San Diego, CA—The rate of major molecular response (MMR) is favorable when pegylated interferon (Peg-IFN) alpha-2b (Peg-Intron) is added to the tyrosine kinase inhibitor nilotinib (Tasigna) in patients with chronic-phase chronic myeloid leukemia (CP-CML), according to results of an interim analysis of Pinnacle, a single-arm phase 2b clinical trial presented at ASH 2018.
In the Pinnacle study, the rate of MMR (defined as a >3 log reduction of BCR-ABL transcript level) at 12 months was 78.3% with the combination of nilotinib and Peg-IFN, said David T. Yeung, PhD, FRACP, FRCPA, MBBS, Department of Haematology, Royal Adelaide Hospital and SA Pathology, Australia.
These rates compare favorably with nilotinib monotherapy as had been seen in previous studies, which showed 12-month MMR rates of 55% to 70.8%.
“For the interim report, we’ve seen high molecular response rates with the combination of nilotinib and pegylated interferon-alpha, with a [blast] transformation rate of 3%,” said Dr Yeung. “The combination is deliverable in the majority of patients.”
Peg-IFN has been shown to be better tolerated than standard IFN, and it improves the molecular response rate when added to imatinib in patients with CP-CML, which served as the rationale for the Pinnacle study.
A total of 60 patients with newly diagnosed CP-CML were enrolled in the Pinnacle study from 12 Australian centers. Patients with active peripheral vascular disease, cerebrovascular disease, or coronary artery disease were excluded.
Eligible patients received nilotinib 300 mg twice daily, alone for the first 3 months. Patients were allowed a dose escalation to 400 mg twice daily per investigator discretion if they failed to achieve optimal 2013 European LeukemiaNet targets.
Peg-IFN was added at 30 mcg weekly in patients without persistent hematologic toxicities, increasing to 50 mcg weekly, as tolerated, over the following month. The use of the combination continued until 24 months, at which point patients reverted to nilotinib monotherapy.
Switching from nilotinib therapy to imatinib (Gleevec), 400 mg to 600 mg once daily, was allowed if patients had persistent grade 2 to grade 4 adverse events with nilotinib therapy. Some 81% of the enrolled patients had low-to-intermediate risk, according to the Sokal Index for CML.
With a median follow-up of 28 months, 33.8% of patients achieved deep molecular responses, and by 24 months, 50.9% of patients achieved deep molecular responses.
By comparison, the 24-month deep molecular response rates were 25% to 38.6% with nilotinib monotherapy in the ENESTnd and ENEST1st studies, respectively, Dr Yeung said.
Overall, 10 patients have withdrawn from the study, including 5 because of adverse events, 2 who withdrew their consent, and 2 who could not maintain the nilotinib dosing intensity because of thrombocytopenia.
At the time of this interim analysis, 70% of patients were still receiving nilotinib, and 13.3% switched to imatinib. The reasons for switching from nilotinib to imatinib included lipase elevation or pancreatitis in 3 patients; liver function transaminase derangements in 2 patients; and hyperthyroidism, thrombosis, and sepsis in 1 patient each.
A total of 6 patients did not achieve early molecular response (BCR-ABL transcript level, >10% at 3 months). Of these patients, 1 patient switched to imatinib and had an MMR at 18 months; 2 patients maintained nilotinib therapy at 300 mg twice daily, which led to MMR at 12 months and 9 months; and another patient had the nilotinib dose escalated to 400 mg twice daily, resulting in BCR-ABL transcript level of 0.77% at 2 years. The remaining 2 patients did not respond to therapy.
Overall, 22 (37%) patients completed more than 90% of their assigned Peg-IFN doses and duration, 8 (13%) patients never started Peg-IFN, and 30 (50%) patients had a reduction in the dose or duration of Peg-IFN.
Nilotinib-related grade 3 or 4 adverse events included neutropenia (12%), lipase elevation (12%), pancreatitis (5%), thrombocytopenia (5%), and rash (5%). In addition, 3 thrombotic events included ischemic colitis, femoral artery thrombosis, and coronary artery disease.
Peg-IFN–attributed grade 3 or 4 adverse events included neutropenia (10%), rash (4%), depression (4%), and myalgia (4%).
The results of this interim analysis indicate that adding Peg-IFN to nilotinib can improve the rate of molecular responses compared with single-agent nilotinib therapy. Although the majority of patients did not tolerate the full dose of Peg-IFN for the long-term, adding this agent did not affect the dose of nilotinib.
Long-term results from this study will provide more information about the rates of remission without treatment after the use of this combination.
