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Systemic glucocorticoids are the principal treatment for acute graft-versus-host disease (GVHD), which remains the major cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT). However, there are no validated biomarkers that measure a patient's response to glucocorticoid therapy, and thus response is evaluated by the change in clinical symptom severity. A major weakness in the predictive power of clinical responses is that changes to all organs are weighted equally even though the major driver of NRM is irreversible damage to the crypts of the GI tract. Recent studies from the Mount Sinai Acute GVHD International Consortium (MAGIC) have validated an algorithm probability (MAP) that combines serum concentrations of two biomarkers of GVHD (REG3α and ST2) to generate an estimated probability of 6 month NRM for individual patients. The MAP has been considered a "liquid biopsy" that estimates the damage caused by GVHD to crypts throughout the lower GI tract (Hartwell et al., JCI Insight, 2017; Major-Monfried et al., Blood, 2018). We hypothesized that the change in MAP between start of treatment and 28 days later could serve as a response biomarker for GVHD and might compare favorably to the change in clinical symptoms that measures response to GVHD treatment, which is widely used as a surrogate for long term survival and is the primary endpoint in most GVHD treatment trials (Martin et al., BBMT, 2009; MacMillan et al., Blood, 2010). We prospectively collected serum samples and clinical staging from 368 sequential HCT patients who received systemic treatment for acute GVHD in one of 20 MAGIC centers between January 2016 and February 2018. We measured the serum concentrations of REG3α and ST2 before and after systemic therapy for acute GVHD and computed MAPs, the changes in MAPs, and clinical responses for each patient. MAPs of patients who experienced 6 month NRM showed significantly greater increases than MAPs of patients who survived (p=0.0004). In patients whose MAPs at the start of treatment were low (Ann Arbor 1, MAP < 0.141) or intermediate (Ann Arbor 2, 0.141 ≤ MAP ≤ 0.290), 6 month NRM clustered among those who had the greatest increases in MAP after 28 days (Fig 1A,B). In patients with high MAPs at the start of treatment (Ann Arbor 3, MAP > 0.290), those who survived tended to have the largest decreases in MAP (Fig 1C). These changes in MAP suggested crossing a single threshold could predict risk of mortality. We found that patients whose MAPs rose above a threshold MAP of 0.290 (5% of Ann Arbor 1, 27% of Ann Arbor 2) had significantly worse survival compared to those who remained below it, whereas the large number patients with initially high MAPs that remained above the threshold (66% of Ann Arbor 3) had a large increases in mortality (Fig 2). When measured at day 28, the MAP was significantly more accurate in predicting NRM than the gold standard of the clinical response, with areas under the receiver operating characteristic curve (AUC) of 0.86 and 0.70, respectively (p<0.0001). An algorithm that combined clinical response with biomarkers generated the same AUC as the MAP alone (0.83 v 0.86, p = NS). We next tested whether the same MAP threshold of 0.290 could predict risk within clinical response subsets. A significant minority (10%) of clinical responders had high MAPs and experienced three-fold greater NRM than those with low MAPs (40% v 12%, p<0.0001) whereas the majority (57%) of non-responders had low MAPs and experienced almost three-fold lower NRM than those with high MAPs (24% v 65%, p<0.0001) (Fig 3). Thus the MAP provides important prognostic information over and above the change in clinical symptoms, further stratifying both responders and non-responders at four weeks of treatment. The MAP threshold classified patients both with and without significant lower GI symptoms because the MAP is a more specific measure of irreversible cryptic damage in patients with copious diarrhea and more sensitive in patients with less than 0.5 liters of daily diarrhea (Fig 4). We conclude that the MAP is, to our knowledge, the first validated laboratory test to serve as response biomarker for the treatment for acute GVHD and a more accurate predictor of survival than clinical response after four weeks of treatment. The MAP may serve as a novel endpoint and an important complement to changes in clinical symptom severity in future trials of GVHD treatment. Disclosures Srinagesh: National Institutes of Health: Research Funding. Ozbek:Viracor: Patents & Royalties: Biomarker Patent. Ayuk:Novartis: Honoraria, Other: Advisory Board, Research Funding. Aziz:Doris Duke Charitable Foundation: Research Funding. Defilipp:Incyte: Research Funding. Grupp:Novartis: Consultancy, Research Funding; Roche: Consultancy; GSK: Consultancy; CBMG: Consultancy; Novartis: Research Funding; Kite: Research Funding; Servier: Research Funding; Jazz: Other: study steering committees or scientific advisory boards; Adaptimmune: Other: study steering committees or scientific advisory boards; Cure Genetics: Consultancy; Humanigen: Consultancy. Hexner:novartis: Research Funding. Kitko:Mallinckrodt: Honoraria; Novartis: Consultancy, Honoraria. Mielke:EBMT/EHA: Other: Travel support; ISCT: Other: Travel support; Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; IACH: Other: Travel support; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; DGHO: Other: Travel support; Bellicum: Consultancy, Honoraria, Other: Travel (via institution); GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau. Merli:Sobi: Consultancy; Amgen: Honoraria; Novartis: Honoraria; Bellicum: Consultancy. Pulsipher:Amgen: Other: Lecture; Miltenyi: Research Funding; Bellicum: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Other: Education for employees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Honoraria. Qayed:Bristol-Myers Squibb: Honoraria. Reshef:Pfizer: Consultancy; Magenta: Consultancy; Kite: Consultancy, Research Funding; Atara: Consultancy, Research Funding; BMS: Consultancy; Pharmacyclics: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Research Funding; Shire: Research Funding. Levine:Incyte: Consultancy, Research Funding; Biogen: Other: non-financial support; Viracor: Patents & Royalties: biomarker patent; Ironwood: Honoraria; bluebird bio: Consultancy; National Cancer Institute: Research Funding; Novartis: Honoraria; Kamada: Research Funding. Ferrara:National Institutes of Health: Research Funding; ViraCor: Consultancy; Incyte: Consultancy; Kamada: Consultancy; Mallinckrodt: Consultancy; Enlivex: Consultancy; Xenikos: Consultancy; CSL Behring: Consultancy.

Key Points The MAGIC algorithm probability, computed from 2 serum biomarkers, predicts mortality in all GVHD grades after 4 weeks of treatment. Dynamic changes in the MAGIC algorithm probability occur within all biomarker risk groups and can guide therapy.

Summary Tumour lysis syndrome (TLS) is a significant complication of haematologic malignancies and their management. The syndrome consists of laboratory abnormalities either alone (laboratory TLS) or with clinical sequelae including renal failure, seizures, and arrhythmias (clinical TLS). Clinical TLS is a predictor for worse overall morbidity and mortality in cancer patients, but can be prevented. Thus, accurate prognostication is critical to appropriate management of patients at risk for TLS, and incorporates both disease factors (tumour type and burden) and patient factors (baseline renal insufficiency or hyperuricaemia). Strategies to prevent TLS include hydration and allopurinol in low‐ and intermediate‐risk patients and rasburicase in high‐risk patients.

Abstract Background: Patients with hematological malignancies are at an increased risk for developing both primary and recurrent Clostridium difficile Infection (RCDI) along with complications such as toxic mega colon and treatment failure likely due to underlying immunosuppression and frequent use of broad spectrum antibiotics that lead to altered gut microbiome. Fecal Microbiota Transplantation (FMT) is an effective treatment for RCDI (Brandt et. al; 2012). However, experience in patients with hematologic malignancies is sparse and most clinical trials exclude these patients due to potential complications. We report the largest case series to date from a single institution evaluating the safety and efficacy of FMT for RCDI in patients with hematologic malignancies. Methods: After IRB approval, a database of 452 RCDI patients treated with FMT between August 2012 and June 2016 was reviewed to identify those with an underlying hematologic malignancy. Data regarding demographics, hematologic disease, C. difficile history, treatments, and outcomes were retrospectively abstracted from the electronic medical record. Results: Sixteen patients (median age 74 years; male 50%) with known hematologic malignancies underwent FMT during the study period. The underlying diagnoses are outlined in Table 1. Five patients had received hematopoietic cell transplantation (3 allogeneic and 2 autologous) prior to FMT. Patients had a median of 4.5 (range 2-9) CDI episodes before FMT, and 4 of them had severe/severe-complicated CDI at some stage. Prior treatments included a median of 3 (range 1-5) standard vancomycin/metronidazole courses, median of 2 (range 0-4) vancomycin taper courses, fidaxomicin in 3 patients, and chronic vancomycin suppression in one patient. Diarrheal symptoms were in remission in all but 3 patients