(9R)-9-chloro-11-17-dihydroxy-17-(2-hydroxy-1-oxoethyl)-10-13-16-trimethyl-6-7-8-11-12-14-15-16-octahydrocyclopenta[a]phenanthren-3-one and Graft-vs-Host-Disease

For over a decade, nonabsorbable corticosteroids have been employed in the treatment of gastrointestinal graft-versus-host-disease (GVHD) in hematopoietic stem cell transplant (HSCT), as monotherapy or in combination with systemic corticosteroids. The majority of the evidence showing a favorable outcome consisted of case series, small phase II trials and a large randomized phase III trial. The 2 most commonly studied molecules were oral budesonide and beclomethasone diproprionate. Although these reports hint at some benefit with the local treatment strategy, their methodologic inconsistencies preclude meaningful adoption to everyday clinical practice. This review evaluates the current evidence of nonabsorbable corticosteroids in HSCT and sets forth recommendations for future trials with these agents.

Topics: Beclomethasone; Budesonide; Clinical Trials as Topic; Gastrointestinal Diseases; Glucocorticoids; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Treatment Outcome

Graft-versus-host disease (GVHD) after allogeneic stem-cell transplantation causes significant morbidity and mortality. An important site of GVHD is the gastrointestinal (GI) tract because development of acute GI GVHD is prognostic of overall survival. The standard of care to treat acute GI GVHD is systemic corticosteroids and immunosuppressants; however, the use of these therapies can cause life-threatening opportunistic infections. To limit the adverse effects of systemic immunosuppression, the topically active corticosteroid beclometasone dipropionate has been investigated in case studies and in randomized placebo-controlled trials for the treatment of acute GI GVHD. In this review, we appraise these studies with beclometasone dipropionate, and discuss future randomized studies to clarify the role of beclometasone dipropionate for the treatment and prevention of acute GVHD. At present, more data are required before the addition of beclometasone dipropionate to systemic corticosteroids for the treatment of acute GVHD can be considered the standard of care.

Topics: Animals; Anti-Inflammatory Agents; Beclomethasone; Biological Availability; Clinical Trials as Topic; Gastrointestinal Diseases; Graft vs Host Disease; Humans; Randomized Controlled Trials as Topic

Topics: Administration, Oral; Anti-Inflammatory Agents; Beclomethasone; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Gastrointestinal Diseases; Graft Rejection; Graft vs Host Disease; Hematologic Neoplasms; Humans; Lung Diseases; Stem Cell Transplantation; Tablets, Enteric-Coated

Beclomethasone dipropionate (BDP) is a topically active anti-inflammatory corticosteroid. Oral BDP is metabolized in the intestine to a potent metabolite, 17-beclomethasone monopropionate (17-BMP). An oral formulation (orBec; DOR BioPharma), consisting of a gastric release and an enteric-coated pill, was studied in patients with acute gastrointestinal graft-versus-host disease, an inflammatory disorder that is common after allogeneic hematopoietic cell transplantation. Randomized trials demonstrated that orBec is safe and effective in treating acute gastrointestinal graft-versus-host disease (GVHD) when used with a short induction course of prednisone, reducing the risk of GVHD treatment failure by > 60% and reducing mortality 1 year after randomization by 45%, with fewer deaths due to infection and recurrent malignancy. The type of conditioning and the type of donor had no effect on the frequency of GVHD treatment failure during the 80-day study period; the greatest benefit in terms of survival was among patients who had received reduced-intensity conditioning therapy and among those who received a graft from other than a human leukocyte antigen-matched sibling. orBec controls the intestinal inflammatory process of GVHD and avoids prolonged exposure to prednisone, which is the present standard of care. Oral BDP is the only therapy to be studied in the last 30 years to effectively treat acute GVHD and reduce mortality.

