-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.

459 Combination of Nilotinib and Pegylated Interferon Alfa-2b Results in High Molecular Response Rates in Chronic Phase CML: Interim Results of the ALLG CML 11 Pinnacle Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia: Therapy: First Line Trials and Prognostic Factors of Treatment-Free Remission
Hematology Disease Topics & Pathways:
Diseases, Non-Biological, Therapies, CML, Clinically relevant, Myeloid Malignancies
Sunday, December 2, 2018: 5:00 PM
Room 6E (San Diego Convention Center)

David T Yeung, PhD, BSc, FRACP, FRCPA, MBBS1,2, Andrew P. Grigg, MBBS, FRACP, FRCPA, MD3*, Naranie Shanmuganathan, MBBS4,5, Ilona Cunningham, MBBS FRACP FRCPA6, Jake Shortt, FRACP, FRCPA, PhD7, Philip Rowling, MBBS FRACP FRCPA8*, John Reynolds, PhD9*, Rachel Cushion10*, Rosemary Anne Harrup, MD11*, David M Ross12*, David Kipp, MBBS, FRCPA, FRACP13, Anthony K Mills, FRACP, FRCPA, MBBS14, Christopher K Arthur15, Anthony P Schwarer, MD, MBBS (Hons), FRACP, FRCPA16, Kathryn Jackson, MBBS FRACP FRCPA17*, Nicholas Viiala, MBBS FRACP FRCPA18*, Robert Weinkove, MD19, Agnes S. M. Yong, MD, PhD1, Deborah L White, PhD1, Susan Branford, PhD20,21, Timothy P. Hughes, MD, MBBS, FRACP, FRCPA1 and On Behalf of the ALLG22*

1Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, Australia
2Department of Haematology, Royal Adelaide Hospital and SA Pathology, Adelaide, Australia
3Department of Clinical Haematology, Austin Hospital, VIC, Australia
4Department of Haematology, Royal Adelaide Hospital and SA Pathology, Brompton, SA, Australia
5Centre for Cancer Biology, SA Pathology, Adelaide, Australia
6Haematology, Concord Hospital, Concord, Australia
7Peter MacCallum Cancer Centre, Clayton, AUS
8Haematology, Calvary Mater Newcastle Hospital, Waratah, Australia
9Biostatistics Consulting Platform, Alfred Health and Faculty of Medicine, Nursing & Health Sciences, Monash University, Melbourne, Australia
10Australasian Leukaemia and Lymphoma Group, Richmond, Australia
11Department of Haematology, Royal Hobart Hospital, Hobart, AUS
12Department of Haematology, Flinders Medical Centre, Bedford Park, Australia
13Andrew Love Cancer Centre, University Hospital Geelong, GEELONG, Australia
14Department of Haematology, Princess Alexandra Hospital, Brisbane, Australia
15Department of Haematology, Royal North Shore Hospital, St Leonards, NSW, Australia
16Department of Haematology, The Alfred Hospital and Box Hill Hospital, Melbourne, Australia
17Nambour General Hospital, Birtinya, Australia
18Liverpool Hospital, Sydney, Australia
19Capital & Coast District Health Board, Wellington, New Zealand
20Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia
21Genetic and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia
22Australasian Leukaemia and Lymphoma Group, Melbourne, Australia

Alfa Interferon, commonly used in chronic phase chronic myeloid leukemia (CML-CP) in the pre-imatinib era, was able to induce a cytogenetic response in a minority of patients (pts). Pegylated interferon (Peg-IFN) is better tolerated than IFN, and increases molecular response rates when used in combination with imatinib (IM) compared with IM monotherapy (Preudhomme NEJM 2010). The phase II Pinnacle (ALLG CML 11) study evaluated the tolerability and molecular response rate of nilotinib (NIL) with Peg-IFN alfa-2B (PegIntron, MSD) in de novo CML-CP.

Pts were screened for cardiac / vascular disease and associated risk factors at baseline (EKG, left ventricular ejection fraction, arterial duplex of carotids and lower limbs, blood HbA1c and lipid profiles). Those with uncontrolled vascular risk factors (diabetes, hypertension, dyslipidemia) or a history of vascular events were excluded. Eligible pts received NIL 300mg BID alone for the first 3 months (mths). PegIntron was then added at 30mcg/week in pts without persistent hematological toxicities, increasing to 50mcg/week as tolerated over the following mth. Combination therapy continued until 24 mths, when pts reverted to TKI monotherapy. Switching to IM 400-600mg QD was allowed for pts with persistent grade II or any grade III/IV toxicity from NIL..

Sixty pts were enrolled from 12 Australian centres. Median age was 48.5 years (range 19-72); 45% were female. Sokal risk was low in 43% and high in 18%. Median follow up (FU) was 28 mths (16-51). Data is presented on an intention to treat basis. Figure 1a shows BCR-ABL1 transcript levels over time. The co-primary end points are MMR (BCR-ABL1 ≤0.1% IS) AT 12 mths and MR4.5 (BCR-ABL1 ≤0.0032% IS) at 24 mths. At 12 mths, MMR and MR4.5 rates were 76.7% (95% CI 63.4-87%). and 43.4% (95% CI 30.1-57.3%), respectively. In 40 evaluable pts at 24 mths, MR4.5 was 50% (95% CI 29.9-70.1%). The median time to MMR and MR4.5 was 5.8 mths and 18 mths respectively for pts achieving these responses (Figs 1B & C). Six pts (10%) had BCR-ABL1 ≥10% at 3 mths – 2 of whom had multiple dose interruptions due to toxicity; 3/6 have since achieved MMR, 1 has BCR-ABL <1%, 2 withdrew of which 1 transformed to AP off study. No BCR-ABL mutation was reported on study.

Dose intensities of NIL were assessed in 3 mth blocks. Median and lower quartile NIL dose intensity was 600mg/d for all 3 mth blocks up to mth 24, except for the lower quartile NIL dose of 567mg for the first 3 mths. Eight pts (13%) did not commence Pegintron (2 due to persistent haem toxicities, 4 from GI disturbance, liver/pancreatic enzyme derangements, and 2 from pt preference). Considering Pegintron as a product of protocol assigned dose and duration, adjusted for time from study entry, 22 pts (37%) received >90% of their assigned dose, 13 (22%) received between 50-90% and 25 pts (41%) received <50% of assigned Peg-IFN (Fig 1D). The median duration of Pegintron exposure was 15 mths.

Grade III/IV adverse events (AE) attributed to NIL were increased lipase and neutropenia (each 12%), pancreatitis (6%), thrombocytopenia and rash (each 5%). Three thrombotic events occurred: ischemic colitis in a patient on IM monotherapy, femoral artery thrombosis in a 56yo man after 2.5 yrs of NIL, and coronary disease in a 51yo man after 4 yrs of NIL. Grade III/IV AEs attributed to Pegintron were neutropenia (10%), and myalgia, depression and rash (4% each); other common AEs included fatigue (35%), myalgia (23%), flu-like symptoms (21%) and depression (17%).

Ten pts (13%) have withdrawn from study: 2 withdrew consent, 5 due to toxicity (pancreatitis, GI upset, rash, high amylase and fatigue), and 3 for failing to consistently achieve BCR-ABL <10% beyond 6 mths. No death occured on study. Three pts lost MMR – 2 were transient; the other was associated with non-compliance. Current TKI treatment for pts on study: 41 on NIL (68%), 9 on IM (15%). Of the 40 pts with 24 mth FU, 15 (38%) received >90% of assigned NIL/IM and Pegintron doses.

This interim analysis suggests that combination therapy with NIL and Peg-IFN leads to favourable rates of molecular responses when compared with with NIL monotherapy (Table 1). While the majority of patients did not durably tolerate full dose Pegintron, there was minimal interference with TKI dose intensity. Longer term results, and impact upon treatment free remission outcome of this combination is awaited.

Disclosures: Yeung: Pfizer: Honoraria; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Specialised Therapeutics Australia: Honoraria; Amgen: Honoraria. Grigg: Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Shanmuganathan: Janssen: Honoraria; Royal Adelaide Hospital Research Fund: Other: Scholarship; Novartis: Honoraria, Other: Travel sponsorship; Bristol-Myers Squibb: Honoraria, Other: Travel sponsorship. Reynolds: Novartis: Equity Ownership, Other: former employee of Novartis AG and holds stock in the company. . Ross: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria; Celgene: Research Funding. Weinkove: Capital & Coast District Health Board: Other: Institution received reimbursement of the costs of conducting trial-related clinical procedures; Health Research Council of New Zealand: Research Funding; Thompson Family Foundation: Research Funding. Yong: Celgene: Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. White: Novartis: Honoraria, Research Funding; BMS: Research Funding. Branford: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cepheid: Honoraria; Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Hughes: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH