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. 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. 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 if untreated, 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.
In the pre-imatinib era, allogeneic hematopoietic stem cell transplantation (HSCT) was the primary treatment with curative intent for children with CML. Published reports from this period described survival rates of 70% to 80% when an HLA-matched family donor (MFD) was used in the treatment of children in early chronic phase, with lower survival rates when HLA-matched unrelated donors were used.[4-6] Relapse rates were low (less than 20%) when transplant was performed in chronic phase.[4,5] The primary cause of death was treatment-related mortality, which was increased with HLA-matched unrelated donors compared with HLA-MFDs in most reports.[4,5] High-resolution DNA matching for HLA alleles appeared to reduce rates of treatment-related mortality leading to improved outcome for HSCT using unrelated donors. As compared with transplant in chronic phase, transplantation in accelerated or blast crisis, as well as a second chronic phase, resulted in significantly reduced survival.[4-6] The use of T-lymphocyte depletion to avoid graft-versus-host disease resulted in a higher relapse rate and decreased overall survival, supporting the contribution of a graft-versus-leukemia effect to favorable outcome following allogeneic HSCT.
The introduction of the tyrosine kinase inhibitor (TKI) imatinib mesylate (Gleevec) as a therapeutic drug targeted at inhibiting the BCR-ABL fusion kinase revolutionized the treatment of patients with CML for both children and adults. As most data for the use of TKIs for CML is from adult clinical trials, the adult experience is initially described, followed by a description of the more limited experience for children.Treatment of CML in Adults with TKIs
Imatinib mesylate is a potent inhibitor of the ABL tyrosine kinase, and also of PDGF receptors (alpha and beta) and KIT. Imatinib mesylate treatment achieves clinical, cytogenetic, and molecular remissions (as defined by the absence of BCR-ABL fusion transcripts) in a high proportion of CML patients treated in chronic phase. Imatinib mesylate 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 (IRIS).[11,12] Patients receiving imatinib mesylate had higher complete cytogenetic response rates (76% vs. 14% at 18 months)  and 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. 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.
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).[13-15] The identification of BCR-ABL kinase domain mutations at the time of failure or of suboptimal response to imatinib mesylate treatment also 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.[13,17,18] Poor adherence is a major reason for loss of complete cytogenetic response and imatinib mesylate failure for adult CML patients on long-term therapy.
Two additional TKIs have received regulatory approval for the frontline chronic phase CML indication, nilotinib and dasatinib. Dasatinib was approved on the basis of a phase III trial comparing dasatinib (100 mg daily) with imatinib mesylate (400 mg daily). Similarly, nilotinib (at a dose of either 300 mg or 400 mg twice daily) was compared in a phase III trial with imatinib mesylate (400 mg daily). For both agents, superiority over imatinib mesylate was demonstrated for complete cytogenetic response rate and for major molecular response rate, which has led to the use of these agents as first-line therapy in adults with CML. These agents have not been extensively tested in children yet. Additional follow-up will be required to demonstrate the impact of these agents on clinical endpoints such as progression to accelerated/blast phase and overall survival.
Although imatinib mesylate is an active treatment for CML, there is limited evidence that it is curative. Most adults with CML treated with imatinib mesylate continue to have BCR-ABL transcripts detectable by highly sensitive molecular methods, although the rate of molecular complete remission does increase with duration of therapy.[22,23] Six of 12 adults with molecularly undetectable disease who stopped imatinib mesylate lost their molecular remission within 18 months of treatment cessation.[24-26] In the STIM (Stop Imatinib) trial, 100 patients older than 18 years and in complete molecular remission for at least 2 years had imatinib mesylate stopped. Of these patients, 41% maintained a complete molecular remission at 24 months. Further research is required before cessation of imatinib mesylate or other BCR-ABL targeted therapy for selected patients with CML in molecular remission can be recommended as a standard clinical practice.Treatment of CML in Children
Imatinib mesylate has shown a high level of activity in children with CML that is comparable to that observed in adults, with approximately 75% achieving a complete cytogenetic response and with approximately 20% showing an unsatisfactory response to imatinib.[28-30,30,30,31] The pharmacokinetics of imatinib mesylate in children appears consistent with prior results in adults. Doses of imatinib mesylate used in phase II trials for children with CML have been 260 mg/m2 to 340 mg/m2, which provide comparable drug exposures as the adult flat doses of 400 mg to 600 mg.[30,31] Because there are no pediatric-specific data regarding optimal timing of monitoring for BCR-ABL transcript levels and for the presence of BCR-ABL kinase domain mutations, the monitoring guidelines described above for adults with CML are reasonable to utilize.
