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577 Results of the Myeloproliferative Neoplasms - Research Consortium (MPN-RC) 112 Randomized Trial of Pegylated Interferon Alfa-2a (PEG) Versus Hydroxyurea (HU) Therapy for the Treatment of High Risk Polycythemia Vera (PV) and High Risk Essential Thrombocythemia (ET)

Program: Oral and Poster Abstracts
Type: Oral
Session: 634. Myeloproliferative Syndromes: Clinical: Interferon Therapy and Mutational Analysis in the MPNs
Hematology Disease Topics & Pathways:
Adult, Diseases, Biological, Therapies, Biological Processes, MPN, Technology and Procedures, Polycythemia vera, thrombocythemia, immunotherapy, Study Population, Clinically relevant, Myeloid Malignancies, immune mechanism
Monday, December 3, 2018: 7:00 AM
Grand Hall D (Manchester Grand Hyatt San Diego)

John Mascarenhas, MD1, Heidi E. Kosiorek, MS2*, Josef T. Prchal, MD3, Alessandro Rambaldi, MD4, Dmitriy Berenzon, MD5*, Abdulraheem Yacoub, MD6, Claire N. Harrison, MD, DM, FRCP, PRCPath7, Mary Frances McMullin, MD8, Alessandro M. Vannucchi, MD9, Joanne Ewing, PhD, BMBS, BSc, FRPATH,10*, Casey L. O'Connell, MD11, Jean-Jacques Kiladjian, MD, PhD12,13, 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, Leah Price30*, Judith D Goldberg, ScD31*, Raajit K. Rampal, MD, PhD32, Ruben A. Mesa, MD, FACP33, Amylou C. Dueck, PhD34 and Ronald Hoffman, MD25

1Icahn School of Medicine at Mount Sinai, New York, NY
2Department of Biostatistics, Mayo Clinic, Scottsdale, AZ
3Division of Hematology and Hematologic Malignancies, University of Utah & The Huntsman Cancer Center, Salt Lake Cty, UT
4Hematology and Bone Marrow Transplantation Unit, ASST Papa Giovanni XXIII, Bergamo, Italy
5Comprehensive Cancer Center, Wake Forest Baptist Health, Comprehensive Cancer Center, Wake Forest Baptist Health, Winston Salem, NC
6Kansas University Cancer Center, Leawood, KS
7Department of Haematology, Guy's Hospital, London, United Kingdom
8Queen's University Belfast, Belfast, United Kingdom
9Azienda Ospedaliero Universitaria Careggi, Firenze, ITA
10Heart of England NHS Foundation Trust, UHB, Birmingham, GBR
11University of Southern California, Keck School of Medicine, Los Angeles, CA
12INSERM U1131, Hopital Saint-Louis, Paris, France
13Hôpital 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
30New York University School of Medicine Departments of Population Health and Environmental Medicine, New York
31Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York
32Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center; Myeloproliferative Neoplasm Research Consortium (MPN-RC), New York, NY
33UT Health San Antonio Cancer Center, San Antonio, TX
34Department of Biostatistics, Mayo Clinic Arizona, Scottsdale, AZ

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: Novartis: Other: Provided Ruxolitinib ; Celgene: Membership on an entity's Board of Directors or advisory committees; Hoffmann-La Roche AG: Other: Provided Pegylated Interferon Alpha 2a; 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. 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; Dimension Advisory boards: Membership on an entity's Board of Directors or advisory committees; Sangamo: Research Funding; Novo Nordisk: Honoraria, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: 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; DSMB: 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: Sensei: Other: Advisory Board; Novartis: Consultancy, Other: Advisory Board; Incyte Corporation: Research Funding, Travel Support (EHA 2018); CTI Biopharma: Research Funding; Genentech: Research Funding; Janssen: Other: Travel Support (EHA 2018); Celgene: Other: Research Funds (to institutions not investigator), Research Funding; H3 Biosciences: Other: Research Funds (to institutions not investigator); Gilead: Research Funding; Onconova: Membership on an entity's Board of Directors or advisory committees; Otsuka: Other: Advisory Board; Sierra Oncology: Consultancy, Honoraria; Pfizer: Other: Advisory Board, Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. 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.

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