Topics: Animals; Anti-Inflammatory Agents; Beclomethasone; Clinical Trials as Topic; Gastrointestinal Tract; Glucocorticoids; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Transplantation, Homologous

We examined the therapeutic strategies for treating mild gastrointestinal (GI) graft-versus-host disease (GVHD) using oral beclomethasone dipropionate (BDP) in 15 Japanese patients based on the donor source. The primary objective was to determine the efficacy and toxicity of oral BDP combined with/without low-dose prednisone (PSL).. Oral BDP was administered with 1 mg/kg/d of PSL in patients undergoing bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT; n=11), and the dose of PSL was tapered off after 22 days. Oral BDP alone was administered in patients undergoing cord blood stem cell transplantation (CBSCT; n=4). The primary endpoint was the rate of treatment success on day 49, as measured according to the improvement or complete resolution of GI symptoms without additional treatment. The secondary endpoints included treatment-related toxicity according to the National Cancer Institute Common Toxicity Criteria version 3.0, the rate of treatment discontinuation due to toxicity, the rate of relapse of acute GVHD by day 100 and the incidence of bacterial, fungal or viral infection, including cytomegalovirus (CMV) antigenemia.. Treatment success was achieved in seven of the 11 (64%) patients undergoing BMT or PBSCT and in all four patients (100%) undergoing CBSCT. Subsequent adverse events included herpes zoster infection, catheter-associated sepsis and CMV enteritis; all affected patients responded well to treatment.. The use of a risk-stratified treatment strategy with oral BDP depending on the stem cell source is effective in patients with mild GI-GVHD.

Topics: Adult; Aged; Beclomethasone; Bone Marrow Transplantation; Cord Blood Stem Cell Transplantation; Drug Therapy, Combination; Female; Gastrointestinal Diseases; Glucocorticoids; Graft vs Host Disease; Humans; Japan; Male; Middle Aged; Peripheral Blood Stem Cell Transplantation; Prednisone; Treatment Outcome

Results from two randomized trials have shown that oral beclomethasone dipropionate (BDP) is effective for treatment of acute gastrointestinal graft-versus-host disease. Here, we report results of a double-blind, randomized placebo-controlled phase II study designed to test the hypothesis that acute graft-versus-host disease could be prevented by administration of oral BDP, beginning before hematopoietic cell transplantation and continuing until day 75 after hematopoietic cell transplantation after myeloablative conditioning. Study drug (BDP or placebo) was administered as 1-mg immediate-release formulation plus 1-mg delayed-release formulation orally four times daily. According to the primary endpoint, systemic glucocorticoid treatment for graft-versus-host disease was given to 60 of the 92 participants (65%) in the BDP arm, versus 31 of 46 participants (67%) in the placebo arm. The secondary efficacy endpoints showed no statistically significant differences between the two arms. The proportion of participants who took at least 90% of the prescribed study drug during the first 4 weeks after hematopoietic cell transplantation was 54% overall. Lower severity of mucositis strongly correlated with higher adherence to the schedule of study drug administration. Inconsistent adherence related to mucositis during recovery after myeloablative conditioning may have obscured a beneficial therapeutic effect in the current study.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Antineoplastic Agents; Beclomethasone; Child; Double-Blind Method; Drug Administration Schedule; Female; Gastrointestinal Tract; Glucocorticoids; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Male; Middle Aged; Mucositis; Myelodysplastic Syndromes; Patient Compliance; Placebos; Transplantation, Homologous

Early non-infectious pulmonary complications represent a significant cause of mortality after hematopoietic cell transplantation (HCT). We tested the hypothesis that oral beclomethasone dipropionate (BDP) is effective for preventing early non-infectious pulmonary complications after allogeneic HCT. We retrospectively reviewed the medical records of 120 patients, 60 in each treatment arm, to identify non-infectious and infectious pulmonary events and pulmonary function test results from all patients who participated in two randomized trials of oral BDP for treatment of acute gastrointestinal GVHD. 17-Beclomethasone monopropionate (17-BMP), the active metabolite of BDP, was evaluated in blood from the right atrium in four patients. Thirty-three of 42 (79%) placebo-treated patients experienced a decrease of the DL(CO) from pretransplant to day 80 after transplant, compared with 27 of 49 (55%) BDP-treated patients (P=0.02). In the first 200 days after randomization, there were no cases of non-infectious pulmonary complications in BDP-treated patients, vs four cases among placebo-treated patients (P=0.04). Levels of 17-BMP were detected in atrial blood at steady state. Delivery of a potent glucocorticoid such as 17-BMP to the pulmonary artery after oral dosing of BDP may be useful in modulating pulmonary inflammation and preventing the development of non-infectious pulmonary complications after allogeneic HCT.

