Childhood chronic myelogenous leukemia (CML) is a rare hematologic disease, with limited literature on the methods of treatment. Previously, allogeneic hematopoietic stem cell transplantation (HSCT) was considered the only curative treatment for this disease. Treatment with imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase (TKI), has resulted in prolonged molecular response with limited drug toxicity. Imatinib is now implemented in the primary treatment regimen for children, but the paucity of evidence on its ability to result in permanent cure and the potential complications that may arise from long-term treatment with TKIs have prevented imatinib from superseding HSCT as the primary means of curative treatment in children. The results of allogeneic HSCT in children with CML are similar to those observed in adults; HSCT-related complications such as transplant-related mortality and graft-versus-host disease remain significant challenges. An overall consensus has been formed with regards to the need for HSCT in patients with imatinib resistance or those with advanced-phase disease. However, issues such as when to undertake HSCT in chronic-phase CML patients or how best to treat patients who have relapsed after HSCT are still controversial. The imatinib era calls for a reevaluation of the role of HSCT in the treatment of CML. Specific guidelines for the treatment of pediatric CML have not yet been formulated, underscoring the importance of prospective studies on issues such as duration of imatinib treatment, optimal timing of HSCT and the type of conditioning utilized, possible treatment pre- and post-HSCT, and the role of second-generation TKIs.
Chronic myelogenous leukemia (CML) is a very rare disease in children, with less than 10% of all CML cases diagnosed in children and adolescents. CML accounts for 3-5% of all childhood leukemias, and has an annual incidence of 1 in 1,000,000
CML is a myeloproliferative disorder defined by the presence of the Philadelphia chromosome, which arises from the reciprocal translocation of genes on chromosomes 9 and 22. It is characterized by the proliferation of a malignant clone containing the Philadelphia chromosome, resulting in bone marrow hyperplasia and peripheral blood leukocytosis and thrombocytosis. The Philadelphia chromosome in CML, t(9;22)(q34;q11), was named in 1960 after the city in which it was first discovered. It consists of a juxtaposition of breakpoint cluster region (
CML is clinically divided into chronic phase (CP), accelerated phase (AP), and blast phase (BP). Most cases of CML are diagnosed in the CP, but about 10% are diagnosed in the advanced phases. Forty to fifty percent of the patients diagnosed in the CP are asymptomatic. Common symptoms include asthenia, splenic discomfort, weight loss, and bleeding
Similar to adults, children progress from the CP to AP, and finally to the BP, but 25% of the patients move directly from the CP to BP. Although the clinical and morphological boundaries of each phase may be blurred, the recognition of disease progression from the CP to either AP or BP is important for both the treatment and overall prognosis of the patient.
Diagnosis is made by complete blood count and bone marrow examination, with the identification of the characteristic Philadelphia chromosome by metaphase studies, fluorescent in-situ hybridization (FISH), and reverse-transcriptase polymerase chain reaction (RT-PCR). The bone marrow tends to be hypercellular. Approximately 50-70% of the patients have a WBC count above 100,000/mm3 in the peripheral blood, 30-50% have thrombocytosis, and 20% have anemia. The peripheral blood smear shows a broad range of myeloid cells that result from myeloid differentiation, including an increase in basophils and eosinophils. Serologic examination is notable for an increase in uric acid, lactate dehydrogenase, vitamin B12, and vitamin B12-binding protein (transcobalamin 1).
