ALBERT

Description: 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 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.

Description: 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.

Description: 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.

Description: Key Points Biomarker scores generated after 1 week of steroid treatment of GVHD are prognostic. Biomarkers reflect prognosis better than early clinical response to GVHD treatment.

Description: 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

Description: 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

Description: Key Points Under current treatment approaches, patients with LA GVHD have poor overall and failure-free survival. Levels of AREG are elevated in LA GVHD, and the AREG/EGF ratio is predictive of overall survival and nonrelapse mortality in LA GVHD.