Metabolomic identification of α-ketoglutaric acid elevation in pediatric chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is the most common cause for non-relapse mortality postallogeneic hematopoietic stem cell transplant (HSCT). However, there are no well-defined biomarkers for cGVHD or late acute GVHD (aGVHD). This study is a longitudinal evaluation of metabolomic patterns of cGVHD and late aGVHD in pediatric HSCT recipients. A quantitative analysis of plasma metabolites was performed on 222 evaluable pediatric subjects from the ABLE/PBMTC1202 study. We performed a risk-assignment analysis at day + 100 (D100) on subjects who later developed either cGVHD or late aGVHD after day 114 to non-cGVHD controls. A second analysis at diagnosis used fixed and mixed multiple regression to compare cGVHD at onset to time-matched non-cGVHD controls. A metabolomic biomarker was considered biologically relevant only if it met all 3 selection criteria: (1) P ≤ .05; (2) effect ratio of ≥1.3 or ≤0.75; and (3) receiver operator characteristic AUC ≥0.60. We found a consistent elevation in plasma α-ketoglutaric acid before (D100) and at the onset of cGVHD, not impacted by cGVHD severity, pubertal status, or previous aGVHD. In addition, late aGVHD had a unique metabolomic pattern at D100 compared with cGVHD. Additional metabolomic correlation patterns were seen with the clinical presentation of pulmonary, de novo, and progressive cGVHD. α-ketoglutaric acid emerged as the single most significant metabolite associated with cGVHD, both in the D100 risk-assignment and later diagnostic onset analysis. These distinctive metabolic patterns may lead to improved subclassification of cGVHD. Future validation of these exploratory results is needed. This trial was registered at www.clinicaltrials.gov as #NCT02067832.

Immune profile differences between chronic GVHD and late acute GVHD: results of the ABLE/PBMTC 1202 studies.

Human graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study (ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1- and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.

Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria.

Chronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients <18 years of age. The objectives of this prospective multi-institution study were to determine: (1) whether the NIH-CC could be used to diagnose pediatric cGVHD and whether the criteria operationalize well in a multi-institution study; (2) the frequency of cGVHD and L-aGVHD in children using the NIH-CC; and (3) the clinical features and risk factors for cGVHD and L-aGVHD using the NIH-CC. Twenty-seven transplant centers enrolled 302 patients <18 years of age before conditioning and prospectively followed them for 1 year posttransplant for development of cGVHD. Centers justified their cGVHD diagnosis according to the NIH-CC using central review and a study adjudication committee. A total of 28.2% of reported cGVHD cases was reclassified, usually as L-aGVHD, following study committee review. Similar incidence of cGVHD and L-aGVHD was found (21% and 24.7%, respectively). The most common organs involved with diagnostic or distinctive manifestations of cGVHD in children include the mouth, skin, eyes, and lungs. Importantly, the 2014 NIH-CC for bronchiolitis obliterans syndrome perform poorly in children. Past acute GVHD and peripheral blood grafts are major risk factors for cGVHD and L-aGVHD, with recipients ≥12 years of age being at risk for cGVHD. Applying the NIH-CC in pediatrics is feasible and reliable; however, further refinement of the criteria specifically for children is needed.

Presence of viremia during febrile neutropenic episodes in patients undergoing chemotherapy for malignant neoplasms.

The importance of viral infections as a leading cause of morbidity and mortality is well documented in severely immunosuppressed patients undergoing allogeneic stem cell transplantation. By contrast, viral infections generally receive less attention in patients with malignant disorders undergoing chemotherapy, where the onset of neutropenic fever is mostly associated with bacterial or fungal infections, and screening for viral infections is not routinely performed. To address the occurrence of invasive viral infections in a clinical setting commonly associated with less pronounced immunosuppression, we have prospectively screened 237 febrile neutropenic episodes in pediatric (n = 77) and adult (n = 69) patients undergoing intensive chemotherapy, primarily for treatment of acute leukemia. Serial peripheral blood specimens were tested by RQ-PCR assays for the presence and quantity of the clinically relevant viruses CMV, EBV, HHV6 and HAdV, commonly reactivated in highly immunocompromised patients. Viremia was documented in 36 (15%) episodes investigated, including the detection of HHV6 (n = 14), EBV (n = 15), CMV (n = 6), or HAdV (n = 1). While low or intermediate levels of viremia (<104 virus copies/mL) were commonly associated with bacterial or fungal co-infection, viremia at higher levels (>104 copies/mL) was documented in patients without evidence for other infections, raising the possibility that at least in some instances the onset of fever may have been attributable to the virus detected. The observations suggest that viral infections, potentially resulting from reactivation, might also play a clinically relevant role in patients receiving chemotherapy for treatment of malignant neoplasms, and routine screening for viremia in this clinical setting might be warranted.