Topics: Adolescent; Aged; Beclomethasone; Child; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lung Diseases; Lung Diseases, Fungal; Male; Middle Aged; Respiratory Function Tests

In this study, we investigated the level of gut absorption following oral beclomethasone dipropionate (BDP) administration by measuring the blood concentration of its metabolites measured by LC-MS/MS using the HPLC method. Five patients who were administered BDP orally for gut GVHD were included. The blood concentrations of beclomethasone-17-monopropionate (17BMP), which is one of the active metabolites of BDP, were 618 approximately 1, 749 pg/mL in 4 of the studied 5 patients, which was comparable to that after inhalation of BDP; however, it was relatively higher in one patient (2,439+/-161 pg/mL). As the blood concentration of 17BMP in this study patient was higher compared with healthy volunteers administered a single oral BDP 4 mg, GVHD patients might have a higher concentration than healthy volunteers. Given that a higher grade of gut GVHD was associated with a higher blood level of 17BMP, BDP absorption might be associated with gut mucosal injury. Thus, the systemic adverse effect following oral BDP administration might not be negligible especially in gut GVHD patients.

Topics: Administration, Oral; Adult; Aged; Anti-Inflammatory Agents; Beclomethasone; Female; Graft vs Host Disease; Humans; Intestinal Absorption; Intestinal Diseases; Male; Middle Aged

The most common approach for the treatment of chronic graft-versus-host disease (cGVHD) has been the long-term use of systemic steroids. Beclomethasone dipropionate (BDP) is a topically active corticosteroid with relatively low absorption from the gastrointestinal mucosa. It has been successfully used to treat acute GVHD (aGVHD), but its use in the cGVHD setting is far more limited. In the current study, BDP was administered to 33 patients who underwent allogeneic transplantation and had biopsy-proven gastrointestinal cGVHD (GI cGVHD). Twenty-six patients with GI cGVHD received BDP as first-line and 7 as either second- or third-line treatment. All patients received BDP together with a calcineurin inhibitor, except for 1 patient who was also receiving mycophenolate mofetil (MMF). BDP was administered for a minimum of 16 weeks and was tapered during 4 additional weeks. Of those patients receiving BDP as the first line of treatment, 22 (84.6%) achieved complete remission (CR) of GI cGVHD, 2 (7.7%) achieved a partial response (PR) and 2 (7.7%) did not respond or progressed. Median time to response was 28 days. Nevertheless, only 7 (27%) patients had maintained the response at last follow-up, whereas 19 (73%) finally relapsed or progressed. Median time to relapse was 147 days after the end of BDP. In the case of the patients who received BDP as a second- or third-line treatment, 3 (42.9%) achieved CR and 2 (28.6%) PR. For the whole series of patients, 13 patients (39.4%) were not receiving immunosuppressive treatment at final follow-up. Only 4 patients developed cytomegalovirus (CMV) reactivation, which was successfully treated with antiviral drugs. No fungal infection was observed during the treatment period. In conclusion, the current study shows that BDP, in the absence of systemic steroids, is a highly effective initial therapeutic approach for GI cGVHD, which helps to avoid complications related to systemic steroids.

Topics: Adolescent; Adult; Anti-Inflammatory Agents; Beclomethasone; Biopsy; Chronic Disease; Female; Follow-Up Studies; Gastrointestinal Diseases; Graft vs Host Disease; Hematologic Neoplasms; Humans; Male; Middle Aged; Mycophenolic Acid; Peripheral Blood Stem Cell Transplantation; Transplantation, Homologous

