Treatment Of Acute Graft-versus-host Disease Research Articles

Use of mycophenolate mofetil in patients received allogeneic hematopoietic stem cell transplantation in Japan

We evaluated the use of mycophenolate mofetil (MMF) after hematopoietic stem cell transplantation (HSCT) in Japan from 1999 to 2008. MMF was administered to 301 patients, including 157 for the prevention of graft-versus-host disease (GVHD), 94 for the treatment of acute GVHD and 50 for the treatment of chronic GVHD. The three most common doses were 500mg twice daily, 250mg three times daily and 1,000mg twice daily, given to 63, 54 and 45 patients, respectively. The incidence of grade II-IV acute GVHD was 30.0% and grade III-IV was 20.0% in the GVHD prevention group. Among treated patients, disappearance or improvement of subjective symptoms occurred in 57.0% of acute GVHD patients and in 52.0% of chronic GVHD patients. With regard to safety, the following major adverse events (grade 3 or more) were recorded: 31 infections, 31 neutropenia, 28 thrombocytopenia, 25 diarrhea and 1 renal disorder. A total of 116 patients developed grade 3 or 4 adverse events, but 79 were successfully treated with supportive treatment. Thus, our findings suggest that MMF is safe and effective for the prevention and treatment of GVHD in patients who have received an allogeneic stem cell transplant.

Prophylaxis and Treatment of Graft Versus Host Disease After Allogeneic Stem Cell Transplantation: A Survey on Center Strategies by the European Group for Blood and Marrow Transplantation (EBMT)

AbstractAbstract 1261Allogeneic stem cell transplantation is a poorly standardized treatment. Reported outcomes vary markedly, partly due to differences in treatment procedures. The EBMT performed a survey among its member centers about their present strategies in preventing and treating graft versus host disease (GvHD). Seventy-three centers from 23 countries participated in this survey. The main prophylactic regimens used in transplantations with myeloablative conditioning were cyclosporine (CsA) + methotrexate (MTX) in 83%, CsA + mycophenolate mofetil (MMF) in 14 %, tacrolimus (tacro) + MTX in 6%, CsA alone in 8%, and tacro alone, tacro + MMF and ex vivo T-cell depletion (TCD) in 1% of the centers. The administration of CsA was initiated on day -6 (1%), day -3 (13%), day -2 (7%), day -1 (78%) or day 0 (1%). CsA was initially given as short i.v. infusions in 56% (twice daily 91%), continuous infusion in 39% and orally in 5% of the centers. The initial CsA dose was most commonly 3 mg/kg/day (49%); 1–2,5 mg/kg/day was given in 16%, 4–6 mg/kg/day in 31%, and 10–12,5 mg/kg/day in 4% of the centers. Further doses were then usually adjusted according to CsA concentrations (88%), measured from whole blood (81%) or serum (19%). When measured from whole blood, the target CsA concentrations at 1 wk post-Tx ranged from 80 to 400 (mean 230) ng/ml, and at 2–4 wks and 2 mths the ranges (means) were 95–400 (210) and 60–350 (200) ng/ml, respectively. The typical duration of CsA prophylaxis was 60–100 (32%), 120–150 (10%), 180 (54%), or 210–365 (14%) days. In 56% of the centers the estimated risk of relapse affected the length of prophylaxis. MTX was given in the dose of 15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6, and +11 in 63% and without the last dose in 28% of the centers. There were 6 other variants. Leucovorin rescue was given in 43% of the centers with variable dose and timing. ATG was included in the prophylaxis for one or more subgroups (one center all patients) in 79%, alemtuzumab in 25%, corticosteroids in 10%, and TCD in 24% (one center all patients) of the centers. The main prophylactic regimens in reduced intensity transplantations (RIC) were CsA + MMF (67%), CsA + MTX (33%), CsA (23%), in vivo TCD (19%), tacro + MMF (10%), ex vivo TCD (3%), and tacro alone and tacro + MTX (1% each). ATG was used in some groups of patients in 73% of the centers. The development of chimerism affected the intensity of prophylaxis in 82% of the centers. All centers used corticosteroids as first line treatment of acute GvHD. The treatment was started at first signs likely to be caused by GvHD (17%) or for grade II or higher (83%). The decision to treat was based on clinical signs only in 70% of the centers while in 30% histological documentation was needed. The corticosteroid of choice was methylprednisolone (83%) or prednisolone (17%). The initial daily dose/kg was 1-1, 5 mg (19%), 2 mg (76%), 3 mg (6%), 5–10mg (3%), or 20 mg (1%), given in 1 (16%), 2 (69%), 3 (9%) or 4 (6%) doses, i.v. (79%) or orally (21%). The severity of aGvHD affected the initial dose in 53% and the organ manifestation in 27% of the centers. The dose per kg/day indicating corticosteroid resistance and need for second line treatment was 1mg (3%), 2 mg (72%), 4–5 mg (13%), or 10 mg or more (12%). The minimum time to confirm corticosteroid resistance was 2 (2%), 3 (11%), 4–5 (27%), 6–7 (44%), 10–14 (13%) or 21 (3%) days. The most widely used second line treatments were MMF (33%), anti-TNF antibodies (31%), other monoclonal antibodies (16%), ATG (27%), extracorporeal photopheresis (ECP, 14%), mesenchymal stem cells (7%), alemtuzumab (7%), pentostatin (5%) and “keep going with corticosteroids” (12%). The initial treatment for newly diagnosed chronic GvHD in patients with no ongoing immunosuppressive treatment was corticosteroid (57%), calcineurin inhibitor (CNI) + corticosteroid (38%), or CNI alone (10%). The minimum duration of first line treatment of chronic GvHD to allow the evaluation of efficacy was 2 wks or less (21%), 2–4 wks (12%), 1 mth (42%), 1,5-4 mths (21%), or 9–12 mths (4%). The most commonly used second line treatments were ECP (53%), MMF (36%), rituximab (12%), CNI (12%), mTOR inhibitors (9%), corticosteroids (8%), and tyrosine kinase inhibitors (6%). In conclusion, the present results show marked differences between centers in the prophylaxis and management of GvHD. These findings underline the need for standardization and prospective controlled studies in GvHD prevention and treatment. Disclosures:No relevant conflicts of interest to declare.

Organ-Specific Protection from CD8+ T Cell-Mediated Acute Skin GVHD by Bortezomib Administration Correlates with Decreased IL-6.

AbstractAbstract 3735We have previously demonstrated that while early administration of bortezomib after murine allogeneic bone marrow transplantation (allo-BMT) can prevent acute graft versus host disease (GVHD), delayed administration of bortezomib results in increased GVHD-dependent gastrointestinal toxicity (PNAS 2004, Blood 2005). This was primarily mediated by donor CD4+ T cells in fully MHC-mismatched allo-BMT (Blood 2008). In the current study, we assessed continuous bortezomib administration on CD8+ T cell-mediated acute GVHD. Using an MHC-matched, mHAg-mismatched model (C3.SW donor cells into lethally irradiated C57BL/6 recipients) in which acute GVHD is primarily induced by CD8+ T cells, we confirmed that significant skin and liver GVHD was observed after CD8+ T cell transfer. Histological evaluation of acute liver GVHD displayed severe lymphocyte infiltrates and severe subacute bile duct hepatitis consistent with hepatic GVHD. Severe acute skin GVHD was noted by persistent fur loss and skin ulcerations. Cutaneous histopathological assessment exhibited severe inflammatory infiltrates, epidermal hypertrophy, loss of hair follicles, satellite cell necrosis and dermal fibrosis. Notably, after allo-BMT, 6 weeks or thereafter, a significant increase in serum IL-6 levels was observed in the mice exhibiting marked skin damage, suggesting organ-specific correlation of higher serum IL-6 expression with acute cutaneous GVHD associated injury. We next investigated the effects of continuous treatment with bortezomib in this GVHD model. Surprisingly, we found that continuous bortezomib administration at the conventional dose of 0.75–1 mg/kg twice per week resulted in fractional GVHD- dependent lethal toxicity, exacerbating lymphocyte infiltration in liver, gut and lung as evidenced by pathological examination. However, skin GVHD pathology was markedly improved. Due to the limitations of conventional doses of bortezomib for treatment of acute GVHD, we then performed a low-dose bortezomib treatment at 0.125 mg/kg, twice per week. We found that mice receiving low-dose bortezomib were protected from lethal toxicity and displayed significant amelioration of skin GVHD pathology. Significant decreases in serum IL-6 levels were also consistently observed consistent with the amelioration of skin GVHD. Interestingly, while skin GVHD was markedly improved, there was no difference in liver, gut and lung pathology compared to control GVHD recipients indicating an organ-specific protection. These results demonstrate that continuous bortezomib can be applied in CD8+ T cell-mediated acute GVHD but necessitates lower dosing and organ-specific protection is observed. Disclosures:No relevant conflicts of interest to declare.

