Spindelboeck et al. 2021 Austria(1, 2) | a prospective cohort study (NCT03819803) with 7 patients, and a compassionate-use program with 2 patients | steroid refractory aGVHD, stage Ⅳ | 9 | 53, 60, 59, 24, 54, 42, 67, 39, 51 | Colonoscopy | Unrelated, 6; related, 3 | 1 ~ 6 | 9-614 days (Day 90) | 4 CR, 1 PR, 4 NR (4 deaths) | 10 infectious events, all but one judged to be unrelated to FMTs: three cases of urinary tract infections, one case of pneumonia with Metapneumovirus, one case of gastroenteritis positive for Cytomegalovirus, and five cases of viremia (1 adenovirus infection possibly related to FMT) |
Qi et al. 2018 China(3) | A pilot study (NCT03148743) | steroid refractory GI aGVHD, stage Ⅳ | 8 | 36–40, 40–45, 26–30, 30–35, 46–50, 40–45, 28, 20 | Nasoduodenal tube | Unrelated | 1 ~ 2 | 90 days (Day 13) | 4 CR, 2 PR and 2 NR (4 deaths) | One case died of intracerebral hemorrhage due to thrombocytopenia; 3 cases died after declining FMT treatment due to complications of GVHD or economic reasons |
Shouval et al. 2018 Netherlands(4) | a single-arm pilot study (NCT03214289) | steroid dependent (1)/resistant (6) GI aGVHD | 7 | 62, 41, 65, 33, 72,64, 59 | Capsules (frozen) | Unrelated | 1 ~ 3 | 40–99 days (Day 28) | 2 CR and 5 NR (4 deaths) | 2 bacteremia (not related to FMT); 3 patients died due to active GVHD, while 1 to an invasive Aspergillosis of the brain |
Malard et al. 2021 France(5) (HERACLES) | Phase 2 clinical trial HERACLES (NCT03359980) | Grade III-IV, steroid-resistant, GI aGVHD | 24 | N/A | MaaT013 | Multiple Unrelated Donor | N/A | 365 days (Day 28) | 5 CR, 2 VGPR, 2 PR, 15 NR (18 deaths) | Well tolerated, with mild infections and gastrointestinal disorders (not clear about the disease name and number) |
Malard et al. 2021 France (5) (EAP) | a compassionate use program (Early Access Program or EAP) | Steroid dependent or steroid resistant, Grade II-IV, GI aGVHD | 52 | N/A | MaaT013 (enema or nasogastric tube) | Multiple Unrelated Donor | 1–6 (median 3) | 365 days (Day 28) | 17 CR, 9 VGPR, 4 PR, 22 NR (32 deaths) | 1 case of sepsis (possibly related to FMT); C. difficile diarrhea 24 hours post-administration (not related to MaaT013) |
van Lier et al. 2020 Netherlands (6) | a prospective, single-center, single-arm pilot study (ISRCTN14530574) | Steroid resistant or steroid-dependent GI aGVHD | 15 | 57 (20–72) | Nasoduodenal tube | 2 related 13 Unrelated | 1 | 180 days (Day 28) | 10 CR, 5 NR(all 5 deaths) | Pneumonia, cystitis, sepsis, otitis, discomfort of nasoduodenal tube, cramps, nausea, transient abdominal distention, regurgitation |
Bilinski et al. 2020 Poland(7) | a prospective, multicenter study (NCT02461199) | Steroid refractory GVHD (11 acute, 2 chronic) | 13 | 23–66 | Nasoduodenal tube | Unrelated | 1 ~ 2 | 17–757 days (After first FMT) | 5 CR, 3 PR, 5 NR (all 8 deaths) | 8 cases of serious adverse events: ileus/subileus, colitis, bronchopneumonia, lobar pneumonia, and one septic shock (not related to FMT) septic shock, sepsis, Norovirus-mediated gastrointestinal tract infection (related to FMT) |
Kakihana et al.2016 Japan(8) | A Pilot Study (UMIN000015115) | Steroid resistant/dependent gut GVHD | 4 | 64, 44, 48, 42 | nasoduodenal tube | Spouse /relative | 1–2 | 28 days | 3 CR; 1 PR | 3 cases of abdominal pain, 2 cases of diarrhea, 2 cases of pharyngolaryngeal pain, 1 case of belch, 1 case of nausea |
Choi et al.2020 Korea(9) | A Pilot Study | refractory GI aGVHD | 4 | N/A | upper endoscopy or colonoscopy (frozen) | unrelated | 1–4 | N/A | 3 PR, 1NR (3 deaths) | Bacteremia (n = 3, not related to FMT) |
Goloshchapov et al.2021 Russia(10) | a prospective single-center study | aGVHD grade II-IV | 7 | 3–10 | 2 EGD; 2 EGD + nasointestinal tube; 3 gelatin capsules with frozen fecal microbiota | 3 relatives; 4 unrelated | 2 ~ 10 | 320–1964 days (Day 120) | 5CR, 1PR, 1NR (1 death) | Nausea, abdominal pain and stomach rumbling (43%), subfebrile rise of body temperature (29%), vomiting, pronounced abdominal flatulence and intestinal paresis (14%) |
