All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional.
Introducing
Now you can personalise
your GvHD Hub experience!
Bookmark content to read later
Select your specific areas of interest
View content recommended for you
Find out moreThe GvHD Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the GvHD Hub cannot guarantee the accuracy of translated content. The GvHD Hub and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.
Bookmark this article
As recently reported on the GvHD Hub, the European Society of Blood and Marrow Transplantation guidelines for graft-versus-disease (GvHD) prophylaxis and treatment, recommends to treat all Grade ≥ 2 acute GvHD (aGvHD) with systemic corticosteroids. In cases of isolated upper gastrointestinal (UGI), it is possible to lower doses of systemic therapy, and add non-absorbable oral steroids.1 Beclomethasone dipropionate (BDP) and budesonide (BUD) are both non-absorbable corticosteroids that are efficacious in treating patients with inflammatory bowel diseases. More recently they have been used to treat mild to moderate gastrointestinal GvHD, however, only as separate treatments or in combination with systemic glucocorticoids.
Chiara Frairia and colleagues of the Moffitt Cancer Center of Tampa, FL, report on the real-life outcomes with BDP alone or BDP in combination with BUD to treat patients with symptomatic UGI aGvHD without the addition of standard systemic glucocorticoids. Their retrospective analysis has been published in Biology of Blood and Marrow Transplantation and is summarized in this article.2
Isolated UGI aGvHD was defined according to previous studies published3 and confirmed with endoscopic biopsies when feasible (63%).
Key exclusion criteria were:
Patients were to receive BDP alone (5 mg/5 ml liquid oil formulation orally twice daily) or BDP (same dose) + BUD (3 mg tablet twice daily) as per physician's choice, and primary endpoint was GvHD response as assessed 28 days after treatment initiation. Other reported outcomes were response at Day 200, treatment failure and mortality.
A total of 157 patients with isolated UGI aGvHD after allogeneic hematopoietic stem cell transplantation were analyzed retrospectively. Some patients presented concomitant aGvHD of skin stage 1 or less (33–37%), but they were treated only with topical agents at the time of UGI aGvHD onset. Other patient characteristics can be found in Table 1.
Table 1. Patient characteristics in each treatment group (BDP or BDP + BUD)
aGvHD, acute graft-versus-host disease; BDP, beclomethasone dipropionate; BUD, budesonide; CLL, chronic lymphocytic leukemia; CSA, cyclosporine; HCT, hematopoietic cell transplantation; HD, Hodgkin disease; MDS, myelodysplastic syndrome; MMF, mycophenolate mofetil; MTX, methotrexate; NHL, non-Hodgkin lymphoma; SIRO, sirolimus; TAC, tacrolimus/mycophenolate mofetil; UGI, upper gastrointestinal *Includes aplastic anemia, myeloproliferative disorders including chronic myelogenous leukemia, paroxysmal nocturnal hemoglobinuria, and multiple myeloma Bold indicates variables significantly unbalanced between both groups |
||
Variable |
BDP (N = 76) |
BDP + BUD (N = 81) |
---|---|---|
Age, years, median (range) |
52 (22-76) |
54 (23-70) |
Diagnosis, n (%) |
||
Acute leukemia |
35 (46) |
42 (52) |
MDS |
14 (18) |
12 (15) |
-cell NHL, HD, CLL |
8 (11) |
15 (18) |
Other* |
19 (25) |
12 (15) |
Conditioning regimen, n (%) |
||
Myeloablative |
48 (63) |
71 (88) |
Reduced-intensity |
28 (37) |
10 (12) |
aGvHD prophylaxis, n (%) |
||
CSA/MMF |
8 (11) |
2 (3) |
TAC/MMF |
9 (12) |
10 (13) |
TAC/MTX |
35 (46) |
46 (57) |
TAC/SIRO |
24 (32) |
23 (27) |
GI biopsy, n (%) |
39 (51) |
60 (74) |
Days of UGI aGvHD onset, median (range) |
31 (14-174) |
26 (10-253) |
Acute skin stage 1 GvHD, n (%) |
25 (33) |
30 (37) |
Treatment duration, days, median (range) |
96 (7-816) |
225 (10-1,176) |
When analyzing responses per treatment group (Table 2), more responses were observed initially with BDP + BUD than BDP alone (odds ratio = 2, 95% CI, 1–4; p = 0.049). However, after adjusting for patient baseline characteristics in a multivariate analysis, responses were not significantly different between treatment groups at both time points (Day 28 and Day 200, p = 0.2). In the BDP arm 26 patients (36%) and in the combinations arm 37 patients (49%) responded to non-absorbable oral steroid treatment without requiring any further systemic treatment. Although numerically superior, the response to BDP + BUD was not statistically different to BDP alone.
