Dueck, Amylou C.

Abstract Introduction: Myeloproliferative Neoplasm (MPN) patients encounter debilitating pain syndromes as a result of their disorder. Opioids are frequently employed in cancer-related pain but have been increasingly recognized for their risk profiles including accidental overdose, addiction and death. With many MPN patients facing near-normal life expectancies, chronicity of opioid use may increase the risk of adverse events. In this survey, we evaluated the prevalence of MPN opioid use, risk factors for negative outcomes and compared the features of this population to MPN patients not receiving opioid therapy. Methods: This study was performed by the MPN Quality of Life Study Group. A survey was designed by a team of MPN investigators experienced with MPN symptomatology. Patients completed the MPN-10, a 10 item survey of MPN symptoms completed on a 0 (absent) to 10 (worst imaginable) scale (Blood. 2011 Jul 14;118(2):401-8). Other surveyed tools included the Opioid Risk Tool (ORT) as well as DSMV criteria for Opioid Use Disorder (OUD). The survey was posted on high-traffic MPN-related webpages focused on patient education and advocacy (MPN Forum, MPN Net, MPN Research Foundation, MPN Voice)for a total of 28 days. Patients currently receiving opioids were compared to patients not receiving opioids and statistical significance was defined as p<0.05. Results Demographics A total of 416 patients completed the survey and were compared by active opioids use (n=69) vs. no active opioid use (n=347). Patients described a history of myelofibrosis (MF, 28.8%), polycythemia vera (PV, 44.2%) and essential thrombocythemia (ET, 26.9%). Most MPNs were diagnosed between 1-3 years ago (22.2%), 3-10 years ago (35.0%) or >10 years ago (30.4%). Patients were furthermore of expected mean age (60.7), primarily female (75.0%) and from the United States (66.6%). Few patients had a history of transformation to acute leukemia (0.5%), severe bleeding (12.3%) or blood clot (26.5%). Mean individual symptom scores and prevalences were 3.0 and 65.6% for abdominal discomfort and 3.3 and 59.4% for bone pain, respectively, indicating a low to moderate symptom burden. Patients Receiving Opioid Therapy Patients on opioid therapy (n=69) displayed a number of high risk features for adverse outcomes including a personal history of substance abuse (20.2%), respiratory disease (33%) and mental health disorders (60.1%). By DSMV criteria, 5.9% of opioid patients scored 'mild' and 2.9% scored 'moderate' for OUD (total 8.8%), consistent with prevalence in the general population. Approximately 24.6% of opioid-using patients scored moderate to high risk on the ORT but despite this, did not appear more likely to meet criteria for OUD (p=0.81). Palliative care and pain management were involved in only 34.3% of patients and side effects of opioids were discussed in only 70.1% of all cases. Opioid vs. Non-Opioid Patients Compared to patients not receiving opioid therapy, patients currently on opioid treatment were more likely to describe more frequent and/or more severe abdominal discomfort (88.4% vs. 61.0%, p<0.001; mean 5.0 vs. 2.6, p<0.001), bone pain (87.0% vs. 53.9%, p<0.001; mean 5.6 vs. 2.4, p<0.001), unintentional weight loss (41.2% vs. 21.4%, p=0.001), inactivity (94.2% vs. 71.5%, p<0.001), early satiety (84.1% vs. 58.2%, p<0.001), and impaired quality of life (mean 4.9 vs. 6.6, p<0.001). They were also more likely to describe regularly taking pain medications (85.5% vs. 34.5%, p<0.001) as well as attempt non-pharmacological treatments to manage symptoms (Figure 1). Despite more aggressive pain treatment approaches, only 42% of opioid patients reported satisfaction with their current pain plan vs. 62.2% of patients not receiving opioid therapy. Conclusions: MPN patients face significant symptom burden despite often limited reduction in life expectancy. Patients furthermore demonstrate a high prevalence of risk factors for opioid-related complications including overdose and substance misuse. Despite aggressive pain regimens, opioid patients are less likely to voice adequate symptom control or satisfaction with their pain treatment plans. Providers should be cognizant of opioid-related complications and consider subspecialty pain management referrals or adaptation of the JCO Clinical Practice Guidelines for Management of Chronic Pain in Survivors of Adult Cancers (J Clin Oncol. 2016 Sep 20;34(27):3325-45). Disclosures Scherber: Orphan Pharmaceuticals: Honoraria; Incyte: Consultancy. Palmer:Novartis: Research Funding. Dueck:Phytogine: Employment; Pfizer: Honoraria; Bayer: Employment. Mesa:Gilead: Research Funding; Novartis: Consultancy; CTI: Research Funding; Galena: Consultancy; Incyte: Research Funding; Promedior: Research Funding; Ariad: Consultancy; Celgene: Research Funding.

