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 1,000,0001 ) . 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 ) , it consists of a juxtaposition of breakpoint cluster region ( bcr ) gene on chromosome 22 with abelson leukemia virus ( abl ) gene , resulting in a fused bcr - abl protein with constitutive tyrosine kinase activity , and subsequent activation of cytoplasmic and nuclear signal transduction pathways including stat , ras , jun , myc , and phosphatidylinositol-3 kinase . the ultimate result of such activation is the myeloid proliferation and differentiation and suppressed apoptosis that is characteristic of cml4 ) . 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 . . with progression to advanced phases , other symptoms such as fever , night sweats , abdominal distension , and bone pain may become more evident , together with complications of leukostasis such as neurologic abnormalities , papilledema , retinal hemorrhage , tachypnea , and priapism . 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 . the phenotype of bp is 60 - 80% myeloid and 20 - 30% lymphoid , with a small proportion showing mixed phenotype . 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 ) . approximately 50 - 70% of the patients have a wbc count above 100,000/mm 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 cml7 - 9 ) . in this review , we discuss the optimal strategies to cure childhood cml in the era of imatinib treatment . 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 cml10 ) . in the mid 1980s , the introduction of interferon- ( ifn- ) as a treatment for cml - cp resulted in 70 - 80% hematologic remission and 20 - 30% complete cytogenetic response . the efficacy of this drug led to numerous attempts to lengthen the response rate and duration through combination treatment with ifn- and hydroxyurea , or ifn- and low - dose cytarabine11 - 13 ) . reports of ifn- treatment for childhood cml are limited , but millot et al14 ) undertook a study of 14 patients , of whom 7 ( 50% ) showed a complete hematologic response and 7 showed a major cytogenetic response , including 2 patients who showed a complete cytogenetic response ( ccyr ) . however , a comparative study of tki versus ifn- among adults established the superiority of tki and its firm role in the primary treatment of cml15 ) . 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 al16 ) initially reported on the specific cytotoxic effect of imatinib on proliferating myeloid cell lines specifically harboring bcr - abl . subsequent phase i and ii trials verified the clinical efficacy of the drug , resulting in approval by the us food and drug administration ( us fda ) in 2001 . the results of a phase iii trial , which enrolled 1,106 patients , underscored the role of imatinib as the initial non - transplant treatment choice for newly diagnosed cml - cp patients ; 87% of the patients treated with imatinib showed ccyr at 18 months with 3.3% disease progression , compared to 14.5% ccyr and 8.5% disease progression in patients treated with ifn- and cytarabine . 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 / m and 340 mg / m have been found to be on par with 400 mg and 600 mg , respectively ; therefore , the recommended starting dose in children is 300 mg / m once daily ( maximum absolute dose , 400 mg ) and 400 - 500 mg / m for advanced - stage disease18 , 19 ) . the evaluation of the response to tki treatment is made through hematologic , cytogenetic , and molecular testing ( table 2)9 , 20 , 21 ) . recently , the european leukemianet has published specific criteria on when and how to make response evaluations9 ) . hematologic response is assessed by complete blood count , whereas differential cytogenetic response ( cyr ) is assessed by analyzing at least 20 marrow metaphase cells and molecular response ( molr ) is measured by checking bcr - abl transcript levels using rt - pcr . the overall evaluation should lead to a classification of treatment response as optimal , suboptimal , or failure ( table 3)9 , 22 ) . the lack of any specific guidelines for children prompts the consideration of such adult - based criteria to measure response and decide upon clinical status such as imatinib resistance , intolerance , noncompliance , or disease progression . in patients with optimal response to imatinib , the drug may be continued until allogeneic hsct is undertaken . in those who fail to respond , imatinib may be continued , possibly at a higher dosage , or second - generation tkis may be introduced . currently , clinical trials are under way in order to expedite the introduction of second - generation tkis to the front - line treatment of childhood cml23 ) . imatinib treatment may result in diverse side effects , but most are of mild to moderate severity , and possibly lesser so for children24 - 26 ) . common toxicities include nausea , vomiting , diarrhea , skin rash , edema , elevated liver enzymes , and cytopenia . a common complaint among children is nausea , and food and liquid intake is recommended with drug ingestion in order to minimize gastrointestinal tract toxicity , as food absorption has little effect on drug absorption . lethargy , weight gain , myalgia , and cramps may also be significant side effects , and bone pain may require analgesics and anti - inflammatory agents . of special consideration in children is the detrimental effect of imatinib on height growth and bone metabolism , which require long - term assessment of physical parameters as well as serum calcium , phosphorus , parathyroid hormone , and bone metabolic markers . however , little has thus far been reported on the incidence and treatment of complications resulting from prolonged imatinib use in children27 - 31 ) . 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 , bcr - abl amplification or overexpression , clonal evolution of disease , and decreased drug bioavailability32 ) . 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 bp33 - 35 ) . outcomes of hsct in the bp are poor , with less than 20% long - term survival . therefore , it is important to undertake treatment with chemotherapy or tkis to achieve at least hematologic response and to schedule hsct as soon as possible , with a less than fully matched donor if necessary , in order to improve outcomes . treatment of the bp that initially may have led to complete molecular response with tkis can rapidly progress to overt relapse ; this emphasizes the need for more frequent monitoring of disease progression in these patients than in those treated at the cp . limited comparative studies are available concerning the best conditioning regimen for childhood cml patients36 ) . in theory , reduced intensity conditioning ( ric ) should limit toxicity and preserve fertility in these patients . however , patients who received ric during the advanced phase of disease may show a high rate of relapse , and such patients should be monitored on a short - term basis to predict the need for donor lymphocyte infusions ( dli ) or reinitiation of tki treatment . if allogeneic hsct were to be reserved for patients who have failed imatinib , then relapse after ric may prove difficult to manage with tkis because of resistance . treatment with early dli , however , may lead to significant graft - versus - host disease ( gvhd ) in these 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- , 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 . 