Citations

Abstract Abstract 3861 Poster Board III-797 Previous studies have reported that multiple myeloma (MM) patients (pts) with t(4;14) identified by FISH who are treated with a single ASCT as part of first-line therapy have worse outcomes than those lacking this adverse cytogenetic marker; two trials have described a median progression-free survival (PFS) of only 8-9 months and median overall survival (OS) of 18 mos in this setting (Chang H, et al. Bone Marrow Transplant 2005; 36: 793; Gertz M, et al. Blood 2005; 106: 2837). Since the novel agent bortezomib appears to have efficacy in patients with t(4;14), we designed a phase II protocol in which pts receive induction with pegylated liposomal doxorubicin, bortezomib and dexamethasone (DBD) x 4 cycles, followed by post-induction therapy with oral cyclophosphamide 300 mg/m2 days 1,8 15, 22 with bortezomib 1.5 mg/m2 days 1,8,15 and prednisone 100 mg q 2 days of a 28-day cycle (CyBor-P) x 8 additional cycles. Maintenance therapy with dexamethasone (dex) 40 mg/month was then administered until progression. Although elective stem cell collection was recommended after induction, routine ASCT was not performed in the absence of disease progression. Between February 2008-August 2009, 153 newly diagnosed MM pts were screened for t(4;14) in 7 Canadian centers, and 14 (9%) were found to be positive by FISH. Four did not meet the critieria for symptomatic MM, 2 had received ≥ 2 mos of prior therapy while 8 were entered onto study. One of these was later determined to have a variant abnormality of chromosome 4 but not t(4;14) and underwent ASCT after induction; this pt is included in the safety analysis only. The median age was 56 (49-69) and 43% were male. The median percent nuclei positive for t(4;14) was 30% (10-41%), serum β2-microglobulin 394 nmol/L (190-1695) and albumin 34 g/L (28-39); one pt had ISS stage 1,3 had stage 2 and 3 had stage 3 MM. Immunoglobulin subtype included IgGκ in 2 and IgAκ in 2 and IgAλ in 3. All pts have completed DBD induction, with the best response in the 7 evaluable pts consisting of PR in 2 and VGPR in 5; one in PR progressed quickly after induction and has achieved nCR after D-PACE followed by ASCT and lenalidomide maintenance. Four are receiving post-induction therapy with CyBor-P currently, with VGPR in 3 and PR in 1. No SAEs or grade3/4 neutropenia or thrombocytopenia has occurred; other toxicities were mild, with grade 2 skin toxicity noted in 37.5% and grade 2 neurotoxicity observed in 7.4%. All pts are alive at a median follow-up (F/U) of 8 mos (2-11), and 6 (86%) are free of progression. We conclude: 1) the incidence of t(4;14) in newly diagnosed MM pts appears to be lower than the 15% anticipated; 2) 28% of newly diagnosed pts with this entity have asymptomatic MM; 3) preliminarily, DBD induction has resulted in ≥ PR in all pts although 1 progressed quickly; 4) this bortezomib-based regimen is very well-tolerated; 5) longer F/U is required to determine the PFS and OS with this approach. Disclosures: Reece: Ortho Biotech: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Off Label Use: Use of bortezomib as part of initial therapy with pegylated liposomal doxorubicin and dexamethasone. Piza Rodriguez:Ortho Biotech: Honoraria. Belch:Ortho Biotech: Honoraria, Research Funding. Shustik:Ortho Biotech: Honoraria. Bahlis:Ortho Biotech: Honoraria; Celgene: Honoraria. White:Ortho Biotech: Honoraria, Research Funding. Chen:Ortho Biotech: Honoraria. Kukreti:Celgene: Honoraria. Stewart:Genzyme, Celgene, Millenium, Proteolix: Honoraria; Takeda, Millenium: Research Funding; Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy. Trudel:Ortho Biotech: Honoraria, Research Funding.

Abstract Background Severe anemia with RBC-transfusion-dependence is common in persons with advanced MPN-associated myelofibrosis. Pomalidomide, an immune-modulating drug with pleiotrophic bone marrow effects, improved anemia in several phase 2 studies. Method Phase 3 double-blind, placebo-controlled trial of pomalidomide (0.5 mg/d) in subjects with MPN-associated myelofibrosis and RBC-transfusion-dependence. The primary endpoint was RBC-transfusion-independence. Criteria for RBC-transfusion-dependence and -independence were based on results of an expert consensus panel RAND-Delphi study. Subjects 252 subjects were randomized 2:1 to receive pomalidomide or placebo with stratifications for age, type of myelofibrosis, and intensity of RBC-transfusions. Median age was 70 y. 75% had primary myelofibrosis. Median units (U) RBC-transfusions/28 d pre-randomization was 3 (range, 2-13). Results Response rates in the cohorts were similar (16% [95% CI, 11-23%] vs 16% [8-26%]), as were response durations. However, median time to response for pomalidomide was 7 w (range, 0-20 w) vs only 2 w (range, 0-15 w) for placebo (p=0.22). Response in both cohorts was more common in subjects with ≤4 vs >4 U RBC/28 d pre-randomization (OR=3.1 [p=0.09] and OR=8.6 [p=0.06]). However, other variables associated with response to pomalidomide: age ≤65 vs >65 y (OR=2.4; p=0.07) and primary myelofibrosis vs other (OR=2.6; p=0.14) and response to placebo: (WBC >25 vs ≤25 x10E9/L; OR=5.0; p=0.08) and interval from diagnosis to randomization >2 vs ≤2 y (OR=5.0; p=0.04) differed. These differences would not be expected were response to pomalidomide identical to response to placebo. Also, a center effect was found in placebo but not pomalidomide responders, which persisted after adjusting for predictive associations. Several pomalidomide responders lost response when therapy was stopped but regained it when pomalidomide was re-started. No pre-randomization therapy (iron-chelation, hydroxyurea, busulfan, folate) was consistently correlated with response to placebo, and durations of RBC-transfusion-dependence pre-randomization were similar between the cohorts. In contrast, platelet response rates, a 2̍° endpoint, were