Abstract Introduction: MPN-related pain, including abdominal discomfort (53.2%), and bone pain (48.5%), is a prevalent complaint within the disorder and is associated with impaired patient quality of life, reduction in most functional domains and overall poor prognosis. Non-targeted treatments for MPN disorders have been previously shown to provide little symptomatic relief for MPN pain. To date, little is known about patient viewpoints on MPN pain, its relationship to other chronic pain syndromes and the impact of pharmacologic and non-pharmacologic pain therapies. In this study, we performed an international survey of MPN patients to better understand the prevalence and management of MPN pain. Methods: This study was performed by the MPN Quality of Life Study Group. A survey was designed by a team of MPN investigators experienced with MPN symptomatology. Survey content included the Barriers Questionnaire II (BQII), a 27-item survey validated to assess patient belief barriers to optimal management of cancer pain measured on a 0 (do not agree at all) to 5 (agree very much) scale (Pain. 2002 Oct;99(3):385-96.). Patients also completed the MPN-10, a 10-item survey of MPN symptoms completed on a 0 (absent) to 10 (worst imaginable) scale (Blood. 2011 Jul 14;118(2):401-8). The survey was posted on high-traffic MPN-related webpages focused on patient education and advocacy (MPN Forum, MPN Net, MPN Research Foundation, MPN Voice) for a total of 28 days. Survey questions evaluated patient demographics, pain histories, current and prior treatment strategies, as well as satisfaction with and barriers to available treatment options. Results: Demographics A total of 502 MPN patients (MF 26.9%, PV 44.2%, ET 28.9%) completed the survey. Patients were of expected mean age (60.5 years) and primarily female (74.9%). Most were from the United States (66.7%) and primarily English speaking (92.2%). Patients described being diagnosed with their MPN 3 to 10 years (35.4%) or >10 years ago (30.8%). Splenic enlargement was vocalized by 36.5% of patients and few patients had had a known history of blood clots (25.4%), severe bleeding (13.3%), conversion to acute leukemia (0.4%) or prior bone marrow transplant (1.4%). Patients described a treatment history of a variety of MPN therapies including aspirin (82.7%), hydroxyurea (60.6%), phlebotomy (40.6%), ruxolitinib (25.9%), interferon (18.5%), anagrelide (17.3%), active clinical trial (5.0%) and radiation treatment (0.4%). Pain Severity, Prevalence and Treatments Among surveyed patients, the MPN-10 mean was 28.3. Mean individual symptom scores and prevalence were 3.1 and 65.6% for abdominal discomfort and 3.0 and 60.4% for bone pain, respectively indicating a low to moderate symptom burden. Most patients had no prior history of chronic pain prior to their MPN diagnosis (47.1%), with chronic abdominal pain and chronic bone/muscle pain noted prior to MPN development in 5.6% and 20.8% of patients, respectively. Most patients felt that their chronic pain has either stayed the same (26.2%), worsened (28.3%) or significantly worsened (14.5%) since their MPN diagnosis. Many patients found pharmacologic and non-pharmacological therapies efficacious for individual pain symptoms, and 42.1% described regularly taking medication to control their pain (Table 1). Barriers to Pain Management Overall, 42.3% of MPN patients reported being unsatisfied with their current pain management plan. Despite this, only 43.5% of patients stated that their MPN providers discussed pain during office visits. Palliative Care (3.1%) and Pain Management (7.3%) were infrequently engaged. On the BQII, patients described being confident that cancer can cause pain (mean 4.2, SD 1.1) but did not necessarily expect to have pain following their MPN diagnosis (mean 2.2, SD 1.8). Conclusion Chronic pain (abdominal, bone) is a prevalent and undermanaged feature of MPN disorders. Chronic non-MPN pain is further complicated by the development of the disorder. Many MPN patients lack understanding on its prevalence and furthermore feel ill-equipped to manage it. Patients have, however, found symptomatic benefit from various pharmacological and non-pharmacological treatment modalities that require further exploration. Results from this study suggest MPN patients should be assessed regularly for pain and offered early referral to specialized services for evaluation, source identification and treatment. Table 1. Table 1. Disclosures Scherber: Incyte: Consultancy; Orphan Pharmaceuticals: Honoraria. Mesa:Ariad: Consultancy; Galena: Consultancy; CTI: Research Funding; Incyte: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Novartis: Consultancy; Celgene: Research Funding. Dueck:Bayer: Employment; Pfizer: Honoraria; Phytogine: Employment. Palmer:Novartis: Research Funding.

Abstract Background: Myeloproliferative neoplasms (MPN) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are clonal hemopathies characterized by burdensome symptom profiles and impaired quality of life. Treatments include pharmacologic approaches, phlebotomy, and bone marrow transplant. Outcome studies have historically focused on hematologic improvement and survival benefit. Few prospective studies have evaluated patient-reported symptoms and quality of life outcomes after standard therapy. The Myeloproliferative Neoplasm Quality of Life (MPN-QOL) Study Group aims to objectively quantify symptomatic response to standard treatments. Here we provide updated results for the prospective MPN Experimental Assessment of Symptoms by Utilizing Repetitive Evaluation (MEASURE) trial. Methods: The MEASURE trial is a prospective international cohort study evaluating responsiveness of the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS or MPN-10) in an anticipated 480 ET, PV, and MF patients receiving non-experimental medical therapy and/or phlebotomy. Patients complete the MPN-SAF TSS (JCO 2012) for seven consecutive days at enrollment then again for seven days between 90 days and six months later. Patients also complete the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) and M.D. Anderson Symptom Inventory (MDASI) instruments at enrollment and on the first day of the second assessment. Physicians report demographic, laboratory, and clinical data. Results: Demographics To date, 340 patients have enrolled and 270 have completed both study visits. Participants include ET (60%), PV (29%), and MF (12%; including 68% primary MF, 12% post-ET, 20% post-PV) patients. Enrolled patients are 51% male. The most common therapies received prior to enrollment were aspirin (34%), phlebotomy (15%), hydroxyurea (14%), and warfarin/clopidogrel/anticoagulation (6%). The most common current MPN therapies were hydroxyurea (67%), aspirin (24%), phlebotomy (9%), and ruxolitinib (8%). Information on mutational analysis was also collected; 77% of patients have a known JAK2 V617F mutation, 3% have an MPL W515 mutation. Symptom Measures On the MPN-SAF TSS, the majority of individual symptoms assessed did not change significantly between the two assessment time points while on standard therapy. Notable exceptions were a significant decrease in weight loss (mean 2.0 vs. 1.7 on a 0=absent to 10=worst imaginable scale, p=0.005) and a significant worsening in quality of life (mean 3.6 vs. 3.8 on a 0=as good as it can be to 10=as bad as it can be scale, p=0.04). No changes were seen in other symptoms including early satiety, abdominal discomfort, night sweats, fatigue, inactivity, poor concentration, bone pain, itching, or fever. Similarly, the cumulative MPN-SAF TSS score remained stable at a mean of 24.4 over the treatment period. These findings were congruent with those observed using the EORTC QLQ-C30 instrument, with no significant changes seen in emotional, physical, role, cognitive, or social functioning. Finally, the MDASI also revealed a lack of change in either symptom severity (mean 2.7) or symptom distress (mean 3.0) scores, which remained stable over the study period. Discussion: Myeloproliferative neoplasms are associated with burdensome symptoms that significantly compromise quality of life. To date, no studies have quantified symptomatic response to standard-of-care treatments. Overall, results from the MEASURE study suggest that standard treatments have limited systematic impact on patient symptomatology over time, with no improvements in overall quality of life. However, we note the relatively low proportion of patients in this cohort treated with ruxolitinib, which has been shown previously to improve symptom burden, and this may have impacted the symptom responses seen in the group as whole; detailed responses by treatment and MPN subtype will be presented. Figure. Figure. Disclosures Dueck: Pfizer: Honoraria; Bayer: Employment; Phytogine: Employment. Ross:BMS: Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Research Funding. Tam:Janssen: Honoraria, Research Funding; Gilead: Honoraria; AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Travel funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria; Beigene: Honoraria, Other: Travel funding; Pharmacyclics: Honoraria; Gilead: Honoraria; Roche: Honoraria; Beigene: Honoraria, Other: Travel funding. Radia:Novartis: Speakers Bureau; Blueprint: Consultancy. Mesa:UT Health San Antonio - Mays Cancer Center: Employment; Celgene: Research Funding; NS Pharma: Research Funding; Pfizer: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Promedior: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy.

Abstract Background: Checkpoint blockade therapies (CBT) have substantially improved outcomes for patients in a variety of cancers. However, they are associated with a unique spectrum of immune-related adverse events (AEs). Additionally, unlike standard chemotherapy, many patients (pts) remain on CBT for prolonged periods of time, thus immune-related symptomatic AEs may be chronic or low grade therefore important to capture long term tolerability when used as a single agent or in combination with chemotherapy. In this study, we applied the Toxicity over Time (ToxT) analytic approach (Thanarajasingam et al, Lancet Oncol 2016), which incorporates the dimension of time and includes chronic lower grade events, to the first 6 cohorts (A-F) of a Phase 1/2 ECOG-ACRIN sponsored study of the combinations of Brentuximab Vedotin (BV) and the CBT therapies ipilimumab (Ipi) and nivolumab (Nivo) in pts with relapsed or refractory Hodgkin lymphoma (R/R HL). Methods: Pts with confirmed R/R HL were treated with BV 1.8mg/kg + Ipi 1or 3 mg/kg (n=23); or Nivo 3mg/kg + BV: 1.2 or 1.8 mg/kg (n=19). BV was administered every 21 days for 16 cycles; Ipi every 21 days x 4 and then every 3 months for one year and Nivo every 21 days for up to 2 years. Seven symptomatic (subjective) AEs were selected: fatigue, peripheral sensory neuropathy (PSN), nausea/vomiting (NV), rash/skin (RS), diarrhea, ocular-all types, and hair loss. Treatment-related AEs of any grade were investigated by conventional maximum grade toxicity analysis (ToxC) and ToxT methods up to 12 cycles. Using ToxT, mean AE grades over cycles were analyzed for time trend with repeated measures models, time to grade 2 or higher AE (gr2+) was analyzed with time-to-event analysis; AE profile over the entire course of the study was summarized by area under the curve (AUC) analyses. Comparisons were performed between treatment groups: BV/Ipi(A-C arms) and BV/Nivo (D-F arms). Results: 9/23 (BV/Ipi) and 6/19 (BV/Nivo) pts completed 10 cycles. For BV/Ipi vs. BV/nivo, ToxC provides overall incidence rates (any grade): fatigue 52% vs 26% (p=0.09); PSN 61% vs 53%; NV 70% vs 53% ; RS 65% vs. 37% (p=0.07); diarrhea 57% vs. 21% (p=0.02); ocular 17% vs. 21% ; and hair loss 17% vs. 0% (p=0.06), respectively. Gr3 AE occurred in 1 pt (2.4%) each for PSN, NV, diarrhea, and 6 pts (14.3%) for RS, and were similar between BV/ipi and BV/nivo. AUC from ToxT which captures chronic lower grade AEs suggested for BV/Ipi: diarrhea (p=0.02) and NV (p=0.03) are significantly more substantial over time with a trend seen for fatigue (p=0.07), RS (p=0.07) and hair loss (p=0.07) . Additionally, ToxT captures the trajectory of AEs, demonstrated a rising incidence and worsening grade of PSN (BV-related) on BV/Ipi (c1: 9% gr1, c2: 21% gr1 5% gr2, c5: 11% gr1 and c10: 22% gr2 [p=0.005], Fig 1a). In contrast there was a slow but significant decreasing incidence of NV on both combinations; for BV/Nivo (c1:52% gr1, c5: 26% gr1 and c10: 22% gr1) and BV/Ipi (c1: 47% gr1 ,c5: 0% and c10 1% gr1) with p=0.006 (Fig 1b). RS and diarrhea appear early on treatment and are not cumulative (Fig1c and 1d). There is no significant difference in the time to gr 2+ toxicities in any of the 7 AE. Combining all 7 AEs and using the maximum grade as a pilot measure of overall AE burden , ToxC indicates no difference in any grade (100% vs 100%) but a significantly higher gr 3+ incidence (35% vs. 11%) for BV/Ipi. Additionally, ToxT further elucidates that BV/Ipi is associated with significantly higher overall AE over time (Fig 2a, p=0.02) and compared to BV/Nivo a significantly higher risk of developing gr 2+ toxicity ( 57% vs 16% gr2 + event by day 50) (HR=0.41, p=0.02, Fig 2b). Conclusions: The CBT therapies Ipi and Nivo, in combination with BV, are overall both well tolerated over time, although BV/Ipi has a higher overall AE burden. Neither regimen has significant cumulative immune toxicity. Results of this analysis should be interpreted in the context of limited number of pts in both cohorts. A larger scale examination of this analysis is planned to incorporate both phase 1 and the ongoing phase 2 components of E4412. Compared with conventional tox analysis, ToxT delineated important additional and clinically relevant depictions of AEs over time and adds a more comprehensive assessment of the tolerability of chronically administered immune therapies for lymphoma. Disclosures Hong: Merck: Consultancy. Ansell:Regeneron: Research Funding; Merck & Co: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding. Cohen:Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; BioInvent: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding. Advani:Kura: Research Funding; Janssen: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Millenium: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Celgene: Research Funding; Agensys: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Forty Seven Inc.: Research Funding; Celgene: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Regeneron: Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Svoboda:Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; KITE: Consultancy; TG Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Regeneron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Kyowa: Consultancy. Karmali:AstraZeneca: Speakers Bureau; Gilead: Speakers Bureau. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dueck:Bayer: Employment; Phytogine: Employment; Pfizer: Honoraria. Kahl:Genentech: Consultancy; Acerta: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; Juno: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; ADC Therapeutics: Consultancy; CTI: Consultancy; Gilead: Consultancy. Diefenbach:Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Acerta: Research Funding; Millenium/Takeda: Research Funding; Genentech: Consultancy; Denovo: Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Research Funding.

