Rondelli, Damiano

Abstract Background: Sickle cell disease (SCD) is a life-limiting inherited hemoglobinopathy that results in significant complications and affects quality of life. Hematopoietic stem cell transplantation (HSCT) is currently the only curative intervention for SCD; however, guidelines are needed to inform how to apply HSCT in clinical practice. Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and health professionals in their decisions about HSCT for SCD. Methods: The multidisciplinary guideline panel formed by ASH included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Mayo Evidence-Based Practice Research Program supported the guideline development process, including performing systematic evidence reviews (through 2019). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 8 recommendations to help patients and providers assess how individuals with SCD should consider the timing and type of HSCT. Conclusions: The evidence review yielded no randomized controlled clinical trials for HSCT in SCD; therefore, all recommendations are based on very low certainty in the evidence. Key recommendations include considering HSCT for those with neurologic injury or recurrent acute chest syndrome at an early age and to improve nonmyeloablative regimens. Future research should include the development of a robust SCD registry to serve as a comparator for HSCT studies.

Background Interferons are recognized as active agents in the treatment of patients with high risk essential thrombocythemia (ET) or polycythemia vera (PV), both in the upfront setting as well as beyond. Several trials have shown high rates of hematologic and molecular responses with the use of interferons, however, data on direct comparison of interferon activity in patients with early disease in comparison to patients refractory or resistant to prior therapies, such as hydroxyurea (HU) are lacking. We conducted a controlled analysis of the activity of pegylated interferon alfa-2a (PEG) in two prospective parallel clinical trials conducted in these two unique patient populations. Methods The MPD-RC 111 (NCT01259817) was an international, multicenter, phase 2 open-label clinical trial that evaluated PEG therapy in patients with high risk PV and high-risk ET who were either refractory or intolerant (R/I) to HU by modified ELN criteria. The MPD-RC 112 trial (NCT01258856) enrolled patients with high risk ET/PV who were treatment-naïve (TN) (HU <3 months) and randomized them (1:1) to PEG or HU. All patients randomized to PEG were included in this analysis. Both protocols were conducted concurrently at the MPD-RC member institutions and utilized a similar primary endpoint of overall response rate (complete and partial response rates) by ELN Criteria at 12 months confirmed by the same blinded central review committee. Both studies utilized the same PEG starting dose of 45 mcg weekly and was titrated for response to a maximum of 180 mcg weekly. Secondary endpoints included safety information, impact on disease biomarkers, bone marrow (BM) response, and quality of life data. Results Patients ET: 39 TN and 65 R/I ET patients were available for this analysis. Median disease duration was 2.9 months in TN and 37.3 months in R/I patients. Baseline characteristics and demographics were similar in the two cohorts except lower baseline hemoglobin level in RI patients. (Table1A) PV: 43 TN and 50 R/I PV patients were included. Median disease duration was 2.5 months in TN and 54.8 months in R/I patients. Baseline characteristics only differed by lower frequency of phlebotomy rate in R/I patients. (Table1B) Baseline symptoms scores and quality of life were similar in TN and RI groups (Table 2) Response ET: CR/PR/ORR at 12 months were observed in 43.1%/26.2%/69.2% in R/I ET patients and in 43.6%/25.6%/69.2% in TN ET patients (p=0.99 for ORR). (Table 3, Figure 1) PV: CR/PR/ORR at 12 months were observed in 22%/38%/60% in R/I PV patients, and in 27.9%/58.1%/86% in TN PV patients (p=0.005 for ORR). (Table 3, Figure 1) Safety PEG was equally well tolerated throughout both treatment groups with treatment discontinuation due to adverse events occurring in 14.6% in TN patients and 13.9% in R/I patients. The mean (SD) dose of PEG was 102.7 (52.3) mcg in R/I ET patients and 128.7mcg (46.4) in R/I PV patients. For TN patients, mean dose was 85.7mcg (59.7) in ET and 93.5 mcg (44.0) in PV. Adverse events were consistent with historic reports of PEG use and the distribution of events was similar in R/I and TN patients. (Table 4) Conclusion This intention to treat response analysis included TN and R/I ET and PV patients with balanced baseline characteristics who received prospective therapy with PEG. Patients with ET had a higher overall response rate at 12 months that was equivalent in patients who were treatment-naïve and in patients who were intolerant or refractory to HU. By contrast, patients with PV who were treatment-naïve had a higher ORR than patients those intolerant or refractory to HU. We conclude that treatment with PEG is an effective therapeutic option both treatment naïve PV and ET as well as those previously treated with HU, however PEG as a second line agent is especially effective in ET patients. Disclosures Yacoub: Hylapharm: Equity Ownership; Agios: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Ardelyx: Equity Ownership; Cara: Equity Ownership; Dynavax: Equity Ownership. Mascarenhas:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche: Consultancy, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merus: Research Funding. Mesa:AbbVie: Research Funding; Samus: Research Funding; Incyte: Research Funding; Sierra Onc: Consultancy; Genotech: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; CTI Biopharma: Research Funding; La Jolla Pharma: Consultancy. Rampal:Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy; Constellation, Incyte, and Stemline Therapeutics: Research Funding. Silver:PharmEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. McMullin:Daiko Sanyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Italopharma: Membership on an entity's Board of Directors or advisory committees. Ewing:Novartis: Honoraria, Other: Meeting attendance sponsorship ; Bristol Myers-Squibb: Other: Meeting attendance sponsorship . O'Connell:Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Mead:Bristol Myers-Squibb: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; CTI: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Pfizer: Consultancy. De Stefano:Alexion: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Baer:Astellas: Research Funding; Al Therapeutics: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Forma: Research Funding; Kite: Research Funding; Takeda: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kremyanskaya:La Jolla: Consultancy; Incyte, Celgene, Constellation, Protagonist.: Research Funding. Hexner:novartis: Research Funding. Rambaldi:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, travel support. Ritchie:Genentech: Other: Advisory board; Tolero: Other: Advisory board; agios: Other: Advisory board; Pfizer: Other: Advisory board, travel support; Celgene: Other: Advisory board; Jazz Pharmaceuticals: Research Funding; Celgene, Novartis: Other: travel support; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; Celgene, Incyte, Novartis, Pfizer: Consultancy. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Celgene: Consultancy. Harrison:Promedior: Honoraria; Incyte: Speakers Bureau; Sierra Oncology: Honoraria; Celgene: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; CTI: Speakers Bureau; AOP: Honoraria; Shire: Speakers Bureau; Roche: Honoraria; Gilead: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Hoffman:Merus: Research Funding. OffLabel Disclosure: Pegylated Interferon Alfa-2a for in Patients with Polycythemia Vera or Essential Thrombocythemia

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 Introduction HU is the treatment of choice for patients (pts) with high risk ET/PV, however, PEG has been proposed as an alternative option due to its proposed potential to modify disease course. An interim analysis of MPN-RC 112 (Blood 2016 128:479;) did not reveal a difference in PR/CR rates between HU and PEG therapy after 12 months in the first evaluable 75 pts treated. Here we present the results and long-term follow-up of all pts participating in this pivotal study [NCT01259856]. Methods MPN-RC 112 was a randomized, open label, phase 3 clinical trial comparing HU and PEG in pts with high risk ET/PV. Pts were treated for up to 12 months to achieve PR or CR (ELN/IWG-MRT response criteria). Pts who achieved a PR/CR continued therapy for up to a maximum of 6 years. Minimum follow up was 1 year from the time the last pt was randomized. The primary objective was to compare the CR rate following HU vs. PEG at 12 months with 3 month confirmation. Secondary objectives included a comparison of toxicity and tolerability; PR rates; incidence of specific pre-defined toxicities and tolerance to therapy; impact of therapy on key biomarkers; survival and incidence of myelodysplastic syndrome, myelofibrosis, or leukemic transformation; and incidence of major cardiovascular events. Bone marrow pathologic responses were evaluated by central blinded expert review at baseline, 12, 24 months and end of study. Results The study accrued 168 pts; 86 were randomized to HU and 82 to PEG. A summary of pt baseline