Our Health Library information does not replace the advice of a doctor. Please be advised that this information is made available to assist our patients to learn more about their health. Our providers may not see and/or treat all topics found herein. This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER. Chronic myeloid leukemia (CML) results from the BCR::ABL translocation. CML is primarily an adult disease but represents the most common of the chronic myeloproliferative disorders in children. CML accounts for approximately 13% to 20% of all childhood myeloid leukemias and 2% of all childhood leukemias.[1,2,3,4] Although it has been reported in very young children, most patients are aged 6 years and older. CML most commonly occurs in older adolescents. CML is a clonal panmyelopathy that involves all hematopoietic cell lineages. 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 patients with CML, this is not a specific finding. CML historically was divided into the following three clinical phases: The 5th edition of the WHO classification now divides clinical presentation into either chronic phase or blast phase and eliminates the accelerated phase. This change was partially due to the impact of TKIs on the disease course, which has reduced the proportion of patients who develop progression. Also, the 5th edition of the WHO classification identifies certain chronic phase characteristics as high risk for disease progression and TKI resistance.[6] These characteristics, present at diagnosis or during TKI therapy, include the following: References: Genomics of CML The cytogenetic abnormality required for diagnosis of CML is the Philadelphia chromosome (Ph), which represents a translocation of chromosomes 9 and 22 (t(9;22)), resulting in a BCR::ABL1 fusion protein.[1] Additional chromosomal abnormalities have been found in studies of adults with CML in the TKI era. These studies have illustrated a number of adverse prognostic variants, including those identified as high risk in the chronic phase.[2,3] References: Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence.[2] This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life: For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care. The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[3] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website. References: Before the tyrosine kinase inhibitor (TKI) era, allogeneic hematopoietic stem cell transplant (HSCT) was the primary treatment for children with chronic myeloid leukemia (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. Lower survival rates were reported when HLA–matched-unrelated donors were used.[1,2,3] Relapse rates were low (less than 20%) when transplant was performed in the chronic phase.[1,2] The primary cause of death was treatment-related mortality, which was increased with HLA–matched-unrelated donors compared with HLA-MFDs in most reports.[1,2] High-resolution DNA matching for HLA alleles appeared to reduce rates of treatment-related mortality, leading to improved outcome for HSCT using unrelated donors.[4] Compared with transplant in the chronic phase, transplant in the accelerated phase or blast crisis and in the second chronic phase resulted in significantly reduced survival.[1,2,3] The use of T-lymphocyte depletion to avoid graft-versus-host disease resulted in a higher relapse rate and decreased overall survival,[5] supporting the contribution of a graft-versus-leukemia effect to favorable outcome after allogeneic HSCT. The introduction of the TKI imatinib as a therapeutic drug targeted at inhibiting the BCR::ABL1 fusion kinase revolutionized the treatment of patients with CML, for both children and adults.[6] Most data on the use of TKIs for CML are from adult clinical trials. For more information, see Chronic Myeloid Leukemia Treatment. The more limited experience in children is described below. References: Treatment options for children with chronic myeloid leukemia (CML) may include the following: TKI Therapy Imatinib Imatinib has shown a high level of activity in children with CML that is comparable with the activity observed in adults.[1,2,3,4,5] As a result of this high level of activity, it is common to initiate imatinib treatment in children with CML rather than proceeding immediately to allogeneic stem cell transplant.[6] The pharmacokinetics of imatinib in children appear consistent with previous results in adults.[7] Doses of imatinib used in phase II trials for children with CML have ranged from 260 mg/m2 to 340 mg/m2, which provide comparable drug exposures as the adult flat-doses of 400 mg to 600 mg.[3,4,5] Evidence (imatinib in children): Early molecular responses, such as the polymerase chain reaction (PCR)–based minimal residual disease (MRD) measurement at 3 months of therapy showing 10% BCR::ABL1 fusion transcripts, have been reported to be associated with improved PFS, similar to early molecular response data in adults.[8] The European LeukemiaNet (ELN) has defined optimal molecular milestones of BCR::ABL transcript levels to be 10% or less at 3 months, 1% or less at 6 months, and 0.1% or less at 12 months or more of therapy.[9] The monitoring parameters described for adults with CML are reasonable to use in children. Monitoring occurs every 3 months until MMR is achieved and confirmed every 3 to 6 months thereafter. For more information, see Chronic Myeloid Leukemia Treatment. Imatinib is generally well tolerated in children. Adverse effects are generally mild to moderate and reversible with treatment discontinuation or dose reduction.[3,4] Growth delay occurs in most prepubertal children who receive imatinib.[10] Children who receive imatinib and experience growth impairment may show some catch-up growth during their pubertal growth spurts, but they are at risk of having lower-than-expected adult height, as most patients do not achieve midparental height.[10,11] Dasatinib Dasatinib is a TKI that is approved by the U.S. Food and Drug Administration (FDA) for the treatment of children with CML. Evidence (dasatinib in children): Nilotinib Nilotinib is a TKI that is approved by the FDA for the treatment of children with CML. Evidence (nilotinib in children): The FDA approved nilotinib in March 2018 for the treatment of children with CML based on two sponsored trials.[15,16] Data from both studies were combined for a pooled-data analysis of 69 patients, which included 25 patients with newly diagnosed CML and 44 patients with resistant or intolerant CML. Both studies used a dose of 230 mg/m2 given twice daily (rounded to the nearest 50 mg; maximum single dose, 400 mg).[15,16] Other TKIs Most data on the use of TKIs for CML is from adult clinical trials. A safe pediatric dose has not yet been established for ponatinib. Bosutinib is a TKI that targets the BCR::ABL1 gene fusion. The FDA approved bosutinib for the treatment of all phases of CML in adults who show intolerance to or whose disease shows resistance to previous therapy with another TKI. The pediatric recommended phase II dose of bosutinib was determined in a phase I study that included 30 screened children, 28 of whom received treatment. For children previously resistant or intolerant to other TKIs, the dose was 400 mg/m2 with food once daily (maximum dose, 600 mg). For children with newly diagnosed CML, the dose was 300 mg/m2 with food once daily (maximum dose, 500 mg).[17] Ponatinib is a BCR::ABL1 fusion transcript inhibitor that is effective against the T315I variant.[18] Ponatinib induced objective responses in approximately 70% of heavily pretreated adults with chronic-phase CML. Responses were observed regardless of the baseline BCR::ABL1 kinase domain variant.[19] The use of ponatinib has been complicated by the high rate of vascular occlusion observed in patients receiving the agent. Arterial and venous thrombosis and occlusions (including myocardial infarction and stroke) occurred in more than 20% of treated patients.[20] Ponatinib is being prospectively studied in the pediatric population. Discontinuation of TKI Therapy Discontinuation of TKI treatment is an accepted strategy for adults with CML who meet strict criteria related to their duration of treatment and response to treatment. Guidelines for discontinuation of TKIs have been developed by both the ELN and the U.S.-based National Comprehensive Cancer Network (NCCN).[9,21] Key elements for both guidelines include the following: These guidelines specify close monitoring of BCR::ABL1 transcript levels after TKI discontinuation. Loss of MMR (or MR3) (BCR::ABL1 transcript level ≤0.1% IS) is generally used as the trigger for reinitiation of TKI therapy. Loss of MMR is most likely to occur within the first 6 months of TKI discontinuation. Loss of MMR occurs much less frequently more than 1 year after TKI discontinuation. A meta-analysis included 3,105 adult patients who initiated a first attempt at TKI discontinuation. The study found that the probability of molecular recurrence was 35% after 0 to 6 months, 8% after 6 to 12 months, 3% after 12 to 18 months, and 3% after 18 to 24 months.[22] These results indicated that approximately 50% of adult patients maintained their molecular responses 2 years after TKI discontinuation. Relapses can occur when TKIs have been discontinued for more than 2 years, but these recurrences appear to be infrequent (<2%). Unfavorable outcomes were uncommon when relapses occurred. In addition, 90% of patients reacquired deep molecular remission after TKI reinitiation. There are limited data regarding TKI discontinuation in children with CML. This limited experience is explained, in part, by the low incidence of CML in children. In addition, few children with CML who are treated with TKIs meet the criteria for TKI discontinuation. For example, among patients enrolled on the International Chronic Myeloid Leukemia Pediatric Study (I-CML-Ped [NCT01281735]), only 9% of children with CML who were treated with TKIs met the criteria for TKI discontinuation.[23] Other reports have also supported this trend.[24,25] Although the small number of children studied is a limitation, it appears that the outcome for TKI discontinuation in children with CML is similar to that of adults. Two of the larger pediatric studies that discuss this topic are summarized below: TKI withdrawal syndrome is observed in approximately 20% to 30% of adults when TKI therapy is discontinued.[26] The syndrome includes musculoskeletal pain that typically develops within 2 months of TKI discontinuation and continues for several months. The JPLSG study did not observe musculoskeletal pain in children after TKI discontinuation. Among the 18 children who stopped taking imatinib, 9 (50%) eventually resumed treatment.