Imatinib mesylate is generally well tolerated in children, with adverse effects usually being mild to moderate and quickly reversible with treatment discontinuation or dose reduction.[30,31] Growth retardation occurs in some children receiving imatinib mesylate. The growth inhibitory effects of imatinib mesylate appear to be most pronounced in prepubertal children compared to pubertal children, and children receiving imatinib mesylate and experiencing growth impairment may show a return to normal growth rates when they reach puberty.
In children who develop a hematologic or cytogenetic relapse on imatinib mesylate or who have an inadequate initial response to imatinib mesylate, determination of BCR-ABL kinase domain mutation status should be considered to help guide subsequent therapy. Depending upon the patient’s mutation status, alternative kinase inhibitors such as dasatinib or nilotinib can be considered based on adult experience with these agents.[20,21,34-36] A pediatric phase I study of dasatinib showed good tolerance for dasatinib in children at doses used to treat adults with CML, and nilotinib is under investigation in children with CML or Ph chromosome–positive ALL (NCT01077544 [CAMN107A2120]). In the presence of the T315I mutation, which is resistant to all FDA-approved kinase inhibitors, strong consideration should be given to performing an allogeneic transplant.
An important question is the impact of imatinib mesylate treatment on outcome for patients who subsequently proceed to allogeneic HSCT. A retrospective comparison of 145 patients who received imatinib mesylate prior to transplant compared with a historical cohort of 231 patients who did not, showed no difference in early hepatotoxicity or engraftment delay. In addition, overall survival, disease-free survival, relapse, and nonrelapse mortality were similar between the two cohorts. The only factor associated with poor outcome in the cohort that received imatinib mesylate was a poor initial response to imatinib mesylate. Further evidence for a lack of effect of pretransplant imatinib mesylate on posttransplant outcomes was supplied by a report from the Center for International Blood and Marrow Transplant Research comparing outcomes for 181 pediatric and adult subjects with CML in first chronic phase treated with imatinib mesylate before HSCT with that for 657 subjects who did not receive the agent before HSCT. Among the patients in first chronic phase, imatinib mesylate therapy before HSCT was associated with better overall survival. A third report of allogeneic HSCT following imatinib supports the efficacy of the strategy of transplantation of patients with imatinib mesylate failure in first chronic phase; 3-year overall survival was 94% for this group (n = 37) with approximately 90% achieving a complete molecular remission following HSCT. The available data suggest that imatinib mesylate prior to transplant does not have a deleterious effect on outcome.Treatment Options Under Clinical Evaluation
The following are examples of national and/or institutional clinical trials that are currently being conducted for patients with refractory CML.
- In an attempt to reduce the adverse side effects of myeloablative HSCT, investigators are testing reduced-intensity conditioning HSCT.
- Second generation BCR-ABL inhibitors (dasatinib and nilotinib) have been approved by FDA for treatment of imatinib-refractory CML in adults.[20,21] These agents are active against many BCR-ABL mutants that confer resistance to imatinib mesylate, although the agents are ineffective in patients with the T315I BCR-ABL mutation. Dasatinib has been studied in children and tolerance is similar to that observed in adults. A pharmacokinetic study of nilotinib in children with BCR-ABL-positive CML or ALL is ongoing (NCT01077544).
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood chronic myelogenous leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
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