Beclomethasone and budesonide to treat patients with upper gastrointestinal acute GvHD

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

Study design and patient characteristics

Isolated UGI aGvHD was defined according to previous studies published³ and confirmed with endoscopic biopsies when feasible (63%).

Key exclusion criteria were:

• other grades of skin aGvHD
• any grade of lower gastrointestinal or liver aGvHD
• any documented infection (bacterial, fungal, or viral)
• patients treated with corticosteroids for any indication other than GvHD during the 30 days prior to UGI aGvHD onset

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)

Results

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:

• patients requiring 1 or more IS agent(s) after 200 days of treatment: 53% 43%
• median time to additional IS agent(s) requirement: 14 29 days
• proportion of UGI aGvHD failures with progression to lower gastrointestinal aGvHD at Day 28: 42% 53% of all patients with local failure of treatment
• cumulative incidence of chronic GvHD of any severity: 67% 73%
• cytomegalovirus infection or disease: 30% 25%

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.

Conclusion

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.