Gowin, Krisstina

Abstract Introduction: Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). Consideration of HCT is recommended by international working groups and national guidelines for MF patients (pts) age <70 with intermediate-1 with adverse indicators, intermediate-2 or high-risk disease by the Dynamic International Prognostic Scoring System (DIPSS) for MF- a recommendation made in the absence of clear data indicating the optimal timing of HCT for MF. In this large multicenter retrospective study, we analyze overall survival in MF pts treated with and without HCT. Methods: Disease characteristics, treatments, and outcome data from MF pts receiving non-transplant therapy at 14 US academic medical centers between 2000-2014 were retrospectively collected. MF pts who underwent HCT were identified from the Center for International Blood and Marrow Transplant Research (CIBMTR). The Cox proportional hazards model was used. The reference time point (time zero) was time of referral for the non-transplant (non-HCT) arm and the time of transplant for the HCT arm. The main effect variable (HCT vs. non-HCT) violated the proportionality assumption where comparing to non-HCT, mortality was higher with HCT in early time period from time zero but then was lower in late time period; therefore, the comparison is presented as early time period and late time period. The Cox model identified 14 months from time zero as the ideal cut point to define early and late time periods. The proportionality assumption is satisfied within each of these two periods. Results: A total of 1377 and 551 pts were included in the non-HCT and HCT arms, respectively (Table 1). In the overall cohort, survival was higher with non-HCT vs. HCT in early time period (relative risk [RR]: 0.34, P< .0001, Figure 1D), but in late time period survival was lower with non-HCT vs. HCT (RR: 2.37, P< 0.001) (Table 2). In the DIPSS low-risk MF group, while survival was higher with non-HCT vs. HCT in the early time period (RR: 0.19, P=0.007, Figure 1A), survival was lower with non-HCT in the late time period, but the latter did not reach statistical significance (RR: 1.45, P=0.39). In the DIPSS intermediate-1 risk group, a survival advantage was present with non-HCT treatments vs. HCT in the early time period (RR: 0.27, P < .0001, Figure 1B), however survival was lower with non-HCT in the late time period (RR: 3.13, P < .0001). Similarly, in those with DIPSS intermediate-2 and high-risk MF, survival advantage was observed with non-HCT in the early time period (RR: 0.41, P< .0001, Figure IC), but survival was lower with non-HCT in the late time period (RR: 2.82, P < .0001). Conclusion: A long-term survival advantage with transplant was observed for pts with intermediate-1 or higher risk MF, but at the cost of potential early mortality. The magnitude of benefit increased as DIPSS risk score increased. Although this retrospective study has limitations, the results have an impact on clinical practice by suggesting that transplantation could be considered earlier in the disease course and supports the recommendation for consideration of HCT in the setting of intermediate-1 risk MF. Disclosures Gowin: Incyte: Consultancy, Other: Scientific Advisory Board, Speakers Bureau. Verstovsek:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding. Gerds:Celgene: Consultancy; Apexx Oncology: Consultancy; CTI Biopharma: Consultancy; Incyte: Consultancy.

Abstract Background: Polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF) are chronic myeloproliferative neoplasms (MPNs) characterized by clonal cell proliferation, splenomegaly, and significant symptom burden. Integrative medicine interventions may offer unique symptom management strategies. (Gowin, et al., EHA 2017). Here we describe integrative interventions utilized and association with symptom burden, quality of life, depression, and fatigue adjusted for lifestyle confounders. Methods:Patients were recruited via social media. Consent and online self-report surveys were completed capturing patient demographics, disease-specific data, integrative medicine utilization, symptom burden via MPN-Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), depression screening via Patient Health Questionnaire (PHQ)-2, fatigue via Brief Fatigue Inventory (BFI), and overall quality of life (QoL). MPN-SAF TSS, QoL, BFI, and PHQ2 were compared by participation in the most frequently utilized interventions (Yes vs No). Intervention comparisons were adjusted for alcohol consumption, smoking status, BMI, current dietary modification, and MPN type using multiple linear and logistic regression. Results: Patients: A total of1087 patient surveys were consented. Of these, 858 had 10 or more responses. See Table 1 for patient characteristics. Integrative Medicine Therapies Descriptive Analysis: Integrative medicine therapies most frequently utilized by patients included aerobic activity (51.5%), massage (28.4%), yoga (25.6%), nutrition (25.2%), strength training (23.8%), acupuncture (19.3%), meditation (19%), breathing exercises (18.4%), chiropractic (16.2%), support groups (14.5%), mindfulness based stress reduction (13.6%), walking meditation (12.0%), pet therapy (9.4%), aromatherapy (8.6%), music therapy (8.0%), progressive muscle relaxation (7.0%), guided imagery (6.4%), homeopathy (6.3%), manual therapy (osteopathy/cranial sacral) (6.2%), reiki (5.8%), therapeutic touch (5.7%), Tai Chi (5.2%), art therapy (4.9%), traditional Chinese medicine (4.3%), Qigong (3.5%), cooking classes (3.0%), laughter therapy (2.9%), Ayurveda (2.4%), biofeedback (2.2%), dance therapy (2.1%), hypnosis (2.0%), resilience training (0.9%), IV vitamin therapy (0.8%), and narrative medicine (storytelling) (0.3%).Diet modification was reported in 47.7% of patients, including Mediterranean diet (19.0%), paleo/high protein/low carbohydrate (8.9%), vegetarian (8.6), plant based (5.2%), gluten free (5.2%), low FODMAP (1.8%), vegan (1.2%), and raw (0.6%) diets. Only 24% of patients reported receiving nutrition advice from their healthcare practitioner (HCP). Supplement utilization by MPN type was 162 patients (48.4%)in ET, 80 patients (42.8%) in MF, and 142 patients (45.2%) in PV. Overall, 20.6% patients reported not disclosing their natural product usage to their HCP. The most frequently utilized supplements included vitamin D, multivitamin, magnesium, omega 3, and calcium. Adjusted symptom association with integrative therapy intervention: MPN symptom burden: Aerobic activity (P=<.001)and strength training (P=.01) was associated with lower mean symptom burden. Use of massage (P=<001) and support groups (P=<.001) was associated with higher levels of symptom burden. QOL:Higher quality of life was reported in those receiving massage (P=.04)and support groups (P=.002). Lower quality of life was noted in those using aerobic activity (P=<.001)and strength training (P=.001). Depression (PHQ-2):Lower depression screening score was noted in those participating in aerobic activity (P=.006), yoga (P=.03), and strength training (P=.02). Fatigue (BFI):Lower fatigue was noted in those participating in aerobic activity (P=<.001) and strength training (P=.03). Higher fatigue was noted in those participating in massage (P=<.001) and breathing techniques (P=.02). See Table 2. Conclusion: In a geographically diverse MPN patient population, and when adjusting for healthy lifestyle practices overall, patterns of lower symptom burden, fatigue, depression, and higher QoL were revealed with integrative medicine utilization. Although limited by gender discrepancy and patient reported data, this study may offer a foundation to structure future integrative medicine trials to complement standard therapies in MPN patients. Disclosures Gowin: Incyte: Consultancy, Other: Scientific Advisory Board, Speakers Bureau. Mesa:UT Health San Antonio - Mays Cancer Center: Employment; Promedior: Research Funding; NS Pharma: Research Funding; CTI Biopharma: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy; Pfizer: Research Funding; Celgene: Research Funding.

Abstract Abstract 2818 Background: Pegylated interferon alpha-2a (Peg INF2a) has been demonstrated to be active therapy for high-risk essential thrombocythemia (ET) and polycythemia vera (PV), as well as treatment for early myelofibrosis (MF). We retrospectively analyzed the outcomes of Peg INF2a therapy in MPN patients treated outside the constraints of a clinical trial in the USA and EU. Methods: Clinical records of MPN patients treated at the participating centers, receiving Peg INF2a outside of the context of a clinical trial, were analyzed for response (ET and PV by ELN criteria; MF by EUNMET and IWG-MRT criteria), toxicity, and duration of response. Results: Patients: 115 patients were identified (54 PV (47%), 44 ET (38%), 17 MF (15%)) with a median age at diagnosis (48) and gender distribution (59% females) typical for the disorders. The patients had been diagnosed with the MPN a median of 44 months (0.0–312 months) prior to initiation of the Peg IFN2a and 64% harbored the JAK2-V617F mutation. The majority of patients (81%) had received at least one prior cytoreductive therapy for their disease (73 hydroxyurea, 39 anagrelide, 37 aspirin, 21 prior interferon (non pegylated), 3 phlebotomy alone). Therapy: Median starting dose of Peg INF2a was 45 micrograms/week (range: 22.5–180) with peak starting doses ranging from 30 to 300 micrograms/week. A total of 84 patients (73%) remain on Peg IFN2a with median duration of treatment of 17 months (range: 1.0–92). Toxicity: Overall the Peg INF2a was well tolerated. Hematological toxicity was Gr 3 or lower. There were 6 cases with anemia (5%), 10 with thrombocytopenia (9%) and 8 had leukopenia (7%). Most common non-hematologic toxicities were Gr 1–3 fatigue in 27 (23%), Gr 1 LFT elevation in 6 (5%), Gr 2–3 skin/allergic reaction in 6 (5%), Gr 1–2 nausea in 5 (4%), and Gr 2 mood disorder in 5 (4%) patients. Twenty patients (17%) discontinued therapy secondary to toxicity. Response: ET-PV: By ELN criteria, 30 PV patients achieved CR (55%), 17 achieved PR (31%), 4 achieved NR (7%), and 3 