Prophylactic, diagnostic, and treatment strategies for acute graft-versus-host disease (aGVHD) may vary across medical centers and physicians. We aimed to investigate the relationship between center volume and the incidence and outcomes of aGVHD. This retrospective study included 28,786 patients who underwent their first hematopoietic stem cell transplantation (HSCT) (entire cohort) and 9498 patients who developed grade II-IV aGVHD (aGVHD cohort). Data were categorized into quartiles (very low, low, high, and very high) based on the number of HSCTs the treating center performed during the study period. We assessed the incidence of aGVHD using the entire cohort and overall survival (OS) using the aGVHD cohort. Higher center volume was associated with a higher incidence of grade II-IV aGVHD than very low center volume, with an adjusted hazard ratio of 1.07-1.11. Conversely, center volume was not associated with the incidence of grade III-IV aGVHD. OS after development of aGVHD was better in the higher center volume group than the very low-volume group, with an adjusted hazard ratio of 0.81-0.89. A very low-volume center was associated with a lower incidence of grade II-IV aGVHD in patients with allogeneic HSCT and poor survival in patients with aGVHD.

Cord blood transplantation (CBT) is associated with a high risk of cytomegalovirus (CMV) infection. Letermovir (LTV) is a prophylactic agent against CMV reactivation after CBT, but data on its effectiveness and the incidence of late CMV reactivation after LTV discontinuation are limited.

A single-center retrospective observational study was conducted in 79 adult CMV-seropositive CBT recipients who received their first transplant for acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome from February 2016 to September 2022. Outcomes were compared between 45 patients who received LTV prophylaxis and 34 patients who did not.

The cumulative incidence of CMV reactivation was significantly lower in patients who received LTV prophylaxis at both day 100 (11.1 % vs. 82.4 %, p < 0.001) and 1 year (45.3 % vs. 82.4 %, p < 0.001). The incidence of late CMV reactivation after LTV discontinuation was 34.2 %. The cumulative incidence of CMV disease was comparable between patients who received and those who did not (0 % vs. 8.8 % at day 100, 2.3 % vs. 8.8 % at 1 year; p = 0.181). Multivariate analysis showed that LTV prophylaxis reduced the cumulative incidence of CMV reactivation (hazard ratio 0.20, 95 % confidence interval 0.09 to 0.42, p < 0.001).

LTV prophylaxis is strongly associated with prevention of CMV reactivation after CBT. Due to the high incidence of late CMV reactivation, close monitoring is required after LTV discontinuation and extension of LTV prophylaxis beyond day 100 should be considered.

Acute Graft versus Host Disease (aGvHD) is a common immunological complication occurring in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Moreover, aGvHD is associated with a higher risk of infections and metabolic complications, affecting non-relapse mortality. Progress in transplantation has changed the prophylactic and therapeutic strategies of aGvHD and improved patient outcomes. The standard first-line therapy remains steroids, with a response rate of about 50%. The Janus Kinase 2 (JAK2) inhibitor, ruxolitinib, is an effective second-line therapy. The management of patients who developed a disease that is refractory to steroids and ruxolitinib, especially in the severe gastrointestinal forms of aGvHD, is not validated and remains an unmet medical need. In the article, we present the current clinical practice, as well as the latest advances targeting pathophysiological pathways of GvHD and gut microbiota, which may be a potential future of aGvHD therapy.

Survival analyses of novel agents with long-term responders often exhibit differential hazard rates over time. Such proportional hazards violations (PHV) may reduce the power of the log-rank test and lead to misinterpretation of trial results. We aimed to characterize the incidence and study attributes associated with PHVs in phase III oncology trials and assess the utility of restricted mean survival time and maximum combination test as additional analyses.

Clinicaltrials.gov and PubMed were searched to identify two-arm, randomized, phase III superiority-design cancer trials with time-to-event primary endpoints and published results through 2020. Patient-level data were reconstructed from published Kaplan-Meier curves. PHVs were assessed using Schoenfeld residuals.

Three hundred fifty-seven Kaplan-Meier comparisons across 341 trials were analyzed, encompassing 292,831 enrolled patients. PHVs were identified in 85/357 [23.8%; 95% confidence interval (CI), 19.7%, 28.5%] comparisons. In multivariable analysis, non-overall survival endpoints [OR, 2.16 (95% CI, 1.21, 3.87); P = 0.009] were associated with higher odds of PHVs, and immunotherapy comparisons [OR 1.94 (95% CI, 0.98, 3.86); P = 0.058] were weakly suggestive of higher odds of PHVs. Few trials with PHVs (25/85, 29.4%) prespecified a statistical plan to account for PHVs. Fourteen trials with PHVs exhibited discordant statistical signals with restricted mean survival time or maximum combination test, of which 10 (71%) reported negative results.

PHVs are common across therapy types, and attempts to account for PHVs in statistical design are lacking despite the potential for results exhibiting nonproportional hazards to be misinterpreted.

Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic haematopoietic stem-cell transplantation (HSCT). In the last 3 years, there has been regulatory approval of new drugs and considerable change in clinical approaches to prophylaxis and management of GVHD. To standardise treatment approaches, the European Society for Blood and Marrow Transplantation (EBMT) has updated its clinical practice recommendations. We formed a panel of one methodologist and 22 experts in the field of GVHD management. The selection was made on the basis of their role in GVHD management in Europe and their contributions to the field, such as publications, presentations at conferences, and other research. We applied the GRADE process to ten PICO (patient, intervention, comparator, and outcome) questions: evidence was searched for by the panel and graded for each crucial outcome. In two consensus meetings, we discussed the evidence and voted on the wording and strengths of recommendations. Key updates to the recommendations include: (1) primary use of ruxolitinib in steroid-refractory acute GVHD and steroid-refractory chronic GVHD as the new standard of care, (2) use of rabbit anti-T-cell (thymocyte) globulin or post-transplantation cyclophosphamide as standard GVHD prophylaxis in peripheral blood stem-cell transplantations from unrelated donors, and (3) the addition of belumosudil to the available treatment options for steroid-refractory chronic GVHD. The EBMT proposes to use these recommendations as the basis for routine management of GVHD during allogenic HSCT. The current recommendations favour European practice and do not necessarily represent global preferences.

Hematopoietic stem cell transplantation (HSCT) is an increasingly utilized therapy for malignant and non-malignant pediatric diseases. HSCT complications, including infection, organ dysfunction, and graft-versus-host-disease (GVHD) often require intensive care unit (ICU) therapies and are associated with mortality. Our aims were to identify the HSCT characteristics, complications and ICU therapies associated with (1) survival, and (2) survival changes over a ten-year period in a national dataset.

A national sample from the Health Facts (Cerner Corporation, Kansas City, MO) database from 2009 to 2018 was utilized. Inclusion criteria were age 30 days to <22 years and HSCT procedure code. For patients with >1 HSCT, the first was analyzed. Data included demographics, hospital length of stay (LOS), hospital outcome, transplant type and indication. HSCT complications included GVHD and infections. ICU therapies were positive pressure ventilation (PPV), vasoactive infusion, and dialysis. Primary outcome was survival to discharge. Statistical methods included bivariate analyses and multivariate logistic regression.

473 patients underwent HSCT with 93% survival. 62% were allogeneic (89% survival) and 38% were autologous (98% survival). GVHD occurred in 33% of allogeneic HSCT. Infections occurred in 26% of all HSCT. ICU therapies included PPV (11% of patients), vasoactive (25%), and dialysis (3%). Decreased survival was associated with allogeneic HSCT (p < 0.01), GVHD (p = 0.02), infection (p < 0.01), and ICU therapies (p < 0.01). Survival improved from 89% (2009-2013) to 96% (2014-2018) (p < 0.01). Allogeneic survival improved (82%-94%, p < 0.01) while autologous survival was unchanged. Survival improvement over time was associated with decreasing infections (33%-21%, p < 0.01) and increasing vasoactive infusions (20%-28%, p = 0.05). On multivariate analysis, later time period was associated with improved survival (p < 0.01, adjusted OR 4.28).

Hospital survival for HSCT improved from 89% to 96% from 2009 to 2018. Factors associated with mortality included allogeneic HSCT, GVHD, infections and ICU therapies. Improving survival coincided with decreasing infections and increasing vasoactive use.

Oral beclomethasone dipropionate (BDP) is known for its use as a therapeutic medicine for gastrointestinal graft-versus-host disease (GI-GVHD). Despite growing demand for oral BDP formulation, no commercial forms have yet been marketed. Therefore, at the Tokyo Metropolitan Cancer and Infectious Disease Centre Komagome Hospital, pharmacists prepare oral liquid forms of BDP for patients with upper GI-GVHD. This study aims to develop a new high performance liquid chromatography (HPLC) method for measuring BDP in the prepared formulations and assessing its quality.

We developed a new HPLC method for measuring BDP in prepared formulations validated according to international guidelines. Three types of formulations were prepared and analysed using the validated HPLC method. One contains 1 mg of BDP per 30 mL aqueous solution, and the others using ethanol for preparation contain 1 mg of BDP per 15 mL aqueous solution. For stability assessment, the BDP contents were assayed while formulations were stored in plastic bottles for 8 weeks under two different conditions of 25°C in bright light and 4°C in darkness. A content determination test was also conducted to assess the individual contents of BDP and lot-to-lot variation in dosage units.

A stability test demonstrated that the remaining BDP content after the storage period was greater than 90% of the initial content in almost all samples regardless of storage conditions. A content determination test showed thattwo new ethanol-containing formulations contained about 0.1 mg more BDP than the original ethanol-free formulation and it was close to the target BDP content of 1 mg. Furthermore, new formulations had less lot-to-lot BDP variation in dosage units than the original formulation.

A new HPLC method for measuring BDP in prepared formulations was developed and validated. The results of the stability test and content determination test indicated that the newly designed formulations were superior to the conventional formulation.

Acute gastrointestinal graft-versus-host disease (GVHD) is a common life-threatening complication after hematopoietic stem cell transplantation (HCT). We aimed to investigate outcomes according to the clinical, endoscopic, and histologic severity of gastrointestinal GVHD in pediatric patients treated with allogeneic HCT.

This retrospective cohort study included pediatric patients who underwent sufficient endoscopic and histopathologic evaluation for clinically suspected acute gastrointestinal GVHD between 2010 and 2020.

