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Gut microbiota restoration after autologous fecal microbiota transfer in patients with AML

Jul 6, 2021
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Intensive chemotherapy for acute myeloid leukemia (AML), along with prolonged exposure to multiple antibiotics, negatively impacts the gut microbiota composition. The resulting dysbiosis, characterized by a reduction of microbial diversity and beneficial bacteria, leads to overgrowth of pathogens, pathobionts, and multidrug-resistant bacteria (MDRB). The consequences for patients can include increased infectious complications, deteriorating of nutritional status, prolonged hospitalization, delayed consolidation courses due to treatment toxicity and MDRB carriage, preventing allogeneic hematopoietic stem cell transplantation (allo-HSCT).

The AML Hub has previously reported results from the ODYSSEE trial evaluating autologous fecal microbiota transfer (AFMT) in AML patients, presented at the 45th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT 2019) by Professor Florent Malard, Steering Committee member of the GvHD Hub. Malard et al.1 recently published the findings from the ODYSSEE trial (NCT02928523) in Nature Communications, and a summary of the key findings is presented below.

Study design

A phase II, single-arm, multicenter, prospective trial in hospitalized patients with AML or high-risk myelodysplastic syndrome (MDS) (n = 25) who received induction chemotherapy (IC). AFMT was planned at the end of IC, after aplasia completion (absolute neutrophil count [ANC] >0.5 G/L) and 24 hours after antibiotics discontinuation, as shown in Figure 1.

  • The co-primary endpoints were efficacy of AFMT in dysbiosis correction and MDRB eradication. Secondary endpoints included dysbiosis biosignature, effect of dysbiosis correction on patient clinical status, short- and mid-term safety of AFMT, and feasibility and acceptability by patients.

Figure 1.  Study treatment*

Feces and blood analysis were carried out on V1 (D0), V2 (D29), and V3 (D40). Feces-only analysis was done on V4 (D70).
AFMT, autologous fecal microbiota transfer; D, day; M, month; V, visit.
*Adapted from Malard et al.1

Results

Baseline characteristics and feasibility of the AFMT procedure

In total, 62 patients with AML were screened and 28 fulfilled all inclusion/exclusion criteria. Three eligible patients refused the AFMT procedure, and so 25 patients were treated with AFMT. Twenty (20/25) patients received the two AFMT after IC and hematopoietic recovery from aplasia and were included in the per-protocol population. Baseline characteristics are listed in Table 1.

The AFMT product retention time was longer than the expected time (120 minutes) for the first AFMT (median, 189 minutes) and after the second AFMT (median, 138 minutes). Quality of life (QoL) was evaluated throughout the study. The QoL questionnaire results after AFMT (V3) were similar or improved compared with V2 (before AFMT), especially for self-care, usual activities, anxiety, and depression parameters.

Table 1. Baseline characteristics*

Characteristic

Treated patients
(n = 25)

Per-protocol patients
(n = 20)

Sex, male/female, %

72/28

75/25

Median age at inclusion, years (range)

52 (24–68)

50 (24–68)

Median BMI at inclusion, (range)

26.33 (19.72–41.34)

26.54 (21.24–41.34)

Induction chemotherapy, %

              Cytarabine + idarubicin

52

60

              Cytarabine + daunorubicin

44

35

              Cytarabine + gemtuzumab ozogamicin

4

5

Antibiotics during induction chemotherapy, %

              PT alone

48

45

              PT + imipenem-cilastatin or meronem

44

45

              Cefepim + imipenem-cilastatin

4

5

              No antibiotic

4

5

Consolidation chemotherapy, %

              Cytarabine

76

70

              Cytarabine + idarubicin

8

10

              Cytarabine + MTX

8

10

              Cytarabine + RIX

4

5

              Unknown

4

5

MRC cytogenetic risk category, %

              Favorable

12

10

              Intermediate

80

80

              Unfavorable

8

10

FLT3-ITD mutation, %

89

88

NPM1 mutation, %

48

55

CEBPA mutation, %

56

65

BMI, body mass index; MRC, Medical Research Council; MTX, methotrexate; PT, piperacilline -tazobactam; RIX, rituximab.
*Data adapted from Malard et al.1