Goloshchapov et al.2020 Russia(11, 12) | a prospective single-center study | Steroid refractory GI GVHD(15 acute, 4 chronic; 10 cases stage Ⅳ) | FMT 19; control group 8 | FMT group: 22 (3–49) Control group: 27 (1–52) | 3 EGD, 7 nasointestinal tube, 13 gelatin capsules, 4 placebo capsules | 15 Unrelated, 4 related | 2 ~ 10 | 120 days (Day 30) | FMT group: 9 CR, 9 PR, 1 NR (1 death); control group: 1 CR, 4 PR, 3 NR (3 deaths) | Nausea, vomiting, abdominal pain, diarrhea, constipation, fever, flatulence, intestinal paralysis, anorexia (milder in the FMT group than control) |
Zhao et al. 2021 China(3) | a non-randomized,open-label,phase I/II,clinical study (NCT 03148784) | Steroid refractory GI GVHD | FMT 23; control group 18 | FMT group: 30 (13–55) Control group: 31.5 (13–59) | nasojejunal or nasogastric tube | Unrelated | 1 ~ 7 | median > 539 days in the FMT group and 107 days in the control group (Day 28) | FMT group: 18 CR, 2 PR, 3NR (3 deaths); control group: 6 CR, 5 PR, 7 NR (3 deaths) (28 days) | Thrombocytopenia, cardiac event, subileus, fever, vomiting, rash |
Huang et al.2021 China(13) | Retrospective study | Steroid refractory acute (18, grade II or III) and chronic (11) GVHD | 29 | 16 ~ 61 | N/A | N/A | 1–3 | N/A | 7CR, 3PR 8 NR in aGVHD; 6PR 5 NR in cGVHD | 11 fever, 3 fecal bacterial culture positive, 2 constipation. No serious adverse events. |
Goeser et al. 2021 Germany(14) | Retrospective study | Steroid refractory GI aGVHD | 11 | 53.8 (30–76) | 2 naso-jejunal tube; 9 oral capsules | 2 related 9 unrelated | 1 | 30 days (Day 30) | 8 PR, 3 NR (1 death) | Abdominal pain, bloating in 3 cases, vomiting in 1 case (all mild); one patient died of CMV bacteremia (not related to FMT) |
Chakrabartty et al.2020 India(15) | Case series | Steroid refractory gut aGVHD | 4 | 54, 32, 14, 14 | naso-jejunal tube | unrelated | 4 (3 patients) or 8 (1 patient) | 14 days | 3 CR; 1 PR (2 deaths) | No AEs |
Bilinski et al.2021 Poland(16) | Case series | Steroid resistant GVHD | 4 | 66, 52, 55, 22 | nasoduodenal tube | 2 related 2 unrelated | 3 or 6 | 264 to 398 days | 3 CR 1 PR (2 deaths) | No serious AEs |
Merli et al.2020 Italy(17) | Case report | Steroid resistant aGVHD | 2 | 1.4–18 | EGD | Unrelated or relatives | 2 | 30 days (7 days) | 1 CR; 1 NR | fever, chills and malaise (negative blood culture) |
Wong et al.2018 America(18) | Case report | grade IV GI-GVHD | 1 | 6 | gastrojejunostomy tube and colonoscopy | Unrelated | 1 | 180 days (28 days) | 1 CR | No AEs |
Zhang et al.2019 China(19) | Case report | Steroid resistant grade IV gut GVHD | 1 | 14 | Duodenojejunal tube | Unrelated | 4 | 120 days | 1 PR | No AEs |
Biernat et al.2020 Poland(20) | Case report | Steroid resistant grade IV gut GVHD | 2 | 25, 32 | NT | Unrelated | 3 and 4 | 128 days | 1 CR 1 PR (2 deaths) | No serious AEs |
Kaito et al.2018 Japan(21) | Case report | Steroid resistant grade IV gut GVHD | 1 | 21 | Oral capsules (frozen) | relative | 2 | 90 days | 1 PR | Transient fever, positivity of galactomannan antigen, and recurrence of herpes zoster |
Mao et al.2020 China(22) | Case report | Steroid resistant grade IV gut GVHD | 1 | 1 | Oral capsules | unrelated | 2 | 60 days | 1 CR | No serious AEs |
Zhong et al.2019 China(23) | Case report | Steroid resistant grade III gut GVHD | 1 | 2 | gastroduodenal tube | unrelated | 2 | 90 days | 1 CR | No serious AEs |
Total | | | FMT: 242; Control: 26 | | FMT: capsules 34; Colonoscopy 9; MaaT013 76; NT or/and EGD 89; Colonoscopy + NT 1; Colonoscopy or NT 4; N/A 29 | Unrelated: 190; related:21; N/A: 31 | 1–10 | | FMT (overall 66.5%): 100 (41.3%) CR, 61 (25.2%) PR, 81 (33.5%) NR (90 deaths); Control: 7 (26.9%) CR, 9 (34.6%) PR, 10 (38.5%) NR (6 deaths) | SAE related to FMT: 1 septic shock, 2 sepsis, 1 Norovirus-mediated gastrointestinal tract infection; 1 adenovirus infection |
aGVHD: acute Graft-versus-host disease; CR: complete response; PR: partial response; NR: no response; NT: nasoduodenal tube or nasogastric tube; EGD: esophagogastroduodenoscopy; N/A: not available; FMT: Fecal microbiota transplantation |
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