Search

Neurolymphomatosis (NL) is a rare condition caused by the lymphomatous or leukemic infiltration of nerves and manifests as neuropathy. Most often, NL is associated with B-lineage non-Hodgkin lymphoma (NHL) and only infrequently occurs in conjunction with T- or NK-lineage NHL. Extranodal NK/T-cell lymphoma (ENKTL)-associated NL is exceedingly unusual, with only 9 cases described in the English language literature, in addition to our case. Diagnosis of NL is challenging, as the entity can mimic neuropathies of more common etiologies, and an adequate biopsy may be difficult to obtain. Timely diagnosis demands a high index of suspicion, especially for patients without a history of hematologic malignancy. We expand upon a unique case of NL exclusively involving cranial nerves and cauda equina nerve roots, as the initial manifestation of ENKTL, and contextualize our findings within the framework of previously reported NK/T-lineage NL cases.

Steroid-refractory (SR) acute graft-versus-host disease (aGvHD) remains a significant complication after allogeneic hematopoietic cell transplantation. Systemic corticosteroids are first-line therapy for aGvHD, but apart from ruxolitinib, there are no approved treatments for SR aGvHD. Vedolizumab is approved for treatment of ulcerative colitis and Crohn’s disease, and may be effective for treatment of SR intestinal aGvHD. We conducted a phase 2a trial (NCT02993783) to evaluate the clinical efficacy, tolerability, and safety of vedolizumab 300 and 600 mg for SR intestinal aGvHD. This study was terminated before full enrollment was completed because early results failed to demonstrate positive proof-of-concept in efficacy. Before termination, 17 participants had enrolled and an early response in intestinal aGvHD was observed in 11 and eight participants at days 15 and 28, respectively. All adverse events observed were consistent with those expected in a population with SR intestinal aGvHD. Overall, vedolizumab did not meet the primary efficacy endpoint (overall response at day 28), likely owing to premature study drug discontinuation, lack of efficacy, and the competing risks inherent with a population with advanced SR intestinal aGvHD. Nevertheless, this study provides valuable insights into the considerations needed when conducting studies in patients with SR intestinal aGvHD.

Purpose Multiple Myeloma (MM), the second leading blood malignancy, has complex and costly disease management. We studied patterns of treatment disparities and unplanned interruptions among the MM patients after the Affordable Care Act to assess their prevalence and effect on survival. Materials and methods This retrospective study of 1002 MM patients at a tertiary referral center used standard guidelines as a reference to identify underuse of effective treatments. We used multivariate logistic regression and Cox proportionate hazard to study the prognostic effect on survival. Results Median age in the cohort was 63.0 [IQR: 14] years. Non-Hispanic White (NHW) patients were older (p = 0.007) and more likely to present with stage I disease (p = 0.02). Underuse of maintenance therapy (aOR = 1.98; 95 % CI 1.12–3.48) and interruptions in treatment were associated with race/ethnicity and insurance (aOR = 4.14; 95 % CI: 1.78–9.74). Only underuse of induction therapy was associated with overall patient survival. Conclusion Age, race, ethnicity and primary insurance contribute to the underuse of treatment and in unplanned interruptions in MM treatment. Addressing underuse causes in such patients is warranted.

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.

Purpose To visualize variation in multiple myeloma (MM) incidence and mortality rates by race-ethnicity and geographic location and evaluate their correlation with neighborhood-level population covariates within New York City (NYC). Methods Trends and racial differences in MM incidence and mortality for the United States [Surveillance, Epidemiology, and End Results Cancer Registry (SEER), National Center for Health Statistics], and NYC [New York State Cancer Registry] were compared using Joinpoint regression. Pearson's correlation coefficients measured neighborhood-level MM–covariate relationships (n = 34). Results MM incidence rates are double in African-Americans compared with Whites, in SEER-13 areas (rate ratio (RR) = 2.27; 95% confidence interval [CI] = 2.22–2.32) and NYC (RR = 2.11; 95% CI = 2.03–2.20). Incidence rates increased faster in NYC (average annual percentage change difference, −1.1; 95% CI, −2.3 to −0.1). NYC African-American men experienced the steepest increase in mortality rates after 2001. In NYC, strong neighborhood-level correlations exist between incidence and mortality rates and high prevalence of residents of African ancestry, Latin American birth, daily sugary beverage and low fruit and vegetable consumption, and neighborhood walkability. Higher MM mortality also correlates with Hispanic ethnicity, obesity, diabetes, poverty, HIV/AIDS, air benzene concentration, and indoor pesticide use. Conclusions NYC neighborhoods with large minority populations have higher prevalence of poverty-related factors associated with MM incidence and mortality, warranting public health policies to address exposures and access to care.

A rare case of acquired amegakaryocytic thrombocytopenia (AATP) in a 35-year-old woman who presented with anaemia and thrombocytopenia at 22 weeks gestation. The first diagnostic impression was of an evolving aplastic anaemia; however, the patient was simultaneously diagnosed with severe vitamin B12 deficiency in the setting of vegetarianism. Once the cyanocobalamin deficiency was corrected, a repeat bone marrow biopsy revealed an isolated depletion of megakaryocytes, which suggested the diagnosis of AATP. Supportive care was provided for her anaemia and thrombocytopenia and she delivered a healthy baby girl with a normal platelet count. The patient was subsequently started on romiplostim with steady improvement in her platelet counts. This rare AATP case presentation highlights the importance of a well-structured diagnostic approach to thrombocytopenia during pregnancy and supports the successful use of thrombopoietin agonists for the management of AATP.