We tested the hypothesis that oral beclomethasone dipropionate (BDP) would control gastrointestinal graft-versus-host disease (GVHD) in patients with anorexia, vomiting, and diarrhea. Patients were randomized to prednisone for 10 days and either oral BDP 8 mg/d (n = 62) or placebo (n = 67) tablets for 50 days. At study day 10, prednisone was rapidly tapered while continuing study drug. On an intent-to-treat basis, the risk of GVHD-treatment failure was reduced for the BDP group at study day 50 (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.35-1.13) and at 30 days follow-up (HR 0.55, 95% CI 0.32-0.93). Among patients eligible for prednisone taper at study day 10, the risk of GVHD-treatment failure was significantly reduced at both study days 50 and 80 (HR 0.39 and 0.38, respectively). By day 200 after transplantation, 5 patients randomized to BDP had died compared with 16 deaths on placebo, a 67% reduction in the hazard of mortality (HR 0.33, P = .03). In 47 recipients of unrelated and HLA-mismatched stem cells, mortality at transplantation day 200 was reduced by 91% in the BDP group compared with placebo (HR 0.09, P = .02). The survival benefit was durable to 1 year after randomization. Oral BDP prevents relapses of gastrointestinal GVHD following tapering of prednisone; survival is statistically significantly better among patients receiving BDP.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anti-Inflammatory Agents; Beclomethasone; Child; Female; Gastrointestinal Diseases; Graft vs Host Disease; Humans; Male; Middle Aged; Placebos; Prednisone; Survival Analysis; Treatment Outcome

Acute graft-versus-host disease (aGVHD) remains one of the most severe complications after allogeneic transplantation; in particular, the presence of gut involvement has been related to increased mortality and poorer response. The use of systemic steroids remains the standard for first-line treatment despite its severe secondary effects. Beclomethasone dipropionate (BDP) is a topically active corticosteroid with low absorption, thereby avoiding many of the deleterious side effects associated with systemic steroids. In the present study we analyzed the efficacy of BDP in a series of 26 patients who were diagnosed with grade 1 and 2 gastrointestinal aGVHD. Twenty patients (77%) responded to BDP treatment, 17 (65.5%) reached complete remission (CR), and 3 (11.5%) showed partial response. Among those patients who reached CR, 5 relapsed, although 1 of them reached second CR after a second course of BDP; therefore, 13 (50%) of the 26 patients did not require systemic steroids to treat gastrointestinal aGVHD. CR rates in those showing gastrointestinal symptoms were 68% for patients with persistent nausea, 50% for those with vomiting, and 54% for those with diarrhea (P=.2). No patient included in the study developed any symptom related to adrenal axis suppression. Thirteen patients (50%) developed >or=1 infectious episode during the first 100 days after transplantation. Transplant-related mortality was 0% at 100 days, and overall transplant-related mortality was 30%, with only 2 patients dying due to infectious complications. Therefore, our study shows that monotherapy with oral BDP is an effective initial therapeutic approach for mild to moderate intestinal GVHD, which avoids complications related to systemic steroids.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anti-Inflammatory Agents; Beclomethasone; Disease-Free Survival; Female; Gastrointestinal Diseases; Graft vs Host Disease; Hematologic Neoplasms; Humans; Male; Middle Aged; Time Factors

Treatment of severe acute and chronic gastrointestinal (GI) graft-versus-host disease (GVHD) with prolonged high-dose systemic corticosteroids has limited success and considerable toxicity. Beclomethasone dipropionate (BDP) is a potent topically active steroid. We treated 15 patients with acute (n = 2) or chronic (n = 13) GI GVHD refractory to systemic corticosteroids with 28-day courses of oral BDP (2 mg 4 times daily). Response was measured by the change in GI score (sum of 6 GI symptoms) as well as the ability to taper or discontinue systemic corticosteroids. Nine (60%) of 15 evaluable patients responded to BDP, including 3 complete responses (a GI score of 0 or 1 and discontinuation of systemic corticosteroids). Attempts to taper calcineurin inhibitor during BDP therapy were unsuccessful. The 2 patients with acute GVHD had no response to BDP. Responders received a median of 3 cycles (range, 1-20), compared with 1 cycle (range, 1-5) in nonresponders. Suppression of the hypothalamic-adrenal axis was seen in 2 of the 5 patients tested, but neither demonstrated clinically significant symptoms. We conclude that BDP is safe and effective for long-term treatment of chronic GI GVHD. Multiple courses may be necessary to achieve or maintain response in some patients, and prolonged BDP therapy is a feasible alternative to prolonged systemic corticosteroids.

