Citations

Abstract Background: The recent discovery of JAK2V617F, as an activating mutation in the majority of patients with myeloproliferative neoplasms, has spurred development of JAK2-selective small molecule inhibitors for the treatment of these diseases. TG101348 is a potent (enzyme IC50=3 nM) and selective (35- and 334-fold selectivity over JAK1 and JAK3, respectively) orally bioavailable JAK2 inhibitor that is effective in treating a murine model of Polycythemia vera (PV) (Cancer Cell. 2008 13:311). TG101348 selectively inhibits growth of hematopoietic colonies harboring V617F, MPLW515K, or JAK2 exon 12 mutations (Leukemia. 2008 Mar 20, Epub). Methods: A Phase I dose-escalation study of TG101348 is ongoing for patients with high- or intermediate-risk (with symptomatic disease) primary myelofibrosis (PMF) and post-PV or post-essential thrombocythemia (ET) myelofibrosis (Cancer.2007109:2083). TG101348 was administered orally once daily in 28-day cycles in cohorts of at least 3 patients. Additional eligibility criteria included absolute neutrophil count of ≥1 × 109/L and platelet count of ≥50 × 109/L, but a JAK2 mutation was not required. Primary objectives were determination of safety and tolerability, as well as pharmacokinetic behavior of TG101348. The secondary objectives were evaluation of treatment response (Blood.2006108:1497), pharmacodynamic activity, and drug effect on V617F allele burden and plasma cytokine levels. The spleen response was documented as change in palpable spleen tip from the costal margin. For patients achieving less than a complete remission after 3 cycles of treatment at their initial dose, step-wise escalation was permitted at each cycle if a cohort had been shown to have tolerated that dose. Results: Fifteen patients (9 males; median age=66 years; range=53 to 79 years) have been enrolled in the study to date – 10 with PMF (8 V617F+) and 5 with post-PV MF (all V617F+). The median follow-up to date is 13 weeks (range 1–28). Treatment was discontinued in 1 patient, in cohort 1, on the 2nd day of dosing after it was discovered that the patient had baseline QTcF prolongation (Grade 1). In the remaining 14 patients, no dose-limiting toxicities or other significant non-hematological adverse events have been observed to date. The pharmacokinetic parameters of TG101348 in plasma were well characterized following single daily oral doses of 30 mg, 60 mg, 120 mg or 240 mg. Dose-proportional pharmacokinetics were observed following single and multiple doses of TG101348. Treatment response data are as follows: Cohort 1 (starting dose=30 mg; 3 patients; median follow-up=26 weeks): 2 of the 3 patients had improvement in constitutional symptoms including fatigue, night sweats and pruritus. No other benefits were noted. These patients have now been dose escalated to either 120 or 240 mg/day. Cohort 2 (starting dose=60 mg; 3 patients; median follow-up=18 weeks): 1 patient had a 40% decrease in spleen size (18 to 10 cm). All 3 patients have now been dose escalated to 120 or 240 mg/day. Cohort 3 (starting dose=120 mg; 3 patients; median follow-up=13 weeks): 2 of the 3 patients reported improvement in constitutional symptoms including fatigue, night sweats, and pruritus. 1 patient had a 25% decrease in spleen size (28 to 21 cm). 2 patients have been dose escalated to 240 mg/day. Cohort 4 (starting dose=240 mg; 3 patients; median follow-up=8 weeks): 1 patient developed Grade 3 anemia (baseline Grade 1) at the end of the first cycle. 1 patient reported decreased fatigue. All 3 patients have experienced a 20 to 53% reduction in spleen size; baseline measurements were 10, 13, and 17 cm. Cohort 5 (starting dose=360 mg; 2 patients; median follow-up=1 week). Both patients had decreased splenomegaly within 1 week of therapy, including 1 with disappearance of palpable splenomegaly from a baseline of 20 cm; this patient also reported significant improvement in constitutional symptoms. Conclusions: Preliminary findings indicate that TG101348 is well tolerated in patients with myelofibrosis. Although it is too early to make valid conclusions, a decrease in spleen size has been noted at higher dose levels. Similarly, improvement in constitutional symptoms has been reported by some patients. Updated results on current and future patients, including data on pharmacokinetics, pharmacodynamics, and changes in V617F allele burden and plasma cytokine levels will be presented at the meeting.