Detection and Monitoring of Lineage-Specific Chimerism by Digital Droplet PCR-Based Testing of Deletion/Insertion Polymorphisms.

Analysis of specific leukocyte subsets for post-transplantation monitoring of chimerism provides greater sensitivity and clinical informativeness on dynamic changes in donor- and recipient-derived cells. Limitations of the most commonly used approach to chimerism testing relying on PCR-based analysis of microsatellite markers prompted us to assess the applicability of digital droplet (dd) PCR amplification of deletion/insertion polymorphisms (DIPs) for lineage-specific chimerism testing in the related stem cell transplantation setting, where the identification of informative markers facilitating the discrimination between donor-derived and recipient-derived cells can be challenging. We analyzed 100 genetically related patient-donor pairs by ddPCR analysis using commercially available DIP kits including large sets of polymorphic markers. At least 1 informative marker was identified in all related pairs analyzed, and 2 or more discriminating markers were detected in the majority (82%) of instances. The achievable detection limit is dependent on the number of cells available for analysis and was as low as 0.1% in the presence of ≥20,000 leukocytes available for DNA extraction. Moreover, the reproducibility and accuracy of quantitative chimerism analysis compared favorably to highly optimized microsatellite assays. Thus, the use of ddPCR-based analysis of DIP markers is an attractive approach to lineage-specific monitoring of chimerism in any allogeneic transplantation setting.

Investigation and Management of Bone Mineral Density Following Hematopoietic Cell Transplantation: A Survey of Current Practice by the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation.

Reduced bone mineral density (BMD) is a well-recognized complication of hematopoietic cell transplantation (HCT), with significant drops in BMD occurring within the first 12 months after HCT. Guidance on identifying and managing this complication is available in several published guidelines. In this study, we investigated current practices in the investigation and management of low BMD in centers registered with the European Society for Blood and Marrow Transplantation (EBMT). A questionnaire about bone health was sent to all registered centers, and responses were received from 99 centers in 25 countries (52%) currently registered with the EBMT. Our data highlight considerable heterogeneity in practices across European centers in relation to investigations, management, and use of guidelines. Our data demonstrate the need for better dissemination and implementation of existing guidelines and also for the development of multidisciplinary guidelines with input from all relevant stakeholders.

Guidance to Bone Morbidity in Children and Adolescents Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) is widely performed in children and adolescents with hematologic diseases, including very high-risk leukemia. With increasing success and survival rates, the long-term sequelae of HSCT have become important. Here, we provide guidance to the prevention and treatment of the most common bone morbidities-osteoporosis and osteonecrosis-emerging in the context of HSCT in children and adolescents. We give an overview on definitions, symptoms, and diagnostics and propose an algorithm for clinical practice based on discussions within the International Berlin Frankfurt Münster (BFM) Stem Cell Transplantation Committee and the Pediatric Disease Working Party of the European Society for Blood and Marrow Transplantation, our expert knowledge, and a literature review.

Pediatric acute graft-versus-host disease prophylaxis and treatment: surveyed real-life approach reveals dissimilarities compared to published recommendations.

Pediatric allogeneic hematopoietic cell transplantation (HCT) practices differ from those of adults, particularly the heterogeneity of transplantable nonmalignant diseases and the lower incidence of graft-versus-host disease (GVHD). Several guidelines regarding the management of acute (a) GVHD in adult HCT have been published. We aimed to capture the real-life approaches for pediatric aGVHD prophylaxis/treatment, and data from 75/193 (response rate 39%) EBMT centers (26 countries) were included, representing half (48%) of the pediatric EBMT-HCT activity. Results with ≥75% approval from respondents (74/75) for GVHD prophylaxis after myeloablative HCT for malignancies partially contradict published guidelines: Single-agent cyclosporine A (CsA) was used for matched sibling donor HCT in 47%; blood CsA levels were reported lower; the relapse risk in malignant diseases influenced GVHD prophylaxis with early withdrawal of CsA; distinct longer duration of CsA was employed in nonmalignant diseases. Most centers used additional anti-thymocyte globulin for matched unrelated and mismatched donor HCT, but not for matched siblings. Regarding prophylaxis in nonmyeloablative conditioning (mainly for nonmalignant diseases), responses showed broad heterogeneity. High conformity was found for first-line treatment; however, results regarding steroid-refractory aGVHD indicate an earlier diagnosis in children. Our findings highlight the need for standardized pediatric approaches toward aGVHD prophylaxis/treatment differentiated for malignant and nonmalignant underlying diseases.