in the week before FMT. FMT was performed via colonoscopy in all patients. At the time of FMT, hematologic malignancies were in complete remission in 9 patients, stable on active treatment in 4, stable off treatment in 2, and relapsed awaiting treatment in 1 patient. Median time from last anti-neoplastic treatment (n = 14) and from last neutropenia (n = 8) to FMT were 10 (range 0-301) and 9.5 (0-68) months, respectively. One patient with hairy cell leukemia was still neutropenic and on prophylactic oral trimethoprim/sulfamethoxazole at the time of FMT. Five patients were on active immunosuppressive medications, including prednisone (n = 2), methotrexate (n = 2), sirolimus (n =1), and cyclosporine (n =1) for related comorbidities at the time of FMT (Table 2). At last follow up (median 12, range 0-32 months), 6 patients had active/relapsed hematological disease, 6 had received additional antineoplastic treatments, and 7 had received additional antibiotics. RCDI developed in two (12%) patients at 8 and 22 months post FMT secondary to exposure to broad spectrum antimicrobials. These patients were successfully treated with a second FMT and with metronidazole, respectively. Severe adverse events included death in one patient that occurred 3 days post FMT due to unexpected cardiac arrest and was deemed unrelated to the procedure. Another patient developed community-acquired pneumonia 15 days post FMT and was treated successfully with oral azithromycin. Minor adverse events within the first two weeks post FMT were noted in 6 (38%) patients (self-limited diarrhea in 3, fecal urgency in 2, abdominal cramps in 2, and constipation in one patient) (Table 3). Only one patient had persistent diarrhea shortly after FMT, with the cause attributed to underlying Crohn's disease. No complications related to the colonoscopy procedure were noted. Conclusion: FMT appears to be a safe and effective therapeutic option for RCDI in patients with hematological malignancies. Considering very few adverse events and particularly no infectious complications in our series, we conclude that immunosuppression should not preclude the use of FMT for treatment of RCDI in this high risk population. These results need prospective validation. Disclosures No relevant conflicts of interest to declare.

Abstract Background : Momelotinib is a JAK1 and JAK2 inhibitor that is currently being evaluated in phase-3 clinical trials for the treatment of myelofibrosis (MF) (NCT01969838, NCT02101268). In a phase-1/2 clinical trial of patients with MF, the drug was shown to improve anemia, reduce spleen size and alleviate symptoms (Leukemia 2013;27:1322). In the current study, we considered 100 consecutive patients from the Mayo Clinic who received momelotinib therapy, in order to identify molecular and cytogenetic predictors of treatment response and survival from the time of study entry. Methods : The study patients constituted part of a phase-1/2 clinical trial (NCT00935987) using momelotinib in MF. Details of the protocol, including inclusion and exclusion criteria were previously published (Leukemia 2013;27:1322). Response was determined by the 2006 response criteria published by the IWG-MRT. Data analysis and interpretation was carried out independent of any influence from the sponsor. Results : 100 patients with MF (median age 66 years; 58% males) were treated at the Mayo Clinic between 11/20/09 and 11/10/10. MF type was primary in 64% of the patients and post-polycythemia vera/essential thrombocythemia in 36%. DIPSS-plus risk distribution was 63% high, 36% intermediate-2 and 1% intermediate-1. Red cell transfusion dependency was documented in 49% and palpable spleen size of >5 cm (median 19 cm) in 92%. All patients were annotated for JAK2/CALR/MPL mutations with respective frequencies of 73%, 16% and 7%. Frequencies for other mutations included 42% for ASXL1 (84 evaluable) and 18% for SRSF2(78 evaluable). All patients were evaluable for karyotype, which was unfavorable in 17%. Previous treatment included other JAK inhibitors in 21 patients, thalidomide/lenalidomide/pomalidomide in 31 and hydroxyurea or other cytoreductive agents in 55. Momelotinib was initiated at 100 mg/day in 3 patients, 150 mg/day in 21, 150 mg twice-daily in 20, 200 mg/day in 3, 300 mg/day in 47 and 400 mg/day in 6. The maximum momelotinib dose was 150 mg/day in 6 patients, 150 mg twice-daily in 20, 300 mg/day in 68 and 400 mg/day in 6. Treatment duration was <6 months in 12 patients, 6-12 months in 22, 12-24 months in 19 and >24 months in 47. Genetic correlates of response to momelotinib : Overall response rate was 57% and included no complete remissions (0%), one (1%) partial remission and 57 (57%) clinical improvements (CI). Response rates for spleen/liver and anemia