significantly different between the cohorts: pomalidomide, 22% (95% CI, 11-35%) vsplacebo, 0 (0-12%; p=0.006). Platelet response was not correlated with RBC-transfusion-independence response. Conclusion There was no significant difference in rate or duration of RBC-transfusion-independence response to pomalidomide vsplacebo despite using what were thought to be sensitive and specific entry- and response-criteria. Unexpectedly, however, most variables associated with response to pomalidomide and placebo differed between the cohorts, as did distribution of times to response. These data suggest responses to pomalidomide and placebo differ but were not distinguished by our response-criteria. Pomalidomide appears to reverse RBC transfusion dependence in some persons with MPN associated MF. However, additional research designs are needed to study this impression. This abstract is presented on behalf of all RESUME Investigators. Study registration: NCT01178281. Disclosures: Cervantes: Novartis: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees. Gisslinger:AOP Orphan Pharmaceuticals: Advisory Board Meeting Other, Honoraria; Novartis: Advisory Board Meeting, Advisory Board Meeting Other, Honoraria; Sanofi-Aventis: Advisory Board Meeting, Advisory Board Meeting Other, Honoraria; Shire: Advisory Board Meeting, Advisory Board Meeting Other, Honoraria; Celgene: Advisory Board Meeting Other, Honoraria; Janssen: Advisory Board Meeting, Advisory Board Meeting Other, Honoraria. Gupta:Incyte Corporation: Consultancy, Grant support through institution Other; Novartis: Consultancy, Grant support through institution, Grant support through institution Other, Honoraria. Harrison:SBio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Shire: Speakers Bureau; Celgene: Honoraria; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Kiladjian:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees; AOP Orphan: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Schiller:Celgene: Research Funding. Mesa:Gilead: Research Funding; Incyte: Research Funding; NS Pharma: Research Funding; Lilly: Research Funding; Genentech: Research Funding; Celgene: Research Funding.

Abstract Background The JAK1/JAK2 inhibitor ruxolitinib (RUX) is approved for treatment of myelofibrosis (MF). However, some patients do not respond to RUX, while others lose responsiveness or develop intolerance to RUX over time. Preclinical data also suggest that certain JAK2 mutations (eg the gatekeeper mutation M929I) may confer resistance to RUX (Leukemia 2012;26:708). Options for these RUX resistant/intolerant patients, particularly with regard to further JAK inhibitor therapy, are unclear. Fedratinib (SAR302503) is a JAK2-selective inhibitor which has demonstrated clinically meaningful reductions in splenomegaly and symptom burden in patients with MF, with an acceptable and consistent safety profile (J Clin Oncol 2011;29:789. Haematologica 2013;98:S1113). Fedratinib sensitivity in vitro is unaffected by the M929I mutation. This pre-specified interim analysis of the JAKARTA-2 study (NCT01523171) investigated the efficacy and safety of fedratinib in MF patients previously treated with RUX. Methods JAKARTA-2 is a Phase II, multicenter, open-label, single-arm study of patients who previously received RUX for MF. Patients ≥18 yrs with splenomegaly and platelet count ≥50 ×109/L received fedratinib 400 mg orally, once daily for consecutive 4-wk cycles (permitted dose adjustment to 200–600 mg daily). Eligible patients had received ≥14 d RUX treatment, and had discontinued RUX for ≥14 d prior to starting fedratinib. Although there is no consensus definition of RUX resistance/intolerance, for the purpose of this study patients were classed (investigator assessment) as resistant (lack or loss of response) or intolerant to RUX. Primary endpoint for the interim analysis: spleen response rate (RR) (≥35% reduction in spleen volume from baseline at Wk 12 [MRI/CT blinded central review]) in the per-protocol (PP) population. Secondary endpoints: symptom RR (≥50% reduction in total symptom score [TSS: modified Myelofibrosis Symptom Assessment Form] from baseline to Wk 12) and safety. Results At the cut-off date for this interim analysis, 27 patients had received fedratinib treatment (median RUX exposure 10.7 months [range 1.9–34.4]): median age 69 yrs; 56% male; 67% primary MF; 63% high-risk MF; 67% JAK2V617F positive; 41% platelet count <100 × 109/L; baseline median spleen volume 3190 mL [1072–7815]; baseline median TSS 19.6 [4.9–46.0]. Eighteen patients were considered resistant by the treating physician (8 lack of response, 3 disease progression, 7 loss of response; median RUX exposure 11.1 months [range 1.9–34.4]) and 9 intolerant (6 hematologic, 3 non-hematologic toxicity; median RUX exposure 9.2 months [2.9–33.2]) to RUX. Median fedratinib exposure to cut-off date: 4 cycles (range 1–10); 19 patients remain on treatment. Spleen RRs were 40% (8/20 PP patients) and 43% (3/7) in patients with baseline platelet count <100 ×109/L. Overall, 19% (5/26 evaluable patients) had a symptom response by Wk 12 (Table). The majority of patients had a reduction in TSS at Wk 12 (Figure). The most common non-hematologic treatment-emergent adverse events (AEs) were gastrointestinal (nausea 67%; diarrhea 56%; vomiting 48%). Grade 3/4 diarrhea occurred in 2 patients; no Grade 3/4 vomiting or nausea. Anemia was the most common hematologic AE (all grades, 93%; Grade 3, 41%; Grade 4, 0%). Thrombocytopenia (all grades) occurred in 19 (70%) patients; Grade 3 in 6 patients and Grade 4 in 2 patients. One patient had Grade 3 AST elevations and 1 patient had Grade 3 hyperbilirubinemia. Seven patients (26%) discontinued treatment due to AEs. There were 2 deaths on study, both due to disease progression. Conclusions Interim results from the JAKARTA-2 study indicate that once-daily fedratinib provides clinical