Late acute (LA) graft-versus-host disease (GVHD) is persistent, recurrent, or new-onset acute GVHD symptoms occurring >100 days after allogeneic hematopoietic cell transplantation (HCT). The aim of this analysis is to describe the onset, course, morbidity, and mortality of and examine angiogenic factors associated with LA GVHD. A prospective cohort of patients (n = 909) was enrolled as part of an observational study within the Chronic GVHD Consortium. Eighty-three patients (11%) developed LA GVHD at a median of 160 (interquartile range, 128-204) days after HCT. Although 51 out of 83 (61%) achieved complete or partial response to initial therapy by 28 days, median failure-free survival was only 7.1 months (95% confidence interval, 3.4-19.1 months), and estimated overall survival (OS) at 2 years was 56%. Given recently described alterations of circulating angiogenic factors in classic acute GVHD, we examined whether alterations in such factors could be identified in LA GVHD. We first tested cases (n = 55) and controls (n = 50) from the Chronic GVHD Consortium and then validated the findings in 37 cases from Mount Sinai Acute GVHD International Consortium. Plasma amphiregulin (AREG; an epidermal growth factor [EGF] receptor ligand) was elevated, and an AREG/EGF ratio at or above the median was associated with inferior OS and increased nonrelapse mortality in both cohorts. Elevation of AREG was detected in classic acute GVHD, but not chronic GVHD. These prospective data characterize the clinical course of LA GVHD and demonstrate alterations in angiogenic factors that make LA GVHD biologically distinct from chronic GVHD.

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.

AML is stratified into risk-categories based on cytogenetic and molecular features that prognosticate survival and facilitate treatment algorithms, though there is still significant heterogeneity within risk groupings with regard to risk of relapse and prognosis. The ambiguity regarding prognosis is due in large part to the relatively outdated criteria used to determine response to therapy. Whereas risk assessment has evolved to adopt cytogenetic and molecular profiling, response criteria are still largely determined by bone marrow morphologic assessment and peripheral cell count recovery. Minimal residual disease refers to the detection of a persistent population of leukemic cells below the threshold for morphologic CR determination. MRD assessment represents standard of care for ALL and PML, but concerns over prognostic capability and standardization have limited its use in AML. However, recent advancements in MRD assessment and research supporting the use of MRD assessment in AML require the reconsideration and review of this clinical tool in this disease entity. This review article will first compare and contrast the major modalities used to assess MRD in AML, such as RQ-PCR and flow cytometry, as well as touching upon newer technologies such as next-generation sequencing and digital droplet PCR. The majority of the article will discuss the evidence supporting the use of MRD assessment to prognosticate disease at various time points during treatment, and review the limited number of studies that have incorporated MRD assessment into novel treatment algorithms for AML. The article concludes by discussing the current major limitations to the implementation of MRD assessment in this disease. The manuscript is bookended by a clinical vignette that highlights the need for further research and refinement of this clinical tool.

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.

Topic Significance & Study Purpose/Background/Rationale Outcomes of older adults with acute lymphoblastic leukemia (ALL) remain poor [PMID 19897583, 28419558, 22409379, 10653870]. PEG-Asparaginase (PEG-Asp) is a key component of the chemotherapeutic regimens for treatment of pediatric and younger adult ALL [PMID 29450465]. Older patients with Ph-negative ALL are often not offered PEG-Asp containing regimen due to concerns related to tolerability and safety [PMID 28355969]. Methods, Intervention, & Analysis The Adult Leukemia Program at Mount Sinai Hospital developed an age-based, dose-adjusted pediatric chemotherapy regimen for adults (≥40 years) with diagnosis of Ph-negative ALL. For patients up to 60 years, prednisone (PRD) dose was reduced to 40 mg/m2/day, and PEG-Asp to 1000 units/m2. For patients aged ≥61 years, PRD was further reduced to 25 mg/m2/day. A PEG-Asp oriented supportive care plan was developed to prevent and treat Asp-related adverse effects (AE) based on Antithrombin III (ATIII) and fibrinogen levels. Findings & Interpretation Fourteen patients with median age 60 years (45 – 76) were evaluable, and three patients were ≥ 70 years. Eleven patients had significant co-morbidities at diagnosis, including diabetes, hypertension, previous history of cancer, coronary artery disease, obesity, alcohol related chronic pancreatitis, and chronic diarrhea. Eleven patients (79%) attained a complete remission (CR) at the end of induction (EOI), four of them with detectable minimal residual disease (MRD). Five patients underwent allogeneic hematopoietic stem cell transplantation (HCT) while in CR (age range 46 – 60), four remain in CR at last follow up (median 563 days, range 259 – 883), and one died of relapsed disease 67 days post-HCT. The other eight patients who are receiving chemotherapy are in remission at last follow up (median 317 days, range 63 – 714). Observed PEG-Asp related AE were asymptomatic hypofibrinogenemia and low ATIII levels (n=10), severe hyperbilirubinemia (n=1), and non-life-threatening venous thrombosis (n=1). No patient experienced early death, severe allergic reaction or clinical pancreatitis. Discussion & Implications This dose-adjusted PEG-Asp containing regimen was associated with an encouraging CR rate and with tolerable and manageable AE in this patient population with significant co-morbidities. Treatment related mortality was 0%. Twelve of the 14 patients are currently in sustained remission (median follow-up 399 days, range 63-883). Further prospective evaluation is under way.

Background aims Stem cell collection can be a major component of overall cost of autologous stem cell transplantation (ASCT). Plerixafor is an effective agent for mobilization; however, it is often reserved for salvage therapy because of its high cost. We present data on the pharmacoeconomic impact of the use of plerixafor as an up-front mobilization in patients with multiple myeloma (MM). Methods Patients with MM who underwent ASCT between January 2008 and April 2011 at the Mount Sinai Medical Center were reviewed retrospectively. In April 2010, practice changes were instituted for patients with MM to delay initiation of granulocyte-colony-stimulating factor (G-CSF) support from day 0 to day +5 and to add plerixafor to G-CSF as an up-front autologous mobilization. Targets of collection were 5–10 × 10 6 CD34 + cells/kg. Results Of 50 adults with MM who underwent ASCT, 25 received plerixafor/filgrastim and 25 received G-CSF alone as an up-front mobilization. Compared with the control, plerixafor mobilization yielded higher CD34 + cell content (16.1 versus 8.4 × 10 6 CD34 + cells/kg; P = 0.0007) and required fewer sessions of apheresis (1.9 versus 3.1; P = 0.0001). In the plerixafor group, the mean number of plerixafor doses required per patient was 1.8. Although the overall cost of medications was higher in the plerixafor group, the cost for blood products and overall cost of hospitalization were similar between the two groups. Conclusions Up-front use of plerixafor is an effective mobilization strategy in patients with MM and does not have a substantial pharmacoeconomic impact in overall cost of hospitalization combined with the apheresis procedure.