were 43% (91 evaluable) and 44% (68 evaluable), respectively. Transfusion independency was achieved in 25 (51%) of 49 evaluable cases. Spleen/liver response rate was significantly affected by JAK2/CALR/MPL mutational status (34% vs 73% vs 60%, respectively, and 50% in triple-negative; p=0.04), CALR mutated vs unmutated status (73% vs 37%; p=0.009), and unmutated vs mutated ASXL1 (53% vs 29%; p=0.035). Furthermore, all 8 (100%) patients who were CALR+/ASXL1- responded vs 6 (25%) of 24 CALR-/ASXL1+ vs 3 (50%) of 6 CALR+/ASXL1+ vs 16 (43%) of 37 CALR-/ASXL1- patients (p=0.003). Spleen/liver response rates were not affected by SRSF2 mutations (p=0.93) or karyotype (p=0.41). Anemia response rate was not affected by JAK2/CALR/MPL (p=0.81), ASXL1 (p=0.16), SRSF2 (p=0.12) or CALR/ASXL1 (p=0.42) mutational status or karyotype (p=0.65). The number of informative cases for EZH2, IDH, SF3B1 and U2AF1mutations were not adequate enough to warrant similar analysis. Genetic correlates of survival from time of protocol entry : Median follow-up after the institution of protocol drug therapy was 35 months (range 1-49). During this period, 57 (57%) deaths and 12 (12%) leukemic transformations were documented. On multivariable analysis, shortened survival was predicted by the presence of ASXL1 (p=0.01; HR 2.1, 95% CI 1.2-3.8) or SRSF2 (0.01; HR 2.4, 95% CI 1.2-4.8) mutations and the absence of CALR mutations (p=0.03; HR 3.2, 95% CI 1.1-8.9). Karyotype was significant on univariate (p=0.01) but not in multivariable (p=0.6) analysis that included the aforementioned mutations. The prognostic relevance of each specific mutation was DIPSS-plus independent. Conclusions : We demonstrate significant associations between CALR and ASXL1 mutational status and spleen response to momelotinib therapy in MF. We also show that momelotinib therapy did not overcome the inferior survival associated with the presence of ASXL1 or SRSF2 mutations or the absence of CALR mutations. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Over 10,000 new cases of myelodysplastic syndrome (MDS) are diagnosed in the US annually (MA X, Cancer 2007). Hypomethylating agents (azacitidine and decitabine), immunomodulating drugs (lenalidomide) and erythropoietin stimulating agents (epoetin α and darbepoetin) have been approved for more than a decade for the treatment of MDS. However, changes in overall outcome after the approval of these treatments are unknown. We used the National Cancer Data Base (NCDB), a nationwide oncology registry covering 70% of the US cancer population to answer these questions. Methods: We identified patients with MDS diagnosed from 2004-2013 using ICD-O-3 codes 9980-9983 and 9985-99912. Overall survival (OS) was estimated using the Kaplan-Meier method. We compared OS using the log-rank test according to demographic subgroups (sex, age [<40, 41-65, and ≥65 years], race [White, Black, Native American, Asian/Pacific Islander, and other], and ethnicity) across years of diagnosis (Period 1: 2004-2006, Period 2: 2007-2009, and Period 3: 2010-2013). Results: i) Characteristics: There were 54,953 MDS patients in our study. The median age at diagnosis was 76 years (78.7% older than 65) and 44% were females. White race (88.9%) was the most common, followed by black (7%). Four percent were Hispanics. A third (30.8%) of all patients were treated in academic centers. Three quarters (75.8%) had either Medicaid or Medicare insurance. ii) MDS Subtypes: 5q Syndrome was seen in 2008 cases (3.7%) while the most common subtype was MDS-Unclassifiable (U) (55.6%). Therapy related MDS (t-MDS) was seen in 1125 cases (2%), however coding for t-MDS was discontinued in 2009. Refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), refractory cytopenia with multilineage dysplasia (RCMD), and refractory anemia with excess blasts were seen in 9%, 7.6%, 6%, and15.6%, respectively. iii) OS: Compared to their counterparts, patients who were male, older, had a diagnosis of RAEB, covered by Medicare insurance, and treated at non-academic centers had the worse OS (all P <0.001). Across Periods 1-3, we did not see improvement in OS among demographic subgroups except for those who were <40 years old (P=0.03). Conclusions: In the past decade, the overall outcome of MDS did not improve despite the advent of new therapies. More than half of the cases were classified as MDS-U reflecting the difficulty of subtyping MDS based on World Health Organization classification. We found disparity in outcomes by demographics and type of treatment facility. This is the largest study of MDS outcome to-date and should help in understanding the gaps and areas that need future research. Figure Figure. Disclosures Al-Kali: Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding.

