Abstract

Abstract 167

Background:

In the ENESTnd study, nilotinib significantly reduced progression to accelerated phase/blast crisis (AP/BC) and demonstrated superior rates of deep molecular response vs imatinib. Data from ENESTnd demonstrated that significantly more patients achieved early molecular response of both < 10% and < 1% BCR-ABLIS at both 3 and 6 months on nilotinib vs imatinib. Here, we report landmark analyses based on BCR-ABL transcript levels at 3 and 6 months using data with a minimum follow-up of 3 years and also provide data on factors associated with poor early molecular response; data based on longer follow-up of 4 years will be presented.

Methods:

The nilotinib 300 mg twice daily (BID; n = 282) and imatinib 400 mg once daily (QD; n = 283) arms from ENESTnd were used for this analysis. Patients were grouped based on BCR-ABL transcript levels of ≤ 1%, > 1% to ≤ 10%, and > 10% at 3 months (n = 258 and n = 264 patients with available PCR samples at 3 months in the nilotinib and imatinib arms, respectively) and at 6 months (n = 257 and n = 256 patients with available PCR samples at 6 months in the nilotinib and imatinib arms, respectively). Rates of major molecular response (MMR; ≤ 0.1% BCR-ABLIS) and molecular response with a 4.5-log reduction in BCR-ABL transcript levels (MR4.5, ≤ 0.0032%IS) as well as rates of progression-free survival (PFS) and overall survival (OS) were evaluated among patients grouped according to their BCR-ABL transcript levels at 3 and 6 months. Data on selected baseline characteristics and dose intensity were also assessed.

Results:

Among evaluable patients at 3 months, 9% of patients (n = 24) in the nilotinib arm vs 33% (n = 88) in the imatinib arm had BCR-ABL transcript levels of > 10%; among evaluable patients at 6 months, 3% of patients (n = 7) in the nilotinib arm vs 16% (n = 40) in the imatinib arm had BCR-ABL transcript levels of > 10%. Patients with a BCR-ABL transcript level of > 10% had a lower probability of future MMR or MR4.5 as well as poorer PFS and OS compared with patients who had BCR-ABL transcript levels ≤ 10% at 3 months (Table). Results were similar based on 6-month landmark analyses. In patients with > 10% BCR-ABL transcript levels at 3 months, the average dose intensity of nilotinib within the first 3 months was 474 mg/day compared with 600 mg/day for patients with ≤ 10% BCR-ABL transcript levels; the average dose intensity of imatinib within the first 3 months was the same (400 mg/day) for patients with both ≤ 10% and > 10% BCR-ABL levels at 3 months (Table). Patients with > 10% BCR-ABL transcript levels at 3 months were also more likely to have high Sokal risk, larger spleen size, and additional chromosomal abnormalities compared with patients with ≤ 10% BCR-ABL transcript levels at 3 months. Other factors associated with early response and further data on long-term outcomes are being assessed and will be presented with a minimum follow-up of 4 years.

Conclusions:

Fewer patients in the nilotinib arm vs the imatinib arm had BCR-ABL transcript levels > 10% at 3 and 6 months. Reasons for poor early response appeared to be related, at least in part, to baseline factors and dose intensity. Early molecular response at 3 and 6 months correlated with future MMR and MR4.5as well as an increased probability of PFS and OS. Nilotinib frontline therapy allows more patients to achieve deeper responses earlier, associated with improved long-term outcomes vs imatinib.

BCR-ABL at 3 monthsNilotinib 300 mg BID (N = 258)*Imatinib 400 mg QD (N = 264)*
≤ 10% n = 234 > 10% n = 24 ≤ 10% n = 176 > 10% n = 88 
MMR n = 209 n = 24 n = 174 n = 88 
    by 1 year, % 61 40 
    by 2 years, % 80 29 58 21 
MR4.5 n = 233 n = 24 n = 176 n = 88 
    by 2 years, % 29 14 
    by 3 years, % 38 24 
Long-term outcomes n = 234 n = 24 n = 176 n = 88 
    PFS at 3 years, % 95.9 82.9 97.7 83.8 
    OS at 3 years, % 97.6 86.7 98.9 84.8 
Factors associated with molecular response at 3 months     
Median dose intensity within the first 3 months, mg/day 600 474 400 400 
    High Sokal risk, % 25.6 41.7 17.6 44.3 
    Splenomegaly, % 38.9 75.0 26.7 59.1 
    Spleen size, cm (median) 5.0 8.0 3.5 10.5 
Additional chromosomal abnormalities, % 9.4 16.7 9.1 14.8 
BCR-ABL at 3 monthsNilotinib 300 mg BID (N = 258)*Imatinib 400 mg QD (N = 264)*
≤ 10% n = 234 > 10% n = 24 ≤ 10% n = 176 > 10% n = 88 
MMR n = 209 n = 24 n = 174 n = 88 
    by 1 year, % 61 40 
    by 2 years, % 80 29 58 21 
MR4.5 n = 233 n = 24 n = 176 n = 88 
    by 2 years, % 29 14 
    by 3 years, % 38 24 
Long-term outcomes n = 234 n = 24 n = 176 n = 88 
    PFS at 3 years, % 95.9 82.9 97.7 83.8 
    OS at 3 years, % 97.6 86.7 98.9 84.8 
Factors associated with molecular response at 3 months     
Median dose intensity within the first 3 months, mg/day 600 474 400 400 
    High Sokal risk, % 25.6 41.7 17.6 44.3 
    Splenomegaly, % 38.9 75.0 26.7 59.1 
    Spleen size, cm (median) 5.0 8.0 3.5 10.5 
Additional chromosomal abnormalities, % 9.4 16.7 9.1 14.8 
*

Response and outcomes were evaluated in patients who had available PCR samples at 3 or 6 months. Patients who achieved the target response within 3 or 6 months were excluded from the respective analysis of response outcomes; patients who had events or were censored within 3 or 6 months were excluded from the respective analysis of time-to-event outcomes.

Disclosures:

Hochhaus:BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Hughes:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Guilhot:Celgene: Consultancy; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ariad: Honoraria. Al-Ali:Novartis: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria. Rosti:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau. Kemp:Novartis Pharmaceuticals Corp: Employment. Fan:Novartis Pharmaceuticals Corp: Employment. Hoenekopp:Novartis Pharma AG: Employment, Equity Ownership. Larson:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding. Kantarjian:Novartis Pharmaceuticals Corp: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding.

Author notes

*

Asterisk with author names denotes non-ASH members.