patients (5%) were lost to follow up or were too early to evaluate for response. In ET, the responses were CR in 27 (61%), PR in 7 (16%), NR in 4 (9%), and 6 patients (14%) were lost to follow up or were too early to evaluate for response. MF: The responses by IWG criteria were 1 CR (6%), 2 PR (12%), 2 CI (12%) and 9 SD (53%). By EUNMET, there were 2 CR (12%), 4 major responses (24%), 4 moderate responses (24%), 1 minor response (6%), 2 no response (12%), and 3 patients (17%) were lost to follow up or were too early to evaluate for response. Conclusions: Peg INF2a used at doses consistent with published clinical trials is active and well-tolerated when administered in a clinical setting outside of the support of a clinical trial. Given the majority of patients had previously failed cytoreductive therapy these results substantiate prior reports of efficacy of Peg INF2a in MPNs. Upcoming randomized clinical trials through the Myeloproliferative Disorders Research Consortium will help further define the role of Peg INF2a as first line therapy in high-risk MPNs. Disclosures: Mesa: Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: 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 Background: Post polycythemia vera (PV) and essential thrombocytosis (ET) myelofibrosis (MF), like primary MF (PMF), are heralded by splenomegaly, cytopenias, heavy symptom burden, and decreased overall survival. Risk prognostication tools, including the dynamic international prognostic scoring system (DIPSS) and the Passamonti risk score for post-PV MF (Passamonti et al. Blood 2010, 2008), are helpful to estimate survival and guide therapeutic decision-making. For Post-PV/ET MF, it is unknown if DIPSS correlates with the Passamonti risk score. Here we evaluate the correlation between the two available risk prognostication tools in post-PV/ET MF. Methods: Retrospective chart review conducted for patients with post-PV/ET MF seen between 2000-2012. Descriptive statistics were used to describe patient demographic and clinical variables in post PV/ET patients. DIPSS Score: calculated at time of last follow up: 1 point for age >65, 2 points for hemoglobin <10g/dL, 1 point for leukocytes >25 x 109, 1 point for circulating blasts 1% and 1 point for constitutional symptoms. Risk group was assigned: low-risk (0 adverse points), intermediate-1 risk (1 adverse point), intermediate-2 risk (2-3 adverse points) and high-risk (4-6 adverse points). Passamonti Risk Scores: calculated at time of last follow up: with 1 point assigned for hemoglobin level less than 100 g/L (10 g/dL), platelet count less than 100 x10 (9)/L, and/or leukocyte count more than 30x10(9)/L. Cross-tabulation of DIPSS score versus Passamonti risk score at time of last follow-up was conducted and the percent agreement was described. Spearman correlation coefficient between DIPSS score at follow-up with Passamonti score was conducted. Results: Patients: Sixty-one (58%) post-ET and 44 (42%) post-PV patients were identified, total N=105. Male to Female ratio was 1:1. Median age was 65 (range 25-87). JAK2 V617Fpresent in 68 (65.4%). Median hemoglobin was 10.9 g/dL (range 5.3-17.0), median platelet count 287 x 109 (range 20-1864), and median WBC was 11.1x 109 (range 1.1-165). Risk prognostication: When DIPSS risk scores were applied 11 patients were low, 48 patients were Intermediate-1, 31 patients were Intermediate-2, and 10 patients were high. When Passamonti risk scores were applied 57 patients received score of 0, 31 patients scored 1, 9 patients scored 2, and 3 patients scored 3. DIPSS and Passamonti risk score agreement: The overall agreement between DIPSS and Passamonti risk scores was low, with 24% of cases in agreement. Spearman correlation: Rho=0.451; p<0.001. See Table #1 with agreement seen in highlighted cells. Table 1. DIPSS and Passamonti Agreement Passamonti Risk Score DIPSS 0 1 2 3 Total Low 9 (75%) 3 (25%) 0 0 12 Int-1 31 (77.5%) 8 (20%) 1 (2.5%) 0 40 Int-2 17 (43.6%) 14 (35.9%) 6 (15.4%) 2 (5.1%) 39 High 0 6 (75%) 1 (12.5%) 1 (12.5%) 8 Total 57 (57.6%) 31 (31.3%) 8 (8%) 3 (3%) 100 Conclusion: Post PV/ET MF represents a unique clinical entity and risk prognostication schemes developed for PMF, such as DIPSS, may not represent accurate prognosis estimation in this subgroup of MF. When DIPSS and Passamonti risk scores were applied to same post PV/ET group, agreement was poor at 24%. Additionally, DIPSS was more likely to assign patients to high-risk category than Passamonti. Further studies are needed to evaluate the DIPSS and Passamonti prognostic risk score application to the post PV/ET MF population. Disclosures Mesa: Incyte Corporation: Research Funding; Pfizer: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Incyte Corporation: Research Funding; Gilead: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Genentech: Research Funding; Promedior: Research Funding; CTI Biopharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; CTI Biopharma: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Pfizer: Research Funding; NS Pharma: Research Funding.