characteristics by treatment arm is shown in Table 1 and were well balanced between the treatment arms except for median age which was higher in the HU arm (p=0.02). Median duration of follow up was 89.9 weeks (range, 0 to 292.3) and the median treatment duration was 86.0 weeks (range, 0 to 287.3). At 12 months, the overall response rate (ORR= PR+CR) was 69.8% and 78% for HU and PEG, respectively (p=0.22). Figure 1 shows the distribution of responses stratified by disease type. At 24 months, 59 pts were on treatment with an ORR of 22/25 (88%) for HU and 31/34 (91%) for PEG. When considering all 106 pts who were eligible to receive treatment for 24 months (due to study closure), the ORR was 22/54 (40.7%, PR: 11 (20.4%), CR: 11 (20.4%)) for HU and 31/52 (59.6%, (PR: 15 (28.9%), CR: 16 (30.8%)) for PEG, p=0.04. Best ORR at any time on study was seen in 70.9% and 81.7% of HU and PEG treated pts, respectively, p=0.10. The median maximum change from baseline spleen volume was -6% (-100.0 - +53.8) in 112 evaluable pts and was similar between arms, p=0.99. Bone marrow morphologic responses are shown in Table 2 and the best response (CR) seen at any time on study for ET treated with HU was 52% (12/23) vs PEG 32% (8/25) and for PV treated with HU 19% (6/31) vs PEG 6% (2/34). Cytogenetic analyses at diagnosis were available in 86% (144/168). An abnormal karyotype was seen in 15% (22/144). Five PV and one ET pt lost their chromosomal abnormalities: 3 after one year (HU=1, PEG=2) and three after two years of therapy (HU=2, PEG=1). AE information is available for 162 pts (HU: 80; PEG: 82) (Table 3). Six pts randomized to HU never received treatment due to study withdrawal prior to initiation of treatment. Sixty pts had a grade 3 or higher event [HU: 22 (27.5%) and PEG: 38 (46.3%)]. 28 PV pts had a grade 3/4 [HU: 10 (24.4%) and PEG: 18 (41.9%)]. Four pts had a grade 4/5 event [HU: 3 (7.3%) and PEG: 1 (2.3%)]. 32 ET pts had a grade 3/4 [HU:12 (30.8%) and PEG:20 (51.3%)]. Two pts had a grade 4/5 event [HU:1 (2.6%), PEG:1 (2.6%)]. Additional outcomes of interest on study include one death attributed to new diagnosis of lung cancer (HU:1), progression to myelofibrosis (HU:1), vertebral artery occlusion (HU:1), and cerebral vascular accident (PEG:1). Reasons for study discontinuation are shown in Table 4. The effect of therapy on symptom burden and quality of life will be presented in a companion abstract (Mesa et al). The impact of mutation status on therapeutic outcome as well as the molecular responses will be presented at the meeting. Conclusion The final analysis of MPN-RC 112 revealed that the CR rates in pts with high risk ET/PV treated with PEG and HU at 12 and 24 months were similar. PEG was associated with a higher rate of grade 3/4 toxicity. Each drug appeared equally capable of modifying the natural history of high risk ET/PV based upon their effects on spleen size, karyotypic abnormalities, histopathological parameters and the low incidence of thrombotic complications and disease evolution in both arms. Disclosures Mascarenhas: Novartis: Research Funding; Promedior: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Merck: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rambaldi:Amgen Inc.: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Omeros: Consultancy; Roche: Consultancy; Celgene: Consultancy. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead: Honoraria, 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:Bristol-Myers Squibb: Consultancy; Elstar: Research Funding; Celgene: Research Funding; ARIAD: Consultancy; Evotek: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Cell Therapeutics: Consultancy. Kessler:Genentech: Research Funding; Sangamo: Research Funding; Bayer: 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; Biomarin: Research Funding; Octapharma: 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; Novo Nordisk: Honoraria, Research Funding; Dimension Advisory boards: Membership on an entity's Board of Directors or advisory committees. Kremyanskaya:Incyte: Research Funding. Rampal:Stemline: Research Funding; Incyte: Honoraria, Research Funding; Constellation: Research Funding; Jazz: Consultancy, Honoraria; Celgene: Honoraria. Mesa:CTI Biopharma: Research Funding; Novartis: Consultancy; Genentech: Research Funding; Promedior: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment; Pfizer: Research Funding; Celgene: Research Funding; Incyte Corporation: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding. Dueck:Pfizer: Honoraria; Bayer: Employment; Phytogine: Employment. Hoffman:Incyte: Research Funding; Formation Biologics: Research Funding; Merus: Research Funding; Janssen: Research Funding; Summer Road: Research Funding.