Abstract Abstract 3842 Background: Dysregulated JAK-STAT signaling is a key feature in MF, which is characterized by splenomegaly, debilitating symptoms, poor quality of life (QoL), cytopenias, and shortened survival. Ruxolitinib is a selective JAK1 and JAK2 inhibitor with clinical activity in MF. COMFORT-I is a Phase III, double-blinded, placebo-controlled study of ruxolitinib in patients with MF. At wk 24, 41.9% of patients receiving ruxolitinib reached the protocol-defined threshold of a ≥35% reduction in spleen volume (SV) compared to 0.7% in the placebo group (p<0.0001). The objective of this analysis was to evaluate the relationship between SV reduction achieved with ruxolitinib treatment and changes in symptoms and QoL. Methods: 309 patients were randomized to receive ruxolitinib (n=155) or placebo (n=154). Initial dosing was based on baseline platelet counts: 15 mg BID for counts of 100–200 x109/L and 20 mg BID for >200 x109/L. SV was measured by blinded imaging (MRI or CT scan) every 12 wks. Via electronic diary, patients reported MF symptoms daily using the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0. The Total Symptom Score (TSS) from the MFSAF represents a combined score for the individual symptoms of abdominal discomfort, pain under ribs on left side, early satiety, itching, night sweats, and bone/muscle pain. The European Organization for Research and Treatment of Cancer Quality-of-Life 30 (EORTC QLQ-C30) and Patient-Reported Outcomes Measurement System (PROMISE) Fatigue questionnaires were administered at each visit; Patient Global Impression of Change (PGIC) was administered at every visit beginning at wk 4. The PGIC rates a patient's overall sense of whether a treatment has been beneficial or not on a 7-point scale, ranging from 1 = very much improved to 7 = very much worse, with 4 = no change. Results: Baseline QoL scores reflected debilitating disease, and were similar to scores for similar-aged patients with other cancers (Scott NW, Fayers PM, Aaronson NK, et al. EORTC QLQ-C30 Reference Values Manual, July 2008). The impact on patients was particularly evident on the PROMIS Fatigue scale and QLC-C30 Global Health, Physical Functioning, Role Functioning, and Social Functioning subscales. Baseline Symptom and QoL Measures* Associations between changes in symptoms and QoL with the objectively measured changes in SV were evaluated. Patients receiving ruxolitinib were grouped according to SV reduction at 24 wks of treatment: ≥35% reduction in SV (n=65), 10-<35% (n=51), and <10% (n=23). Symptom and QoL responses were evaluated among the various subgroups (of the SV reduction percentage strata) and comparisons were made across these and the total placebo group (n=106). Shown in the Figure are mean changes at wk 24 relative to baseline for TSS, QoL indicators, and PGIC scores. Conclusions: Changes in SV as low as 10% in ruxolitinib-treated patients were associated with improvements on EORTC QLQ-C30 Global Health subscale, PROMISE Fatigue scale, and the MFSAF v2.0 diary TSS. Moreover, commensurate improvements in these outcomes were observed as the SV reduction increased. Importantly, the simple PGIC questionnaire allowed patients to characterize a meaningful change in their condition that was consistent with more comprehensive measures of MF symptoms and quality of life, reflecting a doctor-patient assessment easily applied to clinical practice. Disclosures: Mesa: Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding. Gotlib:Incyte: Consultancy, Research Funding. Gupta:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Catalano:Incyte: Honoraria; Novartis: Honoraria. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Shields:Incyte: Consultancy. Miller:Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Winton:Incyte: Consultancy. Hare:Incyte: Employment. Erickson-Viitanen:Incyte: Employment. Sun:Incyte: Employment. Sandor:Incyte: Employment. Levy:Incyte: Employment, Equity Ownership. Kantarjian:Incyte: Research Funding; Novartis: Consultancy, Research Funding. Verstovsek:Incyte: Research Funding.

Abstract Background In the primary analysis of the phase III COMFORT-I study, the JAK1/JAK2 inhibitor ruxolitinib (RUX) significantly improved splenomegaly, myelofibrosis (MF)-related symptoms, and quality of life (QoL) measures in patients (pts) with MF versus placebo (PBO). An additional analysis (median follow-up 51 weeks [wks)]) showed RUX was associated with a survival advantage versus PBO (Verstovsek et al. N Engl J Med2012). Longer term follow-up (median 102 wks) showed durable SV reductions and QoL improvements. At this time point, RUX continued to be associated with a survival advantage, despite all pts originally randomized to PBO having discontinued or crossed over to ruxolitinib shortly after the primary analysis (Verstovsek et al. ASH 2012. abstract 800). We report additional longer-term follow-up of pts from COMFORT-I. Methods In COMFORT-I, 309 pts were randomized (1:1) to RUX or PBO. RUX starting dose depended on baseline platelet count (100–200´109/L: 15 mg BID; >200´109/L: 20 mg BID). Doses could be titrated for lack of efficacy or excess toxicity as specified in the protocol. Pts receiving PBO could crossover to RUX after the primary analysis (ie, when all pts completed 24 wks and half the pts completed 36 wks of therapy) or at any time if they met protocol-specified criteria for worsening splenomegaly. The primary endpoint was the proportion of pts who achieved a ≥35% reduction in spleen volume (SV) at wk 24. Symptoms were assessed up to wk 24 using the modified MF Symptom Assessment Form v2.0. QoL continued to be evaluated beyond wk 24 using the EORTC QoL Questionnaire-Core 30 (QLQ-C30). Survival was estimated by Kaplan-Meier analysis according to original randomized treatment. To better understand the effect of crossover on the PBO arm, statistical modeling of survival was conducted using a generalized Gamma distribution. Results Median follow-up was 149 wks at the time of this updated analysis. Of 155 pts originally randomized to RUX, 77 remain on therapy. Of 154 pts originally randomized to PBO, 111 crossed over to RUX; the median time to crossover was 41.1 wks (range, 5.1–65.4). At wk 24, pts originally randomized to RUX had a mean SV reduction of −31.6%; this was durable for pts who continued on RUX, where the mean SV reduction at wk 144 was −34.1%. Fifty-nine percent (91/155) of pts originally randomized to RUX achieved a ≥35% SV reduction at any time during study; for these pts, the probability of maintaining this response for >132 weeks from the time of their initial response was 0.53. Pts originally randomized to RUX who continued on therapy experienced durable improvements in the Global Health Status/QoL and functional domains of the EORTC QLQ-C30. Overall survival favored RUX (HR=0.69; 95% CI: 0.46, 1.03; P= 0.067; Fig 1), with 42 and 54 deaths among pts originally randomized to RUX and PBO, respectively. Modeling of the hazard function of death over time to explore the effect of crossover to RUX in pts originally randomized to PBO showed a decrease in hazard for these pts, which corresponded to an increased proportion of pts crossing over to RUX. In pts originally randomized to RUX who continued on therapy, there was no substantial change in the rate, distribution, or severity of nonhematologic adverse events (AEs) with longer-term therapy; most nonhematologic AEs were grade 1 or 2. Mean and median hemoglobin and platelet count remained stable with longer-term therapy. Consistent with this, the incidence of new onset grade 3 or 4 anemia and thrombocytopenia observed after the first 6 months of RUX therapy decreased relative to that seen in the first 6 months of therapy (Fig 2). With approximately 1 year of additional follow up, 4 new cases of acute myeloid leukemia were reported: 2 pts originally randomized to PBO (376 and 666 days after crossover to RUX) and 2 pts originally randomized to RUX (848 and 1143 days after starting RUX). Conclusions After a median follow-up of 149 wks, the hazard ratio for overall survival favored pts originally randomized to RUX over those originally randomized to PBO, the majority of whom crossed over to RUX. The hazard of death for pts originally randomized to PBO decreased as pts crossed over to RUX. SV reductions and QoL improvements were sustained with longer-term therapy. The incidence of new onset grade 3 or 4 anemia and thrombocytopenia decreased with longer-term therapy. Collectively, these data reinforce the durable efficacy and longer-term safety of RUX in pts with MF. Disclosures: Verstovsek: Incyte Corporation: Research Funding. Mesa:Genentech: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; Lilly: Research Funding. Gotlib:Incyte Corporation: Travel support, Travel support Other; Incyte Corporation: Membership on an entity’s Board of Directors or advisory committees; Incyte Corporation: Research Funding. Levy:Incyte Corporation: Equity Ownership; Incyte Corporation: Employment. Gupta:Incyte Corporation: Consultancy; Novartis: Consultancy; Inctye Corporation: Research Funding; Novartis: Research Funding; Novartis: Speakers Bureau. Deininger:BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Miller:Novartis: Consultancy; Incyte Corporation: Consultancy; Novartis: Research Funding; Incyte Corporation: Research Funding; Novartis: Honoraria; Incyte Corporation: Honoraria. Talpaz:Ariad: Consultancy; Novartis: Consultancy; BMS: Consultancy; Pfizer: Consultancy; Ariad: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees. Winton:Incyte Corporation: Research Funding; Incyte Corporation: Membership on an entity’s Board of Directors or advisory committees. Arcasoy:Incyte Corporation: Research Funding. Lyons:Lilly: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Incyte Corporation: Research Funding; Gilead: Consultancy; Seattle Genetics: Research Funding; Gilead: Research Funding; Ariad: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding. Paquette:Incyte Corporation: Consultancy. Raza:Novartis: Speakers Bureau; Onconova Inc: Research Funding. Vaddi:Incyte Corporation: Employment; Incyte Corporation: Equity Ownership. Sun:Incyte: Employment; Incyte: Equity Ownership. Peng:Incyte Corporation: Employment; Incyte Corporation: Equity Ownership. Sandor:Incyte: Employment; Incyte: Equity Ownership. Kantarjian:Ariad: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding.