Efficacy

Microbiota reconstitution

  • The median Shannon index for α-diversity in per-protocol patients at V1 (before IC) and V2 (after IC and before AFMT) was 4.0 vs 2.4 (p = 0.0002), and the median inverse Simpson index was 21.5 vs 5.1 (p = 0.0009), respectively. Similarly, median richness of genes was 548,529 vs 81,980 (p < 0.0001) at V1 and V2, respectively.
  • The median Bray-Curtis similarity index for β-diversity from V1 to V2 was 0.12, showing a significant shift of microbial communities with IC and domination of pro-inflammatory bacterial families (Enterobacteriaceae, Enterococcaceae, and Veillonellaceae).
  • The median α-diversity indexes returned to their initial median levels after AFMT treatment compared with V2 (Shannon: 4.0; p = 0.0001, and Inverse Simpson: 21.8; p = 0.0003). The median richness of genes after AFMT, although not the same as the baseline level, still increased significantly to 389,768 (p < 0.0001).
  • The median Bray-Curtis similarity index (0.50, V1–V3) demonstrated restoration of microbial communities after AFMT treatment, especially for Lachnospiraceae and Ruminococcaceae.
  • At V4, gut microbiota diversity was not altered by the high-dose cytarabine-based consolidation chemotherapy, with no significant reduction of α-diversity indexes and a slight reduction of gene richness compared with V3.
  • Patients receiving imipenem-cilastatin or meronem at V2 had decreased α-diversity indexes compared to those receiving piperacilline-tazobactam alone, that persisted after AFMT.

MDRB decolonization

  • The median number of reads mapped against antibiotic resistance genes from V1 to V2 was 166,158 vs 352,140 reads (p = 0.0008) for per-protocol patients. This was significantly reduced at V3 after AFMT (198,374 reads; p = 0.0056) and did not change significantly at V4 (158,229 reads), which indicates that AFMT had a beneficial effect in alleviating microbiota disruption induced by consolidation chemotherapy and antibiotics.

Dysbiosis biosignature

  • Investigation of the correlation between microbiota parameters was focused on bacteria with a role in hematologic malignancies, immune and inflammatory parameters.
  • Fecal neopterin and α-diversity in butyrate-producing bacteria and Bifidobacterium showed a strong negative correlation, whereas the pro-inflammatory bacteria Enterococcus showed a positive correlation with fecal neopterin and ferritin and negative correlation with the butyrate-producing bacteria Roseburia.
  • Akkermansia showed a positive correlation with butyrate-producing bacteria and transforming growth factor beta 2 (TGFb2), and negative correlation with inflammatory parameters.

Safety

  • Within 24-hours after AFMT, five adverse events (AEs) were reported in four patients:
    • Two AEs (moderate abdominal pain and mild diarrhea) were considered related to the procedure, neither required treatment and both patients recovered without sequelae.
    • The other three AEs included a mild transient fever, diarrhea, and weight increase.
    • No serious AEs (SAEs) occurred during the first 24 hours post-AFMT.
  • After the first 24 hours post-AFMT until the end of the 1-year follow-up period, 415 AEs were experienced by 24/25 patients; the majority of which were in line with leukemia patient profiles receiving intensive chemotherapy.
  • No SAEs were reported within 30 days after AFMT:
    • SAEs were mainly reported, between the study inclusion and AFMT (V1–V2) (15 SAEs in five patients) and between V3 and V4.
    • Only one SAE was possibly related to the AFMT treatment by the site investigator.
  • Inflammatory parameters were also measured during the first three visits to evaluate the safety of AFMT:
    • Systemic C-reactive protein levels increased significantly at V2 (as expected after intensive chemotherapy) but returned to baseline at V3. The same variation was noted for systemic and fecal neopterin levels.
    • Similarly, the median fecal neopterin level significantly decreased and returned to baseline after AFMT. Secretory immunoglobulin A (IgA) showed a similar trend of reduction after AFMT. Total antioxidant status was significantly increased after AFMT.

Clinical outcomes

  • The median follow-up time for surviving patients was 30 months (range, 28−37). All treated patients, except one, responded (23 with complete response and one with partial response) to chemotherapy at V3.
  • Leukemia-free survival (LFS) rate was 88% and 60%, and 1-year overall survival (OS) rate was 92% and 72%, at 6 months and 2 years, respectively.
  • Patients with intermediate-high vs low Shannon index at V3, showed higher OS (71% vs 62%; p = 0.79) and LFS (71% vs 38%; p = 0.27), respectively.
  • The cumulative incidence of grade 2−4 acute graft-versus-host disease (GvHD) was 22% at Day 180. Eight patients died during the study, but none were due to AFMT.

Conclusion

The study demonstrated that AFMT is feasible, with a good safety profile and is effective in restoring gut microbiota in patients receiving IC and antibiotics for AML. However, AFMT may not be appropriate in patients with previous antibiotic therapy and these patients may benefit from allogenic fecal microbiota transfer which is currently being investigated (NCT04150393).

  1. Malard F, Vekhoff A, Lapusan S, et al. Gut microbiota diversity after autologous fecal microbiota transfer in acute myeloid leukemia patients. Nat Commun. 2021;12(1):3084. DOI: 1038/s41467-021-23376-6

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