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 . 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 . 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 treatment37 ) . the question of how long imatinib should be given to cml patients is , as yet , unanswered . recently , mahon et al38 ) showed that 38% of patients maintained complete molecular response after imatinib was stopped for 24 months . the data are promising , because they show the possibility of either intermittent imatinib dosing or complete withdrawal of imatinib , but extrapolation of these findings to children is premature . 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 cml10 ) . in the mid 1980s , the introduction of interferon- ( ifn- ) as a treatment for cml - cp resulted in 70 - 80% hematologic remission and 20 - 30% complete cytogenetic response . the efficacy of this drug led to numerous attempts to lengthen the response rate and duration through combination treatment with ifn- and hydroxyurea , or ifn- and low - dose cytarabine11 - 13 ) . reports of ifn- treatment for childhood cml are limited , but millot et al14 ) undertook a study of 14 patients , of whom 7 ( 50% ) showed a complete hematologic response and 7 showed a major cytogenetic response , including 2 patients who showed a complete cytogenetic response ( ccyr ) . however , a comparative study of tki versus ifn- among adults established the superiority of tki and its firm role in the primary treatment of cml15 ) . 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 al16 ) initially reported on the specific cytotoxic effect of imatinib on proliferating myeloid cell lines specifically harboring bcr - abl . subsequent phase i and ii trials verified the clinical efficacy of the drug , resulting in approval by the us food and drug administration ( us fda ) in 2001 . the results of a phase iii trial , which enrolled 1,106 patients , underscored the role of imatinib as the initial non - transplant treatment choice for newly diagnosed cml - cp patients ; 87% of the patients treated with imatinib showed ccyr at 18 months with 3.3% disease progression , compared to 14.5% ccyr and 8.5% disease progression in patients treated with ifn- and cytarabine . 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 / m and 340 mg / m have been found to be on par with 400 mg and 600 mg , respectively ; therefore , the recommended starting dose in children is 300 mg / m once daily ( maximum absolute dose , 400 mg ) and 400 - 500 mg / m for advanced - stage disease18 , 19 ) . the evaluation of the response to tki treatment is made through hematologic , cytogenetic , and molecular testing ( table 2)9 , 20 , 21 ) . recently , the european leukemianet has published specific criteria on when and how to make response evaluations9 ) . hematologic response is assessed by complete blood count , whereas differential cytogenetic response ( cyr ) is assessed by analyzing at least 20 marrow metaphase cells and molecular response ( molr ) is measured by checking bcr - abl transcript levels using rt - pcr . the overall evaluation should lead to a classification of treatment response as optimal , suboptimal , or failure ( table 3)9 , 22 ) . the lack of any specific guidelines for children prompts the consideration of such adult - based criteria to measure response and decide upon clinical status such as imatinib resistance , intolerance , noncompliance , or disease progression . in patients with optimal response to imatinib , the drug may be continued until allogeneic hsct is undertaken . in those who fail to respond , , imatinib may be continued , possibly at a higher dosage , or second - generation tkis may be introduced . currently , clinical trials are under way in order to expedite the introduction of second - generation tkis to the front - line treatment of childhood cml23 ) . imatinib treatment may result in diverse side effects , but most are of mild to moderate severity , and possibly lesser so for children24 - 26 ) . common toxicities include nausea , vomiting , diarrhea , skin rash , edema , elevated liver enzymes , and cytopenia . a common complaint among children is nausea , and food and liquid intake is recommended with drug ingestion in order to minimize gastrointestinal tract toxicity , as food absorption has little effect on drug absorption . lethargy , weight gain , myalgia , and cramps may also be significant side effects , and bone pain may require analgesics and anti - inflammatory agents . of special consideration in children is the detrimental effect of imatinib on height growth and bone metabolism , which require long - term assessment of physical parameters as well as serum calcium , phosphorus , parathyroid hormone , and bone metabolic markers . however , little has thus far been reported on the incidence and treatment of complications resulting from prolonged imatinib use in children27 - 31 ) . 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 , bcr - abl amplification or overexpression , clonal evolution of disease , and decreased drug bioavailability32 ) . 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 bp33 - 35 ) . outcomes of hsct in the bp are poor , with less than 20% long - term survival . therefore , it is important to undertake treatment with chemotherapy or tkis to achieve at least hematologic response and to schedule hsct as soon as possible , with a less than fully matched donor if necessary , in order to improve outcomes . treatment of the bp that initially may have led to complete molecular response with tkis can rapidly progress to overt relapse ; this emphasizes the need for more frequent monitoring of disease progression in these patients than in those treated at the cp . limited comparative studies are available concerning the best conditioning regimen for childhood cml patients36 ) . in theory , reduced intensity conditioning ( ric ) should limit toxicity and preserve fertility in these patients . however , patients who received ric during the advanced phase of disease may show a high rate of relapse , and such patients should be monitored on a short - term basis to predict the need for donor lymphocyte infusions ( dli ) or reinitiation of tki treatment . if allogeneic hsct were to be reserved for patients who have failed imatinib , then relapse after ric may prove difficult to manage with tkis because of resistance . treatment with early dli , however , may lead to significant graft - versus - host disease ( gvhd ) in these 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- , 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 . 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 . 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 . 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 treatment37 ) . the question of how long imatinib should be given to cml patients is , as yet , unanswered . recently , mahon et al38 ) showed that 38% of patients maintained complete molecular response after imatinib was stopped for 24 months . the data are promising , because they show the possibility of either intermittent imatinib dosing or complete withdrawal of imatinib , but extrapolation of these findings to children is premature . 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 .
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 .