benefit, through reduced splenomegaly and symptom burden, in MF patients previously treated with RUX. The safety profile was acceptable and manageable, with safety results to date consistent with those reported in previous trials of fedratinib. Sponsored by Sanofi. Disclosures: Harrison: Novartis: Research Funding; Novartis, Sanofi, YM Bioscience, Celgene, SBio, Gilead: Honoraria; Novartis, Sanofi, Shire: Speakers Bureau; Novartis, Sanofi, YM Bioscience, SBio, Gilead: Membership on an entity’s Board of Directors or advisory committees. Jourdan:Sanofi: Honoraria. Kiladjian:Novartis, Celgene, AOP Orphan: Research Funding; Novartis, Sanofi, AOP Orphan: Honoraria; Novartis, Sanofi, AOP Orphan: Membership on an entity’s Board of Directors or advisory committees. Cervantes:Novartis: Speakers Bureau; Novartis and Sanofi: Membership on an entity’s Board of Directors or advisory committees. Niederwieser:Novartis Pharma: Consultancy. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Passamonti:Novartis, Celgene, Incyte, Sanofi, Roche: Honoraria. Reiter:Sanofi: Honoraria. Heidel:Novartis Inc.: Honoraria; Novartis Inc.: Research Funding; Novartis Inc.: Membership on an entity’s Board of Directors or advisory committees. Silver:Sanofi: Consultancy; Sanofi: Research Funding; Sanofi: Honoraria. Winton:Sanofi: Research Funding. Gupta:Incyte, Novartis: Consultancy; Incyte, Novartis: Research Funding; Novartis: Honoraria. Gisslinger:AOP Orphan Pharmaceuticals, Novartis, Sanofi, Shire, Celgene, Janssen: Membership on an entity’s Board of Directors or advisory committees; AOP Orphan Pharmaceuticals, Novartis, Sanofi, Shire, Celgene, Janssen: Honoraria. Vannucchi:Novartis: Membership on an entity’s Board of Directors or advisory committees. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau. Zhang:Sanofi: Employment. Shi:Sanofi: Employment. Mesa:Incyte, Genentech, Lilly, MS Pharma, Gilead: Research Funding.

Abstract Abstract 3839 BACKGROUND: We have previously reported on the validation of the 18 item Myeloproliferative Neoplasm Assessment Form (MPN-SAF) (Blood 2011;118:401–408) given in conjunction with the 9 item Brief Fatigue Inventory (BFI) (Cancer 1999;85:1186–1196) to assess symptomatic burden in an international sample of MPN patients (pts), including validation in English, Italian, Swedish, German, French, Spanish, and Dutch. We desired to assess the utility of an average total symptom score (TSS) from the most pertinent and representative MPN symptoms for purposes of assessing the burden of symptoms in MPN pts, and subsequent tracking in response to therapy. METHODS: Data was collected among an international cohort of MPN pts and their physicians, including patient demographics and disease features and completion the BFI, MPN-SAF and the EORTC-QLQ-C30. Among pts who completed at least 5 of 10 specific items on the BFI and MPN-SAF, an average score was calculated as the TSS. TSS items included “worst” fatigue from the BFI and 9 items from the MPN-SAF including concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss and fever. The TSS thus had a possible range of 0–10 with 10 representing the highest level of symptom severity. Data was then analyzed for internal consistency, and divergent, convergent validity, and construct validity. RESULTS: Patient Demographic and Disease Characteristics:1433 MPN pts were prospectively enrolled (Argentina 22, France 482, Germany 59, Italy 186, Netherlands 236, Puerto Rico 10, United Kingdom 57, United States 102, Spain 157, Sweden 114, Uruguay 8) including 594 ET, 538 PV and 293 MF pts (8 missing; MF: 61% Primary MF, 23% post-ET MF, 15% post-PV MF). 1408 pts completed at least 5 of the 10 items necessary to calculate a TSS. Pts were of characteristic age (mean 62, range 20–94) and gender (54% female) common to disease. TSS Burden of MPN Symptoms: Consistent with prior studies, the majority of pts (>50%) were symptomatic in each TSS item except for items associated with high disease severity, namely bone pain (48.6%), weight loss (30.6%) and fever (18.4%). Fatigue carried the highest symptom intensity (4.4, SD=2.8), followed by problems with concentration (2.5, SD=2.8) and early satiety (2.5, SD=2.7). Overall mean TSS was 2.1 (SD=1.6). Divergent Validity: TSS significantly differed among MPN disease subtypes (p<0.001) with means of 1.9 (SD=1.5), 2.2 (SD=1.6), and 2.5 (SD=1.7) for ET, PV, and MF pts, respectively. Statistically significant differences in TSS were also observed between pts with clinically deficient (>4, n=480) versus non-clinically deficient QOL (<4, n=894; mean 3.3 versus 1.5; p<0.001). When comparing to MD perceptions, TSS was significantly higher when MDs rated >2 of 6 common MPN-related symptoms as clinically significant (2.8, n=400) versus <2 symptoms (1.6, n=726; p<0.001). No significant trends were observed when comparing disease type by the presence of a current medical therapy. Convergent Validity: The TSS was strongly correlated with patient-reported QOL (r=0.59, p<0.001). Overall excellent correlations existed between the TSS and EORTC-QLQ-C30 functional subscales (all p<0.001 and r>0.50 except social functioning [r=0.48]). Additionally, excellent correlations were observed between the TSS and EORTC-QLQ-C30 fatigue and pain symptom scales (r>0.5, p<0.001). Internal Consistency and Construct Validity: The TSS had excellent internal consistency (Cronbach's alpha=0.83). Factor analysis identified a single underlying construct among the 10 TSS items (significant eigenvalues being >1). Factor loadings ranged from 0.43 for fever and weight loss to 0.71 for inactivity. The single factor suggests that the arithmetic mean of the 10 items is an appropriate global TSS score. CONCLUSION: The TSS demonstrated excellent psychometric properties. Overall, results of validity and internal consistency indicate that the TSS is a concise, valid, and accurate assessment of symptom burden among MPN pts. This new scoring will facilitate ease of implementation of the MPN-SAF into larger clinical trials and reduce ambiguity associated with interpreting response outcomes. Future analyses to investigate the impact of therapies on TSS are ongoing. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1875 Introduction: Carfilzomib (CFZ) is a next-generation proteasome inhibitor that has demonstrated durable single-agent antitumor activity in patients (pts) with relapsed and/or refractory multiple myeloma (R/R MM). Previously we have shown that unfavorable cytogenetic features, defined as presence of any of del 13 or hypodiploidy by metaphase cytogenetic analysis and/or del 17p13, t(4;14), t (14;16) by fluorescence in situ hybridization (FISH), did not appreciably affect overall (≥PR) and clinical benefit (≥MR) response rates (ORR and CBR) in PX-171-003-A1, a large phase 2 study of single-agent CFZ in pts with R/R MM (Jakubowiak et al. Ann Oncol. 2011;22(S4): Abstract 117). The objectives of the present analysis were to evaluate the impact of specific cytogenetic abnormalities on efficacy and treatment outcomes. Methods: Pts with unfavorable cytogenetic abnormalities (defined above) were eligible for inclusion in this analysis. All pts received CFZ at 20 mg/m2 IV on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (C) and were dose-escalated to 27 mg/m2 at C2. Pts were treated for up to 12 C. Responses were assessed by International Myeloma Working Group criteria, with minimal response (MR) by European Group for Blood and Marrow Transplantation criteria. Assessments were confirmed by an Independent Review Committee (IRC). Results: A total of 234 pts were included in this analysis. Metaphase cytogenetic data were available for 203 pts (87%), and FISH data were available for 210 pts (90%); 178 pts had both (76%). Seventy-five of 234 pts (32%) had ≥1 abnormality and represented the unfavorable group in this analysis. Of these, 49 (65%) had abnormalities detected via metaphase cytogenetics, 47 (63%) by FISH, and 21 (28%) by both methods. Characteristics of pts in the unfavorable and normal/favorable groups were comparable overall, with the exception of a higher proportion of pts with International Staging System stage II/III in the unfavorable group (83% vs 64%). Response rates per the IRC, presented previously, included an ORR of 30% for pts with ≥1 abnormality compared with 23% for pts with none. The corresponding CBRs were 34% and 40%, respectively. Duration of response (DOR) and time to progression (TTP) values were 7 months (mo) (95% CI 4–9) and 4 mo (95% CI 3–6), respectively, for pts with ≥1 abnormality and 8 mo (95% CI 6–12) and 5 mo (95% CI 3–6), respectively, for pts with none. The ORRs, CBRs, and disease control rates (DCRs) according to specific cytogenetic abnormalities are presented below. Response rates were largely unaffected by the presence of specific unfavorable cytogenetic abnormalities, with the possible exceptions of trends toward a higher response rate for t(4;14) and a lower rate for t(14;16), although the latter abnormality was only noted in 3 pts. The trend for better response rates in pts with t(4;14) corresponded to a DOR of 5.6 mo (95% CI 2.8–10.2). In contrast, the DOR appeared shorter for the subgroup of pts with del 17p13 (4.6 mo, 95% CI: 3.7–Not reached). Time-to-event endpoints including TTP are being analyzed for these and the other subpopulations, and data on these will be presented, along with overall survival stratified by cytogenetic abnormality. Conclusions: CFZ demonstrated comparable response rates in pts with relapsed/refractory MM in both the absence and presence of unfavorable cytogenetic abnormalities in the 003-A1 study. Similarly, in the phase 2 PX-171-004 study, no significant difference in response rates between unfavorable and normal/favorable groups has been observed in a population of less heavily-pretreated pts with relapsed or R/R MM. Taken together, the results of these and other analyses to date suggest that responses to single-agent CFZ can be achieved in heavily pretreated pts and that overall, these responses appear not to be significantly influenced by poor prognostic cytogenetic features. Further analyses from studies with CFZ in newly diagnosed MM and in less heavily-pretreated pts are needed to determine whether a trend toward lower response rates and DOR for pts with del 17p13 is consistently observed in other populations. Disclosures: Jakubowiak: Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria. Off Label Use: Use of the investigational agent carfilzomib, proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. Siegel:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Singhal:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Onyx Pharmaceuticals: Research Funding. Martin:Celgene: Honoraria; Onyx Pharmaceuticals: Consultancy. Lonial:Onyx: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy; Merck: Consultancy. Kukreti:Celgene: Honoraria. Bahlis:Celgene: Honoraria, Speakers Bureau. Alsina:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allergan: Research Funding. Kunkel:Onyx Pharmaceuticals: Consultancy; Threshold: Consultancy; VLST biothech: Consultancy. Wong:Onyx Pharmaceuticals: Employment, Equity Ownership. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:Celgene Corporation: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Jagannath:Millennium: Honoraria; Celgene: Honoraria; Onyx Pharmaceuticals: Honoraria; Merck: Honoraria; OrthoBiotec. Imedex: Membership on an entity's Board of Directors or advisory committees; Medicom World Wide: Membership on an entity's Board of Directors or advisory committees; Optum Health Education: Membership on an entity's Board of Directors or advisory committees; PER Group: Membership on an entity's Board of Directors or advisory committees. Wang:Onyx Pharmaceuticals: Research Funding.

