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3032 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:  Results of Myeloproliferative Disorders Research Consortium (MPD-RC) 112 Global Phase III Trial

Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical: Poster II
Hematology Disease Topics & Pathways:
apoptosis, Biological, Bleeding Disorders, Diseases, Adult, Therapies, Biological Processes, MPN, Polycythemia vera, Platelet Disorders, immunotherapy, thrombocythemia, Study Population, erythropoiesis, Clinically relevant, Myeloid Malignancies, Thrombocytopenias, hematopoiesis, immune mechanism, inflammation
Sunday, December 2, 2018, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Ruben A. Mesa, MD, FACP1, Heidi E. Kosiorek, MS2*, John Mascarenhas, MD3, Josef T. Prchal, MD4, Alessandro Rambaldi, MD5, Dmitriy Berenzon, MD6*, Abdulraheem Yacoub, MD7, Claire N. Harrison, MD, DM, FRCP, PRCPath8, Mary Frances McMullin, MD9, Alessandro M. Vannucchi, MD10, Joanne Ewing, PhD, BMBS, BSc, FRPATH,11*, Casey L. O'Connell, MD12, Jean-Jacques Kiladjian, MD, PhD13, Adam J. Mead, MD, PhD14, Elliott F. Winton, MD15, David S. Leibowitz, MD16, Valerio De Stefano, MD17*, Murat O. Arcasoy, MD18, Craig M. Kessler, MD19, Rosalind Catchatourian, MD20, Damiano Rondelli, MD21, Richard T. Silver, MD22, Andrea Bacigalupo, MD23, Arnon Nagler, MD24, Marina Kremyanskaya, MD, PhD25*, Lonette Sandy25*, Mohamed E. Salama, MD26, Vesna Najfeld, PhD27, Joseph Tripodi28*, Rona Singer Weinberg, PhD29, Raajit K. Rampal, MD, PhD30, Ronald Hoffman, MD25 and Amylou C. Dueck, PhD31

1UT Health San Antonio Cancer Center, San Antonio, TX
2Department of Biostatistics, Mayo Clinic, Scottsdale, AZ
3Icahn School of Medicine at Mount Sinai, New York, NY
4Division of Hematology and Hematologic Malignancies, University of Utah & The Huntsman Cancer Center, Salt Lake Cty, UT
5Hematology and Bone Marrow Transplantation Unit, ASST Papa Giovanni XXIII, Bergamo, Italy
6Comprehensive Cancer Center, Wake Forest Baptist Health, Comprehensive Cancer Center, Wake Forest Baptist Health, Winston Salem, NC
7Kansas University Cancer Center, Leawood, KS
8Department of Haematology, Guy's Hospital, London, United Kingdom
9Queen's University Belfast, Belfast, United Kingdom
10CRIMM; Center Research and Innovation of Myeloproliferative Neoplasms, AOUC, University of Florence, Firenze, Italy
11Heart of England NHS Foundation Trust, UHB, Birmingham, GBR
12University of Southern California, Keck School of Medicine, Los Angeles, CA
13INSERM U1131, Hopital Saint-Louis, Paris, France
14Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
15Winship Cancer Institute Emory Univ. School of Med., Atlanta, GA
16Oncology Department, Palo Alto Medical Foundation Sutter Health, Cupertino, CA
17Hematology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
18Duke University School of Medicine, Durham, NC
19Georgetown University Medical Center, Washington, DC
20Oncology Department, John H Stroger Jr. Hospital of Cook county Chicago, Illinois, Chicago
21Division of Hematology/Oncology, University of Illinois at Chicago, Chicago, IL
22Richard T. Silver Myeloproliferative Neoplasms Center, NewYork-Presbyterian Weill Cornell Medical Center, New York, NY
23Institute of Hematology, Università Cattolica del Sacro Cuore - Policlinico A. Gemelli, Roma, Italy
24Hematology Department, Chaim Sheba Medical Center, Tel Hashomer, Israel
25Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
26Mayo Medical Laboratories, Rochester, MN
27Division of Hematology/Medical Oncology/Pathology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai; Myeloproliferative Neoplasm Research Consortium (MPN-RC), New York, NY
28Division of Hematology/Medical Oncology/Pathology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
29New York Blood Center, New York, NY
30Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center; Myeloproliferative Neoplasm Research Consortium (MPN-RC), New York, NY
31Department of Biostatistics, Mayo Clinic Arizona, Scottsdale, AZ

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, Travel Support (EHA 2018); Sensei: Other: Advisory Board; Sierra Oncology: Consultancy, Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Other: Advisory Board; Onconova: Membership on an entity's Board of Directors or advisory committees; NS Pharma: Research Funding; Gilead: Research Funding; H3 Biosciences: Other: Research Funds (to institutions not investigator); Janssen: Other: Travel Support (EHA 2018); Pfizer: Other: Advisory Board, Research Funding; Celgene: Other: Research Funds (to institutions not investigator), Research Funding; Otsuka: Other: Advisory Board; Genentech: Research Funding; Promedior: Research Funding; CTI Biopharma: 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: Hylapharm: Equity Ownership; Novartis: Honoraria, Speakers Bureau; Dynavax: Equity Ownership; Cara Therapeutics: Equity Ownership; Ardelyx, INC.: Equity Ownership; Seattle Genetics: Honoraria, Speakers Bureau; Inycte: Honoraria, Speakers Bureau. 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: Novartis: Other: Provided Ruxolitinib ; AOP Orphan: 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; Hoffmann-La Roche AG: Other: Provided Pegylated Interferon Alpha 2a; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. 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: Dimension Advisory boards: Membership on an entity's Board of Directors or advisory committees; 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; Biomarin: Research Funding; 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; Novo Nordisk: Honoraria, Research Funding; Sangamo: 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.

*signifies non-member of ASH