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 is lymphoid, usually of B lineage. Patients in blast crisis will die within a few months.
Before the tyrosine kinase inhibitor era, allogeneic hematopoietic stem cell transplantation (HSCT) was the primary treatment 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. Compared with transplantation in chronic phase, transplantation in accelerated phase or blast crisis and in 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 (OS), supporting the contribution of a graft-versus-leukemia effect to favorable outcome following allogeneic HSCT.
The introduction of the tyrosine kinase inhibitor (TKI) imatinib (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 is a potent inhibitor of the ABL tyrosine kinase, and also of PDGF receptors (alpha and beta) and KIT. Imatinib 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 replaced the use of alpha-interferon in the initial treatment of CML based on the results of a large phase III trial comparing imatinib with interferon plus cytarabine (IRIS).[11,12] Patients receiving imatinib 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 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 was 95% at 60 months.
Guidelines for imatinib 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).[13-16] The identification of BCR-ABL kinase domain mutations at the time of failure or of suboptimal response to imatinib 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.[13,18,19] Poor adherence is a major reason for loss of complete cytogenetic response and imatinib failure for adult CML patients on long-term therapy.
Several 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 (400 mg daily).
- Nilotinib (at a dose of either 300 mg or 400 mg twice daily) was compared in a phase III trial with imatinib (400 mg daily).
- Bosutinib is another TKI that targets the BCR-ABL fusion and has been approved by the U.S. Food and Drug Administration (FDA) for treatment of all phases of CML in adults who show intolerance to or whose disease shows resistance to prior therapy.
For both dasatinib and nilotinib, superiority over imatinib 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. Additional follow-up will be required to demonstrate the impact of these agents on clinical endpoints such as progression to accelerated/blast phase and OS.
The optimal duration of therapy remains unknown and most patients continue TKI treatment indefinitely. However, in an attempt to answer the question of length of treatment, a prospective study reported on 69 adults treated with imatinib for more than 2 years and had been in a cytogenetic major response for more than 2 years. The patients were followed monthly and restarted on imatinib if there was evidence of molecular relapse. Of this group, 61% experienced disease relapse, with about 38% still in cytogenetic major response at 24 months. Of note, all of the patients who had disease recurrence responded again to the reinitiation of imatinib. Another study reported on 12 patients with CML who had been in molecular remission for 32 months and were on imatinib therapy for 45 months before treatment was stopped. At a median follow up of 18 months, 6 of 12 patients remained in remission. Those patients who had disease recurrence responded to reinitiation of imatinib. Further research is required before cessation of imatinib 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 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.[25-28] As a result of this high level of activity, it is common to initiate treatment of children with CML with imatinib rather than proceeding immediately to allogeneic stem cell transplantation. The pharmacokinetics of imatinib in children appears consistent with prior results in adults. Doses of imatinib 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.[27,28] 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 is generally well tolerated in children, with adverse effects usually being mild to moderate and quickly reversible with treatment discontinuation or dose reduction.[27,28] Growth retardation occurs in some children receiving imatinib. The growth inhibitory effects of imatinib appear to be most pronounced in prepubertal children, compared with pubertal children; children receiving imatinib and experiencing growth impairment may show a return to normal growth rates when they reach puberty.
Second generation BCR-ABL inhibitors (dasatinib and nilotinib) have been approved by FDA for treatment of imatinib-refractory CML in adults.[21,22] These agents are active against many BCR-ABL mutants that confer resistance to imatinib, although the agents are ineffective in patients with the T315I BCR-ABL mutation. Based on their activity in adults with CML, other BCR-ABL TKIs have been studied in children. Dasatinib has undergone phase I testing in children and showed drug disposition, tolerability, and efficacy for patients with CML that was similar to that observed in adults.[32,33] Ponatinib is a BCR-ABL inhibitor that is effective against the T315I mutation. Ponatinib induced objective responses in approximately 70% of heavily pretreated adults with chronic phase CML, with responses observed regardless of the baseline BCR-ABL kinase domain mutation. Development of ponatinib has been complicated by the high rate of vascular occlusion observed in patients receiving the agent, with arterial and venous thrombosis and occlusions (including myocardial infarction and stroke) occurring in more than 20% of treated patients. There is no published experience describing the use of ponatinib in children.
In children who develop a hematologic or cytogenetic relapse on imatinib or who have an inadequate initial response to imatinib, 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.[21,22,38-40] 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]). These agents are active against many BCR-ABL mutants that confer resistance to imatinib, although the agents are ineffective in patients with the T315I mutation. 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 unanswered question is the impact of imatinib treatment on outcome for patients who subsequently proceed to allogeneic HSCT. A retrospective study that compared145 patients who received imatinib before transplant with a historical cohort of 231 patients who did not showed no difference in early hepatic toxic effects or engraftment delay. In addition, OS, 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 was a poor initial response to imatinib. Further evidence for a lack of effect of pretransplant imatinib 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 before HSCT with that for 657 subjects who did not receive the agent before HSCT. Among the patients in first chronic phase, imatinib therapy before HSCT was associated with better OS. A third report of imatinib followed by allogeneic HSCT supports the efficacy of this transplantation strategy in patients with imatinib failure in first chronic phase; the 3-year OS rate was 94% for this group (n = 37), with approximately 90% achieving a complete molecular remission after HSCT. Treatment of patients with two different TKIs prior to HSCT also does not appear to influence outcomes of patients in chronic-phase CML. The available data suggest that imatinib before transplant does not have a deleterious effect on outcome.
Treatment Options Under Clinical Evaluation
Based on their activity in adults with CML, other BCR-ABL TKIs are being studied in children. Dasatinib has undergone phase I testing in children and showed drug disposition, tolerability, and efficacy for patients with CML that was similar to that observed in adults. A phase II clinical trial of dasatinib for children with CML is ongoing (NCT00777036). Nilotinib is under investigation in children with CML or Ph chromosome–positive (Ph+) ALL in a clinical trial to determine the pharmacokinetics of nilotinib in children (NCT01077544 [CAMN107A2120]). A phase II evaluation of nilotinib in children with CML has been initiated (NCT01844765).
The following are examples of national and/or institutional clinical trials that are currently being conducted for patients with CML. Information about ongoing clinical trials is available from the NCI Web site
- NCT00777036 (A Phase II Study of Dasatinib in Children and Adolescents With Newly Diagnosed Chronic Phase CML or With Ph+ Leukemias Resistant or Intolerant to Imatinib): A phase II clinical trial of dasatinib is being conducted to determine whether dasatinib is safe and effective in children and adolescents with newly diagnosed CML, or in children with Ph+ ALL, accelerated or blast phases CML who relapse after imatinib or who are resistant or intolerant to imatinib.
- NCT01077544 (A Pharmacokinetic Study of Nilotinib in Pediatric Patients With Ph+ CML or ALL): A clinical trial is assessing the pharmacokinetics of nilotinib in Ph+ CML pediatric patients that are newly diagnosed or resistant or intolerant to imatinib or dasatinib or refractory or relapsed Ph+ ALL. Efficacy and safety are being evaluated as secondary objectives.
- NCT01844765 (Open Label, Phase II Study to Evaluate Efficacy and Safety of Oral Nilotinib in Ph+ CML Pediatric Patients): A phase II clinical trial of nilotinib is evaluating the safety and efficacy of nilotinib in the Ph+ CML in pediatric patients (aged 1 to <18 years).
Current Clinical Trials
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.
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