Interestingly, although there were no differences in overall response rates between both treatment arms, when stratified by prophylaxis treatment (i.e., methotrexate or sirolimus in combination with tacrolimus), significantly more patients treated with sirolimus achieved a response in either group compared to those treated with methotrexate (81% vs. 64%, p = 0.04).
A total of 46 patients (22%) and 64 patients (41%) progressed after 28 and 200 days of treatment, respectively. Progression was mainly limited to the gastrointestinal tract, but cases of GvHD in other organs were also registered, and additional immunosuppression (IS) needed to be administered. After analyzing responses to this second-line treatment for aGvHD in 62 evaluable patients, the authors concluded that progressing after BDP alone or BDP in combination with BUP did not compromise the possibility to control aGvHD with other IS treatment options at a later stage of the disease (overall response rates 95% 28 days after second-line treatment initiation).
Table 2. Responses to BDP and BDP + BUP at 28 days and 200 days after therapy initiation
BDP, beclomethasone dipropionate; BUD, budesonide; CR, complete response; PR, partial response CR was considered when all upper gastrointestinal symptoms were resolved without the addition of other immunosuppressive agents PR was used to define patients who improved but did not fully resolve all symptoms All other situations were classified as “failure” or non-responders *At Day 200, 22 patients were dead and 4 were lost to follow-up |
||||
At Day 28 |
At Day 200 |
|||
---|---|---|---|---|
Variable |
BDP |
BDP + BUD |
BDP |
BDP + BUD |
Response rate, n (%) |
||||
CR |
40 (53) |
54 (67) |
26 (34) |
37 (46) |
PR |
8 (11) |
8 (10) |
2 (3) |
2 (2) |
Failure |
28 (37) |
18 (22) |
31 (41) |
33 (41) |
Not evaluable* |
0 |
1 (1) |
17 (22) |
9 (11) |
Other secondary variables registered in the study showed no statistically significant differences between BDP and BDP + BUD:
The 5-year overall survival rates were slightly better with BDP + BUD compared to BDP alone (57% vs. 51%, median not reached in either group), but these differences were not statistically significant in the multivariate model (HR 0.6, 95% CI, 0.4–1.5, p = 0.07).
In this study, treatment selection was as per physician's choice, and there was a preference observed for the combination regime for patients with earlier UGI aGvHD onset, confirmed by GI biopsy, and those treated with myeloablative conditioning regimens. All these features contribute to a higher risk for treatment failure and might explain why transplantation-related mortality was significantly higher in the BDP + BUP group compared to the BDP group: 50% vs. 28%, respectively (p = 0.04). Other common causes of death registered were chronic GvHD and infections. In 53% of cases the cause of death was related to persistent or recurrent hematological disease and was uncertain in 8% of patients.
Despite the lack of a significant differences in GvHD responses to BDP alone versus BDP + BUD in patients with isolated UGI aGvHD, the combination regime obtained faster responses than BDP alone. The responses observed with non-absorbable glucocorticoids in this study population appear to be comparable to the rates seen with the systemic steroid therapy, with the added benefit of sparing the related systemic toxicity. However, it is important to highlight that the patients included in this study would be classified as standard risk according to the Minnesota aGvHD risk classification,4 and that any up-front treatment approaches should be studied in a risk-stratified cohort.
Overall, the authors considered the results reported sufficiently strong to justify a controlled randomized study comparing BDP + BUD with administration of systemic glucocorticoids in patients with UGI aGvHD. This clinical trial would further confirm the efficacy and feasibility of a better-tolerated first-line regimen to treat patients with isolated UGI aGvHD.
Penack O, Marchetti M, Ruutu T, et al. Prophylaxis and management of graft versus host disease after stem-cell transplantation for hematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation. Lancet Haem. 2020;7(2): e157-167. DOI: 1016/S2352-3026(19)30256-X
Frairia C, Nicolosi M, Shapiro J, et al. Sole Upfront Therapy with Beclomethasone and Budesonide for Upper Gastrointestinal Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2020;S1083-8791(20):30234-2. DOI: 10.1016/j.bbmt.2020.04.023
Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825–828.
MacMillan ML, DeFor TE, Weisdorf DJ. What predicts high-risk acute graft-versus-host disease (GVHD) at onset?: identification of those at highest risk by a novel acute GVHD risk score. Br J Haematol. 2012;157(6):732-741. DOI: 1111/j.1365-2141.2012.09114.x
Subscribe to get the best content related to GvHD delivered to your inbox