Despite the established role of imatinib (IM) in chronic myelogenous leukemia (CML) in adults, there are few reports on its efficacy in children. In this study, we compared the outcomes of children with CML before and after the advent of IM-based treatment.
The study cohort consisted of 52 patients treated for CML at the Department of Pediatrics, The Catholic University of Korea from January 1995 to October 2010. Patients were divided and analyzed according to the preImatinib group (pre-IMG) and imatinib group (IMG).
Median age at diagnosis for the overall cohort (pre-IMG, n=27; IMG, n=25) was 9 years, with a median follow-up duration of survivors of 84 months. Except for 5 patients in the IMG, all were diagnosed in chronic phase (CP). The overall survival (OS) of patients diagnosed in CP was 45.7% and 89.7% for pre-IMG and IMG, respectively (
Similar PFS of patients treated with IM and those who received matched donor HSCT underscore the potential of IM as effective first-line treatment in childhood CML.
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of the Philadelphia chromosome arising from the reciprocal translocation between the long arms of chromosomes 9 and 22, resulting in the
CML is diagnosed mostly in adults, with 10% of patients consisting of children, and comprising 3% of overall pediatric leukemia incidence
However, studies of TKI use in children are few, and the role of TKI in the overall treatment schema of childhood CML has not been established. Recently, several studies have been published concerning TKI use in children, with high overall survival (OS) and progression free survival (PFS) reported
In this study, we attempted to identify the role of IM as possible front-line treatment for childhood CML by analyzing outcomes in a single institution cohort of patients before and after the introduction of IM.
Patients treated for CML at the Department of Pediatrics, The Catholic University of Korea from January 1995 to October 2010 were included in the cohort. Retrospective analysis up till June 2012 was done. Overall, 52 patients were included in the cohort, with a median follow-up duration of survivors of 84 months (range, 17 to 205 months).
Age at diagnosis, gender, clinical symptoms and signs, peripheral blood (PB) and bone marrow (BM) findings, and cytogenetic and molecular findings were investigated. Diagnosis was based on PB and BM findings, and identification of the Philadelphia chromosome through conventional cytogenetic study and fluorescent
The study cohort was divided into PreImatinib group (pre-IMG) and imatinib group (IMG) according to whether IM was used as front-line treatment. Outcomes were analyzed according to whether HSCT was administered for treatment.
In pre-IMG, patients received hydroxyurea, etoposide, and/or IFN-α as means of disease control before allogeneic transplantation which was considered the final curative treatment modality in all patients. All patients in IMG received IM as initial treatment, with a dosage of 260 mg/m2/day for patients in CP and 340 mg/m2/day for patients in advanced disease phase.
Treatment response was assessed according to European Leukemia Net guidelines
Progression was defined as progression to AP or BC or death during follow-up. Side effects of IM were assessed according to National Cancer Institute criteria (Common Terminology Criteria for Adverse Events ver. 4.0 [U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute, Bethesda, MD, USA)
OS, PFS, and time to events were calculated from the date of diagnosis and HSCT, respectively, by the Kaplan-Meier method. Differences in survival curves were compared using the log-rank test. Comparisons among groups were performed using chi-square test and Fisher exact test for categorical variables, and Wilcoxon 2-sample test for continuous variables. All statistical tests of significance were two tailed and analyses were performed using software SPSS ver. 16 (SPSS Inc., Chicago, IL, USA). For all calculations, a
Median age at diagnosis was 9 years (range, 2 to 15 years), and 47 of 52 patients (90.4%) were diagnosed in CP. The complete blood count showed leukocytosis (median, 227.2×109/L), anemia (median, 9.2 g/dL), and thrombocytosis (median, 557.2×109/L). Pre-IMG and IMG consisted of 27 and 25 patients, respectively, with 5 patients in advanced disease states (1 AP, 4 BC) all found in IMG. Except for anemia, no significant clinical difference was found between the 2 groups (
Details of the treatment and clinical course of patients in both Pre-IMG and IMG are shown in
Fifteen patients in the pre-IMG (55.6%) and 10 in the IMG (40%) received HSCT. Median age at transplantation was 9 years and median time from diagnosis to transplant was 9 months (
OS after HSCT was 73.3% and 66.7% for pre-IMG and IMG, respectively (
PFS was 58.7% and 41.7% (
The 12 patients in pre-IMG who did not undergo transplant all received hydroxyurea, supplemented by IFN-α (n=4), etoposide, cytarabine or busulfan. Of these patients, 10 died of disease progression. One patient progressed to AP, achieved CCyR with 6 months of IM, and switched to dasatinib due to skin rash. The other patient maintained CHR during 2 years of hydroxyurea, then switched to IM and is currently in CCyR.
Of the 15 patients in IMG who did not receive transplant, 2 were in advanced disease states, including 1 patient diagnosed in BC who started IM but died without response 8 months afterwards, and 1 patient diagnosed in AP who achieved CCyR in 6 months, MMR in 21 months, and is currently receiving treatment 36 months onwards. The remaining 13 patients were diagnosed in CP, and except for 1 patient, treatment response evaluation was possible in all patients. One patient started IM, but began alternative medicine treatment before achieving CHR. Of the 12 patients, 2 showed progression, including 1 patient who converted to BC and died 7 months into IM treatment, and another patient who relapsed from CHR, had a T315I mutation confirmed, began treatment with a second generation TKI, but has yet to achieve MMR.