e18140 Background: Multiple Myeloma (MM) management has significantly improved disease-free and overall (OS) survival but disparities among racial groups still exist. After the Affordable Care Act, the extent to which induction, autologous stem cell transplant (ASCT), and maintenance therapies are used are uncertain. We sought to describe underuse of induction, ASCT and maintenance in a large referral center. Methods: Between 2010 and 2014, 3101 patients were diagnosed with MM via ICD-9 code from the Data Warehouse and certified hospital tumor registry. NCCN 2014 and CMS guidelines were used to define the categories of treatment underuse, and define transplant eligibility. Demographics including insurance, Charlson Comorbidity Index and treatments received were determined via chart abstraction. To date, 393 confirmed MM from 697 charts were abstracted. Comparison by groups used Chi-square for categorical variables, t-test and ANOVA for continuous variables. Multivariate logistic regression models were applied to predict underuse of induction, harvest, ASCT, and maintenance. Results: Patients were 62 ±11.3 years-old, with no racial differences in age and insurance coverage. More minorities had Medicaid (Black [B] 13%, White [W] 7%, Hispanic [H] 25%; p = 0.001). Almost all patients (97%) received induction (B 99%, W 96%, H 100%; p = 0.3), with no difference by insurance. Among transplant eligible patients, 93% underwent harvest, 87% underwent ASCT, with no racial differences. Patients with Medicare or self-pay were less likely to undergo harvest compared to patients with Medicaid or private insurance (p = 0.01). No difference in ASCT rates by insurance were noted. B patients were less likely to receive maintenance than non-B (73% vs 86%; p = 0.03), with no difference by insurance. OS was 73%, with no racial differences. In multivariate model, older age predicted induction underuse (aOR = 1.15, 95% CI: 1.06-1.25) (c = 0.9, p = 0.005), and B patients experienced more maintenance underuse (aOR = 2.22, 95% CI: 1.09-4.54) (c = 0.61, p = 0.1), controlling for age and comorbidity. Conclusions: While there were no racial or insurance differences in access to induction therapy, fewer Black patients received maintenance therapy. Interviews are underway to understand reasons for observed differences.

e18159 Background: Care coordination affects the quality of cancer treatment. Multiple Myeloma (MM) patients frequently are cared for by local and referral center physicians. We sought to determine whether getting treated at different sites might impact on the quality of MM care. Methods: We used NCCN 2014 and CMS guidelines to define categories of treatment quality and transplant eligibility. We defined high quality MM care as: Induction for all patients with ECOG < 4; harvest & transplant for patients completing induction without progression, with albumin > 2.8, bilirubin < 3 and age ≤77 years; maintenance for transplant ineligible patients completing induction with no progression & for transplant eligible patients completing transplant with no progression; and supportive care of receiving bone targeting agents, anticoagulation and infection prophylaxis for all patients receiving MM therapy. Patients who received care with both local and referral center physicians were considered to have received care at 2 sites. We abstracted 709 charts of patients with ICD-9 diagnosis of MM from 2010-2014 for demographics, site of care and treatments received. We compared groups with chi square and multivariate logistic regression models with age, insurance, race, comorbidity and sites of care to predict care quality. Results: Of the 709, 388 had active MM. On average, patients were 62 ±11 years. Overall, 70% received care at > 1 site. Referred patients had no differences by age, comorbidity index, insurance or race. Having > 1 care site was associated with higher rates of induction and harvest. Conclusions: Historically, hand-offs in care have been associated with poorer quality. However, in a referral center, hand-offs do not negatively affect induction and harvest care quality. Patients referred to a MM center are more likely to get high quality treatments for which they are referred, but referral does not ensure receiving the full gamut of needed MM treatments.[Table: see text]

BACKGROUND. No laboratory test can predict the risk of nonrelapse mortality (NRM) or severe graft-versus-host disease (GVHD) after hematopoietic cellular transplantation (HCT) prior to the onset of GVHD symptoms. METHODS. Patient blood samples on day 7 after HCT were obtained from a multicenter set of 1,287 patients, and 620 samples were assigned to a training set. We measured the concentrations of 4 GVHD biomarkers (ST2, REG3α, TNFR1, and IL-2Rα) and used them to model 6-month NRM using rigorous cross-validation strategies to identify the best algorithm that defined 2 distinct risk groups. We then applied the final algorithm in an independent test set (n = 309) and validation set (n = 358). RESULTS. A 2-biomarker model using ST2 and REG3α concentrations identified patients with a cumulative incidence of 6-month NRM of 28% in the high-risk group and 7% in the low-risk group (P < 0.001). The algorithm performed equally well in the test set (33% vs. 7%, P < 0.001) and the multicenter validation set (26% vs. 10%, P < 0.001). Sixteen percent, 17%, and 20% of patients were at high risk in the training, test, and validation sets, respectively. GVHD-related mortality was greater in high-risk patients (18% vs. 4%, P < 0.001), as was severe gastrointestinal GVHD (17% vs. 8%, P < 0.001). The same algorithm can be successfully adapted to define 3 distinct risk groups at GVHD onset. CONCLUSION. A biomarker algorithm based on a blood sample taken 7 days after HCT can consistently identify a group of patients at high risk for lethal GVHD and NRM. FUNDING. The National Cancer Institute, American Cancer Society, and the Doris Duke Charitable Foundation.