Abstract Background: Adult relapsed/refractory acute lymphoblastic leukemia/lymphoma (rALL) carries a very poor prognosis with limited options for effective salvage therapy. To date, there has been only a single retrospective report on the use of clofarabine in adult rALL demonstrating CR rate of 31% in this setting (Barba P et al. 2012). Aim: To evaluate the efficacy and toxicity of clofarabine based therapy in a relatively large cohort of adult rALL patients. Method: After IRB approval, a retrospective single institution study of all patients (pts) diagnosed with rALL treated with a clofarabine based regimen at Mayo Clinic between 2000 - 2014 was performed. Categorical variables were analyzed using Pearson's chi-squared test while continuous variables were analyzed using the Wilcoxon / Kruskal-Wallis test with P < 0.05 considered statistically significant. Survival estimates were calculated using Kaplan-Meier method and means were compared using log ranks. Results: Presenting features: We identified a total of 22 pts with a diagnosis of rALL who received clofarabine based therapy. 20 patients were evaluable and 2 were excluded (one received clofarabine as salvage for positive MRD and the other as systemic maintenance with CNS directed therapy for an isolated CNS relapse). Among evaluable pts, median age at time of Clofarabine based chemotherapy was 39 years (range 19-65) and 50% were males. Thirteen had B-ALL while 7 had T-ALL. Median leukocyte count was 6 x109 (0.2-28.7), hemoglobin 9.8 g/dL (7-12.9), platelet 65 x109 (12-493), peripheral blood blast 4% (0-88) and bone marrow blasts 80% (0-95) while five pts had extramedullary disease. Median number of prior regimens was 2 (1-7).. 8 (40%) pts were post allogeneic transplant Treatment and Response: 10 pts (50%) received clofarabine monotherapy, 7(35%) clofarabine and cytarabine, and 3 (15%) had clofarabine, etoposide and cyclophosphamide. Overall response rate (CR/CRi + PR) was 35%. Five (25%) achieved CR/CRi, and 2 achieved PR. Among those who achieved CR, 4 out 5 proceeded to further therapy; 2 to allogeneic stem cell transplant and two additional patients received donor lymphocyte infusion (DLI). One pt with PR also proceeded to allogeneic stem cell transplant. In comparative analysis, there were more males 6 (86%) vs 1(14%) in the responding arm (P = 0.014), otherwise the number of regimens prior to clofarabine, type of clofarabine regimen, transplant status, T vs B cell ALL, did not impact response. Median overall survival was 2.4 months (1.3-2.9) in non-responders vs. 12.8 months (3-27.4) in responders (P =0.0007) (Figure 1). All pts who proceeded to transplant or DLI relapsed with a median time to relapse of 6.4 (4.8-13.7) months. Toxicity: Rash/Hand Foot syndrome was observed in 3 pts (19%), Grade III-IV liver toxicity occurred in 4 (26%) with no permanent sequela. Opportunistic infection occurred in 3 pt (17%). Conclusion: Clofarabine based chemotherapy was a well-tolerated salvage regimen in heavily pretreated patients and was an effective bridge to definitive therapy in a significant proportion of cases. Prospective evaluation of these findings is warranted. Figure 1. Figure 1. Disclosures Al-Kali: Celgene: Research Funding.