Topics: Administration, Oral; Adolescent; Adult; Anti-Inflammatory Agents; Beclomethasone; Child; Child, Preschool; Drug Evaluation; Female; Gastrointestinal Diseases; Graft vs Host Disease; Hematologic Diseases; Humans; Male; Middle Aged; Stem Cell Transplantation; Time

Beclomethasone dipropionate (BDP), a topically active steroid, seemed to be an effective treatment for intestinal graft-versus-host disease (GVHD) in a phase I study. The aim of this study was to compare the effectiveness of oral BDP to that of placebo capsules in treatment of intestinal GVHD.. Sixty patients with anorexia and poor oral intake because of intestinal GVHD were randomized to receive prednisone (1 mg.kg-1.day-1) plus either oral BDP (8 mg/day) or placebo capsules. Initial responders who were eating at least 70% of caloric needs at evaluation on day 10 continued to take study capsules for an additional 20 days while the prednisone dose was rapidly tapered. The primary end point was the frequency of a durable treatment response at day 30 of treatment.. The initial treatment response at day 10 was 22 of 31 (71%) in the BDP/prednisone group vs. 16 of 29 (55%) for the placebo/prednisone group. The durable treatment response at day 30 was 22 of 31 (71%) vs. 12 of 29 (41%), respectively (P = 0.02).. The combination of oral BDP capsules and prednisone was more effective than prednisone alone in treating intestinal GVHD. Oral BDP allowed prednisone doses to be rapidly tapered without recurrent intestinal symptoms.

Topics: Administration, Oral; Adult; Aged; Beclomethasone; Female; Graft vs Host Disease; Humans; Inflammatory Bowel Diseases; Male; Middle Aged; Prednisone

Intestinal graft-versus-host disease (GVHD) causes anorexia, vomiting, abdominal pain, and diarrhea. We investigated oral beclomethasone dipropionate (BDP), a potent, topically active corticosteroid, as therapy for this disease. Forty-two allogeneic marrow-graft recipients with biopsy-proven intestinal graft-versus-host disease of mild-to-moderate severity received BDP (8 mg daily) for up to 28 days. Weekly symptom scores, oral intake, and surveillance throat and stool cultures were compared with baseline values. Adrenal testing was performed serially in patients not receiving concurrent prednisone. Improvement was seen in appetite (P < 0.001), oral intake (P < 0.001), nausea (P = 0.013), and diarrhea (P = 0.02) over the course of therapy, and an overall beneficial response was observed in 72% of 40 evaluable patients. Surveillance cultures of throat and stool showed no increase in bacterial or fungal colonization over time. The adrenal axis became suppressed in 11 of 20 evaluable patients (55%) but suppression was not a prerequisite for clinical response, as 6 of 9 patients who retained normal adrenal function improved clinically. We conclude that oral BDP is a safe and effective treatment for mild-to-moderate intestinal graft-versus-host disease. Systemic absorption probably occurs, but adrenal suppression is not a prerequisite for clinical efficacy, suggesting that the biological effect is primarily topical. BDP should be further investigated as a topical therapy for intestinal GVHD.

Topics: Administration, Oral; Adrenocorticotropic Hormone; Anti-Inflammatory Agents; Beclomethasone; Graft vs Host Disease; Humans; Hydrocortisone; Immunosuppressive Agents; Intestinal Diseases; Patient Compliance; Prednisone

The gastrointestinal (GI) tract is a common target organ of graft-vs-host disease (GVHD) in hematopoietic stem cell transplantation (HSCT) patients, and GI tract GVHD is often resistant to standard treatments such as corticosteroids. Moreover, longterm use of systemic corticosteroids sometimes induces adverse events such as infection. Beclomethasone dipropionate (BDP) is a potent, topically active corticosteroid, which is metabolized to an active derivative in the intestinal mucosa. Oral BDP therapy is reportedly effective against GI tract GVHD in adult HSCT patients, but its efficacy and safety in pediatric patients remain undefined. Here, we report three pediatric and young adult cases who were treated with oral BDP.. Three (6-, 7-, and 18-year-old) patients developed stage 2 to 4 lower GI tract GVHD, which was resistant to standard immunosuppressive therapies.. Lower GI tract GVHD in these patients was histopathologically proven by endoscopic biopsy.. Oral administration of enteric-coated capsules of BDP (3-8 mg/day) was started for the treatment of lower GI tract GVHD.. With the introduction of oral BDP therapy, their GI tract symptoms promptly resolved (abdominal pain, within 3-7 days; diarrhea, within 2-3 weeks). Subsequently, systemic immunosuppressive agents such as corticosteroids and mycophenolate mofetil were successfully tapered off. During oral BDP therapy, although cytomegalovirus antigenemia and Acinetobacter Iwoffii sepsis developed in 2 cases, both were curable with conventional treatments. In a young adult case, concomitant BK virus-associated hemorrhagic cystitis resolved after oral BDP was introduced and systemic immunosuppressive agents were reduced. Transient growth restriction was observed in a pediatric case who was treated with oral BDP for approximately 300days.. Our experiences suggest that oral BDP therapy is an effective approach for GI tract GVHD that is resistant to standard immunosuppressive therapies. Of clinical importance, our case suggests the possibility that oral BDP therapy may improve the immunosuppressive condition in GI tract GVHD patients by contributing to the reduction of systemic immunosuppressive medications as a result of prompt improvement of GI tract GVHD symptoms.