Abstract Background: JAK2 inhibition improves splenomegaly and symptoms in patients with myelofibrosis (MF), and the JAK2 inhibitor ruxolitinib has been shown to improve both bone marrow fibrosis and survival in MF patients (Cervantes et al., 2013; Verstovsek et al., 2013). Current prognostic models such as DIPSS plus (Gangat et al., 2011) predict survival in MF based on clinical, laboratory, and cytogenetic information, but predate the era of JAK2 inhibitor use in MF. As such, their value in predicting clinical response or survival during treatment with JAK2 inhibitors remains unknown. We hypothesized that features not considered by DIPSS plus, including bone marrow fibrosis and splenomegaly, have independent effects on therapy response. We therefore conducted a retrospective analysis to create a new model to risk stratify patients with respect to their likelihood of achieving a > 50% reduction in splenic size by palpation with JAK2-inhibitor therapy. Methods: We studied a cohort of 418 patients with bone marrow biopsy-proven MF who were treated with ruxolitinib or one of four other JAK2 inhibitors. An initial cohort of 203 patients seen at University of Michigan, Stanford University, and Mayo Clinic in Scottsdale, AZ was used identify factors that would predict a clinical response to therapy. Response to therapy was evaluated at an early time point (3-4 mos) in 167 patients and at a late time point (5-12 mos) in 138 patients, with 127 patients overlapping between the two. We constructed a multivariable logistic regression model, with Bayesian variable selection, for predicting the probability of early or late splenic response to JAK2 inhibitor therapy. The model was developed with this initial group of 203 patients. The model was then validated with a cohort of 215 patients from the PERSIST1 trial (data supplied by CTI Biopharma). Results: Conclusion: We identified several factors that play a role in predicting whether or not patients with MF are likely to respond to JAK2 inhibitor therapy. The interaction between spleen size and WBC at the time of therapy initiation plays the strongest role in predicting which patients will have an early response to therapy. Additionally, our model suggests that patients who do not have a response to JAK2 inhibitor therapy by about 4 months of treatment are unlikely to develop a later response. Our model is able to discriminate between those likely to benefit after several months of therapy and those for whom a change in therapy should be considered early in their treatment course. Figure 1 The following characteristics were selected for inclusion in the prognostic model based on the data collected from our 418-patient cohort. Spleen size and white blood cell count at the time of therapy initiation were the strongest predictors of early response to JAK2 inhibitor therapy. Achievement of an early response was used to further enhance the model for the late time point (third column) and was the strongest predictor of late response. Interaction terms looked at the interdependence of variables on splenic response. Log odds ratios are provided with 95% credible intervals in parentheses. Figure 1. The following characteristics were selected for inclusion in the prognostic model based on the data collected from our 418-patient cohort. Spleen size and white blood cell count at the time of therapy initiation were the strongest predictors of early response to JAK2 inhibitor therapy. Achievement of an early response was used to further enhance the model for the late time point (third column) and was the strongest predictor of late response. Interaction terms looked at the interdependence of variables on splenic response. Log odds ratios are provided with 95% credible intervals in parentheses. Figure 2 An example of the predicted response for a hypothetical patient. The curves show the interaction of a high initial WBC (red) or a low initial WBC (green) with baseline spleen size (depicted along the X-axis) in predicting whether or not the patient will have a late response to therapy (depicted along the Y-axis). The solid lines show the probability that the patient will respond at the later time point if they had an early response. The dashed lines show the probably of a late response if the patient had not achieved a response by the early time point. Overall, a patient with a higher initial WBC and a larger baseline spleen size is less likely to respond to JAK2 inhibitor therapy. Additionally, the curves clearly separate to show that, for a given baseline WBC and spleen size, a patient who has an early response to therapy is much more likely to have a late response to therapy, whereas a patient who fails to respond early in their treatment course is much less likely to respond with further treatment. Figure 2. An example of the predicted response for a hypothetical patient. The curves show the interaction of a high initial WBC (red) or a low initial WBC (green) with baseline spleen size (depicted along the X-axis) in predicting whether or not the patient will have a late response to therapy (depicted along the Y-axis). The solid lines show the probability that the patient will respond at the later time point if they had an early response. The dashed lines show the probably of a late response if the patient had not achieved a response by the early time point. Overall, a patient with a higher initial WBC and a larger baseline spleen size is less likely to respond to JAK2 inhibitor therapy. Additionally, the curves clearly separate to show that, for a given baseline WBC and spleen size, a patient who has an early response to therapy is much more likely to have a late response to therapy, whereas a patient who fails to respond early in their treatment course is much less likely to respond with further treatment. Disclosures Boonstra: CTI Biopharma: Research Funding. Gowin:Incyte: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis: Consultancy; Ariad: Consultancy; Promedior: Research Funding; Celgene: Research Funding; Galena: Consultancy; Incyte: Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding. Talpaz:Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Novartis: Research Funding; Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding.

Abstract Abstract 3849 Background: CYT387 is a potent JAK-1/2 inhibitor. The maximum tolerated dose (MTD) and preliminary safety and efficacy of once daily dosing of CYT387 were determined in a single center Phase I/II study. Previously reported results from the first 60 subjects enrolled in this study determined a MTD of 300 mg QD and demonstrated improvements in splenomegaly and constitutional symptoms as well as in RBC transfusion requirements. The study was expanded into a multicenter study with planned accrual of 165 subjects at 6 study sites and a twice daily dosing arm was added. The preliminary safety and efficacy results from this expanded multicenter study will be presented. Methods: Subjects with high or intermediate-risk primary myelofibrosis (PMF) and post-polycythemia vera (post-PV) or post-essential thrombocythemia (ET) myelofibrosis were enrolled. In the core expansion study, oral CYT387 was administered either once daily at 150 mg or 300 mg or twice daily at 150 mg for 9 months. Patients who maintained at least stable disease were permitted to continue CYT387 treatment beyond 9 months in an extension phase of the study. Responses were assessed by International Working Group (IWG) Criteria. Results: At present, 163 subjects have been enrolled across the 6 study sites. The diagnoses of enrolled subjects include 64% PMF, 14% post-ET MF and 22% post-PV MF; 67% of the patients were JAK2V617F positive. Starting doses of CYT387 in the dose escalation, confirmation and expansion phases of the study are shown in Table 1. The median duration (range) of treatment was 6.6 months (0.25 to 20.4 months). Patient characteristics were as follows: median age 68 years, 58% male, 87% were spleen evaluable at baseline per IWG criteria (median spleen length was 18 cm by palpation). Sixty three percent (63%) of subjects were anemia evaluable at baseline per IWG criteria; 46% were transfusion dependent. Previous JAK inhibitor and IMiD therapy was reported for 11% and 8% of enrolled subjects, respectively. Reductions in spleen size, improvements in constitutional symptoms and the achievement of transfusion independence were observed in subjects in the expanded multicenter study. CYT387 was well tolerated. Based on currently available data, 73% of subjects reported treatment-related adverse events, with the majority reported as Grade 1. The most common Grade 3–4 treatment related adverse events included thrombocytopenia (16%), and hyperlipasemia (3%). New onset treatment-related Grade 3–4 anemia remains rare (<1%). Grade 1 toxicities included peripheral sensory neuropathy whose incidence and natural history is currently being studied. Twenty-five of 163 subjects (15%) have discontinued from the 9 month core study giving a retention rate of 85%. Conclusions: When examined in an expanded, multicenter study, CYT387 continues to show substantial clinical activity in myelofibrosis, with improvements in splenomegaly, constitutional symptoms and anemia. It appears to be well tolerated when administered in either a once or twice daily dosing regimen. CYT387 continues to demonstrate an ability to induce durable anemia responses in a subset of subjects. Detailed analyses of safety and efficacy will be available at the time of the meeting. Disclosures: Gupta: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Smith:YM Biosciences: Employment, Equity Ownership. Bavisotto:YM Biosciences: Consultancy. Kowalski:YM Biosciences: Employment, Equity Ownership.

Abstract Abstract 3838 Background: SAR302503 (SAR503, formerly TG101348), a potent, oral JAK2-selective inhibitor was studied in a Phase I/II trial for the treatment of patients with high- or intermediate-risk primary, post-polycythemia vera (PV) and post-essential thrombocythemia (ET) myelofibrosis (MF). SAR503 was administered orally once daily in 28-day cycles. Eligibility criteria included platelet count of ≥50 × 109/L. Interim safety and efficacy data from this study up to April 2010 have been previously published (JCO 2011, 29(7):789–796). The aim of this presentation is to report updated safety and efficacy of ongoing patients as well as an analysis of the JAK2V617F allele burden in this cohort. Results: Overall, 59 subjects (median age 64 years) were treated. Forty four patients had PMF, 12 post-PV MF and 3 post-ET MF; 86% were JAK2 V617F-positive. Median palpable spleen size was 18 cm at study enrollment. Twenty eight patients were treated in the dose-escalation cohort (30–800 mg administered as a single daily dose); thirty one patients were treated at the MTD (680 mg) in the dose confirmation cohort. 43/59 patients (73%) completed 6 cycles of treatment and continued treatment on the extension study. Currently, 22 patients (37%) remain on treatment with a median number of 28.5 cycles (24–41 range) and a median of last dose of 440 mg/day. Safety: Treatment-emergent toxicities in cycle 1–6 have been previously reported; toxicities were dose-dependent and generally alleviated with dose-reduction. Five patients discontinued treatment beyond cycle 6 for treatment-related adverse events: thrombocytopenia, depression, mental status changes, creatinine elevation and subdural hematoma. For the subgroup of patients with a baseline platelet count between 50–100 × 109/L (n =13; median 73, range 51–94); the platelet count at defined times points during follow up was: cycle 3; median 50, range 21–138 (p=0.09) and cycle 6; median 47, range 13–85 (p=0.01). Despite 7 of the 13 patients being treated at ≥680 mg/day, only 2 instances of Grade 4 thrombocytopenia were noted in this group Spleen response: As previously reported, spleen responses were seen early, usually within first 3 cycles, with half or more patients in each dose level ≥240 mg/day showing a durable ≥50% decrease in palpable spleen size. Spleen size (mean, median, range, and proportion with ≥50% reduction) at the following time points was: Baseline (n=58; 18.33cm, 18cm, 4–38cm, NA) ; 6 months (n=57; 9.05cm, 9cm, 0–30cm, 54.4%;) 12 months (n=42; 8.55cm, 9cm, 0–28cm, 66.7%) 18 months (n=36; 8.03cm, 8.5cm, 0–33cm, 52.8%); 24 months (n=31; 8.10cm, 8cm, 0–30cm, 54.8%,) 30 months (n=18; 6cm, 7.5cm, 0–16cm, 61.1%,and) 36 months (n=9; 5.89cm, 3cm, 0–16cm, 66.7%). JAK2V617F allele burden: We previously reported a significant decrease in JAK2V617F allele burden at the end of cycles 6 and 12. A durable decrease was also demonstrable after 24 cycles of treatment (n =21; median 9%, range 0–100%) relative to baseline (n =51; median 20%, range 3–100%) (p=0.03). Similarly, for patients with JAK2 V617F allele burden >20% at baseline; there was a significant decrease after cycle 24 (n =12; median 21%, range 6–100%) relative to baseline (n =23; median 60%, range 23–100%) (p=0.03). Conclusions: SAR503 is safe and efficacious treatment with long term effect on spleen size and JAK2V617F allele burden in patients with high- and intermediate-risk myelofibrosis. Additional follow up information will be updated at the time of meeting. Disclosures: Jamieson: Wintherix: Equity Ownership; Pfizer Oncology: Research Funding; Celgene: Research Funding; Novartis: Honoraria. Gao:Sanofi-Aventis: Employment. Zhang:Sanofi-Aventis: Employment. Neumann:Sanofi-Aventis: Employment.

Abstract Introduction Inflammatory bowel disease (IBD) has a significant effect on patients’ overall quality of life (QoL). We hypothesized that an Electronic Health Record (EHR) patient portal (EPIC’s Mychart) can be utilized to improve QoL in IBD patients and increase vaccine uptake. Methods Patients were randomized to receive specific disease (INT) information and to a control arm (CTRL) that received periodic non-IBD related messages. Disease severity was assessed using the Harvey-Bradshaw index, and Simple Clinical Colitis Activity index. QoL was measured using the Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Secondary outcome measures included overall satisfaction with the portal and influenza and pneumococcal vaccine uptake. Results One hundred twenty-seven patients were randomized: At baseline the CTRL group had a statistically significant higher QoL (Median SIBDQ 53.7) compared with the INT group (median SIBDQ 49.3), P = 0.04. At 6 months, the INT group had a trend towards a significantly greater increase in QoL (median SIBDQ 58) when compared with the CTRL group (median SIBDQ 57.5), P = 0.06. At 6 months more frequent portal use showed a significantly lower median SIBDQ (median 53) compared with patients with less frequent portal use (median 59), P = 0.038. At 6 months 88% of patients felt that the MyChart portal was useful with respect to IBD management. Patients had high rates of portal utilization with one-third of patients logging on weekly, and one-third logging on monthly. With respect to vaccine uptake, both influenza and pneumococcal pneumonia had higher rates of vaccine uptake. Conclusions Patients showed a trend towards improved QoL after receiving disease-specific information through our EHR portal. A significant increase in vaccine uptake was also seen. Frequent automated messages sent via an EHR portal can improve patient’s overall QoL. Larger studies will be needed to determine if automated portal reminders have a significant association with improved QoL, and furthermore to determine if there is any impact on disease activity.

AbstractAlthough monoclonal antibody (MoAb) therapy of the human malignant lymphomas has shown success in clinical trials, its full potential for the treatment of hematologic malignancies has yet to be realized. To expand the clinical potential of a promising human-mouse chimeric antihuman B-cell MoAb (chCLL-1) constructed using the variable domains cloned from the murine Lym-2 (muLym-2) hybridoma, fusion proteins containing granulocyte-macrophage colony-stimulating factor (GM-CSF) (chCLL-1/GM–CSF) or interleukin (IL)-2 (chCLL-1/IL–2) were generated and evaluated for in vitro cytotoxicity and in vivo tumor targeting. The glutamine synthetase gene amplification system was employed for high level expression of the recombinant fusion proteins. Antigenic specificity was confirmed by a competition radioimmunoassay against ARH-77 human myeloma cells. The activity of chCLL-1/GM–CSF was established by a colony formation assay, and the bioactivity of chCLL-1/IL–2 was confirmed by supporting the growth of an IL-2–dependent T-cell line. Antibody-dependent cellular cytotoxicity against ARH-77 target cells demonstrated that both fusion proteins mediate enhanced tumor cell lysis by human mononuclear cells. Finally, biodistribution and imaging studies in nude mice bearing ARH-77 xenografts indicated that the fusion proteins specifically target the tumors. These in vitro and in vivo data suggest that chCLL-1/GM–CSF and chCLL-1/IL–2 have potential as immunotherapeutic reagents for the treatment of B-cell malignancies.

Abstract Abstract 2700 Background: Follicular lymphoma is a heterogeneous disease in terms of disease course and prognosis. Clinical risk factors, including age, presence of B symptoms and bulky disease have been shown to have prognostic value. More recently, elements of the tumor microenvironment, including CD68 positive macrophages as well as programmed death-1 (PD-1) expressing lymphocytes, have been shown to be associated with a worse prognosis. However, there is a paucity of data in terms of microenvironment changes that take place in the setting of transformation into diffuse large B cell lymphoma (DLBCL). CD14 is a monocytic marker, and increased numbers of CD14+ cells in the peripheral blood have been associated with a poor prognosis in non-Hodgkin's lymphoma and CLL. It has also been shown that CD14+ cells are present in biopsy specimens in DLBCL and that these cells may support malignant cell growth. This study was designed to examine the presence of CD14+ cells in follicular lymphoma that transformed to DLBCL and to determine the prognostic value of CD14 expression in terms of time to transformation. Methods: Patients with follicular lymphoma who underwent transformation into DLBCL were identified from the Mayo Clinic Lymphoma Database. Controls were follicular lymphoma patients who did not undergo transformation, and were matched 2:1 (control:transformed) on age at diagnosis, year of diagnosis, sex, stage, and length of follow-up time. Tissue specimens at the time of diagnosis were stained for CD14 and CD68, and characterized semiquantitatively based on the presence and distribution of positive cells. Time to transformation (TTT) was assessed using the Kaplan-Meier method. Results: 159 patients were included in the study: 58 patients transformed and 101 did not transform into DLBCL. Median age at diagnosis was 64 years. 