Abstract Background: Bortezomib has efficacy in follicular lymphoma (FL). Though generally well tolerated, it is associated with a few known toxicities, including neurotoxicity. As a chronically administered agent, it is important to investigate the tolerability of bortezomib over time as a single agent and in combination with chemotherapy. The current method of summarizing adverse events (AEs) -focusing on the maximum grade and reporting only grade 3 or higher incidences- fails to capture toxicity that evolves over time or chronic low grade AEs that may occur at significant expense to patients' quality of life. In this study, we applied the Toxicity over Time (ToxT) analytic approach (Thanarajasingam et al, Lancet Oncol 2016), which graphically and analytically depicts AEs longitudinally, to a randomized Phase 2 ECOG-ACRIN sponsored study, E2408, to characterize chronic toxicity of bortezomib (V) when added to standard bendamustine-rituximab (BR) induction in previously untreated high risk FL. Methods: In E2408, patients (pts) were randomized to one of 3 arms at a 1:2:2 ratio: A) BR x 6 followed by maintenance rituximab (MR) x 2 years (yrs) vs B) BVR x 6 (bortezomib 1.3 mg/m2 IV/SQ days 1, 4, 8, 11) then MR x 2 yrs vs C) BR x 6 then MR x 2 yrs + lenalidomide 20mg/day x 1 yr. Pts enrolled 1/2011-5/2015. This analysis focuses on the 6 cycles of induction only, with arms A and C combined. Six AEs of interests were selected, 4 symptomatic (subjective) AEs (peripheral sensory neuropathy (PSN), diarrhea, febrile neutropenia, fatigue); and 2 non-symptomatic (objective) AEs (neutropenia and thrombocytopenia). Treatment-related post baseline AEs of any grade were investigated by conventional maximum grade toxicity analysis (ToxC) and ToxT methods. The mean AE grades over cycles were analyzed by repeated measures models, time to grade 2 or higher (gr2+)AE were analyzed with time-to-event analysis; and AE profile over the entire course of the study was summarized by area under the curve (AUC) analyses. Comparisons were performed between treatment arms (BVR vs. BR). Results: All 280 randomized treated pts (187 on BR, 93 on BVR) were included in the analysis regardless of eligibility status; 87% (163/187 BR, 81/93 BVR) completed all 6 cycles. Analyzing the symptomatic AEs,ToxC indicates that the overall incidence of grade 3+ PSN was significantly higher in BVR (12%) than BR (1%) (p<.0001). Additional, ToxT captures the trajectory, demonstrating a rapid, rising incidence and worsening grade of PSN on BVR vs BR over 6 cycles in a steam plot of mean gr. by cycle (Fig 1a) and bar chart of incidence and grade per cycle (c1: 13% gr1 3% gr2, c6: 36% gr1 12% gr2 6% gr3 on BVR; c1: 3% gr1, c6: 10% gr1 1% gr2 on BR, Fig. 1b). Risk of developing gr2+ PSN was significantly higher in BVR than BR with 28% vs 0.5% by day 100 (HR=0.01, p<.0001, Fig. 1c). ToxC captures a higher incidence of grade 3+ diarrhea on BVR (7% vs. 1% , p=.01) while AUC from ToxT includes chronic lower grade diarrhea, that is substantial over time on BVR vs. BR (p<.0001), but is not cumulative. Furthermore, the risk of developing gr2+ diarrhea affecting drug tolerability is significantly higher on BVR than BR(13% vs 5% by day 100) (HR=0.3, p=.05). Febrile neutropenia appeared to be similar, and fatigue was marginally more severe under BVR (p=.06 by AUC). For objective AEs, ToxC reveals no significant difference in neutropenia or thrombocytopenia BVR vs BR (neutropenia gr 3+: 36% vs 31%, p=.4; thrombocytopenia gr3+: 10% vs. 5%, p=.12). However, ToxT illustrates that neutropenia is cumulative, worsening over repeated exposure to drug (c1: 2% gr1 5% gr2 5% gr 3+ , c6: 7% gr1 10% gr2 12% gr3+ both arms combined; p<.0001) on mean grade over time (Fig. 2a). In contrast, thrombocytopenia does not worsen with continued treatment (Fig 2b, p=.73). Conclusions: Compared with conventional toxicity analysis (ToxC), ToxT delineated important additional and clinically relevant depictions of both symptomatic and laboratory AEs over time for bortezomib added to BR in FL pts. In patients receiving BVR, close monitoring is suggested for PSN, diarrhea and neutropenia for reassessment of risks and benefits, symptom interventions and dose modification. Longitudinal toxicity analyses such as ToxT can guide AE interventions as well as patient and clinician education, and provide a more patient-centered toxicity assessment of chronically administered therapies for lymphoma. Disclosures Hong: Merck: Consultancy. Evens:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy; Abbvie: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Tesaro: Research Funding; Affimed: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees. Advani:Kura: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Celgene: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Infinity: Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Janssen: Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Forty Seven Inc.: Research Funding; Merck: Research Funding; Millenium: Research Funding; Agensys: Research Funding; Celgene: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dueck:Bayer: Employment; Pfizer: Honoraria; Phytogine: Employment. Kahl:Genentech: Consultancy; Acerta: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy; Abbvie: Consultancy; Juno: Consultancy; Gilead: Consultancy; Celgene: Consultancy; CTI: Consultancy; AstraZeneca: Consultancy.