Fifty-one patients were included (male proportion, 68.6% [35/51]; median age at HCT, 6.4 years). When the patients were classified according to the histologic severity of gastrointestinal GVHD, the severe group had an earlier onset of GVHD symptoms and a higher proportion of patients with severe clinical gastrointestinal GVHD than the mild-to-moderate and "absent" groups. In Cox proportional hazards regression analysis, the groups with more severe clinical and histologic gastrointestinal GVHD showed a higher risk of non-relapse mortality (NRM). The 5-year overall survival (OS) rates were 58.3 and 36.4% in the mild-to-moderate and histologic gastrointestinal GVHD groups, respectively (p = 0.0384). Patients with higher clinical and histologic grades of gastrointestinal GVHD showed higher cumulative incidence of NRM.

Our results demonstrated that histologic severity of gastrointestinal GVHD is a relevant factor affecting OS and NRM, and patients with mild-to-moderate or severe histologic gastrointestinal GVHD have worse outcomes than patients without histologic GVHD. These findings support the importance of assessing the histologic grade in the diagnostic evaluation of patients with clinical gastrointestinal GVHD.

Acute graft-versus-host disease (GVHD) is a common immune complication that can occur after allogeneic haematopoietic cell transplantation (alloHCT). Acute GVHD is a major health problem in these patients, and is associated with high morbidity and mortality. Acute GVHD is caused by the recognition and the destruction of the recipient tissues and organs by the donor immune effector cells. This condition usually occurs within the first 3 months after alloHCT, but later onset is possible. Targeted organs include the skin, the lower and upper gastrointestinal tract and the liver. Diagnosis is mainly based on clinical examination, and complementary examinations are performed to exclude differential diagnoses. Preventive treatment for acute GVHD is administered to all patients who receive alloHCT, although it is not always effective. Steroids are used for first-line treatment, and the Janus kinase 2 (JAK2) inhibitor ruxolitinib is second-line treatment. No validated treatments are available for acute GVHD that is refractory to steroids and ruxolitinib, and therefore it remains an unmet medical need.

Acute graft-versus-host disease (GVHD) is a rare complication after solid organ transplantation (SOT) that carries high mortality. Caused by immunocompetent donor leukocytes within the transplanted organ, which become activated against recipient tissues, GVHD typically develops 2 to 12 weeks after SOT and can affect the skin, gastrointestinal tract, liver, and bone marrow. Signs and symptoms are nonspecific and include a rash, nausea, appetite loss, diarrhea, and cytopenias. Pancytopenia from marrow-directed GVHD is the primary driver of mortality. The diagnosis of GVHD is often delayed but should be confirmed by biopsy of an affected organ. Evidence of donor chimerism in blood or marrow supports the diagnosis. When GVHD is diagnosed we initiate treatment with systemic corticosteroids. At that time, if GVHD only involves skin or oral mucosa we also decrease maintenance immunosuppression levels to allow the recipient to reject the donor immune cells. For GVHD involving the marrow we initiate an allogeneic hematopoietic cell donor search early. In this article, we describe 3 cases of GVHD after SOT, outline our approach to diagnosis and management, and then provide analysis of the 3 instructive cases.

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.

We evaluated long-term outcome in 40 patients with MDS or AML, transplanted from related or unrelated donors following conditioning with targeted busulfan (Bu, over 4 days), fludarabine (Flu, 120 [n = 23] or 250 [n = 17] mg/m²) and thymoglobulin (THY). Compared to 95 patients conditioned with Bu/Cyclophosphamide (Cy) without THY, BuFluTHY-conditioned patients had lower rates of chronic graft-vs.-host disease (GVHD). Adjusted hazard ratios (HR) for BuFlu(120)THY and BuFlu(250)THY-conditioned patients were 1.60 (95% confidence interval (CI) 0.66-3.86) and 1.87 (0.68-5.11), respectively, for relapse; 0.77 (0.30-1.99) and 1.32 (0.54-3.23) for non-relapse mortality; 0.81 (0.42-1.57) and 1.38 (0.72-2.57) for overall mortality; and 0.78 (0.30-2.05) and 1.62 (0.63-4.41) for relapse or death (failure for relapse-free survival). At one year, 45% of BuFlu(120 or 250)THY-conditioned patients had mixed CD3+ chimerism compared to 0% with BuCy (p < 0.0001). None of 7 patients with long-term mixed chimerism had chronic GVHD; two relapsed, five remained stable mixed chimeras. THY is effective in reducing chronic GVHD, and long-term mixed T-cell chimerism can be compatible with relapse-free survival. However, Thy may also be associated with an increased risk of relapse and, dose-dependent, with non-relapse mortality.

We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.

Acute graft-versus-host disease (aGvHD) continues to be a leading cause of morbidity and mortality following allogeneic haematopoietic stem cell transplantation (HSCT). However, higher event-free survival (EFS) was observed in patients with acute lymphoblastic leukaemia (ALL) and grade II aGvHD vs. patients with no or grade I GvHD in the randomised, controlled, open-label, international, multicentre Phase III For Omitting Radiation Under Majority age (FORUM) trial. This finding suggests that moderate-severity aGvHD is associated with a graft-versus-leukaemia effect which protects against leukaemia recurrence. In order to optimise the benefits of HSCT for leukaemia patients, reduction of non-relapse mortality-which is predominantly caused by severe GvHD-is of utmost importance. Herein, we review contemporary prophylaxis and treatment options for aGvHD in children with ALL and the key challenges of aGvHD management, focusing on maintaining the graft-versus-leukaemia effect without increasing the severity of GvHD.

After more than 60 years of research in allogeneic hematopoietic cell transplantation (HCT), this therapy has advanced from one that was declared dead in the 1960s to a standard treatment of otherwise fatal malignant and non-malignant blood diseases. To date, close to 1.5 million hematopoietic cell transplants have been performed in more than 1,500 transplantation centers worldwide. This review will highlight the enormous efforts by numerous investigators throughout the world who have brought the experimental field of HCT to clinical reality, examine ongoing challenges, and provide insights for the future.

Skin rash is a first symptom of acute graft-versus-host disease (GvHD) after allogeneic stem cell transplantation (ASCT) but can also be caused by viruses. The relevance of virus DNA analyses in skin rash for diagnosis and clinical outcome is unknown.

To record the frequencies of detection of herpes and parvovirus B19 (ParvoB19) DNA in skin rash within 100 days after ASCT and to analyze their relevance for diagnosis, clinical course, and non-relapse mortality (NRM).

We retrospectively identified 55 patients with virus DNA analysis for CMV, EBV, HHV6, HHV8, HSV, VZV, or ParvoB19. We assessed the rate of virus DNA detection and studied associations with histological diagnosis, virus DNA from concomitantly analyzed blood, clinical presentation, exanthema treatment, and NRM.

CMV, EBV, HHV6, HHV8, HSV, VZV and ParvoB19 DNA were detected in 12.5, 11.8, 10, 0, 0, 2.9, and 26.7% of exanthemas. Histopathological diagnosis was not associated with virus polymerase chain reaction (PCR) results. Detection of CMV, EBV, or HHV6 DNA but not ParvoB19 in skin and blood was associated with PCR results (p = 0.016; p < 0.001; p = 0.067; p = n.a.). Detection of CMV, EBV, HHV6, or ParvoB19 DNA in the skin was not significantly associated with patient, ASCT, or GvHD characteristics. Detection of ParvoB19 but not herpes virus DNA was associated with less immunosuppressive treatment (p = 0.015) and lower NRM (p = 0.041). In multivariate analyses, detection of ParvoB19 was associated with a lower NRM.

Detection of ParvoB19 DNA in exanthema after ASCT might be associated with lower NRM.

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.

Steroid-resistant or steroid-refractory acute graft-versus-host disease (SR-aGVHD) poses one of the most vexing challenges faced by providers who care for patients after allogeneic hematopoietic cell transplantation. For the past 4 decades, research in the field has been driven by the premise that persistent graft-versus-host disease (GVHD) results from inadequate immunosuppression. Accordingly, most efforts to solve this problem have relied on retrospective or prospective studies testing agents that have direct or indirect immunosuppressive effects. Retrospective studies far outnumber prospective studies, and no controlled prospective trial has shown superior results for any agent over others. Truth be told, I do not know how to treat SR-aGVHD. Preclinical work during the past decade has provided fresh insights into the pathogenesis of acute GVHD, and translation of these insights toward development of more effective treatments for patients with SR-aGVHD has at last begun. Given the limited state of current knowledge, this "How I Treat" review highlights the overriding imperative to avoid harm in caring for patients with SR-aGVHD. Prospective trials that are widely available are urgently needed to advance the field.

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.

Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic stem-cell transplantation. Because of the small number of results from well designed, large-scale, clinical studies there is considerable variability in the prevention and treatment of GVHD worldwide. In 2014, to standardise treatment approaches the European Society of Blood and Marrow Transplantation published recommendations on the management of GVHD in the setting of HLA-identical sibling or unrelated donor transplantation in adult patients with haematological malignancies. Here we update these recommendations including the results of study published after 2014. Evidence was searched in three steps: first, a widespread scan of published trials, meta-analyses, and systematic reviews; second, expert opinion was added for specific issues following several rounds of debate; and third, a refined search to target debated or rapidly updating issues. On the basis of this evidence and the 2014 recommendations, five members of the EBMT Transplant Complications Working Party created 38 statements on GVHD prophylaxis, drug management, and treatment of acute and chronic GVHD. Subsequently, they created the EBMT GVHD management recommendation expert panel by recruiting 20 experts with expertise in GVHD management. An email-based, two-round Delphi panel approach was used to manage the consensus. Modified National Comprehensive Cancer Network categories for evidence and consensus were applied to the approved statements. We reached 100% consensus for 29 recommendations and 95% consensus for nine recommendations. Key updates to these recommendations include a broader use of rabbit anti-T-cell globulin; lower steroid doses for the management of grade 2 acute GVHD with isolated skin or upper gastrointestinal tract manifestations; fluticasone, azithromycin, and montelukast should be used for bronchiolitis obliterans syndrome; and the addition of newer treatment options for resteroid-refractory acute and chronic GVHD. In addition, we discuss specific aspects of GVHD prophylaxis and management in the setting of haploidentical transplantation and in paediatric patients, but no formal recommendations on those procedures have been provided in this Review. The European Society of Blood and Marrow Transplantation proposes to use these recommendations as a basis for the routine management of GVHD during stem-cell transplantation.

The gastrointestinal (GI) tract is commonly affected by acute and chronic graft-versus-host disease (GVHD) in patients who have undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT). For patients developing GI GVHD, nonabsorbable corticosteroids such as budesonide may be used alone to reduce the risk of systemic corticosteroid toxicities or combined with systemic steroids to enhance clinical responses and to allow more rapid tapering of systemic corticosteroid doses. This prospective crossover study was conducted to evaluate what effect two commonly used antifungal agents, fluconazole, and voriconazole, would have on the trough (Cmin) and peak (Cmax) levels of budesonide in adult patients who had undergone allo-HSCT who subsequently developed clinical GI GVHD. Fifteen subjects were enrolled and nine completed the study and were evaluable. When coadministered with budesonide, voriconazole significantly increased the geometric mean of budesonide Cmin and Cmax levels by 8.52- and 6.63-fold, respectively. The cohort to evaluate the interaction with fluconazole did not meet accrual goals to reach definitive conclusions. In conclusion, this prospective study demonstrated that when patients with GI GVHD are treated with budesonide concurrently with voriconazole, the systemic concentrations of budesonide increase substantially which could increase the risk of steroid-associated toxicities.

We examined the impact of total body irradiation (TBI) dose and fractionation on risk of subsequent malignant neoplasms (SMNs) in the era of reduced-intensity and nonmyeloablative conditioning regimens for hematopoietic cell transplantation (HCT). Among 4905 1-year survivors of allogeneic HCT for hematologic malignancies (N = 4500) or nonmalignant disorders (N = 405) who received transplants between 1969 and 2014, we identified 581 SMNs (excluding squamous and basal cell of skin) in 499 individuals. With a median length of follow-up of 12.5 years, the cumulative incidence of SMNs by 30 years after HCT was 22.0%. Compared with age-, sex-, and calendar year-matched Surveillance, Epidemiology, and End Results (SEER) population rates, the standardized incidence ratio (SIR) of SMNs was increased 2.8-fold. The highest SIRs were for SMNs of bones (SIR, 28.8), oral cavity (SIR, 13.8), skin (SIR, 7.3), central nervous system (SIR, 6.0), and endocrine organs (SIR, 4.9). The highest excess absolute risks (EARs) were seen with breast cancer (EAR, 2.2) and cancers of the oral cavity (EAR, 1.5) and skin (EAR, 1.5) per 1000 person-years. The highest incidence of SMNs was in survivors exposed to unfractionated (600-1000 cGy) or high-dose fractionated (1440-1750 cGy) TBI. For patients receiving low-dose TBI, the incidence was comparable to myeloablative chemotherapy alone, although still twofold higher than in the general population. These data demonstrate a strong effect of TBI dose, dose fractionation, and risk of SMNs after HCT. The cumulative incidence of SMNs increases with follow-up time; thus, HCT survivors require lifetime monitoring for early detection and effective therapy of SMNs.

Acute graft-versus-host disease (GVHD) is treated with systemic corticosteroid immunosuppression. Clinical response after 1 week of therapy often guides further treatment decisions, but long-term outcomes vary widely among centers, and more accurate predictive tests are urgently needed. We analyzed clinical data and blood samples taken 1 week after systemic treatment of GVHD from 507 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC), dividing them into a test cohort (n = 236) and 2 validation cohorts separated in time (n = 142 and n = 129). Initial response to systemic steroids correlated with response at 4 weeks, 1-year nonrelapse mortality (NRM), and overall survival (OS). A previously validated algorithm of 2 MAGIC biomarkers (ST2 and REG3α) consistently separated steroid-resistant patients into 2 groups with dramatically different NRM and OS (P < .001 for all 3 cohorts). High biomarker probability, resistance to steroids, and GVHD severity (Minnesota risk) were all significant predictors of NRM in multivariate analysis. A direct comparison of receiver operating characteristic curves showed that the area under the curve for biomarker probability (0.82) was significantly greater than that for steroid response (0.68, P = .004) and for Minnesota risk (0.72, P = .005). In conclusion, MAGIC biomarker probabilities generated after 1 week of systemic treatment of GVHD predict long-term outcomes in steroid-resistant GVHD better than clinical criteria and should prove useful in developing better treatment strategies.

Haematopoietic stem cell transplantation (HSCT) is central to the management of many haematological disorders. A frequent complication of HSCT is acute graft-versus-host disease (GVHD), a condition in which immune cells from the donor attack healthy recipient tissues. The gastrointestinal system is among the most common sites affected by acute GVHD, and severe manifestations of acute GVHD of the gut portends a poor prognosis in patients after HSCT. Acute GVHD of the gastrointestinal tract presents both diagnostic and therapeutic challenges. Although the clinical manifestations are nonspecific and overlap with those of infection and drug toxicity, diagnosis is ultimately based on clinical criteria. As reliable serum biomarkers have not yet been validated outside of clinical trials, endoscopic and histopathological evaluation continue to be utilized in diagnosis. Once a diagnosis of gastrointestinal acute GVHD is established, therapy with systemic corticosteroids is typically initiated, and non-responders can be treated with a wide range of second-line therapies. In addition to treating the underlying disease, the management of complications including profuse diarrhoea, severe malnutrition and gastrointestinal bleeding is paramount. In this Review, we discuss strategies for the diagnosis and management of acute GVHD of the gastrointestinal tract as they pertain to the practising gastroenterologist.

Histologic confirmation is considered a standard practice to diagnose gastrointestinal graft versus host disease (GI GVHD) and is often used in making treatment decisions. A histologic grade is often determined in cases that are diagnosed with GI GVHD. Although extensive crypt loss (histologic grade 4) is associated with high nonrelapse mortality (NRM), the prognostic value for the more common grade 1 is poorly understood. As clinical decisions are made on the degree of histologic evidence, it is important to establish its prognostic significance. Therefore, we evaluated 309 patients who underwent endoscopic biopsy for suspected GI GVHD within 6 months posttransplant between 2009 and 2012. The presence of histologic grade 1 was associated with increased NRM (hazard ratio=2.7, P=0.02) when compared with one of negative biopsy in patients with lower but not isolated upper GI GVHD. Multivariate competing-risk regression analysis confirmed the independent impact of histologic grade 1 in patients with early clinical stages of lower GI GVHD (stage 0 to 2) (hazard ratio=2.7, P=0.044). When compared with advanced histologic grades, histologic grade 1 did not lessen the adverse outcome for patients with advanced lower GI GVHD (stage 3 to 4) (cumulative incidence NRM of 84%). In conclusion, the presence of histologic grade 1 is associated with increased NRM in patients presenting with lower GI GVHD (stages 0 to 2) and is sufficient evidence for decision to initiate therapy. At the same time, histologic grade 1 does not lessen the markedly adverse impact of advanced lower GI GVHD (stage 3 to 4) and is not synonymous with "mild" GVHD.

graft-versus-host disease (GVHD) is one of the main complications of hematopoietic stem cell transplantation, affecting about 50% to 80% of the patients. Acute GVHD and its clinical manifestations are discussed in this article, as well as the new NIH criteria for the diagnosis and classification of chronic GVHD. Therapy for both chronic and acute GVHD is an important field of discussion, as there is no proven superiority for the majority of therapies used after primary treatment has failed. Hence, this review is meant to be a useful consultation tool for hematologists dealing with this complex transplantation procedure complication.

We examined the hypothesis that plasma biomarkers and concomitant clinical findings after initial glucocorticoid therapy can accurately predict failure of graft-versus-host-disease (GVHD) treatment and mortality. We analyzed plasma samples and clinical data in 165 patients after 14 days of glucocorticoid therapy and used logistic regression and areas under receiver-operating characteristic curves (AUC) to evaluate associations with treatment failure and nonrelapse mortality (NRM). Initial treatment of GVHD was unsuccessful in 49 patients (30%). For predicting GVHD treatment failure, the best clinical combination (total serum bilirubin and skin GVHD stage: AUC, .70) was competitive with the best biomarker combination (T cell immunoglobulin and mucin domain 3 [TIM3] and [interleukin 1 receptor family encoded by the IL1RL1 gene, ST2]: AUC, .73). The combination of clinical features and biomarker results offered only a slight improvement (AUC, .75). For predicting NRM at 1 year, the best clinical predictor (total serum bilirubin: AUC, .81) was competitive with the best biomarker combination (TIM3 and soluble tumor necrosis factor receptor-1 [sTNFR1]: AUC, .85). The combination offered no improvement (AUC, .85). Infection was the proximate cause of death in virtually all patients. We conclude that after 14 days of glucocorticoid therapy, clinical findings (serum bilirubin, skin GVHD) and plasma biomarkers (TIM3, ST2, sTNFR1) can predict failure of GVHD treatment and NRM. These biomarkers reflect counter-regulatory mechanisms and provide insight into the pathophysiology of GVHD reactions after glucocorticoid treatment. The best predictive models, however, exhibit inadequate positive predictive values for identifying high-risk GVHD cohorts for investigational trials, as only a minority of patients with high-risk GVHD would be identified and most patients would be falsely predicted to have adverse outcomes.

Graft-versus-host disease (GVHD) continues to be the major lethal complication of allogeneic hematopoietic stem cell transplantation (HCT) but the standard of care, high dose steroids, has not changed in 40 years. Approximately 50% of GVHD patients will develop steroid refractory disease, typically involving the gastrointestinal (GI) tract, which has a very poor prognosis. Newly developed GVHD biomarker-based risk scores provide the first opportunity to treat patients at the onset of symptoms according to risk of steroid failure. Furthermore, improvements in our understanding of the pathobiology of GVHD, its different signaling pathways, involved cytokines, and the role of post-translational and epigenetic modifications, has identified new therapeutic targets for clinical trials.

This manuscript summarizes the pathophysiology, diagnosis, staging, current and new targeted therapies for GVHD, with an emphasis on GI GVHD. A literature search on PubMed was undertaken and the most relevant references included.

The standard treatment for GVHD, high dose steroids, offers less than optimal outcomes as well as significant toxicities. Better treatments, especially for GI GVHD, are needed to reduce non-relapse mortality after allogeneic HCT. The identification of high risk patients through a biomarker-defined scoring system offers a personalized approach to a disease that still requires significant research attention.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has a curative potential for many hematologic malignancies and blood diseases. However, the success of allo-HSCT is limited by graft-versus-host disease (GVHD), an immunological syndrome that involves inflammation and tissue damage mediated by donor lymphocytes. Despite immune suppression, GVHD is highly incident even after allo-HSCT using human leukocyte antigen (HLA)-matched donors. Therefore, alternative and more effective therapies are needed to prevent or control GVHD while preserving the beneficial graft-versus-cancer (GVC) effects against residual disease. Among novel therapeutics for GVHD, oncolytic viruses such as myxoma virus (MYXV) are receiving increased attention due to their dual role in controlling GVHD while preserving or augmenting GVC. This review focuses on the molecular basis of GVHD, as well as state-of-the-art advances in developing novel therapies to prevent or control GVHD while minimizing impact on GVC. Recent literature regarding conventional and the emerging therapies are summarized, with special emphasis on virotherapy to prevent GVHD. Recent advances using preclinical models with oncolytic viruses such as MYXV to ameliorate the deleterious consequences of GVHD, while maintaining or improving the anti-cancer benefits of GVC will be reviewed.

Treatment of acute graft-versus-host disease (GVHD) has evolved from a one-size-fits-all approach to a more nuanced strategy based on predicted outcomes. Lower and time-limited doses of immune suppression for patients predicted to have low-risk GVHD are safe and effective. In more severe GVHD, prolonged exposure to immunosuppressive therapies, failure to achieve tolerance, and inadequate clinical responses are the proximate causes of GVHD-related deaths. This article presents acute GVHD-related scenarios representing, respectively, certainty of diagnosis, multiple causes of symptoms, jaundice, an initial therapy algorithm, secondary therapy, and defining futility of treatment.

We conducted a phase III study to test the hypothesis that initial therapy with "lower dose" prednisone is effective and safe for patients with newly diagnosed acute graft-versus-host disease. We hypothesized that a 50% decrease in the initial dose of prednisone for treatment of acute graft-versus-host disease would suffice to control graft-versus-host disease without increasing the incidence of secondary treatment. Patients with grade IIa manifestations (upper gastrointestinal symptoms, stool volumes <1.0 L/day, rash involving <50% of the body surface, no hepatic dysfunction; n=102) were randomized to start treatment with prednisone at 1 mg/kg/day or 0.5 mg/kg/day. Those with grade IIb or higher manifestations (rash involving ≥50% of the body surface, stool volumes ≥1.0 L/day or hepatic involvement; n=62) were randomized to start treatment with prednisone at 2 mg/kg/day or 1 mg/kg/day. The primary study end point (a ≥33% relative reduction of the mean cumulative prednisone dose by day 42 after initial treatment with lower dose prednisone) was not reached. With a median follow up of 36 months (range 7-53), initial treatment with lower dose prednisone appeared to be effective for patients presenting with grade IIa manifestations since it did not increase the likelihood of requiring secondary immunosuppressive therapy. Further exploratory analyses suggested that for patients presenting with skin-predominant grade IIb or higher manifestations, initial treatment with lower dose prednisone was associated with an increased risk of requiring secondary immunosuppressive therapy (41% vs. 7%; P=0.001). In summary, initial treatment of newly diagnosed acute graft-versus-host disease with lower dose prednisone is effective. Within the statistical limitations of the study, results showed no suggestion that initial use of lower dose prednisone adversely affected survival.

We hypothesized that clinical risk factors could be identified within 2 weeks of onset of severe (stage 3 or 4) acute gut GVHD for identifying a patient population with a very poor outcome. Among 1462 patients who had allogeneic hematopoietic cell transplantation (HCT) between January 2000 and December 2005, 116 (7.9%) developed stage 3-4 gut GVHD. The median time for onset of stage 3-4 gut GVHD was 35 (4-135) days after allogeneic HCT. Eighty-five of the 116 patients (73%) had corticosteroid resistance before or within 2 weeks after the onset of stage 3-4 gut GVHD. Significant risk factors for mortality included corticosteroid resistance (hazards ratio (HR)=2.93; P=0.0005), age >18 years (HR=4.95; P=0.0004), increased serum bilirubin (HR 2.53; P=0.0001) and overt gastrointestinal bleeding (HR 2.88; P=0.0004). Among patients with stage 3-4 gut GVHD, the subgroup with 0, 1 or 2 risk factors had a favorable prognosis, whereas the subgroup with 3 or 4 risk factors had a dismal prognosis. This information should be considered in designing future studies of severe gut GVHD and in counseling patients about prognosis.

In a multicenter collaboration, we carried out T cell-replete, peripheral blood stem cell (PBSC) transplantations from related, HLA-haploidentical donors with reduced-intensity conditioning (RIC) and post-transplantation cyclophosphamide (Cy) as graft-versus-host disease (GVHD) prophylaxis in 55 patients with high-risk hematologic disorders. Patients received 2 doses of Cy 50 mg/kg i.v. on days 3 and 4 after infusion of PBSC (mean, 6.4 × 10(6)/kg CD34(+) cells; mean, 2.0 × 10(8)/kg CD3(+) cells). The median times to neutrophil (500/μL) and platelet (>20,000/μL) recovery were 17 and 21 days respectively. All but 2 of the patients achieved full engraftment. The 1-year cumulative incidences of grade II and grade III acute GVHD were 53% and 8%, respectively. There were no cases of grade IV GVHD. The 2-year cumulative incidence of chronic GHVD was 18%. With a median follow-up of 509 days, overall survival and event-free survival at 2 years were 48% and 51%, respectively. The 2-year cumulative incidences of nonrelapse mortality and relapse were 23% and 28%, respectively. Our results suggest that PBSC can be substituted safely and effectively for bone marrow as the graft source for haploidentical transplantation after RIC.

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.

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplant (AHSCT) associated with significant morbidity and mortality. This review focuses on the pathophysiology, prevention, and treatment of acute GVHD. Specifically, we explain how new discoveries in immunology have expanded our understanding of GVHD, in which tissue damage from chemotherapy or radiation results in cytokine release, activating T cells, resulting in proliferation and differentiation, trafficking to target organs, and tissue destruction and inflammation. Insights into the mechanisms of this disease relate directly to the development of preventive strategies and therapies, such as immunosuppression, calcineurin inhibitors, T-cell depletion, CCR5 antagonists, gut decontamination, extracorporeal photopheresis, and more. Understanding the immunobiology of GVHD and developing effective preventions and treatments are critical to the continuing success of AHSCT.

The T cell Ig and mucin domain 3 (Tim-3) receptor has been implicated as a negative regulator of adaptive immune responses. We have utilized a proteomic strategy to identify novel proteins associated with graft versus host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Mass spectrometry analysis of plasma from subjects with mid-gut and upper-gut GVHD compared with those without GVHD identified increased levels of a protein identified with high confidence as Tim-3. A follow-up validation study using an immunoassay to measure Tim-3 levels in individual plasma samples from 127 patients demonstrated significantly higher plasma Tim-3 concentrations in patients with the more severe mid-gut GVHD, compared with those with upper-gut GVHD (P = .005), patients without GVHD (P = .002), and normal controls (P < .0001). Surface expression of Tim-3 was increased on CD8(+) T cells from patients with grade 2 to 4 acute GVHD (P = .01). Mass spectrometry-based profiling of plasma from multiple subjects diagnosed with common diseases provided evidence for restricted release of soluble Tim-3 in the context of GVHD. These findings have mechanistic implications for the development of novel strategies for targeting the Tim-3 immune regulatory pathway as an approach to improving control of GVHD.

To assess current clinical practice in diagnosis and treatment of acute graft-versus-host disease (aGVHD), we performed a survey among German, Austrian, and Swiss allogeneic hematopoietic stem cell transplantation (allo-HSCT) centers. Thirty-four of 72 contacted centers (47%) completed both the diagnostic and therapeutic sections of the survey, representing 65% of allo-HSCT activity within the participating countries in 2011. Three pediatric centers answered as requested only the diagnostic part of the survey. In the presence of diarrhea and decreased oral intake after engraftment, only 4 centers (12%) do not perform any endoscopy before the start of immunosuppressive treatment. In case of a skin rash with the differential diagnosis of drug reaction, only 12 centers (35%) perform a skin biopsy up front, whereas 19 do so after failure of systemic steroids. In the presence of rapidly increasing cholestasis occurring without any other signs of aGVHD, 11 centers (32%) perform a liver biopsy up front and 14 only after failure of steroid treatment, whereas 9 centers do not perform a liver biopsy at all. Twenty centers (59%) use a percutaneous approach, 12 a transvenous approach, and 1 mini-laparoscopy for liver biopsies. First-line treatment of cutaneous aGVHD stage 1 consists of topical treatment alone in 17 of 31 responding centers (61%), whereas isolated cutaneous aGVHD stage III is treated with systemic steroids (prednisolone below 0.5 mg/kg/day n = 2, 0.5 to 1.0 mg/kg/day n = 10, above 1.0 to 2.5 mg/kg/day n = 19) without or with topical agents (steroids n = 10; calcineurin inhibitors n = 3). In gastrointestinal manifestations of aGVHD, 9 centers (29%) add topical to systemic steroids, and 3 consider topical steroids as the only treatment for mild gastrointestinal and cutaneous aGVHD. The choice of agent for second-line treatment as well as the sequence of administration are extremely heterogeneous, most likely due to a lack of convincing data published. Most frequently used are mycophenolate mofetil (n = 14) and extracorporeal photopheresis (n = 10). Our survey also demonstrates that clinicians chose salvage therapies for steroid-refractory aGVHD based on their centers' own clinical experience.

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplant (AHSCT) associated with significant morbidity and mortality. This review focuses on the pathophysiology, clinical features, prevention, and treatment of acute GVHD. Specifically, we explain how new discoveries in immunology have expanded our understanding of GVHD, in which tissue damage from chemotherapy or radiation results in cytokine release, which activates T cells, resulting in proliferation and differentiation, trafficking to target organs, and tissue destruction and inflammation. Insights into the mechanisms of this disease relate directly to the development of preventive strategies and therapies, such as immunosuppression, T-cell depletion, calcineurin inhibitors, CCR5 antagonists, gut decontamination, extracorporeal photopheresis, and more. We also discuss how GVHD affects the gut, liver, and skin, as well as diagnosis, grading, and scoring. We end by examining future directions of treatment, including new immunomodulators and biomarkers. Understanding the immunobiology of GVHD and developing effective preventions and treatments are critical to the continuing success of AHSCT.

Despite prophylaxis with immunosuppressive agents or a variety of other approaches, many patients suffer from acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation. Although consensus has emerged supporting the use of high-dose methylprednisolone or prednisone for initial treatment of aGVHD, practices differ among centers with respect to the initial glucocorticoid dose, the use of additional immunosuppressive agents, and the approach to withdrawal of treatment after initial improvement. Despite many studies, practices vary considerably with respect to the selection of agents for treatment of glucocorticoid-resistant or refractory GVHD. Investigators and clinicians have recognized the lack of progress and lamented the absence of an accepted standard of care for secondary treatment of aGVHD. The American Society of Blood and Marrow Transplantation has developed recommendations for treatment of aGVHD to be considered by care providers, based on a comprehensive and critical review of published reports. Because the literature provides little basis for a definitive guideline, this review also provides a framework for the interpretation of previous results and the design of future studies.