Background Subjects with lower gastrointestinal (GI) acute graft-versus-host disease (aGvHD) generally respond poorly to therapy, and therefore have increased morbidity and mortality. Vedolizumab, a gut-selective antibody targeting α4β7 integrin, is approved for the treatment of inflammatory bowel diseases. Vedolizumab interferes with gut-trafficking of immunocompetent donor T-lymphocytes and may have a role in preventing GI aGvHD. Here we present the 6-month results of a phase 1b study of the safety, tolerability and clinical activity of vedolizumab combined with standard graft-versus-host disease (GvHD) prophylaxis. Methods This is an open-label, dose-finding study of the addition of vedolizumab to standard GvHD prophylaxis in adults undergoing hematopoietic stem cell transplantation (HCT). Cohort 1 comprised subjects aged 18-60 years with a hematologic malignancy undergoing human leukocyte antigen (HLA)-matched or 1 locus-mismatched, unrelated-donor myeloablative transplantation. These subjects received intravenous (IV) vedolizumab (75 mg, on days -1, +13 and +42 of HCT). If subjects in cohort 1 experienced no engraftment failures or dose-limiting toxicities (DLTs), then subsequent subjects were enrolled into a dose-expansion cohort of IV vedolizumab 300 mg (cohort 2), following the same schedule. Key inclusion criteria for cohort 2 were myeloablative regimens (subjects aged 18-60 years) or reduced-intensity conditioning regimens (subjects aged 18-75 years), donor-recipient pairs who were HLA-matched or 1-locus mismatched, and subjects receiving peripheral blood- or bone-marrow-derived stem cells. All subjects received standard GvHD prophylaxis (tacrolimus and methotrexate). The primary objective was to identify an efficacious vedolizumab dose with an acceptable safety profile for future studies, using the following primary safety endpoints: frequency of DLTs from day -1 to day 28, and the number of patients experiencing treatment-emergent adverse events (TEAEs) and serious adverse events from administration of the first dose of vedolizumab until 18 weeks after the final dose. Secondary endpoints included time to neutrophil engraftment, cumulative incidence of grade II-IV aGvHD and frequency by maximum severity of aGvHD by modified Glucksberg criteria. Exploratory endpoints included overall survival (OS) and aGvHD-free survival. Results In total, 24 subjects were enrolled at 5 centers (3 in cohort 1, then 21 in cohort 2). The median age was 55 years (range 18-72 years). Most subjects underwent an unrelated donor HCT (83%), and all except 1 were HLA-matched (Table 1). At 6 months after HCT, no DLTs were observed in either cohort. All subjects engrafted within 28 days; the median time to neutrophil engraftment was 14 days in cohort 2. All subjects experienced at least 1 TEAE, which was serious in 13 subjects (2 in cohort 1, 11 in cohort 2). TEAEs were considered vedolizumab-related in 2 subjects in cohort 1 and 6 in cohort 2, including 1 subject in cohort 2 who experienced 2 serious TEAEs: hypotension and febrile neutropenia. The most frequent infections were cytomegalovirus (4 cases) and Clostridium difficile colitis (3 cases). No adverse events led to discontinuation of vedolizumab. There were no cases of grade II-IV aGvHD at 6 months after HCT in cohort 1. In cohort 2, 4 subjects (19%) developed grade II-IV aGvHD at 6 months after HCT; 3 (14%) grade II (1 skin only involvement, 2 skin and lower GI involvement) and 1 (5%) grade III (liver, skin and lower GI involvement). All cases of lower GI aGvHD were limited to stage 1 disease. At 6 months after HCT, 1 subject died from disease relapse in cohort 1, and 2 subjects died in cohort 2; 1 from disease relapse and 1 from aGvHD-related complications. Among subjects in cohort 2, 6-month OS and non-relapse mortality were 90% and 5%, respectively, and grade II-IV and grade III-IV aGvHD-free survival were 76% and 90%, respectively (Table 2). Conclusions In subjects receiving vedolizumab in addition to standard GvHD prophylaxis, there were no DLTs or engraftment failures at 6 months after HCT, and the TEAEs observed have been as expected in this population. The low cumulative incidences of grade II-IV and grade III-IV aGvHD are promising; there were no cases of lower GI aGvHD greater than stage 1. Intravenous vedolizumab 300 mg added to standard GvHD prophylaxis for the prevention of GI aGvHD merits further study. Disclosures Chen: Takeda Pharmaceuticals: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy. Shah:Lentigen Technology: Research Funding; Oncosec: Equity Ownership; Exelexis: Equity Ownership; Miltenyi: Other: Travel funding, Research Funding; Juno Pharmaceuticals: Honoraria; Geron: Equity Ownership. Jansson:Takeda Pharmaceuticals: Employment. Akbari:Takeda Pharmaceuticals: Employment. Chen:Takeda Pharmaceuticals: Employment. Quadri:Takeda Pharmaceuticals: Employment. Parfionovas:Takeda Pharmaceuticals: Employment. Devine:Kiadis Pharma: Consultancy.