Abstract Introduction Patients with myeloproliferative neoplasms (MPN) typically experience debilitating symptom profiles and profound quality of life (QoL) decrements. Characterizing symptom burden in MPN clinical trials is vital to inform efficacy analyses. Previous studies have shown clinicians and researchers depend on patient-reported outcomes (PROs) to glean disease-related symptoms and signs of QoL decline. The current literature also shows that integrating PROs into the routine care of patients with cancer is associated with increased survival compared with usual care. However, the extent to which PROs are employed in MPN clinical trials is undescribed. ClincalTrials.gov is a registry of clinical trials mandated by the US Congress and implemented in 2000 by the National Institutes of Health. This study used data from ClinicalTrials.gov to evaluate the characteristics of MPN clinical trials over time and their use of PROs as primary and secondary outcomes. Methods The statistical software R and the rclinicaltrials package were used to download data from ClinicalTrials.gov. Trial data were included in this study if the following criteria were met: (1) the words essential thrombocythemia, polycythemia vera, myelofibrosis, or myeloproliferativeneoplasm (MPN) were used in the registered primary disease condition or official trial title; (2) the trial start date was between January 1, 2000 - July 1, 2018; (3) primary/secondary outcome data were available. Trial outcome data were then parsed for PRO text phrases including MPN-Symptom Assessment Form, quality of life, questionnaire, patient-reportedoutcome, and more specific PRO items (e.g., bone pain, concentration problems, and depression). Descriptive statistics and regression analysis were used to assess rates of primary/secondary outcomes over time. Results Clinical trial characteristics There were 535 trials satisfying the inclusion criteria. Since 2000, the number of registered MPN-related clinical trials ranged from 11 to 36 trials per year with 28 trials registered annually on average (Figure 1). Of the 535 trials, 470 (88%) were interventional and 65 (12%) observational. Trials often employed multiple intervention types including: drug (77%); procedure (28%); biological (19%); radiation (13%); genetic (3%); behavioral (2%); device (2%); dietary supplement (1%); other (24%) [percentages do not sum to 100% as categories are not mutually exclusive]. Eligibility criteria varied widely, though most used 18 years old as the minimum age requirement (71%; 379/535) and nearly all included both genders (>99%; 533/535). PRO outcomes over time Of the 535 MPN trials, the number of primary outcomes within MPN trials did not change over time (p=.50) with an average of 1.6 per trial. Around 8% of MPN clinical trials had PRO-related primary outcomes; this rate also did not change over time (Figure 1: solid red line; p=.97). However, the total number of secondary outcomes per trial has increased since 2000 (p<.001). From 2000-2005, 2006-2011, and 2012-2018 there was an average of 2.8, 3.3, and 5.2 secondary outcomes per trial, respectively. Also, the proportion of MPN clinical trials with PRO-related secondary outcomes has increased steadily over time (Figure 1: dashed blue line; p<.001). On average, from 2000-2005, 2006-2011, and 2012-2018 the proportion of MPN clinical trials with PRO-related secondary outcomes increased from 8% to 23%, to 33%. Conclusion Analysis of ClinicalTrials.gov data suggest that patient-reported outcomes are being implemented into MPN clinical trials at increasing rates. While this suggests that MPN trials are becoming more patient-centered, PROs are included more often as secondary endpoints than primary endpoints. This analysis also suggests an increase in the number of secondary endpoints in recent years in MPN clinical trials, consistent with observed trends of growing complexity and increasing amount of data captured in clinical trials in general. Disclosures Mesa: Ariad: Consultancy; Galena: Consultancy; Gilead: Research Funding; Promedior: Research Funding; Incyte: Research Funding; Novartis: Consultancy; CTI: Research Funding; Celgene: Research Funding. Scherber:Orphan Pharmaceuticals: Honoraria; Incyte: Consultancy. Dueck:Bayer: Employment; Phytogine: Employment; Pfizer: Honoraria.

