Abstract

The BCR-ABL T315I mutation is one of the major mechanisms of resistance to tyrosine kinase inhibitors (TKIs). Limited data have suggested that patients harboring a T315I mutation have poor outcomes. The objectives of this study were to estimate overall (OS) and progression-free survival (PFS) for CML in chronic (CP), accelerated (AP), or blastic (BP) phase, and Ph+ ALL patients who developed a T315I mutation; and describe the treatment pattern after T315I detection.

Methods: This was a retrospective, multicenter observational study. Eligible patients included CML and Ph+ ALL patients who developed T315I mutation between 1999 and 2008. The medical records of 222 patients from 9 countries (France, Italy, Korea, USA, Germany, Singapore, Denmark, UK and Japan) were abstracted, and Kaplan-Meier plots and Cox proportional hazard models were used for survival analysis.

Results: Median age at T315I detection was 54 (range, 18–84) years; 57% were male; 75% were Caucasian and 22% were Asian. Before T315I detection, 97% patients received imatinib (25% as a 1st line) and 50% received second generation TKIs. 16% of patients had other mutations detected before T315I detection. The median time between TKI treatment start and T315I detection was 29 months for CP, 15 for AP, 6 for BP, and 9 for Ph+ ALL. After T315I detection, 56% patients received second generation TKIs (30% started after T315I detection), 39% received hydroxyurea (33% started after T315I detection), 35% received imatinib (13% started after T315I detection), 26% received cytarabine, 21% received investigational drugs including 11% MK-0457, 17% underwent stem cell transplantation, and 6% received interferon alpha (5% started after T315I detection). At the time of T315I detection, T315I formed the predominant clone in 87% of patients; 23% had additional mutations detected (11% of these P-loop mutations). OS and PFS from T315I mutation detection are summarized in Table 1. In a preliminary analysis, the following covariates were associated with worse OS in Cox proportional hazard model (adjusted hazard ratio, 95% confidence interval): older age (by median, 2.30, 1.04–5.09) in Ph+ ALL patients, female gender in BP (1.73, 0.96–3.10); worse performance status in Ph+ ALL (1+ vs. 0; 2.18, 1.02–4.68); and detection of T315I by direct sequencing (vs. other methods) in AP (3.03, 0.89–10.29) and Ph+ ALL (2.33, 1.06–5.12). The effect of different treatments on OS will be available at the time of presentation.

Conclusion: These results confirm that survival of patients harboring a T315I mutation is dependent on the disease phase at T315I detection. No clear treatment pattern after T315I detection was observed. Age, gender, performance status, and techniques used for T315I detection might be important prognosis factors affecting OS across different phases of CML and Ph+ ALL.

Table 1. OS and PFS of CML and Ph+ ALL patients from T315I detection

 CML CP (N=82) CML AP (N=38) CML BP (N=56) Ph+ ALL (N=46) 
* Median survival and survival rates were calculated using Kaplan-Meier method. 
Median follow up time (months) 12.4 15.2 3.0 3.6 
Median OS (months) (95% CI) 22.4 (18.2, 48.5) 28.4 (15.9, 49.8) 4.0 (2.0, 5.0) 4.9 (3.4, 7.3) 
1-year OS Rate (95% CI) 71% (58–80%) 69% (50–81%) 23% (13–36%) 12% (3–27%) 
Median PFS (months) (95% CI) 11.5 (9.2, 15.7) 22.2 (9.0, N/A ) 1.8 (1.2, 4.0) 2.5 (1.8, 3.6) 
1-year PFS Rate (95% CI) 46% (34–57%) 56% (38–70%) 16% (7–27%) 7% (1–19%) 
 CML CP (N=82) CML AP (N=38) CML BP (N=56) Ph+ ALL (N=46) 
* Median survival and survival rates were calculated using Kaplan-Meier method. 
Median follow up time (months) 12.4 15.2 3.0 3.6 
Median OS (months) (95% CI) 22.4 (18.2, 48.5) 28.4 (15.9, 49.8) 4.0 (2.0, 5.0) 4.9 (3.4, 7.3) 
1-year OS Rate (95% CI) 71% (58–80%) 69% (50–81%) 23% (13–36%) 12% (3–27%) 
Median PFS (months) (95% CI) 11.5 (9.2, 15.7) 22.2 (9.0, N/A ) 1.8 (1.2, 4.0) 2.5 (1.8, 3.6) 
1-year PFS Rate (95% CI) 46% (34–57%) 56% (38–70%) 16% (7–27%) 7% (1–19%) 

Disclosures: Nicolini:Merck: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Pearson:Merck: Employment. Peter:Merck: Employment. Sanz Rodriguez:Merck: Employment. Zhou:Merck: Employment.

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