Dasatinib in Chronic Myelogenous Leukemia
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《新英格兰医药杂志》
To the Editor: According to the findings of Talpaz et al. (June 15 issue),1 the efficacy and safety profile of dasatinib therapy in patients with Philadelphia chromosome–positive leukemias and resistance to or intolerance of imatinib seem promising. Nevertheless, pleural effusions developed in about 20% of the patients. The authors do not mention how many patients had to undergo thoracentesis or pleurodesis, or whether this complication was dose-dependent.
Satheesh K. Kathula, M.D.
Wright State University
Dayton, OH 45409
kathulask@yahoo.com
References
Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006;354:2531-2541.
To the Editor: Talpaz et al. reported that dasatinib induces a durable response in a broad range of patients with imatinib-resistant BCR-ABL mutations who have chronic myelogenous leukemia (CML). We describe a novel splicing mutation in a 39-year-old man with chronic-phase CML and cytogenetic resistance to imatinib after 9 months of treatment. Treatment with 70 mg of dasatinib twice daily in a phase 2 trial resulted in a complete cytogenetic remission in 3 months and a reduction in the level of the BCR-ABL transcript from 21.5% to 0.18%, as expressed by the international scale.1 Sequencing revealed the insertion of a 35-bp portion of intron 8 (GenBank accession no., U07563 ; bases 74478 to 74512), which contained a stop codon, TAG, into the ABL junction between exons 8 and 9. This splicing mutation predicted the premature termination of translation at P484R and a truncated ABL at its C terminal, which is important for the stability of the inactive conformation.
Unlike imatinib, dasatinib binds to the ABL kinase domain in both the active and inactive conformations (Figure 1).2 Our finding provides support for the idea that dasatinib may be able to overcome mutations that are distant from the imatinib-binding site of ABL, including the splicing mutation described here.
Figure 1. ABL Junctions and ABL–Dasatinib Structure.
Panel A shows the insertion of a 35-bp portion of intron 8 into the ABL junction between exons 8 and 9; this partial intron 8 contained a stop codon, TAG. The splicing mutation predicts the premature termination of translation at P484R. Panel B shows the ABL–dasatinib structure from two angles; the P484 and subsequent residues (484 to 500) observed on x-ray crystallography are shown in blue.
Sung-Chao Chu, M.D.
Buddhist Tzu Chi General Hospital
Hualien 97002, Taiwan
Jih-Luh Tang, M.D., Ph.D.
National Taiwan University Hospital
Taipei 10002, Taiwan
Chi-Cheng Li, M.D.
Buddhist Tzu Chi General Hospital
Hualien 97002, Taiwan
kevinlcc1234@yahoo.com.tw
Dr. Tang reports having served as a principal investigator in a phase 2 dasatinib trial (ClinicalTrials.gov number, NCT00123487 ).
References
Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006;108:28-37.
Tokarski JS, Newitt J, Chang CYJ, et al. The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res 2006;66:5790-5797.
The authors reply: Dr. Kathula requests details regarding the development of pleural effusions in dasatinib-treated patients. In our phase 1 study, 10 patients underwent thoracentesis and 2 underwent pleurodesis. Of the 10 patients, 4 had chronic-phase CML and 6 were in blast crisis. All 10 patients received dasatinib twice daily at total daily doses ranging from 50 to 240 mg.
The rate of drug-related pleural effusion was 21% in a series of five phase 2 studies involving a total of 511 patients with chronic phase, accelerated phase, blast crisis, or Philadelphia chromosome–positive acute lymphoid leukemia. Full details of these studies have not yet been reported, but 28% of the patients had pleural effusions while receiving dasatinib at doses of less than 140 mg per day, with treatment administered twice daily. A randomized study now under way comparing once- with twice-daily treatment with dasatinib at a dose of 100 or 140 mg daily could determine whether the dose of this agent and the schedule affect the incidence of pleural effusion.
Charles L. Sawyers, M.D.