Abstract Background: Myelofibrosis (MF) is a bone marrow disorder characterized by anemia, splenomegaly and constitutional symptoms. There has been substantial work documenting quality of life (QoL) in patients with MF, however, very little data about patients following allogeneic stem cell transplant (alloSCT) for MF. Many patients decline alloSCT due to concerns secondary to QoL. Methods: Medical facts and patient reported outcomes (PRO) measures were collected within a month prior to transplant, at day 30, 100 and 1 year post alloSCT. PRO measures include Brief Fatigue Inventory, Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), global assessment of change and the Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF). The group was measured as a whole, and the patients in the upper quartile of MPN-TSS (the aggregate score of the 10 core items of the MPN-SAF) were also considered. Results: Fifty patients were enrolled on this study, 47 who proceeded with transplant. The median age of the patients was 63, ranging from 35-74. The majority of the patients were male (29, 66%), and Caucasian (43 (96%)). Most patients had primary MF (26, 59%), 9 patients had post-PV MF, and 9 patients had post-ET MF. Twenty patients had DIPSS Intermediate 2 risk disease, and 16 had DIPSS high risk disease. Twenty-six (51%) had a matched unrelated donor, 12 (30%) had a matched related donor and 5 (12%) had a mismatched unrelated donor. The majority of the patients had RIC regimens (35, 88%). At baseline the mean MPN-TSS was 27.7 (out of possible 100), and at day 30, day 100 and 1 year it was 24.6, 32.0, and 25.0, which reflected no significant change between the time points. Interestingly, all the MPN specific symptoms (including fevers, night sweats, pruritis, abdominal pain) had a significant improvement at least one time point following alloSCT. Patients in the highest quartile based on baseline TSS score (12 patients with scores at baseline greater than or equal to 37), had significant improvement in TSS score at day 100, headache at day 30, insomnia at day 100, night sweats at day 100, itching at day 100 and overall QOL at day 100. With regards to the FACT BMT, as would be expected, there was a significant decline in the FACT BMT total score, as well as trial outcome index (TOI) at day 30, but a return to close to baseline by one year. In the global assessment of change, on day 30, 11 (27.5%) of patients reported feeling a little/moderately/very much better overall quality of life since their transplant and 27 (67.5%) felt a little/moderately/very much worse quality of life. At day 100, 11 (31.4%) reported better quality of life and 20 (57%) reported worsening since transplant. By one year, 17 (60.7%) reported feeling better and 7 (25%) reported worsening. These findings did not appear to have a correlation with presence or absence of graft versus host disease. We were unable to assess the impact of conditioning as the majority of the patients had RIC conditioning. Discussion/ Conclusions: Our study evaluated the quality of life in patients with myelofibrosis who have undergone bone marrow transplantation. We have shown that there is very little change in symptom burden over the first year following transplant in general; however, significant improvement was observed in MF specific symptoms, and in patients who had a high symptom burden at baseline. By one year 61% felt that their QoL was better than it was prior to transplant. Our findings suggest that many of the patients do not experience a significant decline in QoL at 1 year after alloSCT, and actually report that their QoL improves. Further investigation is required to validate these findings. Figure. Figure. Disclosures Palmer: Novartis: Research Funding. Dueck:Phytogine: Employment; Pfizer: Honoraria; Bayer: Employment. Mesa:Novartis: Consultancy; NS Pharma: Research Funding; Incyte Corporation: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment; Pfizer: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Genentech: Research Funding.

Abstract Background: Patients (pts) with polycythemia vera (PV) and essential thrombocythemia (ET) suffer from difficult MPN associated symptoms which impact quality of life (QoL). The impact of initial cytoreduction on ET/PV symptoms, resulting toxicity and QoL have not been prospectively studied. Methods: MPD-RC 112 trial (NCT01258856) randomized 168 therapy-naive (hydroxyurea [HU] <3 mo) high risk ET/PV pts (<5 years of disease) to response adjusted pegylated interferon alpha 2a (PEG) or HU. MPN symptoms, in depth toxicity assessment, and QoL were measured by two symptom instruments (MPN-SAF, EORTC QLQ-C30: baseline,3, 6, 9, and 12 mo) and toxicity questions. Blinded response review by European Leukemia Net (ELN) hematological responses (HR) was conducted at 12 months. Individual time point and longitudinal group comparisons were based on mixed models adjusting for age. Results: Patients: Of 168 randomized pts (86 HU, 82 PEG), 164 (98%) completed the survey package at baseline and 151 (HU 83%; PEG 98%) completed at least 1 survey during treatment. Median age was 61 (range 18-87) with 70 (42%) females; 81 (48%) / 87 (52%) with ET / PV; 46 (27%) had a history of a thrombosis. 119 (71%) received prior HU (up to 3 months). Baseline characteristics were balanced between arms with the exception of age (median HU 63 vs. PEG 60 yrs; p=0.02). Baseline Symptom Burden /QoL: Mean MPN-SAF Total Symptom Score (TSS), scale 0 [absent]-100 [worst imaginable] was 15.8 (SD 12.6; range 0-62.0) with means of 15.1 (SD 12.6) / 16.5 (SD 12.6) for ET / PV which were slightly lower than reported means of a previous cohort receiving any line of treatment (Scherber RM, JCO 2012). Median number of moderate (defined as score >=3) symptoms in ET patients was 3.0 and PV 4.0. Most common moderate symptoms were fatigue (65.9%), insomnia (37.2%), numbness (33.5%) , itching (29.9%), dizziness (27.4%), early satiety (26.8%) , headache (23.2%), sad mood (23.2%), inactivity (22%), concentration (20.7%). 50.6% of patients had one or more symptom with a score >=6. Mean QLQ-C30 global health status/QoL (GHS/QoL) was 70.8 (SD 21.9) - comparable to a general population (mean 71.2, SD 22.4) and better than a general cancer population (mean 61.3, SD 24.2; QLQ-C30 Reference Manual 2008). At baseline, TSS, symptoms, and QoL were similar between treatment arms. In patients with TSS >20 at baseline (highly symptomatic, n=50; ET:20, PV:30), median TSS was 28.0 (range 20.0 to 62.0); the highest scored symptom was fatigue (median=7.0), itching (median=4.5) and insomnia (median=4.0). Impact of Therapy on Symptom Burden/QoL: On HU, pts experienced worsening QoL (physical, cognitive functioning, HRQoL) and some persistent or transient worsened symptoms (inactivity, concentration (p<0.05) (Table 1)). On PEG, pts experienced worsening of fever, dyspnea, appetite loss and PEG-related symptoms including flu-like symptoms, injection site irritation, blurry vision, and visual changes (all p<0.05), but not sad mood (not corrected for antidepressants). In comparing arms, change in TSS significantly differed (p=0.01) between arms with increasing symptoms on HU vs PEG at 3 and 6 mo, but lower symptom burden at 9 and 12 mos (Figure 1). In highly symptomatic pts (with a baseline TSS > 20, n=50), improvements in weight loss, abdominal discomfort, fatigue, itching, fever, early satiety (12 m.) were observed in pts on HU. For PEG, in highly symptomatic pts, improvements were observed for overall TSS score, fatigue, inactivity, night sweats, and itching (with similar toxicities to all PEG patients). ELN Response and Symptom Burden/QoL: Among the 133 pts with 12-mo symptom data, complete hematologic response (CHR) rate was 43%. Inactivity and sad mood were worse in those patient achieving a CHR (inactivity: CHR worsening 0.68 vs PHR/NR better 0.26; p=0.03; sad mood: CHR worsening 0.67 vs PHR/NR better 0.67, p=0.002)). These latter changes were not related to higher doses utilized (in either arm), suggesting obtaining CHR may have negative effects on patient symptoms. Conclusions:In pts with a significant baseline MPN symptom burden, cytoreductive therapy has both a beneficial impact on baseline MPN symptom burden but also leads to therapy associated toxicity, although different patterns of efficacy and toxicity between HU and PEG. Achievement of a CHR in PV/ET may be associated with higher rates of drug related toxicities, and the value of achieving CHR may need further validation. Disclosures Mesa: Incyte Corporation: Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment; Genentech: Research Funding; Pfizer: Research Funding. Mascarenhas:Merck: Research Funding; CTI Biopharma: 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; Roche: Research Funding; Promedior: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Research Funding. Rambaldi:Omeros: Consultancy; Roche: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Amgen Inc.: Consultancy. Yacoub:Novartis: Honoraria, Speakers Bureau; Cara Therapeutics: Equity Ownership; Ardelyx, INC.: Equity Ownership; Inycte: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Dynavax: Equity Ownership. Harrison:Gilead: Honoraria, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Kiladjian:AOP Orphan: 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, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Mead:Elstar: Research Funding; Celgene: Research Funding; ARIAD: Consultancy; Cell Therapeutics: Consultancy; Evotek: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy. Kessler:Sangamo: Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Research Funding; Dimension Advisory boards: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; DSMB: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Biomarin: Research Funding. Kremyanskaya:Incyte: Research Funding. Rampal:Incyte: Honoraria, Research Funding; Constellation: Research Funding; Jazz: Consultancy, Honoraria; Stemline: Research Funding; Celgene: Honoraria. Hoffman:Incyte: Research Funding; Janssen: Research Funding; Merus: Research Funding; Formation Biologics: Research Funding; Summer Road: Research Funding. Dueck:Pfizer: Honoraria; Bayer: Employment; Phytogine: Employment.

Abstract Background: The Philadelphia chromosome negative myeloproliferative neoplasms (MPN), including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), carry a propensity to evolve into an accelerated phase (MPN-AP, 10-19% blasts in the blood or marrow) and blast phase (MPN-BP, ≥20% in the blood or marrow). Such disease evolution carries a dismal prognosis with a median survival of 3-5 months, and thus the development of innovative treatment strategies represents an urgent unmet clinical need. Responses in patients with MPN-AP/BP to both hypomethylating agents and single-agent ruxolitinib (RUX) have been reported. In vitro, the combination of RUX and decitabine (DEC) are synergistically active in cells derived from patients with MPN-BP and from a murine model of MPN-BP. These observations led us to explore the safety of the combination in MPN-AP/BP in a phase I study. An MTD for RUX in combination with DEC 20mg/m2/d x 5 days was not reached in this study and the recommended Phase II dose of RUX was selected as 25mg BID for the first cycle of therapy followed by 10mg BID in subsequent cycles with a goal to minimize myelosuppression and maintain ambulatory administration (Rampal et al ASH 2016). Here we report the final results of the phase 2 combination of RUX + DEC in patients with MPN-AP/BP (NCT02076191). Methods: We conducted a multicenter, open label, phase II trial in patients with MPN-AP/BP, following a previous diagnosis of ET, PV or PMF. Patients enrolled were treated with the RPTD dose of RUX + DEC on a 28-day cycle until progression of disease, unacceptable toxicity or patient/physician withdrawal. Adverse events (AEs) were assessed using the NCI CTCAE v4.0. The primary endpoint was response rate by cycle 6 using modified Cheson criteria: CR required 0% peripheral blood blasts, ANC >1000/uL, hemoglobin ≥10g/L, and platelets ≥100x109/L; CRi required 0% peripheral blood blasts with incomplete count recovery; and PR required ≥50% decrease in peripheral blood blasts regardless of blood counts. Results: A total of 25 patients were accrued to study. The median age was 71 years (46.7-85.6). 