150 specimens were sufficient for immunohistochemical analysis. When patients with transformed disease were compared to those who did not transform, those who transformed had greater numbers of CD14+ cells present in their initial diagnostic biopsy (p=0.0415). When only patients who transformed were considered, CD14+ cells in a follicular pattern was associated with a median time to transformation of 3.9 years, CD14+ cells in an interfollicular pattern had a median TTT of 4.9 years and CD14- specimens were associated with a median TTT of 6.2 years (p = 0.0322). The staining pattern for CD68 differed from that of CD14 and was not significantly associated with time to transformation. Conclusions: The presence of intratumoral CD14+ cells at diagnosis in follicular lymphoma is associated with subsequent disease transformation. Our results suggest that when CD14+ cells organize in the follicle, follicular lymphoma patients are likely to transform into DLBCL sooner. Further studies are therefore warranted to define the role of these cells in the tumor microenvironment during transformation to DLBCL. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: There is demonstrated benefit when administering fluoroquinolones as infection prophylaxis in neutropenic patients; however, side effects, drug interactions and increasing drug resistance necessitate investigation toward safe and effective alternative therapies. This study investigates the use of oral third generation cephalosporins as antibacterial prophylaxis during chemotherapy-induced neutropenia to establish knowledge on alternative treatment options. Methods: A retrospective chart review was performed to compare incidence of febrile neutropenia and documented infection rates in Acute Myeloid Leukemia (AML) and intermediate to high International prognostic scoring system (IPSS) risk myelodysplastic syndrome (MDS) patients receiving antibacterial chemoprophylaxis at Mayo Clinic between January 2006 and April 2016. Patients were included if they were 18 years or older, had a diagnosis confirmed on bone marrow biopsy, received induction or first relapse induction-remission chemotherapy regimens and then subsequently were prescribed fluoroquinolone or an oral third generation cephalosporin prophylaxis for anticipated profound and prolonged neutropenia. The main regimens prescribed were cytarabine + anthracycline (7+3), daunorubicin + cytarabine + nilotinib, mitoxantrone + etoposide + cytarabine, all-trans-retinoic acid (ATRA) + anthracycline, all-trans-retinoic acid (ATRA) + arsenic, clofarabine + cytarabine, or an investigational trial. After meeting inclusion criteria the treatment arms were matched via Charlson comorbidity index ( ± 3) and age ( ± 5). Patients with a documented infection 48 hours after switching from either broad spectrum antibiotics to antibacterial prophylaxis, or from levofloxacin prophylaxis to an oral third generation cephalosporin were excluded from the study. All patients provided consent for review of their medical records for research purposes. This study was approved by the Mayo Foundations institutional review board. Results: A total of 565 patients admitted to Mayo Clinic inpatient leukemia service for chemotherapy and concurrently prescribed antibacterial prophylaxis with either levofloxacin or an oral third generation cephalosporin were screened between January 1, 2006 and April 1, 2016. Of those screened 397 patients met the inclusion criteria, and subsequently 123 patients were matched via Charlson comorbidity index and age. Patient characteristics are presented in Table I. Of the 123 study patients, 80 (65%) were male, and the median age was 58.6 years (IQR: 53.3-68.5). The population was comprised of 115 (93.5%) patients with AML, and 8 (6.5%) patients with MDS. By 30 days after prophylaxis start 109 of the 123 patients developed febrile neutropenia (89.9%, 95% CI: (82.8-94.1)). There was no difference in the risk of febrile neutropenia between those on levofloxacin and those on an oral third generation cephalosporin (hazard ratio [HR] = 1.057, 95% CI: 0.64-1.75, p=0.83). The mean ANC value at the time of febrile neutropenia was 0.47 (SD: 1.4). Documented reasons that patients did not receive an oral fluoroquinolone were QTc prolongation (34.2%), rash (21.1%), tendonitis (2.6%), anaphylaxis (5.3%), drug interaction with a treatment study drug (23.7%), or other (13.1%). Three patients died 30 days or less after the last dose of chemoprophylaxis (40 day survival: 96.6%, 95% CI: 92.7-100); two of the reported deaths were due to infection. Of the 111 patients who had a documented febrile episode, 40 (36%) had a culture positive infection. Gram positive organisms caused 27 (71.1%) of the infections, 11 (28.9%) were gram negative organisms, and 1 (2.6%) infection was due to an anaerobic organism. There were 3 (7.5%) polymicrobial infections, and 36 (90%) monomicrobial infections. The majority of the patients had bloodstream as the documented site of infection. Of the documented culture positive infections 15 (39.5%) showed resistance to levofloxacin and 6 (15.8%) had resistance to third generation cephalosporins when susceptibility testing was reported. Conclusions: These findings demonstrate comparable safety and efficacy of oral third generation cephalosporins compared to fluoroquinolones and contribute to the growing body of literature surrounding antibacterial prophylaxis during chemotherapy-induced neutropenia. Further prospective, randomized investigation is warranted. Disclosures No relevant conflicts of interest to declare.