The best endpoint for acute GVHD treatment trials

AbstractThe optimal primary endpoint for acute graft-versus-host disease (GVHD) therapeutic trials has not been established. In a retrospective analysis, we examined the response of 864 patients who received prednisone 60 mg/m2/d for 14 days, followed by an 8-week taper, as initial therapy for acute GVHD from 1990-2007 at the University of Minnesota. Patients received grafts of human leukocyte antigen–matched sibling bone marrow (BM) or peripheral blood (PB; n = 315), partially matched sibling BM or PB (n = 24), unrelated donor BM or PB (n = 313), single (n = 89) or double (n = 123) umbilical cord blood. Day 28 responses were similar to day 56 responses and better than day 14 responses in predicting transplantation-related mortality (TRM). In multiple regression analysis, patients with no response at day 28 were 2.78 times (95% CI, 2.17-3.56 times; P < .001) more likely to experience TRM before 2 years than patients with a response. Other factors associated with significantly worse 2-year TRM include older age, high-risk disease, severe GVHD, and partially matched related BM/PB. No other differences in response by donor source were observed. These data suggest that day 28 is the best early endpoint for acute GVHD therapeutic trials in predicting 2-year TRM.

Mesenchymal stromal cells for steroid-refractory acute graft-versus-host disease: a report of two cases

Severe graft-versus-host disease (GVHD) is a lethal complication of allogeneic hematopoietic stem cell transplantation (HSCT). However, there have been only a few limited therapeutic options for the treatment of GVHD. Here we have reported two cases of the patients with acute steroid-refractory GVHD who underwent allogeneic HSCT. These patients received infusions of third-party clonal mesenchymal stem cells (cMSCs), which were isolated by a subfractionation culturing method (SCM) developed recently by our group, and showed marked improvement of the disease. MSCs represent a new potential therapeutic option in the treatment of steroid-refractory acute GVHD. They showed safety and improved clinical findings of the acute GVHD patients. However, further investigations are needed to understand the accurate mechanisms of MSCs and larger well-designed human clinical trials are necessary to prove further the safety and efficacy of the cMSCs for the treatment of acute GVHD patients.

Safety Profile and Clinical Outcomes in a Phase I, Placebo-Controlled Study of Siplizumab in Acute Graft-Versus-Host Disease

