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3408 Clinical Outcomes In Patients with Chronic Myelogenous Leukemia (CML) and the BCR-ABL 35 Base Pair (bp) Intron 8 Insertion Mutation

Program: Oral and Poster Abstracts
Session: Chronic Myeloid Leukemia - Therapy: Poster III
Monday, December 6, 2010, 6:00 PM-8:00 PM
Hall A3/A4 (Orange County Convention Center)
Poster Board III-187

Ellin Berman, MD1, Jorge Cortes, MD2, Hagop M. Kantarjian, MD3, Thomas O'Hare, PhD4*, Christopher Eide, BS4*, Richard D. Press, MD, PhD5, Brian J Druker, MD6 and Cyrus V. Hedvat, MD, PhD7

1Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
2Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX
3Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
4Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR
5Prof. & Dir. of Molecular Pathology Pathology, Oregon Health & Science Univ., Portland, OR
6Division of Hematology and Medical Oncology, Oregon and Health and Science University Knight Cancer Institute, Portland, OR
7Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY

More than 80% of patients (pts) with CML who are treated with imatinib as first line therapy achieve a complete cytogenetic response (CCR), although approximately 20% of these pts may ultimately progress. The most common mechanism for loss of response is acquired resistance to imatinib due to the development of a point mutation in the ABL kinase domain of BCR-ABL that interferes with optimal imatinib  binding.  An alternatively spliced BCR-ABL mRNA with a 35 bp insertion between exons 8 and 9 was first described in 2008 (Laudadio, 2008: Lee, 2008); this results  in a BCR-ABL protein with 10 novel amino acids inserted after amino acid 474 within the C- terminus of the kinase domain followed by a stop codon.  However, clinical responses to imatinib, dasatinib, or nilotinib have not been previously described in patients with this mutation.  We retrospectively identified 40 pts who had this mutation detected and describe their clinical outcomes.  Of the 40 patients, 24 were male, and the median age was 50, (range 16-70). Six patients had received treatment prior to 2001, and all 40 patients began initial therapy with imatinib.  Twenty nine pts had mutation testing done because of either disease progression or lack of response to imatinib and in 9 pts, the mutation was detected during retrospective analysis. Two pts had the mutation detected at the time of diagnosis (one is still on imatinib). Six pts had additional mutations detected simultaneously:  E255V, E355G, E450G, T315I with F416L, T315I with E255K, and one with another insertion between exons 4 and 5. The median time from start of imatinib to insertion mutation detection was 36 months (range 0-189).  Thirty of the 40 pts (75%) either did not tolerate (n=2) or progressed while on therapy with imatinib (n=28). Eleven pts remain on imatinib, although 5 are on doses of 600 mg/day or higher. Eighteen of the 30 pts (60%) who failed imatinib were changed to dasatinib as second line therapy; 10 of these (56%) did not respond and were changed to nilotinib as third line therapy. Ten of the 30 pts (30%) who did not respond to imatinib were changed to nilotinib as second line therapy; 3 pts achieved an MCR.  In summary, this report provides the first clinical summary of pts with CML who have the 35 bp intron 8 insertion mutation. Although it is not clear whether this insertion mutation directly leads to imatinib resistance, given that 75% of pts progressed on standard dose imatinib, other alternative therapies should be considered once this mutation is detected. However, given the small numbers of pts treated with dasatinib or nilotinib as second line therapy, it is difficult to determine whether either has a superior effect.  Results of biochemical and cellular studies comparing the relative sensitivity of the BCR-ABL 35 bp intron 8 insertion mutation to several ABL kinase inhibitors will be presented.   

Table 1. Response summary for patients with BCR-ABL 35 bp intron 8 insertion mutation.

 

Number of patients (%)

Failure or progression on first-line imatinib

30/40 (75%)

Failure or progression on second-line dasatinib

10/18 (56%)

Failure or progression on second-line nilotinib

7/10 (70%)

Kinase domain mutation concurrently detected with 35 bp insertion mutation

6/40 (15%)

Received non-TKI treatment prior to front-line imatinib

6/40 (15%)

Disclosures: Berman: Novartis Inc: Research Funding. Kantarjian: Genzyme: Research Funding; Eisai: Research Funding. Druker: Molecular MD: Equity Ownership.

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