ALBERT

Description: Introduction: Blinatumomab is a bispecific, CD19-directed CD3 T-cell engager (BiTE®) that activates endogenous cytotoxic T cells to kill target B cells and is FDA-approved for the treatment of relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (B-ALL). Subgroup analyses of pivotal trials revealed lower response rates and higher risk of cytokine release syndrome (CRS) in blinatumomab recipients with high pre-treatment tumor (B-ALL) burden. It has therefore been hypothesized that cytoreduction prior to blinatumomab initiation may improve response and reduce risk of severe CRS in patients (pts) with high baseline B-ALL burden. We therefore sought to describe pt and disease characteristics at diagnosis, patterns of pre-blinatumomab cytoreduction, and treatment outcomes in pts with high burden of R/R B-ALL treated with blinatumomab at our institution. Methods: We retrospectively reviewed medical records of adult (≥ 18 years-old) pts with morphologic R/R B-cell ALL (i.e. ≥5% BM blasts and/or radiographically evident EM disease) treated with blinatumomab at Memorial Sloan Kettering Cancer Center (MSKCC) between January 2011 and March 2019 and characterized pts with ≥ 50% bone marrow (BM) blasts by morphology or ≥ 15,000 peripheral blood blasts/µL as having "high-burden" B-ALL. CRS and neurologic toxicity (NTX) were graded per Common Terminology Criteria for Adverse Events v5.0. Objectives included describing cytoreductive therapy given pre-blinatumomab and determining rates of NTX and CRS (any grade and grade ≥3) and morphologic complete response (CR) following 1-2 cycles of blinatumomab. Results: We identified 14 pts with high-burden R/R B-ALL prior to blinatumomab. These pts had a median age of 52 years (range, 23 - 69 years) and median BM blasts of 73% (range, 52 - 〉95%, n=12 pts with evaluable BM). Of these 14 pts, 8 received cytoreductive therapy prior to blinatumomab initiation. Cytoreductive regimens included dexamethasone alone (n=4), cyclophosphamide + dexamethasone (n=2), dexamethasone and vincristine (n=1), or cyclophosphamide + vincristine + dexamethasone (n=1). One pt transitioned to hospice care prior to completing cycle 1 (C1) of blinatumomab and was considered non-evaluable for response. CR was achieved in 6 of the 13 evaluable pts, including 4 of 7 evaluable pts who received cytoreductive therapy and 2 of 6 pts who did not receive cytoreductive therapy. One pt achieved CR in BM but exhibited refractory extramedullary disease. CRS was observed during C1 of blinatumomab in 11/14 pts (grade 1, n=7; grade 2, n=3; grade 3, n=1). The pt with grade 3 CRS had received blinatumomab without cytoreductive therapy. In 4 pts, blinatumomab was temporarily discontinued for management of CRS. NTX of any grade occurred in 4/13 pts during C1, including 1 pt w/grade 3 NTX (depressed level of consciousness), and was reversible in all cases; the pt with grade 3 NTX had full resolution of symptoms following brief interruption of blinatumomab and administration of dexamethasone. Conclusions: Real-world clinical experience with blinatumomab in pts with high-burden B-ALL at a single institution suggested an efficacy and safety profile comparable to what has been reported in the overall population in clinical trials. Compared to published clinical trial experience, rates and severity of CRS following blinatumomab were similar and rates of NTX appeared slightly higher in this small series. Administration of cytoreductive therapy prior to blinatumomab for pts with high-burden B-ALL appears safe, with no additional toxicities. Larger studies will be required to assess whether pts with high-burden B-ALL treated (vs not treated) with cytoreductive therapy prior to blinatumomab exhibit significantly higher rates of CR. Disclosures King: Incyte: Other: Advisory Board; Genentech: Other: Advisory Board ; Astrazeneca: Other: Advisory board. Bolanos:Amgen Inc.: Employment. Velasco:Amgen Inc.: Employment. Tu:Amgen Inc.: Employment. Zaman:Amgen Inc.: Employment. Geyer:Dava Oncology: Honoraria; Amgen: Research Funding. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy.

Description: Background: Midostaurin (M) is a multi-targeted small molecule FLT3 inhibitor which has single agent activity in both internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutant FLT3 AML. The objective of this global rand phase III trial was to determine if the addition of M to ind and consol therapy followed by one year of maint would improve overall survival (OS) compared to standard chemotherapy in younger adults with activating FLT3 muts. Methods: Between May 2008 and October 2011, 3279 previously untreated AML pts age 18-60 (exclusive of acute promyelocytic leukemia) in 225 sites/17 countries were screened for FLT3 muts at one of 7 academic labs (subject to extensive assay cross-validation). Hydroxyurea was allowed for up to 5 d prior to beginning ind therapy while awaiting results of mut testing. Pts were rand for the duration of therapy to M or P stratified by FLT3 mut subtype (TKD v ITD high allelic mut fraction (〉0.7) vs low mut fraction (0.05-0.7). Ind therapy consisted of D 60 mg/m2 IV d1-3 and C 200 mg/m2 d1-7 CIV plus M or P (50 mg po bid, d 8-22). Re-treatment with a second blinded course was allowed if residual AML was noted on a d 21 marrow exam. Pts achieving complete remission (CR) received 4 cycles of C 3g/m2 over 3h q 12h on days 1, 3, and 5 plus M or P (50 mg po bid, d 8-22) followed by a year of maint therapy with M or P (50 mg po bid). Transplantation (SCT) was allowed. With a sample size of 717 pts, the trial was powered to detect an improvement from 16.3 (P) to 20.9 (M) months in median OS (HR = 0.78) using a one-sided alpha of 0.025 and power of 84%. The final analysis was to occur after 509 deaths, but given the slow rate of events (359 deaths by April 2015), the trial was amended to change the timing of the OS analysis, and promote event free survival (EFS, defined as the earliest of death, relapse, or no CR within 61 d of the start of ind) as a key secondary endpoint. The critical value for this primary analysis is set at 0.02286 (1-sided) accounting for the alpha spent at the interim analysis (0.5%). Support: U10CA180821, U10CA180882, CA31946, Novartis Results: 717 pts (341 FLT3 ITD-Low, 214 FLT3 ITD-High; 162 FLT3 TKD) were rand to either M (n=360) or P (n=357). There were no significant differences between the arms in age (median, 48y), race, FLT3 subtype, or baseline CBC except for gender (M, 48.2% male; P, 40.6% male; p=.04). All pts are off active treatment, with a median follow-up of 57 months for surviving pts. No statistically significant differences were observed in the overall rate of grade 3 or higher hematologic or non-hematologic adverse events (AEs) between M and P (regardless of attribution). A total of 37 grade 5 AEs were reported (M, 5.3%; P, 5.0%; p=1.0). No differences in treatment-related grade 5 AEs were observed (M, 3.1%; P, 2.5%; p=0.82). CR rate is 59% (M) and 54% (P) (p=0.18). The HRs comparing M to P for OS is 0.77 (one-sided p = 0.007; Figure 1), and for EFS is 0.80 (one-sided p = 0.004; Figure 2). 402/717 (57%) pts received an allogeneic SCT (M, 58%; P, 54%) at any time; 177/717 (25%) in CR1 (M, 27%; P, 22%). Median time to allogeneic SCT was similar on each arm (M, 5.0 months; P, 4.6; p=0.23). Secondary analyses for OS and EFS censoring at the time of SCT provided similar results (Table). The benefit of M was consistent across all FLT3 subgroups for both EFS and OS (Figure 3). Conclusions: The C10603 trial demonstrated that a prospective trial in a pre-therapy genetically defined subgroup of AML pts was feasible and that the addition of the multi-kinase inhibitor M to standard chemotherapy and for one year of maint therapy significantly improved EFS and OS (in both uncensored and censored for transplant analyses) in pts whose blasts had a TKD or ITD (low or high FLT3 mut burden). These findings may lead to improved outcomes through the use of M as a component