Abstract Background: Pegylated interferon alpha-2a (Peg INF2a) has been demonstrated to be active therapy for high-risk essential thrombocythemia (ET), polycythemia vera (PV), and early myelofibrosis (MF). We retrospectively analyzed the outcomes of Peg INF2a therapy in myeloproliferative (MPN) patients treated outside the constraints of a clinical trial. Methods: Charts were analyzed for demographic and clinical data. Toxicity to therapy was assessed per CTCAE 3.0 criteria. Therapeutic responses for ET and PV were calculated by the revised ELN/IWG-MRT criteria including complete remission (CR), partial resmission (PR), no response (NR), or progressive disease (PD). Responses in MF were calculated by EUNMET: complete response (CR), major response (MR), moderate response (MoR), minor response (MiR) and NRand the revised IWG-MRT/ELN criteria: CR, PR, clinical improvement (CI), stable disease (SD) or PD. Results: Patients: 75 patients were identified overall. There were 36 PV patients (48%), 20 ET patients (26.7%), and 19 MF patients (25.6%). Thirteen MF patients were post-PV/ET MF. The median age at diagnosis was 51.5 yrs (range 28.8-75.1). JAK2 V617 mutation was present in 53 patients (70.7%). Median baseline hemoglobin (g/dL), leukocyte (x10 9), and platelet count (x109) for PV was 13.6, 8.6, 369, for ET was 12.5, 6.8, 517, and for MF was 11.4, 8.0, and 420, respectively. DIPSS risk category for the 19 MF patients: Low in 6 (31.5%) patients, Intermediate-1 in 3 (15.7%), Intermediate-2 in 8 (42%), and High in 2 (10.5%) patients. The majority of patients (82.2%) had received at least one prior cytoreductive therapy for their disease. Therapy: Median starting dose of Peg INF2a was 45 micrograms/week (range 45-90). The median peak dose was 90 micrograms/week (range 45-270). The median tolerated dose was 60 micrograms/week (range 5.6-180). The median duration of treatment was 24 months (range 3.6-85). Toxicity: Overall the Peg INF2a was well tolerated. Hematological toxicity included: leukopenia at grade 1 in 13 patients (17.3%), grade 2 in 5 patients (6.7%), and grade 3 in 1 patient (1.3%), anemia at grade 1 in 10 patients (13.3%) and grade 2 in 1 patient (1.3%), thrombocytopenia at grade 1 in 13 patients (17.3%) and grade 2 in 1 patient (1.3%). The most common non-hematologic toxicity included: fatigue at grade 1 in 14 patients (18.7%) and grade 2 in 4 patients (5.3%), transaminitis at grade 1 in 6 patients (8%) and grade 2 in 3 patients (4%), myalgias at grade 1 in 4 patients (5.3%). Response: See Table #1 PV/ET: 56 patients were evaluated by ELN/IWG-MRT criteria overall: A complete remission (CR) was seen in 8 patients (14.3%), a partial remission (PR) in 18 patients (32.1%), either a CR or PR in 18 patients (32.1%) when histologic remissions were unable to be documented due to lack of restaging bone marrow examination, no response in 11 patients (19.6%), and progressive disease in 1 patient (1.8%). Of the 12 patients receiving at least1 phlebotomy per month, 10 patients (83.3%) became phlebotomy independent with therapy. Of the 20 ET patients, 12 patients (60%) had platelet normalization (<400 x 109). MF: 19 patients were evaluated by IWG-ELN criteria: a PR was seen in 2 patients (10.5%), CI in 4 patients (21.1%), SD in 12 patients (63.2%), and PD in 1 patient (5.3%). Utilizing EUNMET critieria: 1 patient (5.3%) with a CR, 5 patients (26.3%) with a MR, 3 patients (15.8%) with MoR, 5 patients (26.3%) with MiR, and 5 patients (26.3%) with NR. Table 1. Peg INF2a Patient Responses RESPONSE Disease IWG-ELN response criteria: (Patient #, %) (Barosi, Blood 2013, Tefferi, Blood 2013) EUMET response criteria: (Patient #, %) (Barosi, Blood 2005) PV: N=36 CR: 3 pts (8.3%) PR: 14 pts (38.8%) CR/PR: 14 pts (38.8%) NR: 5 pts (13.8%) PD: 0 NA ET: N=20 CR: 5 pts (25%) PR: 4 pts (20%) CR/PR: 4 pts (20%) NR: 6 pts (30%) PD: 1 (5%) NA MF: N=19 IWG-ELN: PR: 2 pts (10.5%) CI: 4 pts (21.1%) SD: 12 pts (63.2%) PD: 1 pt (5.3%) EUNMET: CR: 1 pt (5.3%) MR: 5 pts (26.3%) MoR: 3 pts (15.8%) MiR: 5 pts (26.3%) NR: 5 pts (26.3%) NA: Not applicable Conclusions: Peg INF2a is active and well-tolerated when administered outside of the support of a clinical trial. Given the majority of patients had previously failed cytoreductive therapy these results substantiate prior reports of efficacy of Peg INF2a in MPNs. Disclosures Mesa: Pfizer: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; NS Pharma: Research Funding; Genentech: Research Funding.

Abstract Introduction: Most myelofibrosis (MF) patients develop anemia during evolution of the disease process predicting decreased survival. Previous studies exploring the effect of danazol for the treatment of anemia in MF demonstrate responses in anemia. In prior randomized-controlled studies, ruxolitinib demonstrated improvements in splenomegaly, symptom burden, and even survival yet improvements in cytopenias were uncommon. We designed a phase II multicenter pilot study to evaluate the efficacy and tolerability of combination therapy with ruxolitinib and danazol in MF patients with anemia. Methods: This was a Simon optimum two-stage phase II trial. Eligible subjects received ruxolitinib, a JAK 1/JAK2 inhibitor, at 10mg (plat >75 x10x9) BID or 5mg (plat <75 x10 x9) BID) representing initial dose reduction for JAK inhibitor naïve patients to minimize cytopenias, in combination with tapered danazol up to 200mg orally TID. Dose escalation was allowed after completion of 28 days for lack of response or for disease progression. Pts without progression continued for 6 cycles at 56 days each. Treatment modifications were allowed for either medication based on emergent adverse events (AE). Treatment responses were evaluated every cycle by IWG-MRT criteria (Blood 2006). Patient reported outcome questionnaires (MPN-SAF, EORTC QLQ-C30) were administered at baseline, prior to treatment cycles, and at study discontinuation. Results: Patients: Fourteen pts enrolled (9 Mayo Arizona, 5 Mount Sinai). Median (Med) age 70.5 (range 43-78), M:F ratio 1.8:1. Ten primary MF, 2 post-essential thrombocythemia MF, and 2 post-polycythemia vera MF. JAK2 V617F positive in 42.9%. DIPSS Low in 1 pt, Int-1 in 1pt, Int-2 in 8 pts, High in 2 pts, and unknown in 2pts. Transfusion dependence in 35.7% at baseline. Med baseline hemoglobin (hgb) was 9.0 g/dL (R: 8.3 - 12.4), platelet (plt)157 x109/L (R:143 - 520). Thirteen pts received prior therapy, with 9 pts (64.2%) on a JAK inhibitor within 3 months of study entry. Tolerability: Nine pts (64.2%) ended active treatment, due to progression of disease in 2 pts (22.2%), adverse event (AE) in 2, pt preference in 2, stem cell transplant in 1, unrelated death in 1, and comorbidity in 1. Med duration of therapy: 91 days (range 24-287). AEs regardless of attrition included: hematologic grade 3 or >: anemia in 7 pts (50%), neutropenia in 2 (14.3%), leukopenia in 1 (7.1%), and thrombocytopenia in 2 (14.3%). Non-hematologic grade 3 or >: electrolyte abnormalities in 3 pts (21.4%), infection in 2 (14.3%), edema in 1(7.1%), hypertension in 1 (7.1%), and intracranial hemorrhage in 1 (7.1%). Efficacy: Of the 5 JAK inhibitor naïve pts, 4 had stable or increasing hgb levels with therapy despite new ruxolitinib therapy. Of the 9 pts on prior JAK inhibitor (5 ruxolitinib, 4 other), 5 (55.5%) and 7 (77.7%) patients had stable or increasing hgb or plt levels, respectively. See Table #1. Four pts (28.6%) had at least 50% improvement from baseline on MPN-SAF TSS (95% CI 8.4%-58.1%). Overall treatment response: (IWG-MRT) stable disease (SD) in 10 pts (71.4%), clinical improvement (CI) in 3 (21.4%) all of which were spleen responses, and progressive disease (PD) in 1 (7.1%). Trial was halted secondary to lack of anemia response. Table 1. Patient Specific Response Patient IWG-MRT Response: Study Cycles (N): Prior therapy (within 3 mo) Hemoglobin Response*: (initial, final g/dL) Platelet Response*: (initial, final 10(9)/L) Ruxolitinib 1 CI-Spleen 5 D (8.8, 7.6) S (221,212) 2 SD 4 D (10.3,7.9) S (54,46) 3 SD 2 S (8.8,8.9) S (82,101) 4 SD 3 I (8.9,9.8) S (441,458) 5 SD 3 S (9.6, 9.5) I (161, 231) JAK Inhibitor: 6 SD 5 Momelotinib S (9.0, 9.2) S (132,113) 7 SD 1 NS-018 D (8.3, 7.1) D (120,43) 8 SD 3 NS-018 D (10.1,9.0) D (138,111) 9 SD 2 LY2784544 S (8.7,9.1) S (56,21) Other: 10 CI-Spleen 9 Procrit I (10.5,11.9) S (153,198) 11 CI-Spleen 7 None I (8.9,10.2) D (338,133) 12 PD 1 Hydroxyurea S (12.4, 12.2) D (310, 82) 13 SD 1 Procrit D (10.1, 8.6) D (192, 71) 14 SD 1 Hydroxyurea S (9.1,8.9) D (346,119 *S=stable (Hgb +/- 0.5g/dL, Plt +/- 50x109, D=decreasing, I=increasing. Conclusions: Although overall well tolerated, the addition of danazol to ruxolitinib therapy has modest incremental efficacy by IWG-MRT criteria. Clinical improvement was observed in 21.4% of treated patients, however responses were limited to spleen reduction. The degree to which danazol may stabilize expected cytopenias is interesting and may require further investigation. Disclosures Hoffman: Promedior: Research Funding; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; All Cells, LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mesa:Gilead: Research Funding; Genentech: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; CTI Biopharma: Research Funding; Pfizer: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Incyte Corporation: Research Funding.

Abstract Introduction: Polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are chronic, Philadelphia-negative myeloproliferative neoplasms (MPNs) that are characterized by deregulated myeloid lineage cell production, leading to a high symptom burden, including abdominal pain/discomfort from splenomegaly, fatigue, depressive symptoms, sleep disturbance, sexual problems, and pruritis, among other symptoms. Yoga interventions have been demonstrated to be efficacious for improving symptom burden in other cancer populations. Additionally weight has been shown to moderate symptom burden response in cancer patients. In MPN patients, it is unknown if weight influences symptom burden response. Therefore, the purpose of this analysis was to examine the differences at baseline and post-intervention in symptom burden between overweight and normal weight MPN patients participating in an online yoga intervention. Methods: MPN patients were asked to participate in 60 minutes of online-streamed yoga weekly for 12 weeks. Participants were asked to complete online self-report surveys administered via Qualtrics at baseline (week 0), mid-point (week 7), post-intervention (week 12), and follow-up (week 16). Survey measures included demographics, total symptom burden and fatigue (MPN Symptom Assessment Form [MPN SAF]) as well as NIH PROMIS measures of pain, anxiety, depression, sleep, and sexual function. BMI status was determined through self-report height and weight obtained in the baseline survey. For statistical analyses, BMI was dichotomized into an overweight (OW) category (BMI ≥25 kg/m2) and a normal weight (NW) category (BMI <25 kg/m2). Results: A total of 38 MPN patients completed the 12-week intervention. The majority of participants were diagnosed with either PV (n=16) or ET (n=16), with MF being less common (n=6). Median age was 56 years (range 29-72) with most participants being female (n=34). A minority were OW (n=12). At baseline, total symptom score (TSS) was descriptively higher in OW vs NW participants (mean 42.8 [SD 16.2] vs 32.7 [SD 10.9], p=0.06) with no other differences observed for PROMIS outcomes. OW participants had significantly improved TSS (p=0.002), anxiety (p=0.002), sleep (p=0.02), and vaginal discomfort (p=0.04) at the end of the intervention (week 12, Table 1). Improvements in NW participants did not reach statistical significance for any scales except sleep at week 12 (p<0.001). From baseline to follow-up (week 16), NW participants had significant improvements in TSS (p=0.003), depression (p=0.003), and sleep (p=0.007). OW participants maintained significant improvements in only sleep at week 16 (p=0.005). Conclusion: In MPN patients participating in a 12-week, online streamed yoga intervention, some differences in response to the intervention were observed between OW and NW participants. However, statistical power for definitive analysis of weight as a moderator for improvement in symptom burden was limited due to a small sample size. Considering the lack of interventions in MPN patients and the potential role that weight has on outcomes in other cancer populations, a randomized controlled trial investigating the effects of online yoga in a larger sample of MPN patients is warranted along with further investigation of effectiveness of the intervention within groups of participants by weight. Disclosures Gowin: Incyte: Membership on an entity's Board of Directors or advisory committees. Mesa:Promedior: Research Funding; Incyte: Research Funding; Ariad: Consultancy; CTI Biopharma: Research Funding; Novartis: Consultancy; Gilead: Research Funding; Galena: Consultancy; Celgene: Research Funding.