Human papillomavirus in female adolescents and young adults after allogeneic hematopoietic stem cell transplantation-Not a problem prior to coitarche.

OBJECTIVES: To evaluate the prevalence of HPV colonization in female adolescents and young adults after allogenic hematopoietic stem cell transplantation. STUDY DESIGN: In this prospective pilot study, we enrolled 18 girls and young women aged 12-22 years cared for at the SCT (stem cell transplantation) Outpatient Clinic of the St. Anna children's hospital. Vaginal, buccal, and rectal HPV swabs were collected twice at intervals of 2-6 months at the Outpatient Clinic for children's and adolescents' gynecology of the University Clinic for Gynecology Vienna. RESULTS: Overall, 3 (16.7%; 95% CL [≥0.0%; 33.9%]) of the 18 patients were vaginally HPV-positive at least at one timepoint. Among these three, two patients belonged to the smaller sub-group (3 patients) of patients after coitarche and one patient belonged to the larger one (15 patients) of patients prior to coitarche. In one of the three vaginally HPV-positive patients, we also found HPV DNA rectally. Orally, HPV DNA could not be detected at all. CONCLUSIONS: According to the data of this study, vaginal, buccal, and rectal HPV colonization seems to be of little relevance in girls and young women after HSCT prior to coitarche. As expected, a higher risk for vaginal HPV colonization could be shown by trend for patients after coitarche, but also for those having been treated with total body irradiation as a conditioning regimen and for those showing signs of vaginal hypoestrogenization-which has not been published so far.

Changes in Immunosuppressive Treatment of Chronic Graft-versus-Host Disease: Comparison of 2 Surveys within Allogeneic Hematopoietic Stem Cell Transplant Centers in Germany, Austria, and Switzerland.

Chronic graft-versus-host disease (cGVHD) remains the leading cause of late morbidity and mortality. Despite the growing number of treatment options in cGVHD, evidence remains sparse. The German-Austrian-Swiss GVHD Consortium performed a survey on clinical practice in treatment of cGVHD among transplant centers in Germany, Austria, and Switzerland in 2009 and 2018 and compared the results. The survey performed in 2009 contained 20 questions on first-line treatment and related issues and 4 questions on second-line scenarios followed by a survey on all systemic and topic treatment options known and applied, with 31 of 36 transplant centers (86%) responding. The survey in 2018 repeated 7 questions on first-line treatment and 3 questions on second-line scenarios followed by an updated survey on all current systemic treatment options known and applied, with 29 of 66 centers (43%) responding. In summary, the results show a large overlap of first-line treatment practice between centers and the 2 surveys because of a lack of new data that changes practice, except significant heterogeneity of treatment of cGVHD progressive onset type, which can be explained by the lack of trials focusing on this high-risk entity. In contrast, treatment options applied to second-line therapy vary considerably, with new agents like ibrutinib and ruxolitinib entering clinical practice. Moreover, treatment of bronchiolitis obliterans syndrome demonstrates heterogeneity in applied therapeutic options and sequence because of a lack of controlled data and different conclusions from already existing evidence. In summary, the survey results demonstrate an increasing number of treatment options applied to cGVHD accompanied by a significant heterogeneity in second-line treatment and underline the urgent need for clinical trials and registry analyses on rare entities with high mortality like progressive onset type and lung involvement of cGVHD.

Gonadal Function after Busulfan Compared with Treosulfan in Children and Adolescents Undergoing Allogeneic Hematopoietic Stem Cell Transplant.

Gonadal impairment is an important late effect with a significant impact on quality of life of transplanted patients. The aim of this study was to compare gonadal function after busulfan (Bu) or treosulfan (Treo) conditioning regimens in pre- and postpubertal children. This retrospective, multicenter study included children transplanted in pediatric European Society for Blood and Marrow Transplantation (EBMT) centers between 1992 and 2012 who did not receive gonadotoxic chemoradiotherapy before the transplant. We evaluated 137 patients transplanted in 25 pediatric EBMT centers. Median age at transplant was 11.04 years (range, 5 to 18); 89 patients were boys and 48 girls. Eighty-nine patients were prepubertal at transplant and 48 postpubertal. One hundred eighteen children received Bu and 19 Treo. A higher proportion of girls treated with Treo in the prepubertal stage reached spontaneous puberty compared with those treated with Bu (P = .02). Spontaneous menarche was more frequent after Treo than after Bu (P < .001). Postpubertal boys and girls treated with Treo had significantly lower luteinizing hormone levels (P = .03 and P = .04, respectively) compared with the Bu group. Frequency of gonadal damage associated with Treo was significantly lower than that observed after Bu. These results need to be confirmed in a larger population.