Abstract Background: Patients (pts) with polycythemia vera (PV) and essential thrombocythemia (ET) suffer from disease related events linked to risk of vascular events, splenomegaly, progression to myelofibrosis/acute leukemia, and disease related symptoms arising from both elevated cytokines and issues of vascular flow. Impact of front line therapy on ET/PV symptoms has not been reported in a systematic fashion. Methods: MPD-RC 112 trial (NCT01258856) enrolled cytoreductive therapy naïve (hydroxyurea [HU] <3 mo) pts with high risk ET or PV within 3 years of diagnosis. Pts were randomized (1:1, stratified by ET vs PV) to either response adjusted pegylated interferon alpha 2a (PEG) or HU. MPN symptoms, treatment toxicities, and quality of life (QoL) were measured by the MPN-SAF and EORTC QLQ-C30 at baseline and 3, 6, 9, and 12 mo. PEG related toxicities were assessed with 5 questions on PEG arm only. European Leukemia Net (ELN) complete hematological responses (CHR) at 12 mo were determined by central blinded review. Individual time point and longitudinal group comparisons were based on mixed models adjusting for age. T-tests were used to compare change scores at 12 mo between pts with and without CHR. Results: Patients: MPD-RC 112 enrolled 168 pts from 9/2011 to 7/2016, with 75 pts included in the interim analysis. 73 (97%; HU 37, 95%; PEG 36, 100%) completed surveys at baseline of which 66 (90%; HU 30, 81%; PEG 36, 100%) completed at least 1 survey during treatment. Median age was 60 (range 19-84) with 32 (44%) females; 30 (41%) / 43 (59%) with ET / PV; 19 (26%) had a history of thrombosis; and 16 (22%) had palpable spleen. Baseline characteristics where balanced between arms with the exception of age (median age: HU 66, PEG 54; p<0.001). Baseline Symptom Burden/QoL: Mean MPN-SAF Total Symptom Score (TSS, scale 0 [absent]-100 [worst imaginable]) was 15.4 (SD 12.5; range 0-52.2) with means of 12.6 (SD 11.7) / 17.3 (SD 12.7) for ET / PV which were somewhat better than reported means of a previous cohort receiving any line of treatment (ET mean 18.7, SD 15.3; PV mean 21.8, SD 16.3; Emanuel RM, JCO 2012). Symptoms (scale 0 [absent]-10 [worst imaginable]) with the highest prevalence (score >0) included fatigue (65/73, 89%) and insomnia (47/73, 64%). The symptom with the lowest prevalence was fever (8/72, 11%). Mean QLQ-C30 global health status/QoL (GHS/QoL) was 73.3 (SD 19.1) which is comparable to a general healthy 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). TSS, symptoms, and QoL did not differ between arms. Impact of Therapy on Symptom Burden/QoL: On HU, pts initially experienced worsening of TSS, fatigue, early satiety, itching, bone pain, and fever (all p<0.05) with some symptoms returning to baseline after 6 mo (Table 1). On PEG, pts experienced improved abdominal pain and discomfort, but worsening of headache, cough, injection site irritation, blurry vision, and vision change (all p<0.05). Sad mood did not worsen on PEG, although this may be confounded by concurrent use of mood stabilizers. Concentration problems on PEG were significantly worse at 9 mo (p=0.04). Both arms experienced worsened QoL (MPN-SAF single item: HU p=0.009, PEG p=0.003). In comparing between arms, TSS significantly differed (p=0.009) with higher symptoms on HU vs PEG at 3 and 6 mo, but lower symptoms at 9 and 12 mo (Figure 1). Similar descriptive profiles were observed for most individual symptoms; however, the only symptom profiles which significantly differed between arms was early satiety (p=0.03). ELN Response and Symptom Burden/QoL: Among 62 pts with symptom and response data at 12 mo, CHR rate was 37% (23/62). Change in sad mood and sexuality were the only significant differences between pts with and without CHR regardless of arm though in the unanticipated direction (sad mood: mean change 1.5 vs -0.8, p<0.001; sexuality: mean change 2.33 vs 0.3, p=0.03). Conclusions: PEG was associated with an initial decrease in MPN symptom burden when compared to HU. However, with longer duration of therapy, this superiority dissipated. Patient-reported PEG toxicities worsened over time. On both arms, symptom worsening was observed in pts achieving an ELN CHR, possibly leading to the observed negative impact on mood and sexuality. Future research on the impact of PEG on disease progression and molecular features will be important to assess whether increased side effects with PEG are justified. Disclosures Mesa: CTI: Research Funding; Celgene: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Harrison:Incyte Corporation: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. McMullin:Novartis: Honoraria, Speakers Bureau. Yacoub:Alexion: Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mead:Novartis: Honoraria, Research Funding, Speakers Bureau. Kessler:Pfizer: Consultancy; Octapharma: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Grifols: Consultancy; Genentech: Consultancy, Research Funding; Biogen: Consultancy; Bayer: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; LFB: Other: Member of DSMB. Ritchie:Pfizer: Honoraria; Novartis: Honoraria; Arian: Speakers Bureau; Celgene: Speakers Bureau; Incyte: Speakers Bureau. Schlenk:Pfizer: Honoraria, Research Funding; Amgen: Research Funding. Mascarenhas:Promedior: Research Funding; Janssen: Research Funding; CTI Biopharma: Research Funding; Novartis: Other: DSMB , Research Funding; Roche: Research Funding; Incyte: Other: Clinical Trial Steereing Committee, Research Funding.

Abstract Introduction: The impact of genomic alterations, such as mutations in ASXL1, on the risk of disease progression and leukemic transformation in patients with myelofibrosis (MF) is well established. Further, emerging data suggests that the number and type of mutations may impact response to therapies such as ruxolitinib or imetelstat. Allogeneic hematopoietic stem cell transplant (allo-HSCT) remains the only potentially curative treatment for MF patients. However, the impact of somatic mutations on overall survival (OS) and relapse-free survival (RFS) is poorly understood. Using next-generation sequencing of pre-transplant blood and bone marrow samples from a well clinically-annotated cohort of MF patients who underwent allo-HSCT, we sought to determine the impact of mutational burden on outcomes. Methods: A multicenter retrospective analysis of a cohort of 84 patients was carried out. This included 52 patients treated on the MPD-RC 101 prospective study (NCT00572897), 18 patients treated at Prince Margaret Hospital, and 14 patients treated at Memorial Sloan Kettering Cancer Center. Patient and transplant characteristics are displayed in Table 1. DNA was extracted from pre-transplant bone marrow aspirate samples or peripheral blood samples. High-throughput sequencing of a panel of genes was performed. Average coverage of 829x (standard deviation of ±130) was obtained. Mutect was utilized to call single point variants (comparing our samples to a pool of normal samples) and PINDEL was used to call short insertions and deletions. We excluded all mutations present in at least one database of known non-somatic variants (DBSNP and 1000 genomes) and absent from COSMIC. Univariate Cox regression and Kaplan-Meier graphics were used to investigate the association of patient, transplant, and disease characteristics with OS and RFS. Results: JAK2V617F was the most frequent mutation detected in 41(48.8%) patients (Table 2). Eighteen patients (21.4%) had triple negative disease (negative for JAK2, MPL, and CALR mutations). Univariate analysis included the following: patient characteristics (age, gender), transplant characteristics (related vs. unrelated donor, matched vs. mismatched donor and myeloablative vs. reduced intensity conditioning) and disease characteristics (DIPSS and presence of mutations). Decreased OS was associated with unrelated donor status (HR 2.09, 95% CI: 1.03-4.23, p=0.04), reduced intensity conditioning (HR 4.21, 95% CI: 