Abstract Abstract 985 Introduction: CFZ is a novel and highly selective epoxyketone proteasome inhibitor currently in clinical development for the treatment of multiple myeloma (MM). Ph 1 and 2 studies with CFZ have demonstrated durable single-agent antitumor activity in pts with relapsed or refractory (R/R) MM. The present study, PX-171-003-A1, was an open-label, single-arm Ph 2b trial and enrolled patients with multiply relapsed MM whose disease was refractory (defined as <25% response on, or progression during or <60 days after completion of, therapy) to their last treatment regimen. Patients must have received ≥2 prior therapies including: 1) bortezomib (BTZ) and either thalidomide (THAL) or lenalidomide (LEN), and 2) an alkylating agent. Materials and Methods: Pts received CFZ at 20 mg/m2 on a QDx2 schedule (Days 1, 2, 8, 9, 15, and 16 every 28 days) in cycle (C) 1 and were dose escalated to 27 mg/m2 on the same schedule thereafter for up to 12 C. Pts completing 12 C were eligible to enter an extension study (PX-171-010). The primary endpoint was overall response rate (ORR) (≥ partial response [PR]). Secondary endpoints included: clinical benefit response (CBR) (ORR + Minimal response [MR]), duration of response for ≥PR (DOR), overall survival (OS), time to progression (TTP), progression free survival (PFS), and safety. Responses and progression were determined according to the International Myeloma Working Group (IMWG) criteria and were assessed and confirmed by an Independent Response Committee (IRC). Results: 266 pts were enrolled with a median duration of MM of 5.4 years including 83% whose disease had progressed on or within 60 d of last therapy and 17% whose disease had achieved <25 % response to the regimen immediately preceding study entry. Of the 266 pts enrolled pts, 257 were evaluable for response; 9 patients were considered not evaluable based on missing baseline or lacking at least one post-baseline M-protein. An ORR (≥PR) of 24% with a median DOR of 7.4 mo (range 6.2–10.3) was determined. Responses are detailed in the table. The CBR (ORR + MR) was 36%. Median DOR of pts with MRs was 6.3 months, indicating that long-term MRs were observed. An additional 32% (83 pts) achieved SD for at least 6 wks. To date, 79 pts (30%) completed ≥6 C and >11% of pts have completed all 12 C of protocol specified therapy and most have entered the extension protocol; 15 pts remain on study (all >10 C). OS and TTP data for the overall population will also be reported. The enrolled pts in this study were heavily pretreated having received a median of 5 prior lines of therapy (range 1–20, median of 13 anti-myeloma agents). 85% of pts had received at least 2 and 37% had received at least 3 drugs in the regimen just prior to entering the study. Prior anti-myeloma agents included 99.6% (265/266 pts) BTZ (median 2 prior regimens containing BTZ), 99.6% either THAL (74%) or LEN (94%), 98% corticosteroids, 91% alkylating agents, and 74% stem cell transplant; 65% of pts were refractory to BTZ at any point in time prior to study entry. The most common treatment-emergent adverse events ≥ Grade (G) 3 regardless of relationship to study drug were predominantly hematologic and included thrombocytopenia (22%), anemia (20%), lymphopenia (10%), pneumonia (8%), neutropenia (8%), fatigue (7%), hyponatremia (5%), and hypercalcemia (5%). Although 206 pts (77%) had G1/2 peripheral neuropathy (PN) at baseline, new onset PN was infrequent and G ≥3 PN occurred in <1%. Interestingly, in this subset of patients, efficacy response was nearly identical to that seen in the full study population with an ORR (≥PR) of 24%. Conclusions: Single-agent CFZ achieved durable responses in pts with R/R MM whose disease had relapsed after all available therapies including BTZ and immunomodulatory agents. The CBR and median DOR achieved with this steroid-sparing regimen establish that CFZ has the potential to offer substantial clinical benefit to patients with relapsed or refractory disease. CFZ was well-tolerated and side effects were clinically manageable with no new or unexpected toxicities observed. Importantly, exacerbation of pre-existing PN was uncommon. Cumulative side effects were not observed, allowing prolonged single-agent dosing for chronic disease control. Disclosures: Siegel: Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Martin:Celgene: Honoraria; Onyx: Consultancy. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Vij:Onyx: Honoraria. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jagannath:Millenium, OrthoBiotec, Celgene, Merck, Onyx: Honoraria; Imedex, Medicom World Wide, Optum Health Education, PER Group: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Alsina:Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. Zonder:Millenium: Consultancy, Honoraria, Research Funding; Cephalon: Research Funding; Celgene: Honoraria. Wong:Onyx Pharmaceuticals: Employment. Vallone:Onyx Pharmaceuticals: Employment. Chang:Onyx Pharmaceuticals: Employment. Kauffman:Onyx Pharmaceuticals: Employment. Stewart:Millennium: Consultancy; Celgene: Honoraria. Singhal:Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx : Research Funding.

Abstract Introduction: Cytogenetic abnormalities in patients (pts) with multiple myeloma (MM) are of prognostic importance and can be associated with poor outcomes (Bergsagel, Blood, 2011). The FIRST trial is a pivotal phase 3 study with the largest data set in transplant-ineligible pts with newly diagnosed MM (NDMM). This subanalysis evaluates the impact of cytogenetics on outcomes in transplant-ineligible pts with NDMM continuously treated with lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous). Methods: Transplant-ineligible pts with NDMM were randomized to 1 of 3 treatment arms: Rd continuous, Rd18 (Rd for 18 cycles [72 weeks]), or melphalan-prednisone-thalidomide (MPT; for 12 cycles [72 weeks]). Cytogenetics were assessed using fluorescence in situ hybridization. Pts were categorized into cytogenetic risk groups according to International Myeloma Working Group criteria. High-risk cytogenetics included del(17p), t(4;14), and t(14;16); all other pts were categorized as non-high risk. The primary endpoint was progression-free survival (PFS; primary comparators were Rd continuous vs MPT), and key secondary endpoints were overall survival (OS), overall response rate (ORR), and safety. Results: A total of 762 of 1623 pts from the intent-to-treat population had validated cytogenetic profiles, with 142 pts in the high-risk group and 620 pts in the non-high-risk group. Baseline characteristics were well balanced across cytogenetic risk groups (Table 1). The median follow-up for OS was 40.2 months for the 762 pts in this analysis (data cutoff, March 03, 2014). In the non-high-risk group, median duration of treatment was 19.4 months with Rd continuous and 16.6 months with both Rd18 and MPT. In the high-risk group, median duration of treatment was 10.0 months with Rd continuous, 8.2 months with Rd18, and 12.0 months with MPT. Rd continuous treatment resulted in a 24% reduced risk of death or progression compared with MPT and an even greater 32% reduced risk in pts