ABSTRACT
The aim of this retrospective study was to evaluate the toxicity profiles of dasatinib in patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) or acute lymphatic leukemia (ALL) who were intolerant to imatinib, and who had been enrolled in our previous clinical trials to evaluate efficacy of dasatinib in patients resistant or tolerant to imatinib therapy. Twenty-four patients with CML and four with ALL were enrolled in the clinical studies to evaluate the efficacy according to the eligibility criteria related to intolerance to imatinib therapy. The toxicities reported during imatinib therapy were non-hematological toxicities in 23 patients and hematological toxicities in six patients. Patients were administered dasatinib 50-70 mg BID or 100 mg QD. Cross intolerance was observed in four patients who showed hematological toxicity after dasatinib treatment. However, it was possible to successfully continue therapy with only temporary interruption. No cross intolerance in non-hematological toxicity was found with the exception of one patient who showed cross intolerance, which did not result in treatment interruption. Dasatinib can be safely administered to imatinib-intolerant CML or Ph-positive ALL patients.
Subject(s)
Antineoplastic Agents , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Piperazines/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Protein Kinase Inhibitors , Pyrimidines/adverse effects , Pyrimidines/therapeutic use , Thiazoles/adverse effects , Thiazoles/therapeutic use , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Benzamides , Dasatinib , Hematologic Diseases/etiology , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Middle Aged , Piperazines/administration & dosage , Piperazines/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/administration & dosage , Retrospective Studies , Thiazoles/administration & dosageABSTRACT
The incidence of chronic lymphocytic leukemia (CLL) is low in Asian countries including Japan, while CLL is the most common type of leukemia in the west. To elucidate which factors contribute to the low frequency of CLL in Japan, we investigated immunoglobulin (Ig) heavy chain gene usage and somatic hypermutation status in 44 Japanese patients with CLL. Only one of these patients used V(H)1-69. The finding is in striking contrast to data from western countries, where the frequency of CLL expressing V(H)1-69 ranges from 12 to 21%.
Subject(s)
Gene Expression Regulation, Leukemic , Immunoglobulin Heavy Chains/biosynthesis , Immunoglobulin Variable Region/biosynthesis , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Neoplasm Proteins/biosynthesis , Somatic Hypermutation, Immunoglobulin , Adult , Aged , Aged, 80 and over , Female , Humans , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Incidence , Japan , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Middle Aged , Neoplasm Proteins/genetics , Risk Factors , Somatic Hypermutation, Immunoglobulin/geneticsABSTRACT
Eosinophilia sometimes occurs in acute myeloid leukemia (AML), especially in core binding factor (CBF) leukemia. However, the pathogenesis of the differentiation from leukemic progenitors to eosinophils is not well understood in this type of leukemia. Recent reports showed that a novel fusion tyrosine kinase, Fip1-like1 (FIP1L1) platelet-derived growth factor receptor alpha (PDGFRalpha), is found in idiopathic hypereosinophilic syndrome. The involvement of another chimeric gene, PDGFRbeta, was also reported in myeloproliferative disorder with eosinophilia. These chimeric genes cause constitutive activation of PDGFR tyrosine kinases. On the other hand, a two-hit model for the pathogenesis of AML, which seems to be caused by inactivating mutations in transcription factors and genetic lesions in tyrosine kinase resulting in constitutive activation, has been proposed. On the basis of these findings, we screened for the expression of the FIP1L1-PDGFRalpha fusion gene and for mutations in the juxtamembrane and tyrosine kinase domains of PDGFRalpha/beta genes in 22 cases of CBF leukemia with eosinophilia. Among these cases, no FIP1L1-PDGFRalpha fusion gene was found. Although cDNA sequencing also detected three types of single-nucleotide alterations at kinase domains in PDGFRalpha/beta genes, all of them were silent changes and polymorphisms. Therefore, PDGFRalpha/beta genes do not appear to play a significant pathogenetic role in eosinophilia or leukemogenesis of CBF leukemia.
