Use of prebiotics as GvHD prophylaxis

Introduction

Chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) conditioning treatment cause significant gut mucosal damage and altered gut microbiome, which are both key pathologies in the development of acute graft-versus-host disease (aGvHD).¹ Established mechanisms include altered metabolism (e.g. translocation of bacterial wall lipopolysaccharides), activation of antigen-presenting cells, increased proinflammatory cytokine production, and priming of donor T cells.^2,3 Enteral nutrition is known to affect the development of aGvHD compared with parenteral nutrition, with decreased mortality and increased overall survival following allo-HSCT.⁴ Hence, treatments that help protect and maintain the mucosal integrity of the gut, and maintain enteral nutrition, may help to mitigate aGvHD. Several prebiotics have shown benefit in mucosal protection, including a commercially available supplement containing glutamine, fiber and oligosaccharide (GFO), and reduced starch (RS).^5,6

In a single-center, case-controlled study, Kota Yoshifuji and colleagues⁷ investigated the impact of prebiotic administration prior to conditioning for allo-HSCT through to Day 28, on the development of mucositis, diarrhea, and aGvHD symptoms. Their results have been recently published in Blood Advances⁷, and are summarized here.

Study aim

To investigate the hypothesis that the administration of GFO and RS to patients undergoing allo-HSCT demonstrated reduced aGvHD, and reduced alteration in their intestinal biome.

Study design

Prospective study:

• Clinical data were assessed from 49 patients undergoing allo-HSCT at the Tokyo Metropolitan Komagome Hospital between July to December 2017
• Patients received GFO and RS from the start of the pretransplantation conditioning regimen until Day 28 after transplantation
• Pretransplantation and Day 28 stool samples were obtained from 30 patients and analysed using 16S ribosomal RNA

 

Historical control dataset (April 2013 to February 2015):

• 142 patients who received allo-HSCT at the Tokyo Metropolitan Komagome Hospital between April 2013 and February 2015
• In 72 patients, fecal samples were available both at the pretransplantation phase and Day 28, and analysed using 16S ribosomal RNA

 

Data collected from allo-HSCT (Day 0) to neutrophil engraftment:

• • Mucositis assessed with the Eilers’ Oral Assessment Guide (OAG)
  • Diarrhea and side effects assessed with the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
  • Use of parenteral nutrition posttransplant
  • aGvHD scored according to established international criteria⁸
  • Microbial colony diversity in stool samples was expressed using the Shannon index (SI)

Primary outcomes: Incidence and duration of mucositis (oral mucositis and diarrhea)

Secondary outcomes:

• • Incidence of aGvHD
  • Duration of total parenteral nutrition

Results

Patient characteristics

Patient characteristics were well balanced between case and control cohorts, including key demographic data (age and sex), diagnosis (including primary diagnosis and risk stratification), transplant criteria (including number of transplants, HLA matching, and donor sex), transplant protocol (including conditioning regimen, use of antithymocyte globulin [ATG], total body irradiation, and choice of aGvHD prophylaxis); see Table 1. There was a higher proportion of female-to-male recipients in the control group (17%) than in the prebiotics group (4%; p = 0.028), and increased use of two lines of antibiotics with relatively high anti-anaerobe activity in the prebiotics group (20%) compared with the control group (4%; p = < 0.001).

Table 1. Core diagnostic, demographic, and clinical data of case and control groups⁷

Patient characteristic	Prebiotics group (n = 49)	Control group (n = 142)
Sex, n
Male	24	87
Female	25	55
Age, n
< 55	34	84
> 55	15	58
Primary diagnosis, n
AML	25	70
ALL	10	25
MDS	4	28
Other	10	19
No. of transplants, n
1	44	123
2 or more	5	19
ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome.

 

Prebiotic intake

Due to treatment-related gut toxicities and mucositis, only 50% of the scheduled prebiotic dose was taken by patients, with a higher intake of GFO (74.3%; median intake 3.7 g/d) compared with RS (39%; median intake 6.6 g/d).

While patient intake of prebiotics was high during the conditioning period, it decreased posttransplant.