1.01-17.59, p=0.049), triple negative disease (HR 2.09, 95% CI: 1.02-4.30, p=0.04), and presence of U2AF1 (HR 2.53, 95% CI: 1.10-5.81, p=0.03) or SUZ12 mutations (HR 3.92, 95% CI: 1.19-12.21, p=0.02). Decreased RFS was associated with unrelated donor status (HR 2.27, 95% CI: 1.16-4.45, p=0.02), and the presence of SUZ12 mutation (HR 6.97, 95% CI: 2.37-20.49, p<0.001). A descriptive decrease in RFS in patients with U2AF1 (HR 2.15, 95% CI: 0.94-4.88, p=0.07) was observed but did not reach statistical significance. Importantly, mutations previously reported to be associated with reduced OS and RFS in the non-transplant setting, such as ASXL1, EZH2, IDH1/2, and SRSF2, were not associated with poorer outcomes in this analysis in transplanted patients. In an exploratory multivariate analysis including donor type (related vs. unrelated) and presence of U2AF1 and SUZ12 mutations, there was a significantly reduced OS and RFS in patients who harbor these mutations regardless of donor type (OS: HR 5.30, 95% CI: 2.08-13.47, p<0.001; RFS: HR 5.49, 95% CI: 2.27-13.30, p<0.001). In patients without the above mutations, having an unrelated donor was associated with worse OS (HR 2.55, 95% CI: 1.09-5.96, p=0.03) and RFS (HR 2.61, 95% CI: 1.17-5.83, p=0.02, Figure 1). Conclusions: Our analysis demonstrates that mutations previously associated with poor prognosis in MF, such as ASXL1, do not appear to confer a worsened prognosis in patients undergoing allo-HSCT, suggesting transplant may be able to overcome the impact of these mutations. However, mutations in SUZ12 and U2AF1 are associated with reduced OS in univariate and multivariate analysis (together with donor type). Further studies with larger cohorts of patients are indicated to validate these findings, and to elucidate the impact of these mutations on disease biology. Disclosures Rampal: Incye and CTI: Consultancy. Mascarenhas:Janssen: Research Funding; CTi Biopharma: Research Funding; Promedior: Research Funding; Merk: Research Funding; Incyte: Research Funding. Mesa:Galena: Consultancy; Gilead: Research Funding; Promedior: Research Funding; Incyte: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding; Ariad: Consultancy; Novartis: Consultancy. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding.

Abstract Background: Cytoreductive therapy with hydroxyurea (HU) has been considered first line therapy for patients with high risk polycythemia vera (PV) and essential thrombocythemia (ET) since the results of the PVSG-08 trial demonstrated thrombotic risk reduction (Fruchtman SM et al 1997) for PV and PT1 for ET (Harrison CN et al 2005). Although HU is well tolerated by most patients and has been shown to reduce thrombotic risk in this setting, concern regarding the leukemogenic potential of this oral ribonucleotide reductase inhibitor balanced by the observation of molecular responses with interferon-α (IFN-α) led us to compare the clinical response and tolerability of pegIFN-α (PEG) and HU in a global, randomized, phase III trial. Methods : MPD-RC 112 trial (NCT01258856) enrolled patients with high risk (age >60 years, history of thrombosis, extreme thrombocytosis, symptomatic splenomegaly, uncontrolled cardiovascular risk factors), newly diagnosed (<5 years), WHO defined ET/PV that were treatment naïve (HU <3 months) and randomized (1:1) to PEG or HU. The primary endpoint was complete hematologic response (CHR) rate by European LeukemiaNet (ELN) criteria between the arms after 12 months of therapy. A planned interim analysis based on intent-to-treat with testing boundaries for efficacy and futility was conducted after 75 patients were on study for 12 months. Response assessment by ELN criteria were conducted by blinded review by 4 investigators (JM, RAM, AY, RH). Intent-to-treat analysis was conducted for efficacy endpoints (HU n=39; PEG n=36). Safety analysis included all patients who received treatment (HU n=36; PEG n=36). Results: Patients: The MPD-RC 112 trial involved 24 centers in 6 