Dasatinib in Chronic Myelogenous Leukemia

4 downloads 115 Views 249KB Size Report
Sep 7, 2006 - The new england journal of medicine correspondence. Dasatinib in Chronic Myelogenous Leukemia. To the Editor: According to the findings of.
The

n e w e ng l a n d j o u r na l

of

m e dic i n e

c or r e sp ondence

Dasatinib in Chronic Myelogenous Leukemia 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.

tions 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 Wright State University Dayton, OH 45409 a stop codon, TAG, into the ABL junction between [email protected] exons 8 and 9. This splicing mutation predicted 1. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib- the premature termination of translation at P484R resistant Philadelphia chromosome–positive leukemias. N Engl and a truncated ABL at its C terminal, which is J Med 2006;354:2531-41. important for the stability of the inactive conformation. To the Editor: Talpaz et al. reported that dasatUnlike imatinib, dasatinib binds to the ABL inib induces a durable response in a broad range kinase domain in both the active and inactive of patients with imatinib-resistant BCR-ABL muta- conformations (Fig. 1).2 Our finding provides support for the idea that dasatinib may be able to overcome mutations that are distant from the this week’s letters imatinib-binding site of ABL, including the splic1062 Dasatinib in Chronic Myelogenous Leukemia ing mutation described here. Sung-Chao Chu, M.D. 1064 Genomic Diagnosis of Burkitt’s Lymphoma 1065 Vitamins C and E and the Prevention of Preeclampsia

Buddhist Tzu Chi General Hospital Hualien 97002, Taiwan

Jih-Luh Tang, M.D., Ph.D. National Taiwan University Hospital Taipei 10002, Taiwan

1067 Panic Disorder 1067 Measured and Estimated Glomerular Filtration Rate 1070 Hematopoietic Stem-Cell Transplantation 1071 Molecular Profiling of a Tumor of Unknown Origin

Chi-Cheng Li, M.D. Buddhist Tzu Chi General Hospital Hualien 97002, Taiwan [email protected] Dr. Tang reports having served as a principal investigator in a phase 2 dasatinib trial (ClinicalTrials.gov no., NCT100123487). 1. Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML

patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current method-

1062

n engl j med 355;10

www.nejm.org

september 7, 2006

The New England Journal of Medicine as published by New England Journal of Medicine. Downloaded from www.nejm.org at BUDDHIST TZU CHI GEN HOSPITAL on August 4, 2010. For personal use only. No other uses without permission. Copyright © 2006 Massachusetts Medical Society. All rights reserved.

correspondence

A ABL

Exon 8

Exon 9

Partial intron 8 (35 bp) ACTTTGATAACCGTGAAGAAAGAACAAGATAGAAG

Coded Amino Acids of ABL Wild type Mutated type

C475–P484: C-W-Q-W-N-P-S-D-R-P C475Y–P484R: Y-F-D-N-R-E-E-R-T-R-Stop

B

Dasatinib

90-Degree rotation

P484 P484

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.

10 patients underwent thoracentesis and 2 underwent pleurodesis. Of the 10 patients, 4 had chronicphase 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 The authors reply: Dr. Kathula requests details 21% in a series of five phase 2 studies involving regarding the development of pleural effusions in a total of 511 patients with chronic phase, acceldasatinib-treated patients. In our phase 1 study, erated phase, blast crisis, or Philadelphia chromoology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006;108:28-37. 2. 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;66:5790-7.

n engl j med 355;10

www.nejm.org

september 7, 2006

1063

The New England Journal of Medicine as published by New England Journal of Medicine. Downloaded from www.nejm.org at BUDDHIST TZU CHI GEN HOSPITAL on August 4, 2010. For personal use only. No other uses without permission. Copyright © 2006 Massachusetts Medical Society. All rights reserved.

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

some–positive acute lymphoid leukemia. Full de- Charles L. Sawyers, M.D. tails of these studies have not yet been reported, Howard Hughes Medical Institute but 28% of the patients had pleural effusions Los Angeles, CA 90095 [email protected] while receiving dasatinib at doses of less than 140 mg per day, with treatment administered Moshe Talpaz, M.D. twice daily. A randomized study now under way University of Michigan comparing once- with twice-daily treatment with Ann Arbor, MI 48109 dasatinib at a dose of 100 or 140 mg daily could Eric Bleickardt, M.D. determine whether the dose of this agent and the Bristol-Myers Squibb schedule affect the incidence of pleural effusion. Wallingford, CT 06492

Genomic Diagnosis of Burkitt’s Lymphoma To the Editor: In the article by Dave et al. (June 8 issue)1 concerning the molecular diagnosis of Burkitt’s lymphoma, almost half the patients with Burkitt’s lymphoma were children. The data in the companion article by Hummel et al.2 were not stratified according to age. If the patients are separated into adults and children, are the results similar? Can the same method be applied to patients with immunodeficiency? Bryan T. Lin, M.D., Ph.D. Encino–Tarzana Regional Medical Center Tarzana, CA 91356 [email protected] 1. Dave SS, Fu K, Wright GW, et al. Molecular diagnosis of

Burkitt’s lymphoma. N Engl J Med 2006;354:2431-42. 2. Hummel M, Bentink S, Berger H, et al. A biologic definition of Burkitt’s lymphoma from transcriptional and genomic profiling. N Engl J Med 2006;354:2419-30.

Drs. Dave and Staudt Reply: The tumors from children and adults with Burkitt’s lymphoma were indistinguishable on the basis of the expression of the predictor genes. There was also no difference in outcome between children and adults who received intensive therapies. However, all nine Burkitt’s lymphoma–discrepant cases (i.e., cases of Burkitt’s lymphoma identified on the basis of gene expression but not standard diagnostic methods) were in adults. Thus, cases in adults may be more variable with regard to morphologic characteristics and other diagnostic criteria than in cases in children, perhaps reflecting the influence of additional genomic abnormalities in adults. Although our study did not examine tumors from Burkitt’s lymphoma associated with immu-

1064

n engl j med 355;10

nodeficiency, it seems to be likely that this type of Burkitt’s lymphoma would share the geneexpression hallmarks of sporadic Burkitt’s lymphoma, but this possibility requires a separate study. The turnaround time for a diagnosis based on DNA microarray could be about 48 hours, which is similar to that for conventional methods used in the diagnosis of Burkitt’s lymphoma. We agree with Dr. Lin that correctly distinguishing Burkitt’s lymphoma from diffuse large B-cell lymphoma is critical, since it dictates the optimal treatment for each patient. Sandeep S. Dave, M.D. Louis M. Staudt, M.D., Ph.D. National Cancer Institute Bethesda, MD 20892 [email protected]

Dr. Hummel and colleagues Reply: In our study, 24 of 44 cases of molecular Burkitt’s lymphoma (mBL), 1 of 128 non-mBL cases, and 6 of 48 intermediate cases arose in children (