Abstract Introduction: Polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are Philadelphia-negative myeloproliferative neoplasms (MPNs) leading to risk of vascular events, splenomegaly and cytopenias in advanced disease as well as disease-originating symptoms, including (but not limited to) fatigue, depressive symptoms, insomnia, inactivity, sexual problems, and pruritis. Current therapy with JAK inhibition has improved MPN symptom burden, yet even in responders, unmet needs remain for alleviating fatigue, mood related symptoms, and insomnia. Yoga used as non-pharmacologic therapy has been shown to be efficacious for improving anxiety, depression, sleep quality, and fatigue in other cancer populations, including hematological malignancies. Due to a lack of this type of research in MPN patients, we undertook the first yoga study in this population as a feasibility trial (i.e., acceptability, demand, practicality) of home-based, online-streamed yoga for improving MPN patient symptom burden. Methods: MPN patients were recruited nationally using social media. Participants were asked to complete 60 minutes of online-streamed yoga weekly for 12 weeks. The yoga video selection included MPN-specific videos as well as others chosen specifically with potential splenomegaly in mind. Additionally, participants were asked to complete online self-report surveys administered via Qualtrics. Survey measures included demographics, total symptom burden and fatigue (MPN Symptom Assessment Form [MPN SAF]) as well as NIH PROMIS measures of pain, anxiety, depression, sleep, and sexual function. Surveys were administered at baseline (week 0), mid-point (week 7), post-intervention (week 12), and follow-up (week 16). Weekly yoga minutes were collected through online self-report. Results:Patients: Two hundred and forty-four MPN patients completed the eligibility survey, 134 were eligible, 55 completed the informed consent, and 38 MPN patients completed the 12-week intervention. The majority of participants were diagnosed with either PV (n=16) or ET (n=16), with MF being less common (n=6). Additionally, the majority of participants were female (n=34), Caucasian (n=37), married (n=30) of a normal BMI category (n=26), and had attained a Bachelor's degree or higher (n=25). Median age of those participating was 56 years (range 29-72). Yoga Participation & Safety:Approximately 37% (n=14) of study participants averaged ≥60 min/week of yoga. Yoga participation averaged 50.8±36.2 min/week. Additionally, 75% of participants felt safe from injury while participating in online yoga. Only one adverse event was reported (irritated enlarged spleen). Feasibility:Overall, 68% of participants were either satisfied or very satisfied with online yoga and 75% felt that is was helpful for coping with MPN-related symptoms (i.e., acceptability, practicality). However, only 43% of participants reported that they were likely or very likely to continue their online yoga practice (i.e., demand). Impact of Yoga Intervention: From baseline (week 0) to post-intervention (week 12, n=30), there were significant improvements in total symptom burden (effect size [ES] in standard deviation units=-0.36, p=0.004), anxiety (ES=-0.67, p=0.002), depression (ES=-0.41, p=0.049), sleep (ES=-0.58, p<0.001), and fatigue (ES=-0.33, p=0.04). These improvements remained significant at follow-up (week 16, n=28) for all outcome measures with a trend for maintained fatigue improvement (ES=-0.34, p=0.06). There were no significant differences in outcomes between those that averaged <60 min/week of yoga compared to those that averaged ≥60 min/week of yoga. Conclusions: A 12-week, home-based, online-streamed yoga intervention is feasible (i.e., accepted, practical) for MPN patients. Although the sample size was small and there was no control group, the results suggest that online yoga may be effective for improving MPN symptom burden, with statistically significant improvements observed in total symptom burden, fatigue, anxiety, depression, and sleep. A randomized, controlled trial is warranted to evaluate home-based, online-streamed yoga on MPN patient outcomes. If effective, yoga may represent a unique non-pharmacologic complement to standard therapies in a population with a heterogeneous symptom profile and significant symptom burden. Disclosures Gowin: Incyte: Membership on an entity's Board of Directors or advisory committees. Mesa:Ariad: Consultancy; Galena: Consultancy; Incyte: Research Funding; Gilead: Research Funding; Novartis: Consultancy; Promedior: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding.