The median follow-up duration of the 12 patients who were diagnosed in CP and received continuous IM treatment was 60 months (range, 28 to 88 months, excluding one patient who died). All achieved CHR at a median of 4.5 weeks (range, 2 to 27 weeks) since treatment. Ten patients (83.3%) achieved CCyR (median, 13 months; range, 3 to 24 months), 8 (66.7%) achieved MMR (median, 35 months; range, 12 to 87 months), and 3 are currently maintaining CMR (
Of the patients who did not receive transplant, the OS of pre-IMG and IMG was 16.7% and 85.7%, respectively (
Of patients diagnosed with CP within the IMG, the OS of matched donor HSCT recipients and IM only treated patients was similar at 83.3% and 91.7%, respectively (
Overall, 36 patients showed adverse effects of IM, including BM suppression, which was most frequently observed, bone or joint pain, nausea, vomiting, diarrhea, and abdominal pain (
Previous to the introduction of TKI's, hydroxyurea, busulfan, IFN-α, and cytarabine were used in the treatment of childhood CML, and allogeneic HSCT was regarded as the only curative mode of treatment. As in other diseases requiring HSCT, MSD transplant is known to result in better survival than unrelated transplant. Our study showed PFS of 58.7% and 41.7% for 13 MSD and 12 alternative transplants respectively, indicating better survival for sibling transplant recipients, although the numbers were too few to show statistical significance. However, past studies done on larger patient cohorts have shown considerably better leukemia-free survival in MSD transplant recipients compared with unrelated donor transplant recipients
IM is the first molecularly targeted drug for CML, with efficacy proven in adults. The few studies that have reported on IM as first-line treatment in children are based on relatively small numbers of patients, and remain inconclusive as to treatment guidelines, mostly due to concern over long-term side effects
Millot et al.
In adults, the overall treatment plan is based on cytogenetic and MRs to TKI treatment
In this single center study, we compared the OS before and after the introduction of IM, and found a higher OS after the start of IM treatment (78.4% vs. 45.7%), although the small numbers in the cohort did not result in statistical significance. However, when considering only patients in CP, a major difference was noted in OS in favor of IMG (89.7% vs. 45.7%,
Efficacy of IM in patients who relapsed after HSCT has been reported previously
The Stop Imatinib (STIM) trial
The 24- to 36-month follow-up data for dasatinib (DASISON study) and nilotinib (ENESTnd study) demonstrate superior cytogenetic and molecular response rates at certain time points and lower rates of progression to accelerated or blast phase compared to imatinib
In conclusion, for patients diagnosed in CP, first-line IM treatment resulted in higher PFS than during the pre-IM treatment period, allowing patients to avoid major consequences of HSCT, such as transplant-related mortality. Careful observation of long-term, drug-related complications should be undertaken in a multicenter setting, and clinical trials of more recently developed TKIs should be initiated in the pediatric setting.
No potential conflict of interest relevant to this article was reported.
Treatment and clinical outcome of the patient cohort. Pre-IMG, pre-imatinib group; CP1, first chronic phase; HSCT, hematopoietic stem cell transplantation; CP2, second chronic phase; HUR, hydroxyurea; AP, accelerated phase; CCyR, complete cytogenetic response; TKI, tyrosine kinase inhibitor; IM, imatinib; PD, progression of disease; IMG, imatinib group;BC, blastic crisis; TRM, treatment related mortality; DFS, disease free survival; NR, no response.
Overall survival of patients diagnosed in chronic phase in the PreImatnib era vs. imatinib era.
Overall survival of patients who underwent hematopoietic stem cell transplantation in first chronic phase in the preimatinib era vs. imatinib era.
Progression free survival of patients who did not receive hematopoietic stem cell transplantation according to imatinib use.
Progression free survival of patients who underwent matched donor hematopoietic stem cell transplantation vs. imatinib only treatment.
The clinical characteristics and laboratory features of patients with chronic myelogenous leukemia
Values are presented as median (range).
HSCT, hematopoietic stem cell transplantation.
Clinical characteristics and outcomes of 25 patients who underwent stem cell transplantation
HSCT, hematopoietic stem cell transplantation; MSD, matched sibling donor; MRD, matched related donor; MUD, matched unrelated donor; MMRD, mismatched related donor; MMUD, mismatched unrelated donor; TBI, total body irradiation.
Treatment response to imatinib given to patients diagnosed in chronic phase
CHR, complete hematologic response; CCyR, complete cytogenetic response; MMR, major molecular response; FU, follow-up; CMR, complete molecular response; NA, not achieved; NE, not evaluable; FU, follow-up.
*Transferred to another hospital using imatinib mesylate without disease progression. †Alive with next generation tyrosine kinase inhibitor after disease progression.
Adverse effects of imatinib (n=36*)
*Including patients who underwent hematopoietic stem cell transplantation.