Acute graft-versus-host disease (GVHD) is a major complication of both bone marrow and hematologic stem cell allografts. T cells and natural killer (NK) cells have been linked to the development of GVHD. Modulation of these cells via the CD2 receptor may be a potentially important approach to the management of this disease. The safety profile and tolerability of siplizumab (MEDI-507), a humanized anti-CD2 IgG-1kappa monoclonal antibody, in the treatment of GVHD were evaluated in a phase I, double-blind, multiple-dose, placebo-controlled study. Thirty-four subjects with at least grade II acute GVHD were randomized to receive four doses of 0.012, 0.04, 0.12, or 0.4 mg/kg siplizumab or placebo intravenously every 3 days. Subjects received concurrent 2 mg/kg per day methylprednisolone for more than or equal to 10 days. No meaningful difference occurred between siplizumab and placebo groups in the incidence or severity of adverse events or laboratory test results. No increase in incidence of infection secondary to siplizumab treatment was observed. During 100 days postinitial infusion, a modest increase in resolution of GVHD, grade 0 (67% vs. 54%, P=0.0629), was reported for the siplizumab-treated group. Siplizumab administered with corticosteroid therapy for grade II or higher acute GVHD treatment exhibited an acceptable safety profile that would support further clinical development.

The Role of Oral Beclometasone Dipropionate in the Treatment of Gastrointestinal Graft-versus-Host Disease

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.

Infliximab treatment for steroid-refractory acute graft-versus-host disease after orthotopic liver transplantation: A case report

Acute graft-versus-host disease (GVHD) following orthotopic liver transplantation is a rare but severe disease with a 75% death rate in adults. Various therapeutic strategies have been proposed for steroid-refractory GVHD, but there is still no consensus. Tumor necrosis factor-alpha is a key inflammatory cytokine involved in acute GVHD physiopathology, and infliximab has shown encouraging results for the treatment of acute GVHD following hematopoietic stem cell transplantation. We report the first case of acute GVHD following liver transplantation that was refractory to steroids and anti-lymphocyte globulin but was successfully treated with infliximab.

Beclometasone dipropionate: a topically active corticosteroid for the treatment of gastrointestinal graft-versus-host disease

Background: 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. Objective: 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. Methods/results: 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%. Conclusion: These results provide a particularly strong rationale for the incorporation of steroid-sparing regimens such as oral BDP in acute GVHD treatment.

Murine bone marrow derived stromal progenitor cells fail to prevent or treat acute graft‐versus‐host disease

Human and murine stromal progenitor cells (SPCs) can suppress alloresponse in vitro, suggesting that SPCs may have clinical application toward prevention or treatment of graft-versus-host disease (GVHD). However, th eresults of in vivo studies have been conflicting. This study utilized an established murine model of acute GVHD to assess the ability of bone marrow derived murine SPCs (mSPCs) to prevent or treat GVHD. GVHD was established by transplantation of B6 bone marrow and spleen cells into lethally irradiated (900 cGy) B6 x BALB/c F(1) recipients. mSPCs were administered using various dose and timing protocols designed to either prevent or treat GVHD. After transplantation, mice were monitored daily for weight and survival. Differences in symptom severity were compared using a clinical GVHD scoring system. All GVHD control mice died of lethal GVHD. All groups treated with mSPCs for the prevention of GVHD went on to develop clinical GVHD with no alteration of the disease course or severity compared to controls. Administration of mSPC after the development of GVHD failed to improve the disease course. We conclude that in this model, the ability of SPCs to suppress alloresponse in vitro does not correlate with in vivo prevention or treatment of acute GVHD.

388: Primary Treatment and Prognosis of Acute Graft-versus-host Disease (GVHD): A Single-center Analysis of 458 Patients

Purpose and Methods: To clarify the optimal primary treatment for acute GVHD (aGVHD) and to identify prognostic factors that can predict outcome after aGVHD, we retrospectively reviewed the data of 458 patients (median age, 47 years: range, 1–68) with hematological malignancies who underwent allogeneic HCT between 2000 and 2006. Patients were conditioned with a reduced-intensity (n = 249) or myeloablative regimen (n = 209). Patients received BM (n = 168), G-CSF-mobilized PBSC (n = 256) or CB (n = 34) from either an HLA-matched relative (n = 214), a mismatched relative (n = 56) or an unrelated volunteer (n = 188). GVHD prophylaxis consisted of cyclosporine (n = 397) or tacrolimus (n = 61), with or without methotrexate. The median follow-up of surviving patients was 1379 days. Results: Grade I-IV aGVHD occurred in 242 patients, and the timing was before disease progression or relapse in 236 patients (grade I, n = 33; grade II, n = 126; grade III, n = 57; grade IV, n = 20). The incidence of nonrelapse mortality (NRM) in these 236 patients with aGVHD was 32% (grade I, 3%; grade II, 26%; grade III/IV, 53%). While 65 patients (28%) were followed without systemic corticosteroids (grade I, n = 28; grade II, n = 37), the remaining 171 patients (72%) received systemic corticosteroids as a primary treatment for aGVHD (mPSL equivalents ≥2 mg/kg/day, n = 35; 1 mg/kg/day, n = 103; 0.2–0.5 mg/kg/day, n = 33). Subsequently, 62 patients were treated with an increased dose of corticosteroids, and 25 required additional treatment. The 2-year NRM in 70 patients with grade II GVHD with skin involvement alone and 19 patients with upper-GI GVHD with or without skin involvement were 20% and 19%, respectively, although 36% and 79% of the patients were treated with ≤0.5 mg/kg/day of mPSL. While the 2-year NRM in 112 patients who had liver or lower-GI involvement was 50%, that in 124 patients who did not was 15% (p < 0.0001). In a multivariate analysis, liver or lower-GI involvement, GVHD onset within 14 days after HCT, older patient age, cyclosporine prophylaxis, and transplant from a donor other than an HLA-matched relative were associated with an increased risk for NRM after the development of aGVHD. Conclusions: The initial dose of systemic corticosteroids can be reduced safely when GVHD manifestation involves mainly the skin and upper GI. Although prospective studies are needed to confirm these findings, our study suggests that GVHD treatment can be tailored depending on ethnicity and transplantation procedures.

Primary Treatment for Acute Graft-Versus-Host Disease (GVHD): A Single-Center Analysis of 458 Japanese Patients.

Background: Although the systemic administration of corticosteroids (2 mg/kg/day of methylprednisone [mPSL]) is the mainstay of primary treatment for acute GVHD (aGVHD), GVHD remains a major cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT). In the era of reduced-intensity conditioning, lower-dose mPSL may be chosen in an attempt to retain a graft-versus-leukemia effect. However, it is not yet clear whether there is some permissible GVHD that can be treated with less systemic corticosteroids.Patients and Methods: To clarify the optimal primary treatment for aGVHD and to identify prognostic factors that can predict outcome after aGVHD, we retrospectively reviewed the data of 458 patients (median age, 47 years: range, 1–68) with hematological malignancies who underwent allogeneic HCT. Patients were conditioned with a reduced-intensity (n=249) or myeloablative regimen (n=209). Patients received BM (n=168), G-CSF-mobilized PBSC (n=256) or CB (n=34) from either an HLA-matched relative (n=214), a mismatched relative (n=56) or an unrelated volunteer (n=188). GVHD prophylaxis consisted of cyclosporine (n=397) or tacrolimus (n=61), with or without methotrexate. The median follow-up of surviving patients was 1379 days.Results: Grade I–IV aGVHD occurred in 242 patients, and the timing was before disease progression or relapse in 236 patients (grade I, n=33; grade II, n=126; grade III, n=57; grade IV, n=20). The incidence of NRM in these 236 patients with aGVHD was 32% (grade I, 3%; grade II, 26%; grade III/IV, 53%), and 65 patients (28%) were followed without systemic corticosteroids (grade I, n=28; grade II, n=37). The remaining 171 patients (72%) received systemic corticosteroids as a primary treatment for aGVHD (mPSL equivalents ≥2 mg/kg/day, n=35; 1 mg/kg/day, n=103; 0.2–0.5 mg/kg/day, n=33). Subsequently, 62 patients were treated with an increased dose of corticosteroids, and 25 required additional treatment including a switch to tacrolimus (n=15), MMF (n=10), or ATG (n=4). While the 2-year NRM in 150 patients who achieved a complete response of GVHD manifestations was 18%, that in 86 patients who did not was 54% (p<0.0001). The 2-year NRM was higher as the dose of systemic corticosteroids as primary treatment increased, i.e. 20% for ≤0.5 mg/kg/day, 35% for 1 mg/kg/day, and 51% for ≥2 mg/kg/day (p=0.0004). The 2-year NRM in 70 patients with grade II GVHD with skin involvement alone and 19 patients with upper-GI GVHD with or without skin involvement were 20% and 19%, respectively, although 36% and 79% of the patients were treated with ≤0.5 mg/kg/day of mPSL. While the 2-year NRM in 112 patients who had liver or lower-GI involvement was 50%, that in 124 patients who did not was 15% (p<0.0001). In a multivariate analysis, liver or lower-GI involvement, GVHD onset within 14 days after HCT, older patient age, cyclosporine prophylaxis, and transplant from a donor other than an HLA-matched relative were associated with an increased risk for NRM after the development of aGVHD.Conclusions: For Japanese patients who are known to be at low risk for aGVHD, the dose of systemic corticosteroids for primary treatment can be reduced safely when GVHD manifestation involves mainly the skin and upper GI. Although prospective studies are needed to confirm these findings, our study suggests that GVHD treatment can be tailored depending on ethnicity and transplantation procedures.

Anti-tumor necrosis factor-a for the treatment of steroid-refractory acute graft-versus-host disease

Allogeneic stem cell transplantation has been increasingly performed for a variety of hematologic diseases. Clinically significant acute graft-versus-host disease (GVHD) occurs in 9 to 50% of patients who receive allogeneic grafts, resulting in high morbidity and mortality. There is no standard therapy for patients with acute GVHD who do not respond to steroids. Studies have shown a possible benefit of anti-TNF-a (infliximab)for the treatment of acute GVHD. We report here on the outcomes of 10 recipients of related or unrelated stem cell transplants who received 10 mg/kg infliximab, iv, once weekly for a median of 3.5 doses (range: 1-6) for the treatment of severe acute GVHD and who were not responsive to standard therapy. All patients had acute GVHD grades II to IV (II = 2, III = 3, IV = 5). Overall, 9 patients responded and 1 patient had progressive disease. Among the responders, 3 had complete responses and 6 partial responses. All patients with cutaneous or gastrointestinal involvement responded, while only 2 of 6 patients with liver disease showed any response. None of the 10 patients had any kind of immediate toxicity. Four patients died, all of them with sepsis. Six patients are still alive after a median follow-up time of 544 days (92-600) after transplantation. Considering the severity of the cases and the bad prognosis associated with advanced acute GVHD, we find our results encouraging. Anti-TNF-a seems to be a useful agent for the treatment of acute GVHD.

Management of acute graft‐versus‐host disease

Acute graft-versus-host disease (GvHD) is a frequent complication of allogeneic haemopoietic stem cell transplantation (HSCT) and donor lymphocyte infusions (DLI). Its incidence and severity depends on several factors, such as prophylaxis method, donor/recipient matching, intensity of the conditioning regimen and composition of the graft. Significant progress has been made in recent years in understanding the pathogenesis of the disease, and some of these advances have been translated into clinical trials. First-line treatment of acute GvHD is based on corticosteroids, and produce sustained responses in 50-80% of patients depending on the initial severity. Non-responders are offered second-line therapy, with combinations of immunosuppressive agents, but 1-year survival is 30% in most large trials. New strategies explored include infusion of expanded mesenchymal stem cells (MSC), down regulation of antigen-presenting cells (APC) and suicide gene transduced T cells. Acute GvHD is complicated by severe immunodeficiency causing life-threatening infections. To date, GvHD has not been differentiated from the graft-versus-leukaemia effect. The present review will discuss some of these aspects.

Place des anticorps monoclonaux dans le traitement de la maladie aiguë du greffon contre l’hôte en 2006

Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice of hematologic malignancies. Acute graft versus host disease (GvHD) is common but important after HSCT, being directly related to graft versus leukemia effect. Recent experimental data indicate that acute GvHD develops in three phases: epithelial-cell injury caused by the conditioning regimen (Pre transplant phase); activation of donor T lymphocytes (T-cell activation phase); and the effector phase. Unfortunately, little progress has been done in the treatment of acute GvHD. The first line treatment is usually high-dose steroids for patients presenting more than grade II. However, 40% of those patients are resistant to this treatment. Other immunosuppressive treatments are then required, generally associated with limited efficacy and high morbidity. Several approaches using monoclonal antibodies against cytokines or other molecules involve in the physiopathology of acute GvHD have been used, especially for the treatment of steroid resistant acute GvHD. The aim of this review is first to remind the main characteristics of acute GvHD pathophysiology. In a second part, we present an updated overview of the mainly used monoclonal antibodies in the treatment of acute GvHD (anti-TNFalpha, anti-interleukin-2 receptor and anti-CD147).

Exposure-Effect Population Model of Inolimomab, a Monoclonal Antibody Administered in First-Line Treatment for Acute Graft-Versus-Host Disease

Inolimomab, a monoclonal antibody against interleukin (IL)-2Ralpha (CD25) has shown promising results in the treatment of corticosteroid-resistant acute graft-versus-host disease (GvHD). The objective of the present study was to characterise the pharmacokinetic and pharmacodynamic properties of inolimomab as first-line treatment in this condition. The data came from 21 patients with acute GvHD (8 with an International Bone Marrow Transplant Registry [IBMTR] score of B, 11 with a score of C and 2 with a score of D) following haematopoietic stem cell transplantation after a median delay of 26 days (range 10-127 days). Inolimomab was administered at 0.1, 0.2, 0.3 or 0.4 mg/kg daily in association with methylprednisolone (2 mg/kg) for 8 or 16 days depending on the status at day 9. Then, for responder patients, administrations were continued three times weekly until day 28. Inolimomab concentrations and pharmacodynamic data (acute GvHD scores) were recorded during the study. The pharmacodynamic data were assessed in four grades according to the IBMTR and Glucksberg classification in parallel with Karnofsky scores. A population analysis was developed using a nonlinear mixed-effects model to define the pharmacokinetic model, to test covariates and, when apparent, to model the exposure-effect relationship by a proportional odds model. The modelling was finally qualified by a predictive check. The best pharmacokinetic model was two-compartmental. For each score, the most demonstrative exposure-effect graphics linked the cumulative area under the concentration-time curve to cumulated probabilities of observing a specific score. This relationship was identified as a maximum effect model for the skin (with two patient subpopulations: sensitive/less sensitive) and a linear model for the intestinal tract and liver. No covariate was identified as influencing any of these parameters. Inolimomab exposure-effect relationships as first-line treatment for acute GvHD have been identified and modelled. The discovered dose-effect relationship allows confirmation of the treatment response, thereby establishing the first step towards optimising the inolimomab dosage in future trials.

Vasoactive Intestinal Polypeptide Induces Regulatory Dendritic Cells That Prevent Acute Graft Versus Host Disease and Leukemia Relapse after Bone Marrow Transplantation

Acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in patients undergoing allogeneic bone marrow transplantation (BMT) for the treatment of leukemia and other immunogenetic disorders. The use of tolerogenic dendritic cells (DCs) with potent immunoregulatory properties by inducing the generation/activation of regulatory T cells (Tr) for the treatment of acute GVHD following allogeneic BMT has been recently established. Here we report the use of the known immunosuppressive neuropeptide, vasoactive intestinal polypeptide (VIP), as a new approach to inducing tolerogenic DCs with the capacity to prevent acute GVHD. DCs differentiated with VIP impair allogeneic haplotype-specific responses of donor CD4+ T cells in transplanted mice by inducing the generation of Tr in the graft. Importantly, VIP-induced tolerogenic DCs did not abrogate the graft versus leukemia response, probably because they do not abrogate cytotoxicity of transplanted T cells against the leukemic cells. Therefore, the inclusion of VIP-induced tolerogenic DC in future therapeutic regimens may facilitate the successful transplantation from mismatched donors, reducing the deleterious consequences of acute GVHD, extending the applicability of BMT.