countries; enrollment began 09/2011 and concluded 7/2016 prior to full accrual due to study drug availability with 168 patients enrolled (Table 1 for 75 patients in the interim analysis). There was no imbalance between arms with respect to history of thrombosis, erythromelalgia, diabetes, hypertension, but age was significantly older on HU. This remained true when analyzing by ET/PV disease strata with the exception of diabetes which was slightly imbalanced within the PV cohort (HU 5/23, 22%; PEG 0/21, 0%; p<0.05). Response: CHR and PHR were observed in 13 (33%) and 14 (36%) patients for an overall response rate (ORR) of 69% (27/39) for HU, and 10 (28%) and 19 (53%) for an ORR of 81% (29/36) for PEG (CHR comparison p=0.60 based on z-test which did not cross either testing boundary). 10 patients randomized to HU were not evaluable for 12-month response due to never initiating treatment (n=3) or early study discontinuation for AEs (n=1), patient withdrawal (n=5), or treatment non-compliance (n=1). 3 patients were not evaluable for response on PEG due to early study discontinuation for AEs (n=1), physician decision (n=1), or patient withdrawal (n=1). Excluding patients who never initiated treatment did not impact the primary endpoint comparison (HU 13/36, 36%; PEG 10/36, 28%; p=0.45). For ET, CHR and PHR were observed in 7 (44%) and 4 (25%) patient on HU, and 6 (40%) and 6 (40%) for PEG (CHR comparison p=0.83). For PV, CHR and PHR were observed in 6 (26%) and 10 (44%) patients on HU, and 4 (19%) and 13 (62%) for PEG (CHR comparison p=0.58). Normalization of spleen by palpation at 12 months was seen in 2/7 (29%) and 5/7 (71%) of the HU and PEG treated patients with palpable spleen at baseline, respectively. Among 38 PV patients, rate of phlebotomy use at 12 months was 0/18 (0%) vs 5/20 (20%) on HU and PEG (p=0.02). From baseline to best score through 12 months, 9/28 (32%) and 12/34 (35%) patients with data on HU and PEG, respectively, had a ≥50% reduction in MPN-SAF Total Symptom Score (p=0.79). Toxicity: No Grade 4 AEs occurred in either treatment arm. Overall, Grade 3 AEs occurred in 5/36 (14%) HU patients and 16/36 (44%) PEG patients (Grade 3 hematologic: 4/36 [11%] HU vs 8/36 [22%] PEG; Grade 3 non-hematologic: 5/36 [14%] HU vs 16/36 [44%] PEG). See Table 2 for Grade 3 AEs regardless of attribution occurring in >10% of patients in either arm. Conclusions: This interim analysis does not show a clear difference in primary endpoint of CHR between HU and PEG. A comparative analysis of the quality of life and symptom burden will provide further insight into the tolerability of these agents (Mesa et al ASH 2016). The final results of this pivotal trial will provide necessary data required to firmly establish the optimal first line therapy for patients with high risk ET/PV. Disclosures Mascarenhas: CTI Biopharma: Research Funding; Janssen: Research Funding; Promedior: Research Funding; Roche: Research Funding; Novartis: Other: DSMB , Research Funding; Incyte: Other: Clinical Trial Steereing Committee, Research Funding. Mesa:Celgene: Research Funding; Promedior: Research Funding; CTI: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Yacoub:Alexion: Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau. Harrison:Baxaltra: Consultancy, Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. McMullin:Novartis: Honoraria, Speakers Bureau. Vannucchi:Novartis: Honoraria, Speakers Bureau. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mead:Novartis: Honoraria, Research Funding, Speakers Bureau. Kessler:Incyte: Honoraria. Ritchie:Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Consultancy, Research Funding; Astellas Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding; NS Pharma: Research Funding. Schlenk:Amgen: Research Funding; Pfizer: Honoraria, Research Funding.

Yacoub et al report excellent responses to pegylated interferon alfa-2a in patients with hydroxyurea-resistant/intolerant polycythemia vera or essential thrombocythemia.