Allogeneic hematopoietic stem cell transplantation (HSCT) was previously considered the only curative treatment available. However, perspectives on treatment changed dramatically in 1996 with the development of imatinib mesylate (STI 571, Gleevec), a tyrosine kinase inhibitor (TKI). Currently, treatment with TKIs, including imatinib, has replaced HSCT as the primary treatment in the adult CML population, and its role is becoming more prominent in childhood CML
In the 1950s and 1960s, the only medications available were busulfan and hydroxyurea, and the aim was cytoreduction and a decrease in hepatosplenomegaly rather than a durable cure of CML
The treatment of CML has changed dramatically over the past few years. In the past, HSCT was the only known curative therapy and was the recommended treatment. In recent years, complete responses have been documented with TKIs directed against BCR-ABL, and front-line use of a BCR-ABL targeting TKI is now the standard treatment for most patients with CML. Imatinib, the first TKI to be developed, is a small-molecule inhibitor of various tyrosine kinases, including ABL tyrosine kinase, c-KIT, and plateletderived growth factor. In 1996, Druker et al
The results of clinical trials with imatinib in the adult patient population have been applied to children, and imatinib is now also the front-line treatment for childhood CML. Since the approval by the US FDA in 2003, several reports have been published on the effects and toxicities of imatinib in children. With regard to the dosage of imatinib, pediatric doses of 260 mg/m2 and 340 mg/m2 have been found to be on par with 400 mg and 600 mg, respectively; therefore, the recommended starting dose in children is 300 mg/m2 once daily (maximum absolute dose, 400 mg) and 400-500 mg/m2 for advanced-stage disease
The evaluation of the response to TKI treatment is made through hematologic, cytogenetic, and molecular testing (
Imatinib treatment may result in diverse side effects, but most are of mild to moderate severity, and possibly lesser so for children
Cases precluding treatment with imatinib include drug resistance and intolerance due to hematologic or non-hematologic toxicities. Resistance can be further divided into primary and secondary (relapse) types, which are characterized by lack of response from the start and loss of initial response to treatment, respectively. Mechanisms of resistance are varied and include mutations in the BCR-ABL kinase domain that prevent imatinib binding,
Allogeneic HSCT was the only curative option in the pre-imatinib era. However, the good outcomes of imatinib treatment and accurate monitoring of minimal residual disease (MRD) has relegated HSCT to salvage therapy for patients with early signs of disease progression or resistance. For patients without a human leukocyte antigen (HLA)-matched sibling donor (MSD), the search for an unrelated donor should begin at diagnosis, since several months may pass before an appropriate donor is identified. The optimum time for HSCT is during the CP before progression to the AP or BP
Limited comparative studies are available concerning the best conditioning regimen for childhood CML patients
The most difficult scenario is in the case of children who have not responded to imatinib and also lack appropriate donors. Treatment without transplantation would require administration of drugs used in the past such as IFN-α, hydroxyurea, or low-dose cytarabine, but life prolongation would be difficult. These medications, however, may be used to lengthen survival until other experimental, targeted therapeutic measures that are currently being tried on adult patients become available for children. Other options include alternative transplantation measures such as cord blood transplantation and haploidentical transplantation.
Risk of relapse after HSCT in CP is relatively high at 20%, emphasizing the need for MRD monitoring. The effects of TKI treatment for the prevention of relapse after HSCT are still unclear, and require future prospective studies. Methods of treatment after relapse are without consensus, but further remissions may be obtained with DLI and TKI treatment. Imatinib treatment failure before HSCT may require dasatinib for relapse after transplantation.
There is general agreement that for adults, HSCT should be considered after trials of second-line treatment. For children, the most appropriate time for HSCT remains controversial. Whether HSCT should be considered as a first-line treatment when an MSD is not available and what should be the duration of imatinib treatment before HSCT are questions that remain to be answered. Treatment selection may also depend on national resources as well treatment efficacy. Developing countries with limited financial resources may favor one major curative attempt such as HSCT rather than lifelong treatment with an expensive drug. Advanced-phase patients would need to show hematologic or cytogenetic response before undergoing HSCT as first-line treatment
Treatment of CML is a model of targeted therapy based on disease pathogenesis and effective monitoring of MRD to improve patient survival. In adults, allogeneic HSCT is no longer considered for patients in the CP, and in children, its role is gradually being replaced by TKI treatment. However, the objective for treatment of childhood CML is not palliation, but cure. Hence, the possible adverse effects that stem from long-term TKI treatment and the potential for disease progression while on TKIs weigh more heavily in the childhood CML population. The development of novel drugs with greater efficacy and less toxicity may allow these patients to be free of the burden of HSCT, with its inherent risk of transplant-related mortality and significant long-term complications. The introduction of new medications into the treatment regimens of children and international studies concerning the efficacy of these medications should take place as soon as possible.
Definition of Accelerated Phase and Blast Phase Chronic Myeloid Leukemia (by WHO2008 and IBMTR Criteria)*
*Adapted from Swerdlow SH, et al
Criteria for Cytogenetic and Hematologic Remission in Chronic Myelogenous Leukemia*
*Adapted from Faderl S, et al
Recommendation for Definitions of Treatment Response to Imatinib Used in Early Chronic Phase*
Abbreviations: NA, not applicable; CHR, complete hematologic response, CyR; Cytogenetic response, PCyR; partial cytogenetic response, CCyR; complete cytogenetic response, MMolR; major molecular response, Ph+; philadelphia chromosome positive
†MMolR indicated a ratio of BCR-ABL1 to ABL1 or other housekeeping genes of ≤0.1% on the international scale.
Modified from Suttorp M, et al