Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment

• Published in: Blood Vol. 101; no. 12; pp. 4701 - 4707
• Main Authors: Bhatia, Ravi, Holtz, Melissa, Niu, Ning, Gray, Rachel, Snyder, David S., Sawyers, Charles L., Arber, Daniel A., Slovak, Marilyn L., Forman, Stephen J.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.06.2003; The Americain Society of Hematology
• Subjects: Adult; Aged; Antigens, CD34 - analysis; Benzamides; Biological and medical sciences; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 8; Chromosomes, Human, Pair 9; Enzyme Inhibitors - therapeutic use; Female; Fusion Proteins, bcr-abl - genetics; Hematologic and hematopoietic diseases; Hematopoietic Stem Cells - pathology; Humans; Imatinib Mesylate; In Situ Hybridization, Fluorescence; Karyotyping; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Piperazines - therapeutic use; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrimidines - therapeutic use; Remission Induction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Translocation, Genetic; Trisomy; Human; Enzyme; Transferases; Stem cell; Imatinib mesylate; Hematopoietic cell; Enzyme inhibitor; Minimal residual disease; Malignant hemopathy; Myeloproliferative syndrome; Chemotherapy; Chronic; Treatment; Protein kinase; Chronic myelocytic leukemia; Remission; Fusion protein; Hybrid gene
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2002-09-2780

The BCR/ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec, STI571; Novartis, Basel, Switzerland) has shown remarkable efficacy in the treatment of chronic myelogenous leukemia (CML), with a high proportion of patients achieving complete cytogenetic responses (CCRs). However, it is not clear whether remissions will be durable and whether imatinib mesylate can eliminate the malignant primitive progenitors in which the disease arises. We investigated whether residual BCR/ABL+ hematopoietic progenitors were present in patients who achieved CCRs with imatinib mesylate treatment. CD34+ progenitor cells were selected from bone marrow mononuclear cells (MNCs) and analyzed for the presence of the BCR/ABL fusion gene by fluorescence in situ hybridization (FISH). CD34+ cells were also plated in committed progenitor (colony-forming cell, or CFC) and primitive progenitor (long-term bone marrow culture-initiating cell, or LTCIC) cultures and resulting colonies analyzed for the presence of BCR/ABL+ cells by FISH. Using these assays, residual BCR/ABL+ progenitors were detected in all patients studied. Quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) analysis demonstrated increased levels of BCR/ABL mRNA in CD34+ cells compared with total MNCs. Evaluation of samples collected at different time points demonstrated persistence of BCR/ABL+ progenitors despite continued treatment with imatinib mesylate. Our results indicate that inhibition of BCR/ABL tyrosine kinase activity by imatinib mesylate does not eliminate malignant primitive progenitors in CML patients. Patients in CCR with imatinib mesylate treatment need to be followed carefully to assess for risk of relapse.