10 patients (40%) had MPN-AP and 15 patients (60%) had MPN-BP. 6 patients (24%) had been previously been treated with single-agent RUX, and 2 patients (8%) had been treated with single-agent DEC. Median palpable spleen size was 7cm (range 0 - 20cm). The median number of cycles of treatment received on study was 4 (range 1 - 20). The most common grade 3/4 non-hematologic AEs observed were pneumonia (16%), febrile neutropenia (16%) and infection (8%). The most common grade 3/4 hematologic AEs were anemia (16%), neutropenia (12%) and leukopenia (8%). The most common reasons for study discontinuation were AEs in 9 patients (36%), disease progression in 5 (20%) patients and hematopoietic cell transplantation in 2 (8%) patients. Eighteen (72%) patients were evaluable for response. The overall response rate (CR+CRi+PR) was 61% (11/18 patients). CRi was observed in 2 patients (11%), PR in 9 patients (50%) and no response in 7 patients (39%). The median time to CR/PR was 3.4 mos (95% CI: 2.1 - not estimated). The median peripheral blood blast count reduction was 80.1% (range 71.4-100%) (Figure 1A). The median reduction in spleen size by palpation was 70.5% (range 0-100%) (Figure 1B). Median overall survival for all patients was 7.6 months (95% CI: 4.3 - Not estimated); 9.7 months (95% CI: 4.3 - Not estimated) for MPN-BP and 5.8 months (95% CI: 3.6 - Not estimated) for MPN-AP (Figure 2). Three patients (17%) were able to proceed to HCT. The results of ongoing genomic, histopathologic and cytokine profiling studies will be available for presentation at the meeting. Conclusions: The combination of RUX+DEC has activity in patients with MPN-AP/BP. The drug combination is generally well tolerated and can be administered as an outpatient, a distinct advantage over intensive induction therapies that have not shown significant benefit in these patients. Additional work is ongoing to assess the genomic and clinical variables predictive of response with this combination therapy approach. Given the tolerability and efficacy, this regimen may be of particular benefit to patients who are not candidates for intensive therapies. Disclosures Rampal: Constellation: Research Funding; Celgene: Honoraria; Stemline: Research Funding; Incyte: Honoraria, Research Funding; Jazz: Consultancy, Honoraria. Mascarenhas:Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Novartis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Promedior: Research Funding. Wang:Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Novartis: Speakers Bureau. Gerds:Celgene: Consultancy; Apexx Oncology: Consultancy; Incyte: Consultancy; CTI Biopharma: Consultancy. Heaney:Roche: Consultancy, Research Funding; Incyte: Research Funding; Blueprint: Research Funding; Novartis: Research Funding; Decipheral: Research Funding. Abboud:Agios: Honoraria; Jazz: Honoraria, Speakers Bureau. Kremyanskaya:Incyte: Research Funding. Odenike:ABBVIE: Honoraria, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI/Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncotherapy Science: Research Funding; Agios: Research Funding; Celgene: Research Funding; NS Pharma: Research Funding; Janssen: Research Funding; Astex: Research Funding; Gilead Sciences: Research Funding. Levine:Roche: Consultancy, Research Funding; C4 Therapeutics: Equity Ownership; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Epizyme: Patents & Royalties; Prelude: Research Funding; Qiagen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Loxo: Consultancy, Equity Ownership; Imago: Equity Ownership; Novartis: Consultancy; Isoplexis: Equity Ownership. Mesa:Novartis: Consultancy; NS Pharma: Research Funding; Genentech: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment; CTI Biopharma: Research Funding; Gilead: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; Incyte Corporation: Research Funding; Promedior: Research Funding. Dueck:Phytogine: Employment; Bayer: Employment; Pfizer: Honoraria. Hoffman:Incyte: Research Funding; Formation Biologics: Research Funding; Janssen: Research Funding; Merus: Research Funding; Summer Road: Research Funding.

Abstract Abstract 4479 Background: In vivo T-cell depletion with antithymocyte globulin (ATG) is known to decrease the incidence of acute and chronic graft vs. host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). However, the detailed patterns of GVHD (incidence, severity, timing, and quality) after ATG-based conditioning have not been examined in large patient cohorts, and it is unknown whether they differ from those seen in patients who do not receive ATG during conditioning therapy. Patients and Methods: We analyzed the incidence and characteristics of acute and chronic GVHD, requirements for immunosuppressive therapy (IST) and survival in a cohort of 174 patients who underwent a first HCT for hematologic malignancy with ATG as a part of their conditioning regimen. The median age was 54 years (range 19–76); all but 5 pts received PBSC, and median follow-up of survivors was 16.9 months (range 3–70 months). Donors were matched related in 18% (n=32), matched unrelated in 44% (n=77), and mismatched unrelated in 37% (n=65). Conditioning regimens were myeloablative in 33% (n=57) and reduced intensity in 67% (n=117). Additional GVHD prophylaxis included tacrolimus in all patients combined with either methotrexate (42%) or MMF (58%). Results: The cumulative incidence of grade II-IV and III-IV acute GVHD at 100 days was 34% and 7%, respectively, with the median time of onset at 43 days (range 11–98 days) after transplant. Eleven patients (6.3%) required additional immunosuppressive treatment due to steroid refractory GVHD. Late/persistent acute GVHD without any evidence of chronic occurred in 25% of patients. NIH chronic GVHD developed in 25 patients, with a cumulative incidence of 24.4% at 2 years. Forty four percent of these patients were classified as classic chronic, and 56% as overlap. The onset of chronic GVHD was quiescent in 20 (80%), progressive in 3 (12%), and de-novo in 2 (8%) patients. The global severity was mild in 9 (36%), moderate in 11 (44%) and severe in 5 (20%) cases. The median time of onset for chronic GVHD was 185 days (range 99–763). In a multivariate analysis of factors predictive for development of chronic GVHD, the only factor associated with development of chronic GVHD was prior grade II-IV acute GVHD (HR 2.5, p =.03). The most common diagnostic organ was mouth (n=16), followed by skin (n=8) and eye (n=1). The median number of sites involved during the course of chronic GVHD was 4 (range 1–7), and the median number of systemic immunosuppressive agents for treatment was 2 (range 0–4). Among the 25 chronic GVHD patients, 5 have discontinued immunosuppression at a median time of 13.1 months (range 6–26) since the diagnosis of chronic GVHD. The cumulative incidence of discontinuation of IST was 23% at one year and 50% at two years. Three deaths in the overall cohort were attributed to complications related to acute (n=2) or chronic GVHD (n=1). At 2 years, the overall survival among all 174 pts was 62.4%, cumulative incidence of relapse was 23.1%, and non-relapse mortality was 22.7%. Conclusion: These data from a large, uniformly treated and graded, predominantly peripheral blood stem cell transplant recipient population, confirm that ATG decreases both the incidence and severity of acute and chronic GVHD. In particular, the rate of moderate to severe chronic GVHD is extremely low, resulting in minimal need for tertiary treatment and decreased duration of immunosupression. Disclosures: No relevant conflicts of interest to declare.