCorrespondence1277Bone Marrow Transplantation (2023) 58:1275 – 1278and JAZZ Pharmaceuticals, lecture honoraria from Celgene, Amgen, BMS, Takeda, andPfizer, grants from Roche, all outside the submitted work. The other authors declareno competing financial interests. RD reports research funding from Ligue contre leCancer, Arthur Sachs, Monahan Foundation, Servier Foundation, Philippe Foundation,DCP AP-HP, honoraria from Novartis and Takeda, non-financial support from KitePharma/Gilead, all outside the submitted work.ADDITIONAL INFORMATIONSupplementary information The online version contains supplementary materialavailable at https://doi.org/10.1038/s41409-023-02078-1.Correspondence and requests for materials should be addressed to Florent Malard.Reprints and permission information is available at http://www.nature.com/reprintsPublisher’s note Springer Nature remains neutral with regard to jurisdictional claimsin published maps and institutional affiliations.Correspondence1278Bone Marrow Transplantation (2023) 58:1275 – 1278

Microbiota dysbiosis after high-dose melphalan and autologous hematopoietic cell transplantation in multiple myeloma

https://www.iris.unina.it/bitstream/11588/993405/1/2023%20-%20malard%20-%20dysbiosis%20in%20MM%20-%20BMT.pdf

Microbiota dysbiosis after high-dose melphalan and autologous hematopoietic cell transplantation in multiple myeloma

Abstract

Similar works

Full text

Available Versions

Archivio della ricerca - Università degli studi di Napoli Federico II