without high-risk cytogenetics (Table 2). In non-high-risk pts, median PFS was 31.1 months with Rd continuous compared with 21.2 and 24.9 months with Rd18 and MPT, respectively (Figure). However, in high-risk pts, the observed numerical median PFS favoring Rd18 is mainly due to small pt numbers influenced by long runners (n = 5), and the greatly overlapping 95% CIs from all 3 arms show the difference is likely to be minimal. Rd continuous treatment resulted in a 28% reduced risk of death vs MPT overall and a 34% reduced risk in pts without high-risk cytogenetics. OS was similar across treatment arms for high-risk pts. ORRs in all cytogenetic risk groups favored Rd continuous vs MPT. In pts with high-risk cytogenetics, higher-quality responses were also observed with Rd continuous vs MPT treatment. Similar results were seen with Rd continuous compared with Rd18, although OS and ORR benefits overall and in pts without high-risk cytogenetics were not as pronounced. In all 3 treatment arms, adverse events were consistent across cytogenetic risk groups. Conclusions: Rd continuous treatment resulted in PFS and OS benefits vs MPT in pts with validated cytogenetic profiles. This was largely due to PFS and OS improvements in pts without high-risk cytogenetics. In the high-risk group, the longest PFS was observed with Rd18 treatment and OS was similar across treatment arms. Despite being on the continuous vs fixed duration treatment arm, high-risk pts on Rd continuous received a shorter duration of treatment than those on MPT, which may explain why PFS favored MPT vs Rd continuous. Higher response rates were observed with Rd continuous vs MPT, regardless of cytogenetic risk, and greater quality responses were observed in pts with high-risk cytogenetics. The safety profile of Rd continuous was manageable and consistent between cytogenetic risk groups. Results support Rd continuous as a standard treatment option for pts with NDMM who are ineligible for transplant, especially those without high-risk cytogenetics. Additional PFS and OS benefits may be achieved in pts with high-risk cytogenetics when Rd continuous is used as a backbone for combination therapy with a novel agent. Promising activity in pts with high-risk cytogenetic abnormalities has been demonstrated using this approach (Lonial et al, N Engl J Med, 2015; Stewart et al, N Engl J Med, 2015). Disclosures Hulin: Celgene Corporation: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Dimopoulos:Celgene: Honoraria; Onyx: Honoraria; Novartis: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Genesis: Honoraria. Reece:Lundbeck: Honoraria; Amgen: Honoraria; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Millennium Takeda: Research Funding; Otsuka: Research Funding. Catalano:Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria. Pinto:Takeda: Honoraria, Research Funding; Celgene Corporation: Honoraria; Spectrum: Honoraria. Ludwig:Takeda: Research Funding; Celgene Corporation: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau. Bahlis:Celgene Corporation: Honoraria, Research Funding. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Moreau:Takeda: Other: Adboard; Janssen: Other: Adboard; Novartis: Other: Adboard; Amgen: Other: Adboard; Celgene: Honoraria, Other: Adboard. Qiu:Johnson & Johnson: Speakers Bureau; Celgene Corporation: Speakers Bureau; Roche: Speakers Bureau. Schots:Celgene Corporation: Research Funding. Marek:Celgene Corporation: Employment, Equity Ownership. Chen:Celgene Corporation: Employment, Equity Ownership. Yiu:Celgene Corporation: Employment, Equity Ownership. Ervin-Haynes:Celgene Corporation: Employment. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees.

Background Ixazomib is the first orally administered PI studied in the clinic. The feasibility of combining ixazomib weekly and lenalidomide-dexamethasone (Rd) in the first all-oral PI- and immunomodulatory drug-containing triplet regimen was evaluated in a phase 1/2 trial of 65 pts with newly diagnosed MM. Results indicated a 90% ORR (62% ≥VGPR) using ixazomib 4 mg (recommended phase 2/3 dose), with a manageable safety profile, including 14% gr ≥3 skin/subcutaneous tissue disorders and limited (4% gr 3) peripheral neuropathy (PN) (Kumar et al, Lancet Oncol 2014). These data provided the rationale for phase 3 investigation of IRd vs placebo-Rd in pts with RRMM in this randomized, double-blind, placebo-controlled, international, multicenter study. Methods Adults with RRMM after 1-3 prior lines of therapy who were not refractory to prior lenalidomide or PI-based therapy were randomized 1:1 to receive ixazomib 4 mg or matching placebo weekly on d 1, 8, and 15, plus lenalidomide 25 mg PO on d 1-21 (dose reduced for renal impairment per local label/practice) and dexamethasone 40 mg PO on d 1, 8, 15, and 22, in 28-d cycles. Randomization was stratified by number of prior therapies (1 vs 2/3), PI exposure (naïve vs exposed), and ISS disease stage (I/II vs III). Cycles were repeated until disease progression or unacceptable toxicity. Primary endpoint was PFS as assessed by an independent review committee blinded to treatment, per IMWG criteria. Key secondary endpoints were OS and OS in high-risk pts with del(17). Sample size was determined to provide 80% power for the OS endpoint and adequate power to test PFS. Three interim analyses (IAs) and a final analysis were planned to test PFS and OS; here, we report data from the first IA, the final analysis for PFS. Results 722 pts were randomized (360 IRd; 362 Rd). Baseline characteristics were balanced between groups; overall median age was 66 yrs (30-91), 70% were PI-exposed, 88% were ISS stage I/II, 59% had received 1 prior therapy, and 77%/11%/11% were relapsed/refractory/relapsed and refractory, with 6% primary refractory. Based primarily (97%) on central laboratory evaluation, 19% had high-risk cytogenetics by FISH (del(17), t(4;14), or t(14;16)), including 10% del(17). Prior therapies included 69% bortezomib, 45% thalidomide, and 12% lenalidomide. The study met the primary endpoint at the first IA (median follow-up 14.8 vs 14.6 mos with IRd vs Rd), demonstrating a 35% improvement in PFS with IRd vs Rd (HR 0.742; p=0.012; Table). In pts with high-risk cytogenetics, the PFS HR was 0.543 with IRd vs Rd (HR 0.596 in pts with del(17)), with a median PFS similar to the overall IRd group, indicating ixazomib may overcome the negative impact of cytogenetic alterations. OS data were not yet mature. Key response data are shown in the Table. Pts received a median of 13 (1-26) vs 12 (1-25) cycles of IRd vs Rd; 55% and 52% of pts remained on treatment. With IRd vs Rd, 68% vs 61% of pts had gr ≥3 AEs (driven by thrombocytopenia), 40% vs 44% had serious AEs, 13% vs 11% discontinued all study drugs due to AEs, and 3% vs 5% died on treatment. AEs observed with IRd were consistent with reported safety profiles for the individual agents. Common gr ≥3 AEs were neutropenia (19% vs 16%), anemia (9% vs 13%), thrombocytopenia (13% vs 5%), and pneumonia (6% vs 8%). Gastrointestinal events included 42% vs 36% diarrhea (6% vs 2% gr 3), 26% vs 21% nausea (2% vs 0% gr 3), and 22% vs 11% vomiting (1% vs <1% gr 3). PN