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4271 Impact on MPN Symptoms and Quality of Life of Front Line Pegylated Interferon Alpha-2a Vs. Hydroxyurea in High Risk Polycythemia Vera and Essential Thrombocythemia: Interim Analysis Results of Myeloproliferative Disorders Research Consortium (MPD-RC) 112 Global Phase III Trial

Myeloproliferative Syndromes: Clinical
Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical: Poster III
Monday, December 5, 2016, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Ruben A. Mesa, MD1, Ronald Hoffman2, Heidi E. Kosiorek, MS3*, Josef T. Prchal, MD4, Claire N. Harrison, DM, FRCP, FRCPath5, Mary Frances McMullin, MD6, Abdulraheem Yacoub, MD7, Alessandro Rambaldi, MD8, Dmitriy Berenzon, MD9*, Alessandro M. Vannucchi, MD, PhD10, Joanne C Ewing, PhD, BMBS, BSc, FRPATH,11*, Casey L O'Connell, M.D.12, Jean-Jacques Kiladjian, MD, PhD13, Adam Mead, MD, PhD14*, Elliott F. Winton, MD15, David S. Leibowitz, MD16, Valerio De Stefano, MD17*, Murat O. Arcasoy, MD18, Craig M. Kessler, MD19, Rosalind Catchatorian20*, Damiano Rondelli, MD21, Richard T. Silver, MD22, Ellen K. Ritchie, MD23, Arnon Nagler24, Marina Kremyanskaya, MD PhD25, Richard F. Schlenk, MD26, Rona Singer Weinberg, PhD27, Mohamed E Salama, M.D.28, Gianni Tognoni29*, Giuseppe Prosperini29*, Alessandra Di Lelio29*, Eliseo Serone29*, Lorenzo Marfisi29*, Alicia Orellana, MEd30*, Tiziano Barbui, MD31*, Amylou C. Dueck, PhD3 and John O. Mascarenhas, MD, MS32

1Mayo Clinic, Scottsdale, AZ
2Division of Hematology and Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
3Mayo Clinic Cancer Center, Phoenix, AZ
4Division of Hematology, University of Utah, Salt Lake City, UT
5Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom
6Queen's University Belfast, Belfast, United Kingdom
7University of Kansas Medical Hospital, Westwood, KS
8Hematology and Bone Marrow Transplant Unit, University of Milan, ASST Papa Giovanni XXIII, Bergamo, Italy
9Comprehensive Cancer Center, Wake Forest School of Medicine, WINSTON SALEM, NC
10Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
11Heart of England NHS Foundation Trust, Birmingham, United Kingdom
12Norris Comprehensive Cancer Center, Jane Anne Nohl Division of Hematology, University of Southern California, Los Angeles, CA
13Hôpital Saint-Louis and Paris Diderot University, Paris, France
14MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
15Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA
16Palo Alto Medical Foundation, Palo Alto, CA
17Hematology, Catholic University, Rome, Italy
18Duke University Health System, Durham, NC
19Lombardi Cancer Center, Washington, DC
20John.H.Stroger hospital, chicago
21Division of Hematology/Oncology, University of Illinois at Chicago, Chicago, IL
22Department of Hematology/Medical Oncology, Weill Cornell Medicine, New York, NY
23Weill Cornell Medical College, New York, NY
24Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-HaShomer, Ramat Gan, Israel
25The Myeloproliferative Research Consortium, The myeloproliferative Program, Tisch Cancer Institute, Icahn Schoool of Medicine at Mount Sinai, New York, NY
26Department of Internal Medicine III, University of Ulm, Ulm, Germany
27NY Blood Center, White Plains, NY
28Department of Pathology, University of Utah, Salt Lake City, UT
29Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
30Icahn School of Medicine at Mount Sinai, New York, NY
31Research Foundation (FROM) Hospital Papa Giovanni XXIII, Bergamo, Italy
32Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY

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: Amgen: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AROG: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Pfizer: Honoraria, 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.

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