of therapy in younger adults with mutant FLT3 AML. Table.ArmMedian, mos (95% CI)p-value 15-year Event rate% (95% CI)HR2(95% CI)OSM74.7 (31.5, * )0.00750.8 (45.4-55.9)0.77 (0.63, 0.95)P26.0 (18.5, 46.5)43.1 (37.6-48.4)OS, SCT censoredM* (*,*)0.04762.6 (54.6-69.7)0.77 (0.56,1.05)P* (36.9, *)54.9 (46.2-62.8)EFSM8.0 (5.3, 10.6)0.004426.7 (22.2-31.5)0.80 (0.67, 0.95)P3.0 (1.9, 5.8)19.1 (15.1-23.6)EFS, SCT censoredM8.2 (5.5, 10.7)0.02524.2 (18.9-29.8)0.84 (0.70, 1.0020)P3.0 (1.9, 5.8)21.8 (16.8-27.3)1Stratified on FLT3 subtype; one-sided, log-rank p-value.2Cox model stratified on FLT3 subtype.*= not attained Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Stone: Celgene: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Novartis: Research Funding; Amgen: Consultancy; Agios: Consultancy; Roche/Genetech: Consultancy; Merck: Consultancy; Pfizer: Consultancy; AROG: Consultancy; Celator: Consultancy; Juno: Consultancy; Abbvie: Consultancy; Karyopharm: Consultancy. Off Label Use: midostaurin- FLT 3 inhibitor. Thiede:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AgenDix GmBH: Equity Ownership. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Medeiros:Celgene: Honoraria, Research Funding; Agios Pharmaceuticals: Honoraria. Schlenk:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Arog: Honoraria, Research Funding; Teva: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding. Larson:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Ariad: Consultancy, Research Funding; Pfizer: Consultancy.

Description: 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

Description: Pediatric-type nodal follicular lymphoma (PTNFL) is a variant of follicular lymphoma (FL) characterized by localized presentation and excellent behavior despite its often high-grade histologic appearance. We recently identified high proliferation index and the absence of BCL2, BCL6, and IRF4 gene rearrangements as defining features of PTNFL in both children and adults (Louissaint, Blood 2012). In contrast to typical FL, children with PTNFL consistently have persistent remissions after surgical excision alone. Therefore, it is critically important to identify PTNFL in order to avoid unnecessary therapy. Considering the unique clinical behavior of PTNFL, we hypothesized that the mutational landscape of this disease would differ from that of typical FL. Twenty-four cases were collected from several institutions (MGH, Brigham & Women's, Weill Cornell, Chicago Children's, Boston Children's, University of Pittsburgh, SUNY Downstate, and Stanford). PTNFL was defined by the following criteria: 1) nodal involvement, 2) architectural effacement by a clonal follicular proliferation, 3) high proliferation index and 4) absence of both MUM1/IRF4 expression and BCL2/BCL6 rearrangements by FISH. All cases presented with localized nodal involvement and demonstrated no evidence of recurrence or progression after chemotherapy (n=5), radiation (n=3) or surgical excision alone (n=13) (therapeutic approach to be confirmed in 3 cases), with a median follow-up of 33.1 months (range 10-124 months). Subjects ranged in age from 4-60 years, including 14 children (4-18 years; median 15) and 10 adults (20-60 years; median 29.5). Whole exome sequencing performed on 7 PTNFL cases showed a strikingly low mutation burden (7.1 non-silent mutations/exome), more than an order of magnitude lower than the exomic mutation burden of typical FLs (Green, PNAS 2015; Pasqualucci, Cell Rep 2015). Given these findings, we pursued targeted exome capture and next-generation sequencing for 112 genes previously reported to be recurrently mutated in FL across a panel of 20 PTNFLs. Targeted sequencing (mean depth, 250) again demonstrated very low mutation burden in PTNFL, with a median number of non-silent mutations of 1.67/case compared with 4 mutations/case (P