Howard Hughes Medical Institute
Los Angeles, CA 90095
csawyers@mednet.ucla.edu
Moshe Talpaz, M.D.
University of Michigan
Ann Arbor, MI 48109
Eric Bleickardt, M.D.
Bristol-Myers Squibb
Wallingford, CT 06492
Satheesh K. Kathula, M.D.
Wright State University
Dayton, OH 45409
kathulask@yahoo.com
References
Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006;354:2531-2541.
To the Editor: Talpaz et al. reported that dasatinib induces a durable response in a broad range of patients with imatinib-resistant BCR-ABL mutations who have chronic myelogenous leukemia (CML). We describe a novel splicing mutation in a 39-year-old man with chronic-phase CML and cytogenetic resistance to imatinib after 9 months of treatment. Treatment with 70 mg of dasatinib twice daily in a phase 2 trial resulted in a complete cytogenetic remission in 3 months and a reduction in the level of the BCR-ABL transcript from 21.5% to 0.18%, as expressed by the international scale.1 Sequencing revealed the insertion of a 35-bp portion of intron 8 (GenBank accession no., U07563 ; bases 74478 to 74512), which contained a stop codon, TAG, into the ABL junction between exons 8 and 9. This splicing mutation predicted the premature termination of translation at P484R and a truncated ABL at its C terminal, which is important for the stability of the inactive conformation.
Unlike imatinib, dasatinib binds to the ABL kinase domain in both the active and inactive conformations (Figure 1).2 Our finding provides support for the idea that dasatinib may be able to overcome mutations that are distant from the imatinib-binding site of ABL, including the splicing mutation described here.
Figure 1. ABL Junctions and ABL–Dasatinib Structure.
Panel A shows the insertion of a 35-bp portion of intron 8 into the ABL junction between exons 8 and 9; this partial intron 8 contained a stop codon, TAG. The splicing mutation predicts the premature termination of translation at P484R. Panel B shows the ABL–dasatinib structure from two angles; the P484 and subsequent residues (484 to 500) observed on x-ray crystallography are shown in blue.
Sung-Chao Chu, M.D.
Buddhist Tzu Chi General Hospital
Hualien 97002, Taiwan
Jih-Luh Tang, M.D., Ph.D.
National Taiwan University Hospital
Taipei 10002, Taiwan
Chi-Cheng Li, M.D.
Buddhist Tzu Chi General Hospital
Hualien 97002, Taiwan
kevinlcc1234@yahoo.com.tw
Dr. Tang reports having served as a principal investigator in a phase 2 dasatinib trial (ClinicalTrials.gov number, NCT00123487 ).
References
Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006;108:28-37.
Tokarski JS, Newitt J, Chang CYJ, et al. The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res 2006;66:5790-5797.
The authors reply: Dr. Kathula requests details regarding the development of pleural effusions in dasatinib-treated patients. In our phase 1 study, 10 patients underwent thoracentesis and 2 underwent pleurodesis. Of the 10 patients, 4 had chronic-phase CML and 6 were in blast crisis. All 10 patients received dasatinib twice daily at total daily doses ranging from 50 to 240 mg.
The rate of drug-related pleural effusion was 21% in a series of five phase 2 studies involving a total of 511 patients with chronic phase, accelerated phase, blast crisis, or Philadelphia chromosome–positive acute lymphoid leukemia. Full details of these studies have not yet been reported, but 28% of the patients had pleural effusions while receiving dasatinib at doses of less than 140 mg per day, with treatment administered twice daily. A randomized study now under way comparing once- with twice-daily treatment with dasatinib at a dose of 100 or 140 mg daily could determine whether the dose of this agent and the schedule affect the incidence of pleural effusion.
Charles L. Sawyers, M.D.
Howard Hughes Medical Institute
Los Angeles, CA 90095
csawyers@mednet.ucla.edu
Moshe Talpaz, M.D.
University of Michigan
Ann Arbor, MI 48109
Eric Bleickardt, M.D.
Bristol-Myers Squibb
Wallingford, CT 06492