Hematopathology / IMATINIB MESYLATE (GLEEVEC) FOR CHRONIC MYELOID LEUKEMIA Chronic Myeloid Leukemia Following Therapy With Imatinib Mesylate (Gleevec) Bone Marrow Histopathology and Correlation With Genetic Status

We evaluated bone marrow pathologic features and cytogenetic and molecular genetic status of 13 patients with interferon-resistant, chronic-phase chronic myeloid leukemia (CML), treated with imatinib mesylate (Gleevec). All had morphologic evidence of CML in the blood and bone marrow and were positive for bcr-abl by reverse transcriptase–polymerase chain reaction, fluorescence in situ hybridization (FISH), or both. Follow-up marrow biopsies, interphase FISH for bcrabl, and conventional cytogenetics were performed at 3-month intervals (up to 24 months) after therapy initiation. All patients exhibited a reduction in bone marrow cellularity with decreases in myeloid/erythroid ratios at 3 to 6 months after therapy. The percentage of bcr-abl–positive cells by FISH decreased in all patients (pretherapy median, 73%; 3 months median, 47%). Cytogenetic and FISH data defined 2 groups after 6 months of follow-up: 5 patients became negative for bcr-abl by FISH; 8 remained positive, 4 of whom developed signs of clonal cytogenetic evolution. Patients who became negative for bcr-abl had no morphologic evidence of CML at 15 to 24 months of follow-up, whereas patients who remained positive redeveloped morphologic features of CML as cellularity increased. Some bcr-abl–positive patients showed signs of progression, including 2 patients who developed myeloid blast phase. Although all patients demonstrated an initial decrease in bone marrow cellularity after imatinib mesylate therapy, continued follow-up showed that histopathologic findings correlated with genetic response. Chronic myeloid leukemia (CML) is a clonal stem cell disorder characterized by excessive proliferation of cells of the myeloid series. The hallmark of CML is the Philadelphia chromosome that arises from a reciprocal translocation between chromosomes 9 and 22.1,2 The molecular consequence of this translocation is a bcr-abl chimeric gene whose protein product (bcr-abl) exhibits enhanced tyrosine kinase activity. This constitutively activated enzyme activity is essential to the transforming function of bcr-abl and is a major factor in the pathophysiology of CML.3 The presence of bcr-abl in all patients with CML and the requirement of kinase activity for bcr-abl function make this an attractive target for a selective kinase inhibitor. In the 1990s, Druker and colleagues4 discovered a molecule, imatinib mesylate, that inhibited bcr-abl kinase activity.4,5 This novel inhibitor was shown to be highly effective in blocking abl tyrosine kinase activity by binding and inactivating the adenosine triphosphate–binding pocket of abl6 in the leukemic cells in CML. It also inhibited the stem cell factor receptor c-kit (CD117)7 and the plateletderived growth factor receptor8 but had little effect on other tyrosine kinases. These encouraging laboratory findings led to clinical trials of imatinib mesylate, which included patients with chronic-phase CML in whom treatment with interferon had failed9 and patients with CML in blast crisis or Philadelphia chromosome–positive acute lymphoblastic leukemia.10 Treatment with this agent reduced the leukocyte count to less than 10,000/μL (10.0 × 109/L) within weeks in patients with chronic-phase CML. In many cases, cytogenetic analysis showed a reduction of the proportion of metaphases positive for the Philadelphia chromosome to low levels or to zero. Am J Clin Pathol 2003;119:833-841 833 833 DOI: 10.1309/A4RGP4LF12GGH8MW 833 © American Society for Clinical Pathology Frater et al / IMATINIB MESYLATE (GLEEVEC) FOR CHRONIC MYELOID LEUKEMIA Imatinib mesylate (Gleevec, Novartis, Basel, Switzerland) also showed substantial activity against blast crisis of CML and Philadelphia chromosome–positive acute lymphoblastic leukemia.10 The patients tolerated the agent well and experienced few side effects. In May 2001, STI571 (imatinib mesylate) was licensed for use in the United States.11 Follow-up of patients treated with imatinib mesylate is still short, but it has emerged as the treatment of choice in CML, particularly in patients without a suitable donor for hematopoietic stem cell transplantation.12 Imatinib mesylate is effective against gastrointestinal stromal tumor,13-15 nearly all cases of which are positive for CD117/c-kit. Therefore, it is important that clinicians and pathologists be familiar with the hematologic changes that occur after therapy with this agent. The purpose of this article is to report the bone marrow biopsy characteristics of patients with CML who were treated with imatinib mesylate. Bone marrow findings were correlated with the genetic status of the patients at the time of the biopsies. Materials and Methods