Ileostomy for steroid-resistant acute graft-versus-host disease of the gastrointestinal tract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for hematological malignancies. However, it may result in graft-versus-host disease (GvHD) which is associated with a high mortality rate. The standard-of-care treatment of GvHD is high-dose steroids as a first-line treatment, while no standard second-line treatment is established.¹ Steroid-resistant GvHD, in particular, of the gastrointestinal tract (GI-GvHD) is a major concern to allo-HSCT recipients.  Therefore, new approaches are needed to improve the treatment of steroid-resistant GI-GvHD.

On 23 July 2019, Amin T. Turki and colleagues from University Hospital Essen, DE, published the results from this retrospective study in Annals of Hematology and demonstrated that ileostomy induced significant clinical responses in patients with steroid-resistant GI-GvHD along with a reduction of activated T-cells and changes of the intestinal microbiota.

Study design²

Conventional therapy plus ileostomy (CT+I) vs Conventional therapy (CT)

• Sixty-five patients who underwent allo-HSCT between September 2009 and December 2015 were included in this study
• Patients were analyzed retrospectively and divided into two groups: CT (n= 55) vs CT+I (n= 10) (Table 1)
• The CT+I cohort consisted of eight adults and two pediatric patients
• Differences between both cohorts (CT+I vs CT) involved diagnosis of myelodysplastic syndrome (0% vs 20%), myeloablative conditioning regimen (100% vs 67%), cytomegalovirus (CMV) risk profile serostatus (100% vs 35%), and Epstein-Barr virus (EBV) risk serostatus (50% vs 100%)
• Established GvHD risk factors were evenly distributed between cohorts, with unrelated donor stem cells (70% vs 76%) and HLA mismatch (40% vs 37%)

Table 1. GvHD patient characteristics

Characteristic	Conventional therapy plus ileostomy		Conventional therapy
n	%	n	%
GvHD; graft-versus-host disease
Total enrolled and treated	10	100	55	100
Overall GvHD grade
III	0	0	6	11
IV	10	100	49	89
Gastrointestinal GvHD stage
3	0	0	8	15
4	10	100	47	85
Liver GvHD stage
1	3	30	4	7
2	1	10	5	9
3	4	40	9	16
4	2	20	10	18
Skin GvHD stage
1	1	10	0	0
2	4	40	13	24
3	1	10	20	36
4	2	20	10	18
Fecal calprotectin	3000	124–3079	360	47–3010

Assessments:

• In the experimental cohort, GI-GvHD was histologically confirmed using the Freiburg criteria
• Daily clinical assessment and standard laboratory parameters were obtained from outpatients
• Fecal volumes were assessed seven and 14 days before and after ileostomy and confirmed before discharge

Results²

CT+I vs CT unless stated otherwise

Patient characteristics

• All patients of the CT+I cohort and 85% of the CT cohort developed stage IV GI-GvHD
• Patients had GvHD of more than one site including stage III-IV liver (60% vs 34%) and stage III-IV skin GvHD (30% vs 54%)
• ECOG performance and Charlson comorbidity scores at diagnosis of steroid-resistant GvHD were similar between both cohorts

Safety and efficacy

• Eight patients (80%) in the CT+I cohort had a complete response (CR) of their GvHD and could be discharged at a median time of 62 days after ileostomy (range 14–199)
• In the ileostomy cohort, the 5-year overall survival (OS) was significantly (p = 0.002) higher than in the conventional therapy cohort (30% vs 6%) indicating a clear OS benefit of ileostomy (hazard ratio (HR) 0.54 (95% confidence interval (CI), 0.36–0.81; p = 0.003)
• Fecal volume at 14days pre-ileostomy was approximately 3,000 ml and 2,500 ml 14 days post-ileostomy. Significantly declined fecal volumes (p = 0.001) after ileostomy suggests intestinal adaptation
• The absolute number of activated T cells significantly decreased by more than 50% (p = 0.04) after ileostomy
• Ileostomy recipients had enhanced intestinal microbial diversity, changing from strict anaerobic to facultative anaerobic and aerobic bacteria after ileostomy

 Safety

• GvHD-associated gastrointestinal bleeding was reduced in the CT+I group and patients reported a significantly improved individual pain assessment
• The leading cause of death in the conventional therapy cohort was infectious disease (56%) including sepsis, aspergillosis, and respiratory failure, followed by uncontrolled GvHD (31%)
• Both acute GvHD-related mortality (10% vs 31%) and mortality caused by a severe infection (20% vs 56%) were significantly lower in the ileostomy cohort

Multivariant analysis

• Patients with GvHD response to any second-line therapy (such as ATG, ruxolitinib, mycophenolate mofetil, basiliximab) had a significant survival benefit (HR 0.30; 95% CI, 0.16–0.57; p < 0.0005)
• In Stage IV acute GvHD, the involvement of all three organs, was associated with significantly reduced OS (HR 4.23; 95% CI, 1.22–14.7)
• Subgroup analysis of the ileostomy cohort revealed no significant difference regarding the time point of aGvHD diagnosis and subsequent ileostomy surgery

Table 2. Cause of death

Cause of death	CT+I		CT
	n	%	n	%
Acute GvHD	1	10	17	31
Chronic GvHD	1	10	0	0
Sepsis	1	10	15	27
Aspergillosis	1	10	9	16
ARDS	0	0	7	13
Encephalopathies	0	0	2	4
Viral encephalitis	0	0	1	2
Cardiovascular	2	20	1	2
Secondary neoplasia	1	10	0	0
CT, conventional therapy; GvHD, graft-versus-host disease

Limitations

• Data have been analyzed retrospectively and the absolute number of patients in the ileostomy cohort was small
• As patients in this study have been treated between 2009 and 2015, treatment varied between cohorts, however without resulting in a significant OS difference

Conclusion

This study shows ileostomy as a promising treatment choice for steroid-resistant GI-GvHD. Correlative studies indicate that ileostomy resulted in a significant reduction of fecal volumes through intestinal adaptation, reduction of activated T-cells, and enhanced diversity of the intestinal microbiota. The authors suggest that ileostomy should be performed as early as possible, as GvHD-associated infectious mortality increased with time.  The authors concluded that a controlled, randomized trial comparing ileostomy to other second-line GvHD treatments should corroborate these results.