[23] Seven of these nine patients experienced loss of MMR (BCR::ABL1 transcript level ≤0.1% IS). Six of the seven patients regained MR4 within a median of approximately 5 months after TKI reinitiation. The remaining patient achieved MMR after TKI reinitiation. Two additional patients who had a one-log increase in BCR::ABL1 transcript levels, but did not meet the criteria for loss of MMR, were restarted on imatinib by their physicians. For the other nine patients who remained in treatment-free remission, the median follow-up period after imatinib discontinuation was 50 months. TKI withdrawal syndrome was not reported in any patients discontinuing imatinib. Treatment Options Under Clinical Evaluation Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website. The following is an example of a national and/or institutional clinical trial that is currently being conducted: References: Treatment options for children with recurrent or refractory chronic myeloid leukemia (CML) may include the following: Alternative TKI Therapy In children who develop a hematologic or cytogenetic relapse during treatment with imatinib or who have an inadequate initial response to their initial TKI agents, determination of BCR::ABL1 kinase domain variant status should be considered to help guide subsequent therapy. Depending on the patient's variant status, alternative TKIs such as dasatinib, nilotinib, or bosutinib can be considered on the basis of the adult and pediatric experience with these agents.[1,2,3,4,5,6] Evidence (dasatinib in children with resistant or intolerant CML): Evidence (nilotinib in children with resistant or intolerant CML): Dasatinib and nilotinib are active against many BCR::ABL1 variants that confer resistance to imatinib, although the agents are ineffective in patients with the T315I variant. In the presence of the T315I variant, which is resistant to all U.S. Food and Drug Administration (FDA)–approved TKIs, an allogeneic HSCT should be considered. Ponatinib, the BCR::ABL1 inhibitor effective against the T315I variant in adults, has not been prospectively studied in the pediatric population. Allogeneic HSCT The question of whether a pediatric patient with CML should receive an allogeneic HSCT when multiple TKIs are available remains unanswered. However, reports suggest that PFS does not improve when using HSCT, compared with the sustained use of imatinib.[8] The potential advantages and disadvantages need to be discussed with the patient and family. While HSCT is currently the only known definitive curative therapy for CML, patients discontinuing treatment with TKIs after sustained molecular remissions, who remained in molecular remission, have been reported.[9] Treatment Options Under Clinical Evaluation Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website. The following are examples of national and/or institutional clinical trials that are currently being conducted: References: The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above. Treatment of Childhood CML Added text about the results of a phase I study in children that determined the recommended phase II dose of bosutinib (cited Brivio et al. as reference 17). Treatment of Recurrent or Refractory Childhood CML Added NCT03934372 as an open clinical trial available for pediatric patients with recurrent or refractory leukemias. This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages. Purpose of This Summary This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood chronic myeloid leukemia. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions. Reviewers and Updates This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH). Board members review recently published articles each month to determine whether an article should: Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary. The lead reviewers for Childhood Chronic Myeloid Leukemia Treatment are: Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries. Levels of Evidence Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Permission to Use This Summary PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]." The preferred citation for this PDQ summary is: PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Chronic Myeloid Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/leukemia/hp/child-aml-treatment-pdq/childhood-cml-treatment-pdq. Accessed <MM/DD/YYYY>. 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Questions can also be submitted to Cancer.gov through the website's Email Us. Last Revised: 2024-06-14 This information does not replace the advice of a doctor. Ignite Healthwise, LLC disclaims any warranty or liability for your use of this information. Your use of this information means that you agree to the Terms of Use and Privacy Policy. Learn how we develop our content. Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Ignite Healthwise, LLC.Topic Contents
Childhood Chronic Myeloid Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI]
Incidence and Clinical Presentation
Cytogenetics of CML
Special Considerations for the Treatment of Children With Cancer
Historical (Pre-Tyrosine Kinase Inhibitor) Therapy for Childhood CML
Treatment of Childhood CML
Treatment of Recurrent or Refractory Childhood CML
Latest Updates to This Summary (06 / 14 / 2024)
About This PDQ Summary
Our Health Library information does not replace the advice of a doctor. Please be advised that this information is made available to assist our patients to learn more about their health. Our providers may not see and/or treat all topics found herein.Childhood Chronic Myeloid Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI]