Single-Arm, Open-Label, Multicenter Study Of Deep Molecular Response (MR4.5) With Nilotinib In Adult Patients (pts) With Newly Diagnosed Philadelphia Chromosome–Positive Chronic Myeloid Leukemia In Chronic Phase (CML-CP): ENESTnext Study Update
Authors: Mauro Michael , Radich Jerald , Cortes Jorge E. , Dakhil Shaker , Keir Christopher , Yi Sandy , Wadleigh Martha , Oehler Vivian G. , Ervin Thomas , Goldberg Stuart , Savona Michael 
Published: October 2019

Abstract

Background
Pivotal treatment-free remission (TFR) trials require prolonged deep molecular response (MR), often MR4.5, for study entry (Mahon et al. 2010), which has led to increasing focus on MR4.5 as a treatment goal for pts with CML-CP. New tyrosine kinase inhibitors (TKIs), such as nilotinib, more potently inhibit BCR-ABL and elicit significantly deeper and faster MRs than imatinib (Larson et al. 2012), requiring more sensitive techniques to monitor residual disease. In ENESTnext (registered as NCT01227577), MR was evaluated using standard reverse transcriptase quantitative polymerase chain reaction (RQ-PCR) and a microfluidic “digital” PCR assay, which is >1-log more sensitive than conventional methods.

Methods
Pts diagnosed with CML-CP within 6 mo of enrollment were treated with nilotinib 300 mg twice daily (BID) for up to 2 years. RQ-PCR was performed on peripheral blood samples by a central laboratory according to the International Scale (IS). Samples were taken monthly in mo 1-3 and every 3 mo thereafter. The primary endpoint was the rate of confirmed MR4.5 at 2 years, defined as ≥ 2 samples taken 3 mo apart with ≥ 4.5-log reduction of BCR-ABL transcript levels (≤ 0.0032%IS) with a minimum of 25,614 ABL control copies. Pts with suboptimal response or failing treatment (per European LeukemiaNet 2009 recommendations) could dose escalate to nilotinib 400 mg BID per physician discretion. Complete cytogenetic response (CCyR) and major MR (MMR, 3-log reduction of BCR-ABL transcript levels [≤ 0.1%IS]) were also assessed. In an exploratory analysis, samples identified as MR4.5 using conventional RQ-PCR were also evaluated using the Fluidigm digital PCR platform (Oehler et al. 2009). BCR-ABL copy number was estimated by Poisson distribution; samples were positive if copy number was > 0. The data cutoff date for this analysis was April 30, 2013.

Results
Of 128 pts, 64 (50%) were male and 103 (80%) were white. The mean age was 55.6 y (range, 21.0-89.0). Pts were treated for a median of 8.5 mo (range 0.1-24.1); median daily nilotinib dose was 600 mg. As of the data cut, 87, 36, 23 and 18 pts have been treated for ≥ 6, ≥ 12, ≥ 18 and ≥ 22 mo, respectively. Cumulative incidence of MR4.5, MMR and CCyR was 22 (17%), 76 (59%) and 72 (56%) pts, respectively.
In the 22 pts who achieved MR4.5, the mean time to first MR4.5 was 6.4 mo (range, 1.0-22.7). Digital PCR was performed on 57 samples from these 22 pts; 15/22 pts had ≥ 2 samples from different time points. Of these, 8 were initially positive for BCR-ABL and became negative, 5 were initially negative and remained negative and 2 were initially positive and remained positive. Achieving BCR-ABL negativity using digital PCR generally occurred rapidly (within 3 mo of MR4.5).
The most common (≥ 2 pts) grade 3 adverse events (AEs) were nausea (n = 4), headache (n = 3), elevated lipase level (n = 12), thrombocytopenia (n = 6), neutropenia (n = 6), hypophosphatemia (n = 5), anemia (n = 4) and increased amylase level (n = 3). Grade 4 AEs were myocardial infarction (n = 2), device-related infection (n = 1), elevated lipase level (n = 4), thrombocytopenia (n = 3), neutropenia (n = 2) and hyponatremia (n = 1).
To date, 22 (17%) pts have discontinued treatment. Reasons included AEs (n = 11), withdrawn consent (n = 3), protocol deviation (n = 2), unsatisfactory therapeutic effect (n = 2), abnormal laboratory values (n = 2), abnormal test procedure result (n = 1) and loss to follow-up (n = 1).

Conclusions
Treatment with nilotinib 300 mg BID in pts with newly diagnosed CML-CP resulted in rapid and substantial rates of MR4.5 using conventional RQ-PCR, with a safety profile similar to that reported in previous studies. The digital PCR assay detected residual BCR-ABL in approximately 50% of samples with at least MR4.5 by RQ-PCR, and showed declining BCR-ABL levels with continued therapy. Thus, use of digital PCR may help better identify appropriate candidates for TFR studies. Based on results from the ENESTnd trial (Larson et al. 2012), MR4.5 rates are expected to increase over time. Other studies have demonstrated that pts who achieve early, deep MR have improved long-term outcomes (Marin et al. 2012). Evaluation of longer-term outcomes for patients with negative digital PCR results is ongoing.

Disclosures:
Mauro: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Off Label Use: This abstract describes a clinical trial evaluating the investigational agent midostaurin for use in patients with advanced systemic mastocytosis. Radich:novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Cortes:Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Ariad: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Keir:Novartis: Employment, Equity Ownership. Yi:Novartis: Employment. Goldberg:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau.