-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

479 Interim Analysis of the Myeloproliferative Disorders Research Consortium (MPD-RC) 112 Global Phase III Trial of Front Line Pegylated Interferon Alpha-2a Vs. Hydroxyurea in High Risk Polycythemia Vera and Essential Thrombocythemia

Myeloproliferative Syndromes: Clinical
Program: Oral and Poster Abstracts
Type: Oral
Session: 634. Myeloproliferative Syndromes: Clinical: Clinical Trials with Agents Other Than JAK Inhibitors
Sunday, December 4, 2016: 5:30 PM
Marriott Grand 8-9 (Marriott Marquis San Diego Marina)

John O. Mascarenhas, MD, MS1, Josef T. Prchal, MD2, Alessandro Rambaldi, MD3, Ruben A. Mesa, MD4, Dmitriy Berenzon, MD5*, Abdulraheem Yacoub, MD6, Claire N. Harrison, DM, FRCP, FRCPath7, Mary Frances McMullin, MD8, Alessandro M. Vannucchi, MD, PhD9, Joanne C Ewing, PhD, BMBS, BSc, FRPATH,10*, Casey L O'Connell, M.D.11, Jean-Jacques Kiladjian, MD, PhD12, Adam Mead, MD, PhD13*, Elliott F. Winton, MD14, David S. Leibowitz, MD15, Valerio De Stefano16*, Murat O. Arcasoy, MD17, Craig M. Kessler, MD18, Rosalind Catchatorian19*, Damiano Rondelli, MD20, Richard T. Silver, MD21, Ellen K. Ritchie, MD22, Arnon Nagler23, Marina Kremyanskaya, MD PhD24, Richard F. Schlenk, MD25, Rona Singer Weinberg, PhD26, Mohamed E Salama, M.D.27, Gianni Tognoni28*, Giuseppe Prosperini28*, Alessandra Di Lelio28*, Eliseo Serone28*, Lorenzo Marfisi28*, Jill Kleczko1*, Heidi E. Kosiorek, MS29*, Tiziano Barbui, MD30*, Amylou C. Dueck, PhD29 and Ronald Hoffman31

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

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; 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.

*signifies non-member of ASH