rates were 28% vs 21% (2% vs 2% gr 3), 35% vs 21% had rash events (4% vs 1% gr 3), 4% vs 6% had renal failure (2% vs 3% gr ≥3), and 4% vs 3% had heart failure (2% vs 2% gr ≥3). Conclusion At this first prespecified IA, addition of ixazomib to Rd in pts with RRMM increased median PFS to 20.6 from 14.7 mos without a substantial increase in overall toxicity, including cardiac and PN toxicity. Benefit with IRd was also noted in pts with high-risk cytogenetics, including those with del(17), in whom median PFS was similar to all IRd-treated pts indicating that ixazomib may have a favorable impact on the adverse prognosis associated with genetic mutations. If approved, this all-oral combination of IRd may become a new standard of care in this setting. Table. Key efficacy data IRd Rd HR / OR Median PFS, mos 20.6 14.7 HR 0.742; 95% CI: 0.587-0.939; p=0.012 Confirmed ORR, % 78.3 71.5 OR 1.44; p=0.035 CR 11.7 6.6 OR 1.87; p=0.019 ≥VGPR 48.1 39.0 OR 1.45; p=0.014 Median time to first response (ITT analysis), mos 1.1 1.9 Median duration of response (≥PR), mos 20.5 15.0 Disclosures Moreau: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Investigational proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma. Masszi:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Bahlis:Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Johnson & Johnson: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sandhu:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Ganly:Novartis: Honoraria; Roche: Honoraria; Medipics: Equity Ownership. Baker:Janssen-Cilag New Zealand: Membership on an entity's Board of Directors or advisory committees. Stoppa:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Simpson:Celgene: Honoraria; Janssen-Cilag: Honoraria; Onyx Pharmaceuticals: Research Funding; Roche: Honoraria. Gimsing:Amgen: Honoraria. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria. Garderet:Bristol-Myers Squibb: Consultancy. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Kumar:AbbVie: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria; Millenium/Takeda: Research Funding. Touzeau:AbbVie: Research Funding. Laubach:Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Lin:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment. DiBacco:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Richardson:Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background Myelofibrosis (MF) is a clonal myeloproliferative neoplasm (MPN) associated with a high degree of symptomatology, progressive cytopenias and potential to transform into acute myelogenous leukemia (AML). Thrombocytopenia amongst MF patients is a proven negative prognostic indicator and predictor of transformation to AML. Ruxolitinib is an effective JAK inhibitor for MF symptoms and splenomegaly, but is not indicated in patients with severe thrombocytopenia. Phase III trials of pacritinib have shown alleviation of the MF symptom burden amongst patients with thrombocytopenia (ASCO 2015 Mesa et. al.). In this study, we assessed the symptom burden of MF patients with significant thrombocytopenia who were naïve to pacritinib. Methods Data was assessed from a prospectively collected international database of MF patients in which demographics, disease features, and MF symptoms utilizing the myeloproliferative neoplasm symptom assessment form (MPN-SAF; Scherber et al, 2011). The MPN-SAF includes the patient's perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. Total symptom score (TSS) was computed based on symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. MF risk scores were calculated using the DIPSS criteria (Gangat, 2011). Thrombocytopenia was defined as a platelet count <100 x 10(9)/L, anemia was defined as hemoglobin<10 g/dL and leukopenia was defined as a white blood cell count <4.0 x 10(9)/L. Associations between the MPN-SAF individual symptoms were investigated using Pearson correlations. Results Demographic and Disease Features: A total of 418 patients with (n=89) and without (n=329) thrombocytopenia completed the MPN-SAF. Patients with thrombocytopenia were slightly younger (57.4 vs. 61.0, p=0.01) with longer disease durations (11.9 years vs. 8.8 years, p=0.0489) and had a higher prevalence of primary myelofibrosis (PMF; 82% vs. 66%, p=0.01). The presence of thrombocytopenia was associated with other laboratory abnormalities including anemia (60.7% vs. 25.3%, p<0.001) and leukopenia (34.8% vs. 52.3%, p<0.001), along with the need for red blood cell transfusions (34.8% vs. 14.6%, p<0.001). Patient cohorts did not differ by gender, DIPSS risk score, history of prior thrombosis or hemorrhage. In comparing patients with severe thrombocytopenia (<50 x 10(9)/L, n=43) to those with moderate thrombocytopenia (51-100 x 10(9)/L, n=46), severe thrombocytopenia patients were more likely to have anemia (74.4% vs. 47.8%, p=0.01) and require red blood cell transfusions (51.2% vs. 19.6%, p=0.002). Symptoms Scores for individual MPN-SAF items were assessed for each subgroup. Patients with thrombocytopenia had markedly higher total symptom scores than patients without thrombocytopenia (32.8 vs. 24.1, p<0.001). Individual scores were also higher for most items (fatigue, early satiety, inactivity, dizziness, sad mood, sexuality, cough, night sweats, itching, fever, weight loss, overall QOL)[Figure 1]. No significant differences in MPN SAF TSS or individual symptom scores were observed in comparing severe vs. moderate thrombocytopenia patients. Discussion MF patients with thrombocytopenia have distinctive clinical characteristics and face a significantly more severe symptom burden. Importantly, despite thrombocytopenia being a recognized risk factor for disease advancement, no correlations are noted between patient symptomatology and risk category. In addition, patients with severe thrombocytopenia do not differ symptomatically from patients with moderate thrombocytopenia despite having more severe anemia, leukopenia and transfusion requirements. This implies that the degree of symptomatology expressed by thrombocytopenic MF patients occurs independent from the exact platelet value. Conclusion The results of this study suggest that patients with thrombocytopenia will benefit from aggressive symptomatic control, potentially from targeted agents. Figure 1. MF Symptoms in Patients With and Without Thrombocytopenia Figure 1. MF Symptoms in Patients With and Without Thrombocytopenia Disclosures Kiladjian: Novartis: Consultancy; Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Incyte Corporation: Consultancy. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Shire: Speakers Bureau; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Gilead: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau. Cervantes:Novartis: Consultancy, Speakers Bureau; Sanofi-Aventis: Consultancy; CTI-Baxter: Consultancy, Speakers Bureau. Barbui:Novartis: Speakers Bureau. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Roy:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Vannucchi:Shire: Speakers Bureau; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis. Research- incyte, Gilead, cti, Genentech, promedior, NS Pharma: Consultancy.

Abstract Background: The Philadelphia chromosome negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) all have a time dependent risk of progression to either an advanced myelofibrotic state (post ET/PV MF) and/or to acute myeloid leukemia. The impact of disease duration upon the MPN symptom burden is not well understood, nor are the precise mechanisms of disease progression. We sought to better understand the impact of disease duration on MPN symptom burden. Methods: Symptom burden data was collected utilizing the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) amongst MPN patients, collected at the time of an office visit in an international cohort of MPN patients as previously described (Scherber et. al.). Symptom burden assessment was a previously validated 27-item symptom burden questionnaire scored on a 0-10 scale (0= as good as it can be, 10 = as bad as it could be). The patient or provider was asked to report the time since MPN diagnosis. MPN duration was determined to be early if the diagnosis was established between 0 to 5 years ago, intermediate if the diagnosis was established between 6 to 10 years ago, and late if the diagnosis was established 11 years ago or more. Anemia was defined as a red blood cell count less than 10 g/dL, leukopenia was defined as a white blood cell count was below 4 x 109, and thrombocytopenia if the platelet count was below 150 x109. Statistical significance was calculated using ANOVA f-test and chi squared. Results: Patient demographics and disease burden: A total of 1443 patients responded to the survey, including 592 (41%) ET, 549 (38%) PV, and 302 (21%) MF patients, including 181 (60%) primary MF, 67 (22%) post-ET MF, and 54 (18%) post-PV MF. Among MF patients, mean duration of MPN diagnosis was 9 years, and mean duration MF diagnosis was 4.7 years. Among respondents, 757 fit criteria for early disease duration, 353 fit criteria for intermediate disease duration, and 333 fit criteria for late disease duration. Respondent mean age was 62 years and approximately half of respondents were female (55%). Patients with longer diagnosis duration tended to be older (p=0.009) and were most likely to have anemia (0.02), leukopenia (p=0.01), or thrombocytopenia (p=0.03). These individuals were also most likely to have a history of hemorrhage (p=0.007) or require red blood cell transfusions (p<0.001). Combined cohort symptom burden: On average among the combined cohort of ET, PV and MF patients, symptoms tended to worsen with time with this effect being significant for symptom items of fatigue (BFI, p<0.04), concentration (p=0.007), insomnia (p=0.02), sexual difficulties (p=0.002), cough (p=0.03), night sweats (p=0.002), and pruritus (p=0.02). Symptoms of early satiety (p=0.004), concentration difficulties (p=0.01), insomnia (p=0.03), sexual difficulties (p=0.02), cough (p=0.01), and night sweats (p=<0.001) had significantly higher prevalence in those with longer disease duration. Similarly, the total calculated MPN-10 score (p=0.008) and quality of life assessment (0.03) demonstrated worsened outcomes with time (Table 1). No significant differences in symptoms for the combined cohort were observed among individuals diagnosed 0 to 1 years ago compared to those with a diagnosis established between 2 and 5 years ago. Symptom burden in MPN subtypes. When evaluating specific MPN types, patients with essential thrombocythemia experienced significantly greater sexual difficulties over time (p=0.03). The severity (p=0.01) and incidence (p=0.03) of pruritus and incidence of night sweats (p<0.001) were significantly increased over time for individuals with PV. For those with MF, the severity (p= 0.01) and incidence (p=0.009) of cough also significantly increased with longer diagnosis duration. Discussion Overall, significant worsening in symptom burden can be recognized over time for individuals diagnosed with MPNs. Diagnosis may not necessarily correlate with disease duration as the timing of diagnosis may be delayed from onset of disease. Given the intent of this abstract to evaluate changes with disease duration, we did not investigate correlations between symptom burden and cytopenias. We do know that risk factors for survival in the MPNs include older age and thrombosis, however, disease duration should be investigated as an alternative marker of burden in future survival studies. Disclosures Harrison: CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Shire: Speakers Bureau; Gilead: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Kiladjian:Incyte Corporation: Consultancy; Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Novartis: Consultancy. Zweegman:Celgene: Research Funding; Janssen: Research Funding; Takeda: Research Funding. Barbui:Novartis: Speakers Bureau. Etienne:Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; ARIAD: Consultancy, Honoraria, Speakers Bureau. te Boekhorst:CTI Biopharma: Consultancy; Novartis: Consultancy. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis. Research- incyte, Gilead, cti, Genentech, promedior, NS Pharma: Consultancy.