Topics: Beclomethasone; Child; Gastrointestinal Diseases; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Young Adult

Topics: Abdomen; Adrenoleukodystrophy; Beclomethasone; Child; Glucocorticoids; Graft vs Host Disease; Humans; Intestinal Diseases; Male; Nitriles; Pyrazoles; Pyrimidines; Stem Cell Transplantation; Ultrasonography; Ultrasonography, Doppler, Color

Systemic glucocorticoids remain the standard treatment for gastrointestinal (GI) acute graft-versus-host disease (aGVHD) despite their toxicity and incomplete efficacy. Controlled trials have tested poorly absorbable steroids as adjuncts with systemic glucocorticoids, but only small case series have reported treatment with poorly absorbed beclomethasone dipropionate (BDP) and budesonide (BUD) alone. Our team has adopted the practice of administering BDP or BDP+BUD without systemic glucocorticoids as first-line therapy for isolated upper GI (UGI) aGVHD. We report results in 76 patients treated with BDP alone and in 81 patients treated with BDP+BUD, with allocation by physician choice. Almost all patients received peripheral blood stem cells (92%) from a fully HLA-matched related or unrelated donor (80%) after myeloablative conditioning (76%) for acute leukemia (49%), myelodysplastic syndrome (17%), non-Hodgkin lymphoma (14%), or another hematopoietic disorders (20%). After 28 days of treatment with BDP, 46% of the patients had a complete response (CR) and 10% had a partial response (PR); after 200 days, 61 (80%) patients were alive, 34% maintained a CR, and 3% maintained a PR, whereas 53% required additional immunosuppression (IS). After 28 days of treatment with BDP+BUD, 67% had a CR and 10% a PR; after 200 days, 74 (91%) patients were alive, 46% maintained a CR, and 2% maintained a PR, whereas 43% required additional IS. Among the entire cohort of 157 patients, 66 (42%) were treated successfully without systemic glucocorticoids. This study reports the efficacy of poorly absorbable steroids alone for patients with isolated UGI aGVHD. Prospective trials should test for the potential advantages of BDP and BUD use over systemic glucocorticoids.

Topics: Adult; Aged; Anti-Inflammatory Agents; Beclomethasone; Budesonide; Female; Graft vs Host Disease; Humans; Male; Middle Aged; Prospective Studies

Many drugs are used for unapproved indications in Japan for post hematopoietic stem cell transplant (HCT) complications. To investigate unapproved or off-label drug usage for graft-versus-host disease (GVHD) and virus infections after allogeneic HCT, we analyzed the data of Japanese HCT registry. Between 2006 and 2017, 39,941 adults and children received HCT for a variety of disease and their transplant data were captured in the registry. Among them, 14,687 and 8914 patients receiving treatment for acute and/or chronic GVHD, 24,828 patients with cytomegalovirus (CMV) infection or receiving therapies for CMV, and 4943 who received treatment for other viral infections were included in the analyses of off-label or unapproved drugs. For GVHD, mycophenolate mofetil was the most frequently used off-label drug, followed by beclomethasone, infliximab, and etanercept. For viral infections other than CMV, foscarnet was the most frequently used off-label drug. Cidofovir, which is not approved for use in Japan, was mainly used for adenovirus infection. This study demonstrated that numerous off-label and unapproved drugs have been used as key drugs for GVHD and post-transplant viral infection, and the real world date in the transplant registry may serve as an important asset to regulatory purposes.

Topics: Acute Disease; Adult; Beclomethasone; Chronic Disease; Cidofovir; Cytomegalovirus Infections; Etanercept; Female; Foscarnet; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infliximab; Japan; Male; Middle Aged; Mycophenolic Acid; Off-Label Use; Postoperative Complications; Registries; Transplantation, Homologous; Virus Diseases

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Allografts; Anti-Inflammatory Agents; Beclomethasone; Cord Blood Stem Cell Transplantation; Female; Gastrointestinal Diseases; Graft vs Host Disease; Hematologic Neoplasms; Humans; Male; Middle Aged

Graft-versus-host disease (GVHD) is a major concern in transplantation patients. Gut GVHD is accompanied by diarrhea, abdominal pain, and/or melena. Although oral treatment with corticosteroids (CSs) is effective in treating gut GVHD, it can cause adverse reactions that affect the entire body. Topical administration of CSs can be effective in treating diseases in which lesions are limited locally, because adverse reactions can then be alleviated. In this study, we examine and discuss an enteric-coated beclomethasone dipropionate (BDP) capsule (BDP-EC) formulated at Okayama University Hospital. The BDP-EC did not dissolve in solution 1 (pH1.2), and began disintegrating in solution 2 (pH6.8) after 5min, with a mean dissolution rate at 15min of 85%. We then used the capsule to treat a patient who developed gut GVHD after allogeneic hematopoietic stem cell transplantation. Clinically, the frequency of diarrhea decreased after BDP-EC administration. In addition, we were able to decrease the prednisolone equivalent dose. Symptoms associated with adverse reactions to BDP were not observed during the hospitalization period. These findings suggest that the administration of BDP-EC in the early stages of gut GVHD may allow a reduction in the initial doses of systemic CSs.

Topics: Aged; Beclomethasone; Capsules; Glucocorticoids; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Intestinal Diseases; Leukemia-Lymphoma, Adult T-Cell; Male; Tablets, Enteric-Coated; Transplantation, Homologous

Topics: Anti-Inflammatory Agents; Beclomethasone; Biopsy; Budesonide; Calcinosis; Colonic Diseases; Endoscopy, Digestive System; Female; Gastric Mucosa; Graft vs Host Disease; Humans; Middle Aged; Stem Cell Transplantation

Acute graft-versus-host disease (GVHD) is one of the most severe complications following allogeneic transplantation and the involvement of the gut has been associated with increased mortality and a poorer response to transplant. The use of systemic corticosteroids remains the standard first-line treatment, despite their severe secondary effects.. Beclometasone dipropionate (BDP) is a topically active corticosteroid with low absorption into the systemic circulation, which minimises many of the deleterious side effects associated with systemic corticosteroids.. Phase II and III trials evaluating the efficacy of BDP were reviewed. In the Phase II trials, 77% of patients with gastrointestinal GVHD who received BDP as a single agent responded and 50% did not require systemic corticosteroids, thus avoiding prolonged exposure to prednisone. Randomised trials demonstrated that BDP is safe and effective in treating acute gastrointestinal GVHD when used with a short induction course of prednisone, reducing the risk of GVHD treatment failure by > 60% and reducing mortality one year after randomisation by 45%.. These results provide a particularly strong rationale for the incorporation of steroid-sparing regimens such as oral BDP in acute GVHD treatment.

Topics: Adrenal Cortex Hormones; Beclomethasone; Clinical Trials as Topic; Drug Tolerance; Drug-Related Side Effects and Adverse Reactions; Gastrointestinal Tract; Graft vs Host Disease; Humans

Topics: Acute Disease; Administration, Oral; Adult; Aged; Beclomethasone; Cord Blood Stem Cell Transplantation; Feasibility Studies; Female; Gastrointestinal Diseases; Graft vs Host Disease; Humans; Male; Middle Aged; Treatment Outcome

Topics: Adolescent; Anti-Inflammatory Agents, Non-Steroidal; Beclomethasone; Child; Female; Graft Rejection; Graft vs Host Disease; Humans; Intestine, Small; Male; Transplantation, Homologous; Treatment Outcome

Topics: Beclomethasone; Drug Therapy, Combination; Graft vs Host Disease; Humans; Inflammatory Bowel Diseases