Deep Molecular Responses In Patients With Newly Diagnosed Chronic Myeloid Leukemia Receiving Nilotinib As Assessed Within The EUTOS Laboratory Network In The ENEST1st Study

Nilotinib is a selective BCR-ABL tyrosine kinase inhibitor (TKI) that has been shown to be more active than imatinib at inducing earlier and deeper molecular responses in the frontline treatment of chronic myeloid leukemia (CML; Larson, et al. Leukemia. 2012). ENEST1st (Evaluating Nilotinib Efficacy and Safety in clinical Trials as First-Line Treatment, NCT01061177) is the largest study ever in TKI-treated patients (pts) with CML. Its primary endpoint was the rate of MR⁴ (defined as BCR-ABL ≤ 0.01% on the International Scale [BCR-ABL^IS] or undetectable BCR-ABL in cDNA with ≥ 10,000 ABL transcripts) at 18 mo. Molecular response (MR) was assessed by standardized quantitative polymerase chain reaction (RQ-PCR) in the 14-laboratory network of the European Treatment and Outcomes Study (EUTOS).

ENEST1st is a phase 3b, open-label study of nilotinib 300 mg twice daily (BID) in adults with newly diagnosed BCR-ABL-positive CML in chronic phase. MR was assessed every 3 mo by peripheral blood RQ-PCR at 1 of 14 EUTOS laboratories. Following completion of the 18-mo primary efficacy time point, all pts continued to receive treatment and were followed for an additional 6 mo.

1160 pts were screened, with 1086 eligible pts treated in 26 European countries. Overall, median age was 53 y (range, 18-91 y); 59.2% of pts were male, 96.9% had typical b2a2 and/or b3a2 BCR-ABL transcripts (intent-to-treat population for MR analyses), and 90.3% were Philadelphia chromosome–positive by bone marrow metaphase cytogenetics. Per protocol, efficacy and safety analyses were conducted in the initial 819 pts (75.4% of enrolled pts) who were on study for 24 mo or discontinued early. In this group, median age was 53 y (range, 18-91 y), and 58.5% were male; Sokal risk scores were low, intermediate, and high in 33.7%, 39.5%, and 18.7% of pts, respectively (8.1% missing). EUTOS scores were low in 83.8% and high in 9.2% of pts (7.0% missing).

A total of 658 pts (80.3%) completed 24 mo of treatment; 161 pts (19.7%) discontinued early. The most common reasons for discontinuation included adverse events (AEs; 10.5%), withdrawal of consent (2.7%), and disease progression (as indicated by the investigator; 1.7%).

MR⁴ rate at 18 mo was 43.0% (95% CI, 39.3-46.8). Rates of major MR (MMR, BCR-ABL^IS ≤ 0.1%), MR⁴, and MR^4.5 (BCR-ABL^IS ≤ 0.0032% or undetectable cDNA with ≥ 32,000 ABL transcripts) at 18 and 24 mo are shown in the Table. Cumulative incidence of MR⁴ by 18 mo was 50.1%.

All pts were followed up for progression or death for 24 months after start of treatment: 7 pts (0.85%) experienced progression to accelerated phase/blast crisis (AP/BC) while on core treatment or after discontinuation. Overall, 12 pts (1.5%) died; 2 of them died following progression to AP/BC.

The safety profile of nilotinib was similar to that observed in other frontline studies. The most common AEs of any relationship were rash (21.4%), pruritus (16.8%), and headache (15.0%); most AEs were grade 1-2. Rates of grade 3-4 hematological AEs were low, with thrombocytopenia and neutropenia reported in 8.2% and 2.9% of pts, respectively. Peripheral arterial occlusive disease (PAOD) occurred in 13 pts (1.6%), ischemic heart disease in 31 (3.8%), and ischemic cerebrovascular conditions in 4 (0.5%). Three cases of pain in extremities are under investigation for potential relationship to PAOD.

ENEST1st confirms that frontline nilotinib results in high rates of deeper and earlier MR and very low rates of progression to AP/BC. By 18 mo, half of pts achieved a response of MR⁴. This MR⁴ rate supports the use of frontline nilotinib as a treatment of choice on which to develop treatment-free remission studies. Finally, the molecular response rates measured in a standardized and validated network of 14 EUTOS laboratories in ENEST1st provide prospective confirmation of the centrally reviewed molecular response rates reported in the ENESTnd trial.

Giles:Novartis: Consultancy, Research Funding. Baccarani:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Ariad: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Brümmendorf:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy. Mahon:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Brisol Myers Squibb: Consultancy, Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Rosti:Novartis: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau. Saglio:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Steegmann:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ossenkoppele:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Echeveste:Celgene: Consultancy; Novartis: Consultancy. Gattermann:Novartis: Honoraria, Research Funding, Speakers Bureau. Griskevicius:Novartis: Consultancy, Research Funding. le Coutre:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria. Masszi:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Rea:Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Richter:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Stentoft:Novartis: Consultancy, Financial support for relevant congress participation Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Danish Regions: Membership on an entity’s Board of Directors or advisory committees. Tulliez:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Schuld:Novartis: Employment, Equity Ownership. Pellegrino:Novartis: Employment. Walasek:Novartis: Employment. Cross:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria. Hochhaus:Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Ariad: Research Funding; Pfizer: Research Funding.