Background The outcomes of older adults with acute lymphoblastic leukemia (ALL) remain poor when compared to younger ALL patients [PMID 19897583, 28419558, 22409379, 10653870]. Asparaginase (Asp) induces death of human lymphoblasts, and effective asparagine depletion is associated with improved outcomes in ALL. PEG-Asparaginase (PEG-Asp), which has a longer half-life than Asp, is a key component of the intensive chemotherapeutic regimens utilized for treatment of pediatric and younger adult ALL [PMID 29450465]. Frequently, older patients with Ph-negative ALL are not offered PEG-Asp containing pediatric chemotherapy regimen because of concerns related to tolerability and safety in this population [PMID 28355969]. Methods The Adult Leukemia Program at Mount Sinai Hospital developed an age-based, dose-adjusted, CALGB 10403 based intensive chemotherapy regimen for adults (≥40 years) with a diagnosis of Ph-negative ALL. For patients up to 60 years, prednisone (PRD) dose was reduced from 60 to 40 mg/m2/day from D1 to D28, and PEG-Asp reduced from 2500 to 1000 units/m2 (D4). For patients aged 61 years and above, PRD was further reduced to 25 mg/m2/day, and PEG-Asp to 1000 units/m2 on D4. In CD20+ ALL, rituximab x 8 doses were added to the regimen. CNS-prophylaxis consisted of intrathecal methotrexate at D1, D8 and D29 during induction, and during subsequent courses of chemotherapy based on the CALGB 10403 protocol. A PEG-Asp oriented supportive care plan was developed to prevent and treat Asp-related adverse effects. After the administration of PEG-Asp, Antithrombin III (ATIII) and fibrinogen levels were monitored on the same day, twice a week, for at least two weeks. If ATIII levels were < 70% and/or fibrinogen levels < 120 mg/dL, levels were corrected with the administration of ATIII concentrate and/or cryoprecipitate, respectively. Results Twelve patients with a median age of 58 years (45 - 76) were evaluable, and three patients were ≥ 70 years. Nine patients had B-cell ALL and three T-cell ALL. Three patients had a white blood cell count > 30 x103/µL at diagnosis. An ECOG status ≤ 2 at diagnosis was described in all patients, and all of them had multiple complex cytogenetic and molecular abnormalities. Ten patients had significant co-morbidities at diagnosis, including diabetes, hypertension, previous history of cancer, coronary artery disease, obesity, alcohol related chronic pancreatitis, and chronic diarrhea. Nine out of the twelve patients (75%) attained a bone marrow morphological complete remission (CR) at the end of induction (EOI), three of them with detectable minimal residual disease (MRD) that became undetectable after completing course II. Of the three patients who had ≥5% bone marrow blasts at EOI, one attained a CR with undetectable MRD at the end of course IA and another when switched to blinatumomab, and the third one died of progressive disease. No patient experienced early death. Five patients underwent allogeneic hematopoietic stem cell transplantation (HCT) while in CR (age range 46 to 60 years) and four remain in CR at last follow up (median 489 days, range 181 - 841), and one died of relapsed disease 67 days post-HCT. The other six patients who are receiving chemotherapy are alive and in remission at last follow up (median 272 days, range 52 - 639). The common adverse effects associated with PEG-Asp administration in this older group of patients were asymptomatic hypofibrinogenemia and depleted ATIII levels requiring supplementation (n=8), severe hyperbilirubinemia (n=1), and non-life-threatening venous thrombosis (n=1). Severe allergic reaction, clinical pancreatitis and cognitive impairment were not observed. Conclusion This age-based dose-adjusted PEG-Asp containing regimen was associated with an encouraging CR rate and a tolerable and manageable adverse event profile in this older patient population with significant co-morbidities. Treatment related mortality was 0%. Ten of 12 patients are currently in sustained remission, either with chemotherapy alone or following allogeneic HCT (median follow up 422 days, range 52 to 841 days). Treatment optimization for older patients with ALL utilizing an intensified, age-adjusted PEG-Asp containing induction and consolidation therapy regimen is associated with favorable outcomes and provides an effective bridge to potentially curative therapies such as HCT. Further prospective evaluation is under way. Table. Table. Disclosures Kremyanskaya: Incyte: Research Funding. Mascarenhas:Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Promedior: Research Funding; Janssen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding.

138 Background: Trimethoprim-sulfamethoxazole (TMP-SMX) is preferred for prevention of Pneumocystis pneumonia (PCP), toxoplasmosis and other opportunistic infections after allogeneic hematopoietic cell transplantation (HCT), but it is often withheld due to potential adverse events (AE). From July 2016-June 2017 we observed that 31% of allogeneic HCT recipients at our hospital were prescribed TMP-SMX throughout the high risk period (day +30-180). Therefore, we developed an intervention to explore reasons for such a low prescription rate and to optimize TMP-SMX use. Methods: Our institution’s HCT practice guidelines were revised to include indications for TMP-SMX and alternative agents for PCP and Toxoplasma prophylaxis and specific clinical and laboratory criteria for withholding TMP-SMX. Education on the guidelines was provided to transplant clinicians. Outpatient encounters were prospectively audited from January to April 2018. Providers received real-time feedback with recommendations in accordance with our guidelines prior to patients’ visits. Results: We reviewed 321 outpatient encounters among 112 patients. Seventy-six (68%) patients were on TMP-SMX prophylaxis at the first reviewed encounter. Cytopenias were the most common reason for withholding TMP-SMX, occurring in 50 (57%) encounters, followed by elevated liver function tests (LFTs) (13.6%), hyperkalemia (3.4%), elevated creatinine (3.4%), rash or hypersensitivity (3.4%), and unknown/other (22%) . In 73 encounters in which patients received alternative or no PCP prophylaxis, we recommended changing to TMP-SMX. This intervention was accepted in 15 patients, 11(73%) of whom tolerated TMP-SMX well. In the remaining four patients, TMP-SMX was subsequently discontinued due to unrelated AE (N = 3) and possible TMP-SMX-associated elevated LFTs (N = 1). Conclusions: Provider education and real-time feedback led to increased utilization of TMP-SMX for prevention of PCP and other opportunistic infections in HCT recipients without an increase in TMP-SMX-related adverse effects. Further study is needed to understand the low clinician acceptance rate of the intervention.

Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation. The clinical staging of GVHD varies greatly between transplant centers and is frequently not agreed on by independent reviewers. The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multicenter clinical trials. We developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in a large international GVHD research consortium. During the first year of use, the guidance followed discussion of complex clinical phenotypes by experienced transplant physicians and data managers. These guidelines increase the uniformity of GVHD symptom capture, which may improve the reproducibility of GVHD clinical trials after further prospective validation.

[Figure][1] A 25-year-old woman with FLT3-ITD positive acute myeloid leukemia underwent cord blood transplantation with fludarabine, cyclophosphamide, and total body irradiation conditioning. Despite prophylaxis with mycophenolate and tacrolimus, she suffered from grade 4 gastrointestinal

Serum free light chain trends between orthotopic heart transplantation and auto-SCT in patients with AL amyloidosis

Introduction: Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand that can restore integrity to damaged intestinal mucosa in murine models of acute graft-versus-host disease (aGVHD). We previously described AREG as a circulating biomarker of late-onset aGVHD, but its relevance combined with clinical risk factors has not yet been tested in a large cohort of patients with aGVHD occurring prior to day 100 post-transplant. We therefore tested samples from two aGVHD first-line treatment trials, Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0302 and 0802, and identified a clinically relevant threshold level of circulating AREG at aGVHD onset. We then investigated whether incorporating AREG into the refined Minnesota Risk Score could further risk-stratify patients. Patients and Methods: Blood samples were obtained at the onset of systemic aGVHD treatment within BMT CTN 0302 (serum) and BMT CTN 0802 (plasma). All patients with response data and samples for analysis from both trials were included (N=251). We determined the association of AREG with clinical outcomes, including risk stratification by the refined Minnesota criteria, day 28 complete/partial response (CR/PR) to first-line therapy, 2-year overall survival (OS) and 6-month and 2-year non-relapse mortality (NRM). We investigated the effect of AREG on clinical endpoints per a doubling in the value of AREG, defined a clinically relevant threshold level in the AREG values using two-fold cross-validation, and confirmed the clinical relevance of this cut-point in independent samples (N=92) from pooled from drawn from the Chronic GVHD Consortium and the Mount Sinai Acute GVHD International Consortium (MAGIC). Results: In patients enrolled in BMT CTN 0302/0802, AREG levels were 1.7-fold higher in patients with Minnesota high-risk (HR) compared to standard-risk (SR) aGVHD (HR median 53.4 vs SR 31 pg/ml, p Conclusion: AREG is elevated in patients with poor aGVHD outcomes and adds to the accuracy of risk stratification when combined with the refined Minnesota Risk Score. AREG ≥33 pg/mL at aGVHD onset is associated with lower day 28 CR/PR and higher mortality in samples from 4 multicenter cohorts. The mechanism of elevated circulating AREG in severe aGVHD is not yet known, although we hypothesize the degree of AREG elevation reflects the intensity of immune-mediated tissue injury resulting in AREG release. With accumulating evidence of altered EGFR ligands in aGVHD, further investigation into epithelial repair pathways involving AREG may lead to new adjunctive therapies to overcome poor steroid response in high-risk aGVHD. Disclosures Holtan: Incyte: Other: One-time advisory board member. Khera: Novartis: Consultancy. Lee: Mallinckrodt: Honoraria; Amgen: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Kadmon: Other: One-time advisory board member. Chen: Immudex: Research Funding. Arora: Takeda Oncology: Consultancy. Flowers: Pharmacyclics: Consultancy. Cutler: Pfizer: Consultancy; Kite: Consultancy; Incyte: Consultancy; Bristol-Myers Squibb: Consultancy; Pharmacyclics: Consultancy; Astellas: Consultancy. Jagasia: Janssen: Consultancy, Research Funding; Therakos: Consultancy, Research Funding; Mallinckrodt: Consultancy. Hexner: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Levine: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. MacMillan: Magenta Therapeutics: Research Funding.

s / Biol Blood Marrow Transplant 20 (2014) S151eS164 S160 period with no DLT being identified and the third subject in cohort 4 (last cohort) is being treated. Median age was 54 (range 45-68). Median number of prior lines of therapy was 3 (range 2-6) and 7 subjects had previously received AHSCT. Median CD34+ dose was 4.6 x 106/kg (range 2.21-9.34). Median time for neutrophil engraftment was 11 days (range 8-15) and for platelet engraftment 18 days (range 11-24). There were no non-hematologic grade 4 toxicities. The most frequent grade 3 toxicity was infection in 8/14 subjects consisting of 1 episode of pneumonia, 1 episode of bacteremia, 1 episode of urinary tract infection and 5 episodes of febrile neutropenia. Other grade 3 toxicities were rash (n1⁄42), hypertension (n1⁄41), hypophosphatemia (n1⁄41) and hypocalcemia (n1⁄41). Twelve subjects, from cohorts 0, 1, 2 and 3 have reached day +100 response assessment. Distribution of subjects by category of response before and after AHSCT is displayed in Figure 2. Conclusion: Conditioning with carfilzomib and melphalan prior to AHSCT is well tolerated in patients with relapsed MM. Final results of this phase 1 study will be presented at the meeting. TheMTD cohort (or cohort 4 if noMTD is found) will be subsequently expanded to 28 subjects for better determination of this regimen’s activity and toxicity.

Background: Kaposi’s sarcoma associated-herpesvirus causes all forms of Kaposi’s sarcoma, and six major subtypes have been described based on the amino acid sequences of the open reading frame K1. Main observations: A 71-year-old man from China, HIV negative, presented with nodules on the dorsal aspect of his toes. Biopsy confirmed the diagnosis of Kaposi’s sarcoma and virology studies of his blood and saliva confirmed the presence of Kaposi’s sarcoma associated-herpesvirus infection. Viral genotyping was consistent with subtype C3. Intervention has been deferred as our patient has remained clinically asymptomatic and without evident growth of his lesions over a 2-year follow up. Conclusions: We herein report the first known case of Kaposi’s sarcoma restricted to the toes caused by the viral subtype C3 in an HIV-negative patient from Harbin, China. ( J Dermatol Case Rep . 2013; 7(3): 97-100)

