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Update from the Heracles trial and expanded access program of MaaT013 in patients with SR aGvHD

Mar 29, 2022
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Gut dysbiosis in acute graft-versus-host disease (aGvHD) is associated with poor outcomes. Fecal microbiota transplant has been assessed as a potential treatment for patients with gastrointestinal (GI) aGvHD; however, the issue of donor sourcing of microbiota remains. One potential solution is the creation of a standardized fecal microbiota transplant product. This is the idea behind MaaT013, a pooled allogeneic fecal microbiotherapy product. The results of the expanded access program (EAP) have been reported on previously by the GvHD Hub here.

During the 63rd American Society of Hematology (ASH) Annual Meeting & Exposition and the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), Florent Malard1,2 discussed the results of MaaT013 in the Heracles phase IIa trial (NCT03359980) and the EAP in patients with steroid refractory (SR) aGvHD.

Study design

Heracles trial

Figure 1. Study design, including eligibility and exclusion criteria*

aGvHD, acute graft-versus-host disease; allo-HSCT, allogeneic hematopoietic stem cell transplant; FMT, fecal microbiota transplant; GI, gastrointestinal; NIH, National Institutes of Health; SR, steroid refractory
*Adapted from Malard.1
Saliba et al.3
Jagasia et al.4

Expanded access program

The EAP allowed patients to be treated who were not eligible for the Heracles trial. This included:

  • patients with SR or steroid dependent aGvHD of any grade with GI involvement; and
  • patients on any line of treatment.

Results

Patient characteristics were similar between the two cohorts, with a median age of 57 years in the EAP cohort and 61 years in the Heracles cohort. Acute myeloid leukemia was the most common diagnosis, for 44% of the EAP cohort, compared with 38% of the Heracles cohort. In both cohorts, most patients had Grade III aGvHD (Table 1).

Table 1. Patient characteristics*

Characteristics, % (unless stated otherwise)

EAP
(N = 52)

Heracles
(N = 24)

Median age (range), years

57 (18−73)

61 (20−69)

Sex

 

 

              Male

60

67

              Female

40

33

Diagnosis

 

 

              AML

44

38

              MDS

15

12

              MPN

19

25

              ALL

12

8

              TCL

8

0

              MM

2

0

              Others

0

17

Steroid status

 

 

              Resistant

83

aGvHD grade at the time of FMT request

 

 

              0

0

0

              I

0

0

              II

6

0

              III

94

96

              IV

0

4

Organ involvement

 

 

              Gut

100

100

              Skin

32

54

              Liver

13

25

Median number of previous aGvHD treatments (range)

3 (1−6)

Used ruxolitinib before

77

Median number of MaaT013 delivered (range)

3 (1−3)

aGvHD, acute graft-versus-host disease; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; EAP, expanded access program; FMT, fecal microbiota transplant; GvHD, graft-versus-host disease; MDS, myelodysplastic syndrome; MM, multiple myeloma; MPN, myeloproliferative neoplasm; TCL, T-cell lymphoma.
*Adapted from Malard.1

Glucksberg criteria.
Data from Malard.2

Efficacy

In the Heracles trial, 38% of patients achieved a positive GI GvHD response at Day 28, compared with 58% in the EAP. The best overall response until Day 28 was 54% in the Heracles trial and 67% in the EAP (Figure 2).

Figure 2. Outcomes in the Heracles trial compared with EAP*

CR, complete response; GI, gastrointestinal; GvHD, graft-versus-host disease; PR, partial response; VGPR, very good partial response.
*Adapted from Malard.1

Overall survival at 12 months was 25% in the Heracles trial and 38% in the EAP. The median follow‑up for the patients who were still alive in the EAP was 361 days (range, 63−731 days) (Table 2). Overall survival at 12 months was significantly increased in the patients who responded compared with non-responders in the Heracles (p = 0.047) and EAP  (p < 0.0001) cohorts.

Table 2. Overall survival in the Heracles trial and EAP*

 

EAP (N = 52)

Heracles (N = 24)

OS depending on timepoint, %

 

 

              6 months

49

29

              12 months

38

25

OS at 12 months depending on response category, %

 

 

              CR/VGPR/PR

59

44

              NR

7

13

CR, complete response; EAP, expanded access program; NR, no response; OS, overall survival; PR, partial response; VGPR, very good partial response.
*Adapted from Malard.1

Safety

Heracles

Within 24 hours of MaaT013 administration, 39 adverse events (AEs) were reported.

Serious AEs included:

  • Two Grade III AEs: Escherichia sepsis (E. coli strain not found in MaaT013 sample received by patient) and thrombotic microangiopathy
  • One Grade IV AE: cerebral infarction
  • One Grade V AE: decrease in overall physical health

In patients who responded, there was a significantly improved alpha diversity of the patients’ gut microbiome and higher proportions of MaaT013-derived species in the gut microbiota following MaaT013 treatment.

EAP

Following MaT013 administration, GI symptoms (abdominal pain and anorectal disorder) were recorded in two patients. Infectious complications occurred in 11.5% of patients and a connection to MaaT013 could not be ruled out. These included bacterial arthritis, sepsis, Escherichia bacteremia, bacterial translocation, bacteroides infection, and septic shock.

Conclusion

Malard concluded by highlighting that MaaT013 has been used to treat >80 patients so far between the Heracles trial and EAP and demonstrated improved alpha diversity of the gut microbiome. For patients with SR or steroid dependent aGvHD, an overall response rate at Day 28 of 38% was achieved in the Heracles trial and 58% in the EAP. Malard went on to highlight the ongoing ARES phase III single-arm trial (NCT04769895), which aims to assess MaaT013 treatment as a third line treatment in this patient group.

  1. Malard F. Pooled allogenic fecal microbiotherapy MaaT013 for the treatment of steroid-refractory gastrointestinal acute graft-versus-host disease: Results from the phase IIa Heracles study and expanded access program. Oral abstract #262. 63rd American Society of Hematology Annual Meeting and Exposition; Dec 11, 2021; Atlanta, US.
  2. Malard F. Pooled allogenic fecal microbiotherapy MaaT013 for the treatment of steroid-refractory gastrointestinal acute graft-versus-host disease: Results from the phase IIa Heracles study and expanded access program. Oral abstract #OS10-06. 48th Annual Meeting of the European Society for Blood and Marrow Transplantation; Mar 23, 2022; Virtual.
  3. Saliba RM, Lima MD, Giralt S, et al. Hyperacute GVHD: risk factors, outcomes, and clinical implications. 2007;109(7):2751–2758. DOI: 10.1182/blood-2006-07-034348
  4. Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015;21(3):389-401.e1. DOI: 1016/j.bbmt.2014.12.001