Description: Introduction: Asparaginase (ASP) has demonstrated a survival benefit in pediatric patients (pts) with acute lymphoblastic leukemia (ALL) and is now part of standard-of-care frontline treatment. As a result, asparaginase preparations have been incorporated into the treatment of adult ALL to improve outcomes. Pegaspargase (PEG-ASP), a modified version of asparaginase with prolonged asparagine depletion, appears to be safe in adults up to age 40 (Stock, et al., Blood, 2019), but is associated with a unique spectrum of toxicities, the risks of which appear to increase with age. Therefore, the safety of PEG-ASP remains a significant concern in older adults w/ ALL. Methods: We conducted a single center retrospective chart review of pts age ≥40 years who received PEG-ASP as part of frontline induction/consolidation or reinduction, between March 2008 and June 2018 at Memorial Sloan Kettering Cancer Center. The primary objective was to evaluate the tolerability and toxicity of PEG-ASP based on the incidence and severity of ASP-related toxicities (hypersensitivity reactions, hypertriglyceridemia, hyperbilirubinemia, transaminitis, pancreatitis, hypofibrinogenemia, etc) according to the Common Terminology Criteria for Adverse Events, version 4.03. Laboratory values recorded were either the peak or the nadir, the more appropriate for toxicity assessment, within a 4-week period following PEG-ASP administration. Secondary objectives were to determine the total number of doses of PEG-ASP administered in comparison to the number of doses intended, and to characterize the rationale for PEG-ASP discontinuation when applicable. Fisher's exact test was used to compare the incidence of PEG-ASP toxicities with respect to pt and treatment characteristics (regimen, age, BMI, gender, Philadelphia chromosome positive (Ph+) vs. Ph-, presence of extramedullary disease, PEG-ASP dose). P values were not adjusted for multiple comparisons. Results: We identified 60 pts with ALL (40 B-ALL and 20 T-ALL) who received at least one dose of PEG-ASP. Nine pts were Ph+. The median pt age at initiation of the treatment was 53, (range, 40 to 80), and 19 pts had a BMI ≥30 kg/m2. Forty-four pts received treatment for newly diagnosed ALL, and 16 pts for relapsed disease. Table 1 lists pt baseline characteristics. Among the 44 pts with newly diagnosed ALL, 27 pts received PEG-ASP as part of pediatric or pediatric-inspired regimens at doses of 2000 - 2500 units/m2, and 1 pt received a modified dose of 1000 units/m2 due to age. The remaining 16 pts received PEG-ASP at doses of 1000 - 2000 units/m2 for consolidation, per established adult regimens (ALL-2 and L-20; Lamanna, et al., Cancer, 2013). Grade 3/4 ASP-related toxicities with a 〉10% incidence included: hyperbilirubinemia, transaminitis, hypoalbuminemia, hyperglycemia, hypofibrinogenemia, and hypertriglyceridemia. Frontline treatment regimens in which PEG-ASP was used in consolidation cycles only (ALL-2, L-20) were associated w/ a lower incidence of hyperbilirubinemia (p=0.009) and hypertriglyceridemia (p

Description: The CD3/CD19-targeted bispecific T-cell engager blinatumomab (BLIN) is active in pts w/ relapsed/refractory B-ALL or persistent minimal residual disease. Notable toxicities include cytokine release syndrome (CRS), a constellation of symptoms related to brisk systemic inflammatory response, and a spectrum of neurologic toxicities (NTX). BLIN prescribing information provides basic CRS/NTX management guidance, but limited reports describe "real-world" toxicity management strategies (TMS) and outcomes. We further previously reported association between higher baseline and peak levels of acute phase reactants (APR; C-reactive protein [CRP]/ferritin), time to APR peak, and incidence of CRS/NTX post-BLIN (King et al. ASH Annual Meeting, 2017). While CRS is also mediated in part by IL-6, routine monitoring of IL-6 levels during BLIN is not currently standard. As such, we sought to determine rates/severity of CRS/NTX at our institution, efficacy of TMS, and utility of APR/IL-6 in predicting CRS/NTX post-BLIN. We reviewed electronic medical records of pts ≥ 18 years (yrs) old w/ previously treated B-ALL receiving BLIN between 1/1/2011 and 3/31/19 at Memorial Sloan Kettering Cancer Center (MSK). NTX was classified/graded w/ CTCAEv5.0 (Common Terminology Criteria for Adverse Events). CRS was graded per CTCAEv5.0 and American Society for Transplantation and Cellular Therapy (ASTCT) criteria. The primary objective was to characterize rates/clinical features of CRS/NTX. Secondary objectives included assessing the nature/efficacy of TMS, and association of APR/IL-6 levels w/ CRS. Maximal (max) fold increase in APR/IL-6 was measured from pre-BLIN baseline to peak value during BLIN cycle 1 (C1). APR/IL-6 levels/fold changes were compared between groups using the Wilcoxon-Mann-Whitney test w/o adjustment for multiple comparisons. 59 pts were identified, including 31 male pts (52%). Median age at start of BLIN was 57 yrs (range, 20-76). Median number of prior therapies was 1, including 8 pts w/ previous allogeneic hematopoietic cell transplant (alloHCT) and 5 w/ prior chimeric antigen receptor T-cell therapy (CAR-T). No pt had baseline organ dysfunction or central nervous system (CNS) disease. All pts were admitted for initiation of BLIN C1. BLIN was started at 9 mcg/day IVCI w/ escalation to 28 mcg/day IVCI on day 8 (per recommended dosing for R/R ALL) in 52 pts and at 28 mcg/day IVCI in 7 pts for MRD (per Gökbuget et al., Blood, 2018). During BLIN C1, 34/59 pts experienced CRS (57%), w/ max grade (G) 1 (n=24), G2 (n=9) or G3 (n=1). CTCAEv5.0/ASTCT grading was concordant in all cases. Eight of 34 (23%) were managed w/ brief interruption of blinatumomab (BIB) for G1 (n=3) and G2 (n=5) CRS. Median duration of BIB was 39 hours (h) (range, 21-91h). Three pts had concomitant NTX and received brief courses of dexamethasone (DEX, daily dose of 24 mg). One pt w/ grade 2 CRS received tocilizumab for hypotension suboptimally responsive to fluid boluses (FB) w/ IL-6 level = 25754 pg/mL. Remaining pts w/ BIB (5/8) received FBs for hypotension. One pt permanently discontinued BLIN during C1 due to rapidly progressive B-ALL. All pts managed w/ BIB were successfully re-challenged w/ BLIN and finished C1 w/o recurrence of CRS. Of the 25/34 (74%) pts w/ CRS not managed w/ BIB, 5 received FBs, w/ 1 pt receiving a FB and a single dose of DEX. Five pts developed recurrent CRS (≥24 hours after resolution); 4/5 recurrences occurred in pts not managed w/ BIB. NTX, excluding isolated headache, was observed in 8/59 pts (14%) during BLIN C1 (Table 1) w/ max G1 (n=4), G2 (n=3), or G3 (n=1). Four pts w/ NTX were managed w/ BIB and a brief course DEX; 3/4 had concomitant CRS. Median time to onset of CRS and NTX were 1 day (d) (range 0-15) and 2 d (range 0-10), respectively. Non-significant trend toward higher peak IL-6 was noted in pts w/ G1 vs. G0 CRS (p=0.07; Fig 1A, note log scale); median peak levels of CRP were higher in pts w/ G1 vs G0 CRS (p=0.01, Fig 1B); median peak ferritin levels were higher in pts w/ G2 vs. G0 CRS (p=0.01, Fig 1C). While CRS was common during C1 of BLIN, supportive management was sufficient in most pts; BIB was an effective strategy and allowed successful BLIN re-challenge. The incidence of ≥G2 NTX was low and all cases of NTX were reversible w/ supportive care or BIB ± DEX. Peak APR levels correlated w/ CRS severity. Authors noted concordance of CRS grading between CTCAE and ASTCT, suggesting the feasibility of a single, BITE-specific grading system. Disclosures King: Astrazeneca: Other: Advisory board; Genentech: Other: Advisory Board ; Incyte: Other: Advisory Board. Park:Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Allogene: Consultancy. Geyer:Amgen: Research Funding; Dava Oncology: Honoraria.

Description: Background: The treatment indications for venetoclax in CLL are broadening quickly. While the initial approval was for relapsed patients with del 17p (Stilgenbauer S, et al. JCO 2018), it has subsequently been extended to all patients (Seymour J, et al. NEJM 2018, Fischer K, et al. NEJM 2019). The duration of therapy with each approval has evolved as well, from continuing therapy until progression/toxicity to 1 year in front-line CLL. The limited durations of therapy were applied to all patients based on trial design and were not dependent on response to treatment. Undetectable minimal residual disease (U-MRD) with venetoclax is associated with improved progression-free survival (PFS), both as a single agent and in combination with rituximab (Stilgenbauer S, et al. JCO 2018, Seymour J, et al. NEJM 2018). Early phase data suggest that patients who discontinue venetoclax after achieving MRD negativity can be monitored off therapy and successfully retreated upon relapse (Seymour J, et al, Lancet Onc 2017). However, patients who discontinue therapy with persistent residual disease have a higher incidence of relapse (Kater A, et al. JCO 2019). Together, these data suggest that the duration of venetoclax therapy should be individualized, based on the depth of response one achieves and not a fixed duration schedule. Therefore, we propose a prospective clinical trial, utilizing MRD assessment with a next generation sequencing (clonoSEQ®) assay to guide clinical decision making in patients with CLL receiving venetoclax-based regimens. Methods: This is a multicenter, phase II clinical stopping trial for 80 venetoclax-treated CLL patients. The clonoSEQ® assay is used to assess MRD, and patients who achieve U-MRD (defined as

Description: Introduction: Signaling through JAK1 and/or JAK2 is common among tumor and non-tumor cells within peripheral and cutaneous T cell lymphomas (PTCL and CTCL). We conducted a phase II study of the JAK1/2 inhibitor, ruxolitinib, in patients (pts) with PTCL and CTCL and assessed the predictive value of genetic, immunohistochemical (IHC) and multiparametric immunofluorescence (mIF) biomarkers of JAK/STAT pathway activation for ruxolitinib response. Methods: This is an investigator-initiated multi-center phase II study for pts with relapsed or refractory (RR) PTCL or CTCL following at least 1 systemic therapy. Biopsies from each patient were subjected to next-generation sequencing for JAK1, JAK2, STAT3, STAT5 and other relevant genes along with IHC assessment for phosphorylated STAT3 (pSTAT3). Pts enrolled into biomarker-defined cohorts: 1) activating JAK and/or STAT mutations (allele frequency of 0.1 or greater); 2) no JAK/STAT mutation but ≥ 30% pSTAT3 expression among tumor cells by IHC; or 3) neither. Pts received treatment with ruxolitinib 20 mg BID until progression and were assessed for response after cycles 2, 5 and every three cycles thereafter. Tissue samples collected at baseline, on-treatment, and at progression were collected and assessed by mIF (Vectra platform, HALO analysis) using markers specific for lymphoma subtype, macrophage activation, JAK/STAT and PI3 kinase signaling. Results: The study completed enrollment with 53 pts, including 18 in cohort 1, 14 in cohort 2, and 21 in cohort 3. Cohort 3 includes 10 pts for whom JAK/STAT characterization is pending. Disease histologies per cohort are detailed in table 1. Treatment-related serious adverse events included HSV-1 stomatitis (n=1), spontaneous bacterial peritonitis (n=1), febrile neutropenia (n=3), and herpes zoster (n=1). Additional grade 3 or 4 drug-related adverse events affecting 〉1 pt included neutropenia (n=13), anemia (n=8), thrombocytopenia (n=5), and lymphopenia (n=3). Among the 53 pts, 4 have not yet reached first response assessment and 1 withdrew consent following only 1 week of treatment; therefore 48 are evaluable for response. Among 48 pts, there were 3 (6%) complete responses, 8 (17%) partial responses, and 6 (12.5%) with cytopenia improvement and disease stabilization lasting more than 6 months (SD〉6 mo). Overall response rate (ORR) was 23% and overall clinical benefit rate (CBR) (ORR plus SD〉6 mo) was 35%. Median duration of response was 7.3 months (range 1.3-26.1 months). ORRs in cohorts 1, 2 and 3 were 28%, 31%, and 12% (cohorts 1&2 vs 3, p=0.28). CBRs in cohorts 1, 2 and 3 were 44%, 46%, and 18% (cohorts 1&2 vs. 3, p=0.07) (table 2). More frequent responses were observed in the following histologies: angioimmunoblastic T cell lymphoma, peripheral T cell lymphoma with T-follicular helper phenotype, T-cell prolymphocytic leukemia, and large granular lymphocyte leukemia (table 3). Nine pre-treatment biopsies were analyzed by mIF from 4 ruxolitinib responders and 5 non-responders. The most notable finding was that responders to ruxolitinib had markedly lower pS6 expression within tumor cells of pre-treatment biopsies (mean pS6 expression 9.03 +/- 4.8 vs 48.19 +/- 6.6 for nonresponders; p=0.0027). In a patient with prolonged CR on ruxolitinib, progression biopsy was characterized by a marked increase in tumor cell pS6 staining. Additional samples are being analyzed and updated results will be reported at the meeting. Conclusion: The JAK1/JAK2 inhibitor ruxolitinib is a well-tolerated and readily available therapy for pts with relapsed/refractory PTCL and CTCL. Among patients with IHC and/or genetic evidence of JAK/STAT activation, ruxolitinib has similar efficacy to approved agents for relapsed/refractory T-cell lymphoma. The association between pS6 expression and response to ruxolitinib suggests that active PI3K/mTOR signaling confers intrinsic and acquired resistance to ruxolitinib. Disclosures Moskowitz: ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Jacobsen:Acerta: Consultancy; Novartis: Research Funding; Astra-Zeneca: Consultancy; F. Hoffmann-LaRoche: Research Funding; Merck: Consultancy, Research Funding; Takeda: Honoraria; Pharmacyclics: Research Funding. Ruan:Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie company: Research Funding; Kite: Consultancy; Juno: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Geyer:Amgen: Research Funding; Dava Oncology: Honoraria. Noy:Medscape: Honoraria; Janssen: Consultancy; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Weinstock:Celgene: Research Funding. Horwitz:Aileron: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Trillium: Research Funding; Kyowa Hakko Kirin: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Miragen: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Forty-Seven: Research Funding; Portola: Consultancy; Miragen: Consultancy; Mundipharma: Consultancy; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Innate Pharma: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Astex: Consultancy; Astex: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Celgene: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Aileron: Research Funding; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Forty-Seven: Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Trillium: Research Funding; Aileron: Research Funding; Kura: Consultancy; Miragen: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy; Portola: Consultancy; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Affimed: Consultancy; Affimed: Consultancy. OffLabel Disclosure: Off-label use of ruxolitinib for T-cell lymphoma will be discussed

Description: Background: Quality of life (QOL) is predictive of survival in many malignancy types, including myeloproliferative neoplasms (MPNs; Scherber 2017, Sloan 2012, Montazeri 2009, Nilsson 2017). We have previously characterized that an association exists between symptom burden and QOL among MPN patients, but due to the disease specificity of symptoms, symptoms rather than QOL remains a key therapeutic endpoint (Scherber 2017, NCCN Guidelines). Despite these advancements, our understanding of the extent that different patient and disease characteristics, including symptoms, contribute to overall QOL has remained elusive. In this analysis, we utilized information from a large survey of MPN patients to develop a model of QOL that establishes the degree that individual variables contribute to QOL, including psychosocial variables, comorbidities, and MPN disease symptoms. Methods: The FATIGUE survey of MPN patients (Scherber 2016) investigated self-reported symptoms using the MPN10 (Scherber 2012), depression utilizing the Profile of Mood States-Brief (POMS-B, McNair 1971), Patient Health Questionnaire (PHQ-2, Kroenke 2003) and Mental Health Inventory (MHI-5, Berwick 1991), and QOL utilizing a single numeric analog scale (range 0-10) regarding overall quality of life. Linear regression analysis was utilized to establish the relationship between individual symptoms and QOL, and a structural equation model (SEM) was used to identify complex relationships among patient demographics, behavioral factors, comorbidities, and QOL. Results: A total of 914 patients from the online survey lived in the USA and provided data for this analysis. Average age was 62 with 67% of patients being female and the mean BMI was 25. Education varied across middle school or high school education (22%), undergraduate or college degree (44%), masters (26%), to doctorate (8%). 43% of respondents were employed. Fatigue (β coefficient 0.23, p

Description: 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