Graft-versus-host disease (GVHD), the primary cause of non-relapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation, does not always respond to treatment with high dose systemic corticosteroids. We have recently shown that a combination of three biomarkers (TNFR1, ST2, and REG3α) measured at onset of GVHD can predict day 28 response to treatment and 6-month NRM (Levine, Lancet Haem, 2015). Our goal in the current study was to determine if the same biomarker-based Ann Arbor GVHD algorithm can alsopredict treatment response andmortality whenapplied after one week of systemic corticosteroid treatment. The study population consisted of 378 patients (pts) with acute GVHD from 11 centers in the Mount Sinai Acute GVHD International Consortium. All pts were treated with systemic steroids and provided a plasma or serum sample obtained after one week of treatment (±3 days). The median starting dose of systemic steroids for Grade II-IV GVHD was 2.0 mg/kg/day and for Grade I was 1.0 mg/kg/day, after which treatment varied. Patients were divided into test (n=236) and validation (n=142) cohorts. We applied the Ann Arbor GVHD algorithm to concentrations of TNFR1, ST2, and REG3α measured after one week of treatment to generate a predicted probability of 6-month NRM, which we term the treatment score (TS). We employed unsupervised k-medoidclustering to partition TS values from the test cohort into two groups (high and low). This unbiased approach identified a high score group made up of 25% of pts (n=58) in the test cohort. We observed that the day 28 response rate (complete, CR + partial, PR) was significantly lower in pts with high scores compared to low scores in the test cohort (24% vs 65%, p Approximately half of the pts in each cohort (test: 48%; validation: 44%) responded (CR+PR) to the first week of steroids and these ptshad significantly lower 6-month NRM than non-responders (NR) (test: 17% vs 36%, p=0.0002; validation: 13% vs 36%, p=0.0014). Yet the TS continued to stratify mortality risk independently of clinical response. In the test cohort, pts with a high score comprised 16% of all early responders and experienced more than twice the NRM of early responders with a low score (33% vs 13%, p=0.022) (Fig 2A). Conversely, test cohort pts who did not respond by day 7, but had a low score, fared much better than non-responders with a high score (NRM 21% vs 68%, p In conclusion, a treatment score based on three GVHD biomarkers measured after one week of steroids stratifies pts into two groups with distinct risks for treatment failure and 6-month NRM. It is particularly noteworthy that the TS identifies two subsets of pts with steroid refractory (SR) GVHD who have highly different outcomes (Fig 2B/D). The much larger group, approximately two thirds of all SR pts, may not need the same degree of treatment escalation as is traditional for clinical non-response, and thus overtreatment might be avoided. Because the TSis measured at a common decision making time point, it may prove useful to guide risk-adapted therapy. Disclosures Mielke: Novartis: Consultancy; MSD: Consultancy, Other: Travel grants; Celgene: Other: Travel grants, Speakers Bureau; Gilead: Other: Travel grants; JAZZ Pharma: Speakers Bureau. Kroeger:Novartis: Honoraria, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Jagasia:Therakos: Consultancy. Kitko:Therakos: Honoraria, Speakers Bureau. Ferrara:Viracor: Patents & Royalties: GVHD biomarker patent. Levine:Viracor: Patents & Royalties: GVHD biomarker patent.

No laboratory test can predict non-relapse mortality (NRM) after hematopoietic cellular transplantation (HCT) prior to the onset graft-versus-host disease (GVHD). Recently, we have shown that a signature of three GVHD plasma biomarkers (TNFR1, ST2, and REG3α) can predict response to GVHD therapy and NRM at the onset of clinical GVHD (Levine, Lancet Haem, 2015). Our goal in the current study was to identify a blood biomarker signature that could predict lethal GVHD and six-month NRM well in advance of the onset of GVHD symptoms. Patient samples on day +7 after HCT were obtained from 1,287 patients from 11 HCT centers in the Mount Sinai Acute GVHD International Consortium (MAGIC). Samples from two large centers (n = 929) were combined and randomly assigned to a training set (n = 620) and test set (n = 309). 358 patients from nine others centers constituted an independent validation set. The overall cumulative incidences of 6-month NRM were 11%, 12%, and 13% for the training, test, and validation sets respectively. The incidence of lethal GVHD, defined as death without preceding relapse while under steroid treatment for acute GVHD, were 18%, 24%, and 14% in the same groups, respectively. The median day of GVHD onset was 28 days in the training set and 29 days in the test and validation sets. We measured four GVHD related biomarkers [ST2, REG3α, TNFR1, and IL2Rα] in all samples and used the training set alone to develop competing risks regression models that used all 13 possible combinations of one to four biomarkers to predict 6-month NRM. The best algorithm, which we rigorously confirmed through Monte Carlo cross-validation of 75 different combinations of training sets, included ST2 and REG3α. No combination of one, three, or four biomarkers was superior to the combination of these two biomarkers. The day 7 algorithm identified high risk (HR) and low risk (LR) groups with 6-month NRMs of 28% and 7%, respectively (p In conclusion, we have developed a blood biomarker algorithm that predicts the development of lethal GVHD seven days after HCT, which performed successfully in large multicenter validation sets. The GVH reaction is already in progress by day +7, even though clinical symptoms may not occur until days or weeks later. We speculate that the blood biomarker concentrations at this early time point reflect subclinical GI pathology, a notion that is reinforced by the fact that ST2 and REG3α, the two biomarkers in the algorithm, are closely associated with GI GVHD. The algorithm identified HR and LR strata in several patient groups with different overall risk for lethal GVHD (donor, HLA match, conditioning regimen intensity, age). This day +7 algorithm should prove useful in clinical BMT research by identifying patients at high risk for lethal GVHD who might benefit from aggressive preemptive treatment strategies. Disclosures Chen: Novartis: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagasia:Therakos: Consultancy. Kitko:Therakos: Honoraria, Speakers Bureau. Kroeger:Novartis: Honoraria, Research Funding. Levine:Viracor: Patents & Royalties: GVHD biomarkers patent. Ferrara:Viracor: Patents & Royalties: GVHD biomarkers patent.