Mucositis

• Oral mucositis was identified in all patients
• No significant difference in maximum OAG score between groups (p = 0.101)
• Reduced OAG score in the prebiotics group on Days 0–9 after allo-HSCT (p < 0.05)
• Shorter duration of moderate to severe mucositis in the prebiotics group vs control (median 11 vs 14 days; p < 0.001)

Diarrhea

• No statistical difference between number of patients developing Grade 3 or higher diarrhea between groups
• Duration of diarrhea was reduced in the prebiotics group vs control (median 7 vs 9 days; p = 0.049)

Secondary outcomes

• At Days 100 and 200 post allo-HSCT, all Grade (1–4) aGvHD and Grade 2–4 aGvHD were significantly reduced in the prebiotics group vs control group, both at Day 100 and Day 200; see Table 2.
• By contrast, only a trend for improved Grade 3–4 aGvHD was found in the prebiotics group compared with control at Day 100 (4.1 vs 14.1%; p = 0.062), and Day 200 (10.2 vs 15.5%; p = 0.351)
• No statistical difference in the duration of total parenteral nutrition given between the two groups was observed
• No statistical difference was seen between the two groups in terms of gut or liver aGvHD
• No statistical difference was found between the two groups in terms of overall survival, nonrelapse mortality or cumulative relapse.

Table 2. Presence of GvHD at Days 100 and 200 post allo-HSCT in the prebiotics and control groups⁷

Day post allo-HSCT	Prebiotics group, %	Control group, %	p value
aGvHD, acute graft-versus-host disease; HSCT, hematopoietic stem cell transplantation.
Day 100
All grade aGvHD	53.1	73.2	0.004
Grade 2–4 aGvHD	24.5	46.1	0.006
Grade 3–4 aGvHD	4.1	14.1	0.062
Day 200
All grade aGvHD	63.3	75.4	0.018
Grade 2–4 aGvHD	32.7	47.9	0.032
Grade 3–4 aGvHD	10.2	15.5	0.351

Microbial diversity

• The SI was significantly higher in the prebiotics group than in the control group on pretransplantation sampling (p = 0.11)
• At Day 28 post allo-HSCT, no significant difference was identified between SI in the two groups, with an equivalent decrease in SI
• At Day 28 post allo-HSCT, there was an increase in the proportion of butyrate-producing bacteria in the prebiotics group (p = 0.027), compared with the control group (p = 0.331), suggesting this population was better sustained in patients receiving prebiotics
• While fecal butyrate concentrations were elevated in the control group pretransplantation, no statistically significant difference was seen between the two groups at Day 28 post allo-HSCT

Key findings

• No adverse events directly attributable to prebiotic intake
• From the patient characteristics collected (e.g. diagnosis, sex, age, nature of transplant [first or later transplant, conditioning, etc], and concurrent antibiotic use), multivariate analysis revealed that prebiotic intake was the only independent patient factor that reduced the development of all grade aGvHD at 100 and 200 days.
• The use of antibiotics with high anti-anaerobe activity did not affect the development of aGvHD.

Conclusion

 This study demonstrates that the administration of prebiotics to patients undergoing allo-HSCT can benefit them in terms of reduced duration of diarrhea, reduced severity of early mucositis, and reduced duration of moderate to severe mucositis.

Whilst no difference was observed between the prebiotics and control groups in terms of overall survival or nonrelapse-related mortality, the prebiotics group was found to have a statistically significant lower incidence of all grade and Grade 2–3 aGvHD at Days 100 and 200 post allo-HSCT.

The limitations of the study include a time difference of 17 months between the end of data collection for the control group (February 2015) and the start of data collection for the prebiotic group (July 2017). The study also identifies a significant difference in the gut biome between the two groups, with a lower bacterial diversity and lower butyrate levels in the prebiotics group compared with the control group in pretransplantation fecal samples. While the authors were unable to explain the differences in gut biodiversity, they highlighted that more patients in the prebiotics group received two lines of anti-anaerobic antibiotics, a known cause for increased aGvHD. Improved diversity and reduced administration of anti-anaerobic antibiotics are important confounding factors, which may have led to better outcomes after allo-HSCT for the historical control group compared with the prebiotics group.

This study suggests that prebiotics may have a role in reducing the burden of transplantation-related symptoms in the early phase of allo-HSCT (from Day 0 to Day 9), and demonstrates efficacy in the reduction of all stage GvHD at Days 100 and 200. This may allow for a reduction or delay in the use of steroids to treat aGvHD in some patients. Larger, prospective, randomised studies are required to further evaluate the utility of prebiotics for the prophylaxis and treatment of GvHD.