Abstract Introduction/Background Recurrent deletions of chromosome 5 and 7 are characteristic of the myeloid malignancies MDS and AML, determine prognosis and influence therapeutic decision. The pathogenetic contribution of individual genes to MDS/AML development has been shown for several of these genes. However, how and if these genetic losses may relate to therapeutic interventions or represent haploinsufficient targets has remained elusive for the most part. We hypothesized that genes found within the commonly deleted regions (CDRs) of chromosome 5/7 (chr 5/7) represent targetable vulnerabilities in malignant myeloid cells. Therefore we generated a custom RNAi library to functionally interrogate these genomic regions alone or under 5-Azacitidine (5-Aza) treatment, to identify individual genes whose silencing modulate 5-Aza responsiveness. Methods/Materials Custom siRNA plates against ~270 genes (3x sequences/gene, Qiagen) on CDRs of chr 5/7 were assembled. Genes were silenced by siRNA for 48 hours followed by 48-72 hour 5-Aza treatment after which cell viability was determined. Four cell lines (TF1, THP1, MDS-L and HEL) were investigated in parallel with combined siRNA/5-Aza incubations and appropriate 5-Aza and siRNA only control. Hits were selected as > 2 standard deviation changes in viability from the median log2 value of the ratio [(siRNA + 5-Aza)/(siRNA only)], normalized per plate and across the entire screen. Duplictae RNAis screens were performed. Synergy between 5-Aza and the SMO inhibitors LDE225 (Sonidegib) and GDC0449 (Vismodegib) was assessed with CalcuSyn in a panel of AML cell lines. Ex vivo viability and clonogenic re-population experiments in primary patient derived AML and MDS cells were performed with Sonidegib. Results Several genes within the Hedgehog (HH) pathway emerged as sensitizers to 5-Aza when silenced by siRNA in three of four cell lines examined. Specifically Shh siRNA sensitized to 5-Aza in both TF-1 and THP-1 cells, SMO in HEL and GLI3 in THP-1 cells. Shh silencing alone (siRNA only) resulted in reduction of viability only in TF-1 cells but not in THP-1 cells, while SMO and GLI3 siRNA alone did not result in significant reductions in viability but sensitized to 5-Aza, indicating true sensitization and an interactions between the HH pathway and 5-Aza treatment. The SMO inhibitor Vismodegib synergized with 5-Aza in drug dose response assays in a panel of four AML cell lines (TF-1, THP-1, ML-2, HL-60) with Combination Index (CI) values of around 0.6 or lower at low doses of both drugs. Similar results were also observed with Sonidegib in vitro in 5 molecularly heterogeneous AML cell lines. Given stem cell modulation capacity of SMO inhibition, we examined ex vivo proliferation and more importantly clonogenic growth capacity. Highly interesting, ex vivo viability was reduced and synergy observed by the Sonidegib/5-Aza combination to a much greater extend in CD34+ selected primary MDS and AML cells as compared to bulk or CD34 depleted (normal) MNCs. Clonogenic growth was reduced in the combination over single agent 5-Aza or Sonidegib in ~ 50% of samples assessed to date. No direct correlations to cytogenetics were observed. A clinical Phase 1b trial was designed based on these results and is currently accruing in the first cohorts. Conclusions RNAi screening of CDRs of chr 5/7 yielded potential targetable therapeutic vulnerabilities with several genes within the HH pathway sensitizing to 5-Aza. SMO inhibitors pharmacologically validate this concept in vitro and ex vivo with the potential to more selectively affect leukemia stem/progenitor cells. Clinical data will show if this is a specific effect involving chr 5/7 or a general concept in malignant myeloid cells. Thus, SMO inhibition in combination with 5-Aza may be a novel rational combination in AML and MDS. Disclosures Off Label Use: LDE225/Sonidegib on a clinical trial. Mesa:Incyte, CTI, NS Pharma, Inc., Gilead, Celgene: Research Funding.