Type II diabetes mellitus accounts for 90% of all cases of diabetes, and its inclusion in health evaluation has shown that its complications have a considerable impact on the population's quality of life. The current article presents the results of the Global Burden of Disease Study in Brazil for the year 1998, with an emphasis on diabetes mellitus and its complications. The indicator used was disability-adjusted life years (DALY), using a discount rate of 3%. In Brazil, ischemic heart disease, stroke, and diabetes accounted for 14.7% of total lost DALYs. Brazil showed a higher proportion of years lived with disability (YLDs) among total DALYs for diabetes as compared to other countries. Retinopathy and neuropathy were the complications that contributed most to YLDs. According to forecasts, diabetes mellitus will have an increasing impact on years of life lost due to premature death and disability in the world, shifting from the 11th to 7th cause of death by 2030. It is thus urgent to implement effective measures for prevention, early diagnosis, counseling, and adequate follow-up of patients with diabetes mellitus. O diabetes mellitus tipo II é responsável por 90% de todos os casos de diabetes, e sua inclusão na avaliação de saúde evidencia que as suas complicações têm um considerável impacto na qualidade de vida de uma população. O presente artigo apresenta os resultados do Estudo de Carga Global de Doença, realizado no Brasil para o ano de 1998, com ênfase no diabetes mellitus e suas complicações. O indicador utilizado foi o disability-adjusted life years (DALY), ao qual aplicou-se a taxa de desconto de 3%. No Brasil, doenças isquêmicas do coração, doenças cardiovasculares e diabetes contribuíram com 14,7% do total de DALY. Observou-se uma maior participação do years lived with disability (YLD) no total de DALY para o diabetes quando comparado a outros países. As complicações retinopatias e neuropatias foram as que mais contribuíram para o YLD. Projeções indicam que o diabetes mellitus terá crescente impacto sobre a perda de anos de vida por morte prematura e incapacidade no mundo, e que se deslocará de 11ª para 7ª causa de morte em 2030. Faz-se urgente a implantação e implementação de medidas efetivas para prevenção, diagnóstico precoce, aconselhamento e adequado acompanhamento dos pacientes com diabetes mellitus.

Background The rupture of the anterolateral papillary muscle is less common than the posteromedial papillary muscle since the anterolateral muscle has dual blood supplies, while the posteromedial papillary muscle has a single blood supply. Case presentation We present a case report of a 42 year old male presenting with heart failure being diagnosed to have mitral regurgitation from the partial rupture of the anterolateral papillary muscle due to coronary artery disease. The patient underwent a mitral valve replacement and concomitant coronary artery bypass grafting of the first and the second obtuse marginal arteries. Conclusion Acute mitral regurgitation can be precipitated by acute myocardial infarction due to rupture of the anterolateral papillary muscle.

Clinical GVHD staging varies between centers and is not agreed upon by independent reviewers (Weisdorf, BBMT 2003). These inconsistencies help explain why promising GVHD treatments from single center studies have not reproduced in multicenter trials. To address this issue, our international GVHD research consortium has developed guidance that has been refined through consensus following case discussions, resulting in uniform and reproducible GVHD clinical symptom reporting. We record all raw target organ symptom data and apply staging based upon this data (Table 1). Only areas of erythema, bullae and desquamation are quantified because other skin changes are not typical of active GVHD rash. Upper GI symptoms must meet thresholds to diagnose GVHD: anorexia with associated weight loss, nausea and/or 2+ vomiting episodes/day lasting 3+ days. For lower GI GVHD we collect stool volumes excluding formed/mostly-formed stools. Unquantified episodes are counted at 200 ml per episode (3 ml/kg for children We classify biopsy report interpretation into four standardized categories: Positive (unequivocal presence of GVHD), Equivocal (findings suggestive of GVHD, but the pathologist cannot confirm the diagnosis), Non-diagnostic (no abnormalities or subtle findings insufficient to determine etiology), and Non-GVHD etiology (definitive evidence of another diagnosis without concomitant features suggestive of GVHD). We then combine the biopsy interpretation with clinical decision making to assign an overall confidence level to the diagnosis of GVHD in each target organ (Table 2): Confirmed (positive biopsy, regardless of clinician treatment decision), Probable (GVHD diagnosis is sufficiently favored that treatment is given without a positive biopsy), Possible (symptoms present without a positive biopsy; not treated as GVHD), Negative (no symptoms or symptoms are present but a GVHD diagnosis is not entertained and a non-GVHD etiology is identified). Uniform clinical data collection is essential for future GVHD trials and requires application of clear guidance. While still subject to refinement, these guidelines, in use for 2 years by an international research consortium, are designed to be clear, easy to apply, and for clinical trial use. Table 1. GVHD Target Organ Staging Stage Skin (active erythema only) Liver (bilirubin) Upper GI Lower GI (stool output/day) 0 No active (erythematous) GVHD rash < 2 mg/dl No or intermittent nausea, vomiting or anorexia Adult: < 500 ml/day or 50% BSA 6.1-15 mg/dl - Adult: >1500 ml/day or >7 episodes/day Child: > 30 ml/kg/day or >10 episodes/day 4 Generalized rash (>50% BSA) and bullous formation or desquamation > 5% BSA >15 mg/dl - Severe abdominal pain with or without ileus, or grossly bloody stool (volume independent) Table 2. Confidence Levels Pathologic evidence Clinician assessment Treatment for acute GVHD Comments Confirmed Unequivocal evidence of GVHD GVHD is the etiology for symptoms Not required GVHD is clearly present even if other etiologies co-exist simultaneously Probable Not required (includes equivocal and non-diagnostic biopsies) GVHD most likely etiology for symptoms Yes GVHD is most likely present but other etiologies may also explain the symptoms and there insufficient evidence to make a confirmed diagnosis Possible GVHD in differential diagnosis (but no treatment is being provided) No GVHD may be present, but other etiologies are favored Negative Unequivocal evidence of a diagnosis other than GVHD (e.g., drug rash) GVHD is not considered as an explanation for the symptoms No and the symptoms resolve without GVHD treatment A "negative" biopsy (e.g., normal skin) is not unequivocal evidence of a diagnosis other than GVHD Disclosures Devine: Genzyme: Research Funding. Chen:Bayer: Consultancy, Research Funding. Porter:Novartis: Patents & Royalties, Research Funding. Levine:Novartis: Consultancy.