Abstract

Abstract 3292

Poster Board III-1

Background:

Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor, approved for the treatment of Philadelphia positive CML patients (pts) in CP or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. A recent analysis demonstrated an association between BCR-ABL transcript levels at 3 months (mos) and response in pts treated with second-line tyrosine kinase inhibitors (Branford et al. Blood. 2008). This multi-center analysis was conducted to examine the association specifically between the initial molecular response to nilotinib with response and outcomes.

Methods:

CML-CP pts (N = 321) with imatinib resistance or intolerance were included and post-baseline BCR-ABL transcript levels were available for 294 patients. Intolerant pts also exhibited some degree of resistance to imatinib and were not eligible for the study if demonstrating major cytogenetic response (MCyR), the primary study endpoint. We aimed to determine if the initial molecular response to nilotinib could predict the response and outcome of patients with or without BCR-ABL mutations at baseline or those with imatinib resistance or intolerance. BCR-ABL transcript levels at 3 mos were used to perform a landmark analysis to assess the association between the initial molecular response and estimated probability of MCyR, major molecular response (MMR), and event-free survival (EFS) at 24 mos. Events were defined as loss of hematologic or cytogenetic response, progression to AP/BC, discontinuation due to progression or death. The analysis excludes patients who had already attained MCyR (n = 111) or MMR [BCR-ABL% (IS) ≤ 0.1%] (n = 28) or who had an event (n = 22) within the first 3 mos of therapy for each respective landmark analysis. Patients censored within the first 3 mos were also excluded. Patients were then grouped according to their level of BCR-ABL% (IS).

Results:

BCR-ABL% (IS) at 3 mos correlated with MCyR rates at 24 mos; pts with BCR-ABL% (IS) ≤ 10 had better probability of response compared with pts with BCR-ABL% (IS) > 10 (62% vs 35%, respectively). This difference in MCyR rate was most significant for pts with baseline mutations (60% vs 19%, P = .006) and those with imatinib resistance (63% vs 33%, P = 0.0007). A similar trend was observed for patients without baseline mutations (64% vs 47%) and imatinib intolerance (57% vs 40%). BCR-ABL% (IS) at 3 mos was highly predictive of MMR rates at 24 mos (Table). Pts with BCR-ABL% (IS) values > 0.1 - ≤ 1 had significantly higher probability (65%) of achieving MMR for all patient groups, whereas those with BCR-ABL% (IS) > 10 had estimated rates of 10% or less. The BCR-ABL% (IS) value at 3 mos was also found to correlate with EFS at 24 mos (Table). The estimated EFS rate at 24 mos was highest for pts with BCR-ABL% (IS) values of ≤ 1 at 3 mos for each patient group and ranged from 75% to 100%. Patients with BCR-ABL% (IS) values > 10 at 3 mos had the poorest outcome and the estimated EFS rates ranged from 36% for patients with baseline mutations to 57% for those without baseline mutations.

Conclusion:

BCR-ABL% (IS) at 3 mos predicts response and long-term outcomes of imatinib-resistant and intolerant pts regardless of baseline mutation status at 24 mos on nilotinib therapy. Rapid reduction of BCR-ABL may be important for optimal response and outcome. Pts whose BCR-ABL % (IS) levels decreased below 10% at 3 mos demonstrated a high probability of achieving MMR and MCyR at 24 mos. Pts who achieve early molecular response may also have an increased probability of improved long-term outcomes on nilotinib therapy, while pts with BCR-ABL% (IS) value > 10 at 3 mos may have poorer prognosis.

Estimated MMR and EFS at 24 mos by BCR-ABL% (IS) at 3 mos on nilotinib therapy

BCR-ABL% (IS) at 3 Months ≤ 1 > 1 – ≤ 10 > 10 P-value 
MMR at 24 Monthsa     
Pts with BL mutations, n = 83 86%c 34% 9% 0.018d, 0.007e 
Pts without BL mutations, n = 126 60%c 26% 9% 0.013d, 0.010e 
Resistant pts, n = 150 63%c 30% 9% 0.011d, 0.002e 
Intolerant pts, n = 59 70%c 27% 10% 0.064d, 0.053e 
EFS at 24 Monthsb     
Pts with BL mutations, n = 74 100% 54% 36% 0.011f, 0.582e 
Pts without BL mutations, n = 141 78% 79% 57% 0.946f, 0.026e 
Resistant pts, n = 152 75% 64% 47% 0.138f, 0.188e 
Intolerant pts, n = 63 89% 91% 54% 0.705f, 0.015e 
BCR-ABL% (IS) at 3 Months ≤ 1 > 1 – ≤ 10 > 10 P-value 
MMR at 24 Monthsa     
Pts with BL mutations, n = 83 86%c 34% 9% 0.018d, 0.007e 
Pts without BL mutations, n = 126 60%c 26% 9% 0.013d, 0.010e 
Resistant pts, n = 150 63%c 30% 9% 0.011d, 0.002e 
Intolerant pts, n = 59 70%c 27% 10% 0.064d, 0.053e 
EFS at 24 Monthsb     
Pts with BL mutations, n = 74 100% 54% 36% 0.011f, 0.582e 
Pts without BL mutations, n = 141 78% 79% 57% 0.946f, 0.026e 
Resistant pts, n = 152 75% 64% 47% 0.138f, 0.188e 
Intolerant pts, n = 63 89% 91% 54% 0.705f, 0.015e 

aExcludes patients with MMR at 3 months

bExcludes patients with event for EFS within first 3 months of therapy

cBCR-ABL% (IS) > 0.1 – ≤ 1

dComparison of > 0.1 – 1 vs > 1 – ≤ 10

eComparison of > 1 – ≤10 vs > 10

fComparison of ≤ 1 vs > 1 – < 10

Disclosures:

Branford:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Kim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Haque:Novartis: Employment. Shou:Novartis: Employment. Woodman:Novartis: Employment. Kantarjian:Novartis: Research Funding. Radich:Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Hochhaus:Novartis: Research Funding.

Author notes

*

Asterisk with author names denotes non-ASH members.