Allogeneic hematopoietic stem cell transplantation from unrelated donors is associated with higher infection rates in children with acute lymphoblastic leukemia-A prospective international multicenter trial on behalf of the BFM-SG and the EBMT-PDWP.

Severe infections (SI) significantly impact on non-relapse mortality after hematopoietic stem cell transplantation (HSCT). We assessed 432 children and adolescents with acute lymphoblastic leukemia (ALL) after total body irradiation based myeloablative HSCT within the multicenter ALL-BFM-SCT 2003 trial for SI grade 3 or higher according to common terminology criteria for adverse events. A total 172 patients experienced at least one SI. Transplantation from matched unrelated donors (MUD) was associated with any type of SI in the pre-engraftment period (hazard ratio [HR]: 2.57; P < .001), and with any SI between day +30 and + 100 (HR: 2.91; P = .011). Bacterial (HR: 2.24; P = .041) and fungal infections (HR: 4.06; P = .057) occurred more often in the pre-engraftment phase and viral infections more often before day +30 (HR: 2.66; P = .007) or between day +30 and + 100 (HR: 3.89; P = .002) after HSCT from MUD as compared to matched sibling donors. Chronic GvHD was an independent risk factor for any type of SI after day +100 (HR: 2.57; P < .002). We conclude that allogeneic HSCT from MUD in children and adolescents with pediatric ALL is associated with higher infection rates, which seems attributable to an intensified GvHD prophylaxis including serotherapy and methotrexate.

Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study.

BACKGROUND: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. OBJECTIVE: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. METHODS: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. RESULTS: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. CONCLUSIONS: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.

Low incidence of symptomatic osteonecrosis after allogeneic HSCT in children with high-risk or relapsed ALL - results of the ALL-SCT 2003 trial.

Osteonecrosis (ON) was prospectively assessed in 557 children and adolescents in the Berlin-Frankfurt-Münster Stem Cell Transplantation in children with acute lymphoblastic leukaemia 2003 trial. Median age at haematopoietic stem cell transplantation (HSCT) was 10·3 years (range 0·5-26). Cumulative incidence of symptomatic ON (sON) was 9% at 5 years (standard deviation 1%), median time from HSCT to diagnosis of sON was 12·4 months (range 1-126). Multivariate analysis identified age at HSCT [10-15 years vs. <10 years: hazard ratio (HR) 3·73, P = 0·009; >15 years vs. <10 years: HR 5·46, P = 0·001], diagnosis of sON prior to HSCT and chronic graft-versus-host disease (yes versus no: HR 2·696, P = 0·015) as significant independent risk factors for the development of sON.

Long-term Effects of Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients with Acute Lymphoblastic Leukemia.

PURPOSE OF REVIEW: Allogeneic hematopoetic stem cell transplantation (HSCT) is a curative option for children and adolescents with high-risk leukemia. Although acute complications were reduced during the last decade, considerable late effects are still limiting the overall success rate. This article emphasizes the specific pediatric aspects of long-term aftercare following myeloablative HSCT and provides an organ-based overview that covers main clinical patterns, incidence, and risk factors enhanced by current references and screening guidelines. RECENT FINDINGS: In the last years, several attempts were made to separate pediatric outcome data from findings in adults. It turned out that not only the indication for but also the time and the procedures of HSCT substantially differ. Nearly any organ might be affected after the complex transplantation process and includes endocrinopathies, musculoskeletal disorders, cardiopulmonary complications, and secondary malignancies. Patients after HSCT in childhood have a high risk for developing a wide range of late sequelae and may benefit from regular screening and early intervention. The occurrence and patterns of late effects depend on the intensity and severity of conditioning and are strongly associated with patient's age at transplant and beginning of complications.

Peripheral blood late mixed chimerism in leucocyte subpopulations following allogeneic stem cell transplantation for childhood malignancies: does it matter?

The impact of persistent mixed chimerism (MC) after haematopoietic stem cell transplantation (HSCT) remains unclarified. We investigated the incidence of MC in peripheral blood beyond day +50 after HSCT and its impact on rejection, chronic graft-versus-host disease (c-GvHD) and relapse in 161 children receiving allogeneic HSCT for haematological malignancies. The 1-year incidence of late MC was 26%. Spontaneous conversion to complete donor chimerism (CC) occurred in 43% of patients as compared to 62% after donor lymphocyte infusions. No graft rejection occurred. The 1-year incidence of c-GvHD was 20 ± 7% for MC, and 18 ± 4% for CC patients (P = 0·734). The 3-year cumulative incidence of relapse (CIR) according to chimerism status at days +50 and +100 was 22 ± 4% for CC patients vs. 22 ± 8% for MC patients (day +50; P = 0·935) and 21 ± 4% vs. 20 ± 7% (day +100; P = 0·907). Three-year CIRs in patients with persistent MC and patients with CC/limited MC were comparable (8 ± 7% vs. 19 ± 4%; P = 0·960). HSCT for acute leukaemia or myelodysplastic syndrome as secondary malignancies (hazard ratio (HR) 4·7; P = 0·008), for AML (HR 3·0; P = 0·02) and from mismatched donors (HR 3·1; P = 0·03) were independent factors associated with relapse. Our data suggest that late MC neither protects from c-GvHD nor does it reliably predict impending disease relapse.

Risk assessment of relapse by lineage-specific monitoring of chimerism in children undergoing allogeneic stem cell transplantation for acute lymphoblastic leukemia.

UNLABELLED: Allogeneic hematopoietic stem cell transplantation is required as rescue therapy in about 20% of pediatric patients with acute lymphoblastic leukemia. However, the relapse rates are considerable, and relapse confers a poor outcome. Early assessment of the risk of relapse is therefore of paramount importance for the development of appropriate measures. We used the EuroChimerism approach to investigate the potential impact of lineage-specific chimerism testing for relapse-risk analysis in 162 pediatric patients with acute lymphoblastic leukemia after allogeneic stem cell transplantation in a multicenter study based on standardized transplantation protocols. Within a median observation time of 4.5 years, relapses have occurred in 41/162 patients at a median of 0.6 years after transplantation (range, 0.13-5.7 years). Prospective screening at defined consecutive time points revealed that reappearance of recipient-derived cells within the CD34(+) and CD8(+) cell subsets display the most significant association with the occurrence of relapses with hazard ratios of 5.2 (P=0.003) and 2.8 (P=0.008), respectively. The appearance of recipient cells after a period of pure donor chimerism in the CD34(+) and CD8(+) leukocyte subsets revealed dynamics indicative of a significantly elevated risk of relapse or imminent disease recurrence. Assessment of chimerism within these lineages can therefore provide complementary information for further diagnostic and, potentially, therapeutic purposes aiming at the prevention of overt relapse. This study was registered at clinical. TRIALS: gov with the number NC01423747.

Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report.

In 2005, the National Institutes of Health (NIH) Chronic Graft-versus-Host Disease (GVHD) Consensus Response Criteria Working Group recommended several measures to document serial evaluations of chronic GVHD organ involvement. Provisional definitions of complete response, partial response, and progression were proposed for each organ and for overall outcome. Based on publications over the last 9 years, the 2014 Working Group has updated its recommendations for measures and interpretation of organ and overall responses. Major changes include elimination of several clinical parameters from the determination of response, updates to or addition of new organ scales to assess response, and the recognition that progression excludes minimal, clinically insignificant worsening that does not usually warrant a change in therapy. The response definitions have been revised to reflect these changes and are expected to enhance reliability and practical utility of these measures in clinical trials. Clarification is provided about response assessment after the addition of topical or organ-targeted treatment. Ancillary measures are strongly encouraged in clinical trials. Areas suggested for additional research include criteria to identify irreversible organ damage and validation of the modified response criteria, including in the pediatric population.

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group Report.

The 2006 National Institutes of Health (NIH) Consensus paper presented recommendations by the Ancillary Therapy and Supportive Care Working Group to support clinical research trials in chronic graft-versus-host disease (GVHD). Topics covered in that inaugural effort included the prevention and management of infections and common complications of chronic GVHD, as well as recommendations for patient education and appropriate follow-up. Given the new literature that has emerged during the past 8 years, we made further organ-specific refinements to these guidelines. Minimum frequencies are suggested for monitoring key parameters relevant to chronic GVHD during systemic immunosuppressive therapy and, thereafter, referral to existing late effects consensus guidelines is advised. Using the framework of the prior consensus, the 2014 NIH recommendations are organized by organ or other relevant systems and graded according to the strength and quality of supporting evidence.

Current practice in diagnosis and treatment of acute graft-versus-host disease: results from a survey among German-Austrian-Swiss hematopoietic stem cell transplant centers.

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.