Vasoactive intestinal peptide induces regulatory dendritic cells that prevent acute graft-versus-host disease while maintaining the graft-versus-tumor response

Acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in patients undergoing allogeneic bone marrow transplantation (BMT) for the treatment of leukemia and other immunogenetic disorders. The use of tolerogenic dendritic cells (DCs) that induce the generation/activation of regulatory T (Tr) cells for the treatment of acute GVHD following allogeneic BMT has been recently established. Therefore, the identification of factors that contribute to the development of tolerogenic DCs is highly relevant. We report on the use of the known immunosuppressive neuropeptide, the vasoactive intestinal peptide (VIP), as a new approach to induce tolerogenic DCs with the capacity to prevent acute GVHD. DCs differentiated in the presence of VIP impair allogeneic haplotype-specific responses of donor CD4(+) cells in mice given transplants by inducing the generation of Tr cells in the graft. VIP-induced tolerogenic DCs did not abrogate the graft-versus-leukemia response presumably by not affecting the cytotoxicity of transplanted T cells against the leukemic cells. Therefore, the inclusion of VIP-induced tolerogenic DCs in future therapeutic regimens may minimize the dependence on nonspecific immunosuppressive drugs used currently as antirejection therapy, and facilitate the successful transplantation from mismatched donors, by reducing the deleterious consequences of acute GVHD and extending the applicability of BMT.

NK026680, a novel compound suppressive of dendritic cell function, ameliorates mortality in acute lethal graft-versus-host reaction in mice

A role for dendritic cells (DCs) has been emphasized in the onset of acute graft-versus-host disease (GVHD). We have made efforts to develop a new strategy for suppression of DC functions with a chemical compound in the treatment of acute GVHD. We here describe the immunological characterization of the new chemical compound NK026680. It was found that NK026680 significantly suppressed (1) expression of CD83, CD86, and major histocompatibility complex (MHC) class I and II antigens on human monocyte-derived DCs, (2) excretion of interleukin-12p40 on activation of monocyte-derived DCs, (3) allogeneic responses of human and mouse T cells and (4) mortality in mice with acute GVHD evoked across MHC class I or II. The beneficial effect of NK026680 administered orally was without any recognizable adverse effects. Early intervention in acute GVHD was required for this effect, indicating that an early event in acute GVHD is a critical target of NK026680. We propose the use of NK026680 as a prophylactic for acute GVHD.

Tacrolimus-Related Encephalopathy following Allogeneic Stem Cell Transplantation in Children

Tacrolimus is a potent immunosuppressive drug widely used to prevent and treat graft-versus-host disease (GVHD) in stem cell transplantation (SCT). Among 49 patients receiving tacrolimus who underwent SCT from January 2000 to July 2003, 10 patients (20%) developed encephalopathy. The commonly observed symptoms were convulsions and drowsiness, and most patients complained of signal symptoms such as headache, nausea, and cortical blindness before onset. The most common abnormality on neuroimages was high-intensity lesions in white matter on magnetic resonance imaging T2-weighted or fluid-attenuated inversion recovery images. At onset, all patients were receiving treatment for acute GVHD (grade II/III) or extensive chronic GVHD and demonstrated an abrupt increase in blood pressure from baseline levels. The serum tacrolimus concentration was generally within acceptable levels at onset. Symptoms gradually improved in all patients when the blood pressure was lowered with antihypertensive medication, regardless of continued tacrolimus administration following a short-term suspension. The pathogenesis of tacrolimus-related encephalopathy is multifactorial, although refractory GVHD and a sudden increase in blood pressure seem to be major predisposing factors. Because the withdrawal of tacrolimus or switching to less potent anti-GVHD agents usually worsens the GVHD, the administration of tacrolimus should be managed by closely monitoring serum levels and controlling blood pressure.