Chronic Myelogenous Leukemia
Chronic myelogenous leukemia (CML) accounts for less than 5% of all childhood leukemia, and in the pediatric age range, occurs most commonly in older adolescents.[1] The cytogenetic abnormality most characteristic of CML is the Philadelphia chromosome (Ph), which represents a translocation of chromosomes 9 and 22 (t[9;22]) resulting in a bcr-abl fusion protein.[2] CML is characterized by a marked leukocytosis and is often associated with thrombocytosis, sometimes with abnormal platelet function. Bone marrow aspiration or biopsy reveals hypercellularity with relatively normal granulocytic maturation and no significant increase in leukemic blasts. Although reduced leukocyte alkaline phosphatase activity is seen in CML, this is not a specific finding.
CML has three clinical phases: chronic, accelerated, and blast crisis. Chronic phase, which lasts for approximately 3 years, usually presents with side effects secondary to hyperleukocytosis such as weakness, fever, night sweats, bone pain, respiratory distress, priapism, left upper quadrant pain (splenomegaly), and, rarely, hearing loss and visual disturbances. The accelerated phase is characterized by progressive splenomegaly, thrombocytopenia, and increased percentage of peripheral and bone marrow blasts, along with accumulation of karyotypic abnormalities in addition to the Ph chromosome. Blast crisis is notable for the bone marrow, showing greater than 30% blasts and a clinical picture that is indistinguishable from acute leukemia. Approximately two-thirds of blast crisis is myeloid and the remainder lymphoid, usually of B lineage. Patients in blast crisis will die within a few months.[3]
The only known curative treatment for CML is allogeneic hematopoietic stem cell transplantation (HSCT). Published reports describe survival rates of 70% to 80% when an HLA-matched family donor (MFD) is used in the treatment of children in early chronic phase, with lower survival rates when HLA-matched unrelated donors are used.[4,5,6] Relapse rates are low (less than 20%) when transplant is performed in chronic phase.[4,5] The primary cause of death is treatment-related mortality, which is increased with HLA-matched unrelated donors compared with HLA-MFDs in most reports.[4,5] High-resolution DNA matching for HLA alleles may reduce rates of treatment-related mortality leading to improved outcome for HSCT using unrelated donors.[7] As compared with transplant in chronic phase, transplantation in accelerated or blast crisis as well as a second chronic phase results in significantly reduced survival.[4,5,6] The use of T-lymphocyte depletion to avoid graft-versus-host disease results in a higher relapse rate and overall decreased survival,[8] supporting the contribution of a graft-versus-leukemia effect to favorable outcome following allogeneic HSCT.
The introduction of imatinib mesylate (Gleevec) as a therapeutic drug targeted at inhibiting the bcr-abl fusion kinase has revolutionized the treatment of patients with CML.[9] Imatinib mesylate treatment can achieve clinical, cytogenetic, and molecular remissions (as defined by the absence of bcr-abl fusion transcripts) in a high proportion of patients when treated in chronic phase.[10] Imatinib mesylate has replaced the use of alpha-interferon in the initial treatment of CML based on the results of a large phase III trial comparing imatinib mesylate with interferon plus cytarabine.[11,12] Patients receiving imatinib mesylate had higher complete cytogenetic response rates (76% vs. 14%) and had a complete cytogenetic rate of 87% at 5 years. The rate of treatment failure diminished over time, from 3.3% and 7.5% in the first and second years of imatinib mesylate treatment, respectively, to less than 1% by the fifth year of treatment.[12] After censoring for patients who died from causes unrelated to CML or transplantation, the overall estimated survival rate for patients randomly assigned to imatinib mesylate was 95% at 60 months.[12] Guidelines for imatinib mesylate treatment have been developed for adults with CML based on patient response to treatment, including the timing of achieving complete hematologic response, complete cytogenetic response, and major molecular response (defined as attainment of a 3-log reduction in BCR-ABL/control gene ratio).[13,14,15] Development of BCR-ABL kinase domain mutations during imatinib mesylate treatment also appears to identify a group of patients at high risk of disease progression.[16] Identification of these kinase domain mutations has clinical implications, as there are alternative bcr-abl kinase inhibitors (e.g., dasatinib and nilotinib) that maintain their activity against some (but not all) mutations that confer resistance to imatinib mesylate.[17,18]
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