Page 24 - 2021_04-Haematologica-web

I. Henig et al.
Case 2
A 25-year old female with intermediate-risk AML in CR underwent an allo-HSCT with BuCy myeloablative condi- tioning from her matched sibling. Her neutrophils engraft- ed by day +14. On day +34 she developed grade 3 aGvHD of the lower GI tract which was steroid refractory (SR). She did not respond to the addition of budesonide, extracorpo- real photopheresis (ECP), mofetil mycophenolate or inflix- imab.
Can fecal microbiota transplantation mitigate prevailing acute gastrointestinal graft-versus- host disease?
The current data regarding the use of FMT for the treat- ment of acute GI GvHD are limited to case reports and small case series (Table 2). A total of 58 described patients were treated with FMT for SR GI grade 2-4 aGvHD. The FMT source was an unrelated donor in 36 cases, a related donor – in six cases and in eight cases a commercial pooled highly diverse FMT was used. FMT was processed and either given fresh within a few hours of collection or it was frozen and later thawed before administration. FMT was administered orally as packed capsules, through a nasogas- tric/nasoduodenal tube or an enema. Of 58 patients, 28 received FMT after two or more therapy lines, while 19 received it as second-line therapy right after steroid failure. Response was observed in 74% (43 of 58) of patients, with complete response in 57% (33 of 58) and partial response in 17% (10 of 58). Complete response was observed in 73% of patients receiving FMT as second-line therapy. Ten of the responding patients relapsed and 29 patients were alive at the last follow-up (54%; 29 of 54 patients with available data).
Response to treatment was seen within a median of 14
days (range: 3-28), with a median of two FMT (range: 1-7),
and a median of 7 days between treatments (range: 2- 60).46,98-106
Infectious complications occurred in 11 patients. Two had sepsis with bacteria not originating from FMT,102 and one patient developed diarrhea due to Norovirus that was traced to FMT.106 Other infections were attributed to the severe immunocompromised state of patients. However, a possible association with FMT could not be ruled out. In responding patients in whom the stool microbiome was sequenced post-FMT, it was found to be significantly more diverse and enriched with Bacteroides, Lactobacillus, Bifidobacterium and Faecalibacterium compared to pre-FMT microbiome.46,98-101 Notably, the diversity increased only upon discontinuation of anti-anaerobic systemic antibiotic treatment, such as piperacillin-tazobactam. However, con- tinuous use or re-initiating treatment with cefepime did not reduce FMT efficiency.46,98,99
These results are highly encouraging and support FMT therapy to be relatively safe and effective in SR GI aGvHD.
Case 2: conclusions
Available data suggest a potentially beneficial effect of FMT in acute lower GI GvHD. It should probably be used earlier rather than later, so that patients' response will not be overcome by infectious complications related to exten-
sive immunosuppressive therapy. Discontinuation of antibiotic treatment prior to FMT administration appears to be an important factor contributing to successful response. If antibiotic treatment is required, using cefepime may allow attenuating microbiome insult while maintaining clinical response.
Current information is based on case reports and small series with a wide variability in patient selection, FMT preparation and mode of administration. However, the reported feasibility, safety and clinical benefit appear to be similar across the studies, implying that intestinal micro- biota can be recovered with FMT, irrespective of its admin- istration method. Safety remains a concern,107 especially in advanced GI aGvHD, and if an infectious complication occurs post-FMT, the pathogen should be sequenced and traced to find out if it originates from the FMT.
Case 2: recommendations
Currently, ruxolitinib is the only FDA-approved drug for the treatment of SR aGvHD, while other modalities are also commonly used in this scenario (e.g., extracorpo- real photopheresis). Thus, FMT could be recommended for patients with grade 2-4 steroid refractory or depend- ent aGVHD of the lower GI tract, albeit in the context of a clinical study only.108-110 Other treatment approaches could also be considered, such as adding it to steroids as part of the first-line therapy (clinicaltrials gov. Identifier: 04269850).
Although clinical trials are still ongoing, given the grave prognosis of SR aGvHD with more than 50% mortality,111 and the high rate of response to FMT, we recommend considering FMT as a therapeutic option in this setting.
Practical considerations for fecal microbiota transplantation treatment
As FMT has become the standard of care in recurrent
and refractory CDI,112,113 more and more centers are gaining
access to FMT programs through either establishing their
own stool banks or acquiring FMT from universal stool banks.114,115
One of the limiting factors to wider application of stool banks and FMT programs is the lack or variance of regula- tory standards. In different countries, FMT is regulated as a drug, tissue or a combined product composed of both human cells and non-human components (microbial DNA and metabolites). Stool banks are recommended to operate under the designated authority in each country. In the absence of local directives, the scientific committee should be responsible for establishing regulatory protocols.114
FMT donor screening should follow national regulations and international recommendations.114 Screening should include medical history related to the risk for transmitting infections, as well as medical conditions and treatments associated with perturbed microbiome (Table 3). Special considerations are to be applied when planning FMT use in allo-HSCT patients, such as testing the donor for Cytomegalovirus and Epstein-Barr virus IgG and IgM, and administering FMT from seronegative donors to seronega- tive patients. However, when weighing suitability of an FMT donor, one should be cognizant of the fact that no data are available to support the advantage of a particular
940
haematologica | 2021; 106(4)