A multicentric phase 2 study was conducted to determine the efficiency and the tolerance of imatinib mesylate in children with chronic myelogenous leukemia (CML) in advanced phase of the disease, in relapse after stem cell transplantation, or in case of failure to an interferon α-based regimen. In all, 30 children from eight European countries were enrolled. In 18 children assessable for hematologic response, imatinib mesylate induced complete hematologic response in eight (80%) of the 10 patients included in chronic phase and in six (75%) of eight enrolled in advanced phase of the disease with acceptable toxicity. In 27 patients assessable for cytogenetic response, imatinib mesylate induced disappearance of Philadelphia chromosome-positive bone marrow cells in 12 (60%) of 20 children included in chronic phase and in two (29%) of seven included in advanced phase. A reduction of the bcr-abl/abl ratio to less than 10−4 was achieved in 11 (50%) of the children included in chronic phase. Estimated 12-month overall survival rate was 95% (95% CI, 87–100%) for the patients included in chronic phase and 75% (95%CI, 45–100%) for those enrolled in advanced phase. Imatinib mesylate is well tolerated and molecular remission can be achieved in children with CML.
Chronic myelogenous leukemia (CML) is a very rare disease in children accounting for 2–3% of leukemias in children and adolescents with an annual incidence of one case per million children in western countries. 1 Allogeneic stem cell transplantation (SCT) is the only known curative treatment for CML. Reported event-free survival in children with CML transplanted in chronic phase is about 70% with a matched-related donor and from 40–60% with a matched-unrelated donor.2, 3, 4, 5, 6 In some children with CML in chronic phase without an appropriate donor, interferon α (IFN)-based therapy may offer an alternative to SCT before the imatinib mesylate era.7, 8 Imatinib mesylate is a specific inhibitor of the bcr-abl kinase and has considerably changed the treatment of CML in adults.9, 10 The Children's Oncology Group conducted a phase 1 study testing imatinib mesylate in 31 children with Philadelphia (Ph) chromosome-positive leukemia suggesting efficacy of this drug in this age group.11 Given these preliminary results, we performed a phase 2 study testing imatinib mesylate in children with either CML in advanced phase, refractory or intolerant to IFN therapy or relapsing after SCT.
Patients and methods
Aims of the study
The objectives of this phase 2 study were to determine in children with CML receiving imatinib mesylate the hematological, cytogenetic and molecular response rate, the time and duration of hematological and cytogenetic responses, the tolerability of the treatment and the overall survival.
To be eligible, patients were required to be less than 18 years old at study entry with Ph chromosome-positive CML in blast or accelerated phase, in chronic phase refractory or intolerant to IFN-based regimens or in either hematological, cytogenetic or molecular relapse after SCT. Blast crisis was defined as more than 30% of blasts+promyelocytes in peripheral blood and/or more than 50% blasts+promyelocytes in bone marrow. Accelerated phase was defined as the presence of at least one of the following criteria: percentage of blasts in blood or bone marrow more than 10% but less than 30%, a percentage of blasts+promyelocytes in the peripheral blood or bone marrow of more than 20%, peripheral basophils more than 20%, thrombocytopenia less than 100 × 109/l, progressive splenomegaly or karyotypic evolution (chromosomal abnormalities in addition to a single Ph chromosome). Resistance or relapse to an IFN-containing regimen, were defined as any of the following: hematologic resistance – failure to achieve a complete hematologic response despite 6 or more months of an IFN-containing regimen; hematologic relapse – a rising leukocyte count to a level more than 20 × 109/l in patients achieving a complete hematological response while receiving an IFN-containing regimen; cytogenetic resistance – bone marrow cytogenetics showing more than 65% Ph chromosome positivity after 1 year of IFN-based therapy; cytogenetic relapse – an increase in the Ph+bone marrow cells by at least 30 percentage points or an increase to more than 65%.
Written voluntary informed consent of the parents was obtained before entry into the study. The study was approved by the local ethic review board of each institution and conducted in accordance with the Declaration of Helsinsky.
Patients were treated continuously with once daily oral administration of imatinib mesylate at a dose range of 260–340 mg/m2. This dose range was selected on the basis of the previous pediatric phase 1 study11 and to avoid splitting of the 100 mg capsules supplied by the manufacturer (Novartis, Switzerland). After completing 24 weeks of therapy (part one of the study), patients were eligible to receive additional therapy (second part of the study) provided that in the opinion of the investigator the patient was benefiting from treatment with imatinib mesylate. Dose reductions of imatinib mesylate were allowed in patients with grade 2–4 hematologic or nonhematologic toxic effects according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC). Dose reductions of imatinib mesylate for hematologic or nonhematologic toxic effects were as follows: for persistent nonhematologic grade 2 toxicity, imatinib mesylate was withheld until recovery to grade 1 or less and resumed at the original dose level. For grade 3 or 4 nonhematologic toxicity, the study drug was withheld until the toxicity resolved to grade 1 or less. Upon recovery, therapy was resumed at a dose of 2/3 of the initial dose. For grade 3 or 4 hematologic toxicity, no dose modifications was permitted during the first 28 days of therapy. After 28 days of therapy, dose modifications were performed according to the following rules. For patients included in advanced phase who developed grade 4 neutropenia that had lasted more than 2 weeks, a bone marrow analysis was performed. Treatment was continued at the same dose if bone marrow cellularity was more than 10% and/or blasts more than 10%. Otherwise, dose of imatinib mesylate was reduced to 2/3 of the initial dose. In patients refractory to IFN or in relapse after SCT who experienced grade 3/4 hematologic toxicity, imatinib mesylate was withheld until the toxicity has resolved to grade 2 and resumed at the initial dose if the toxicity resolved within 2 weeks. Patients developing anemia were transfused at the discretion of the investigator. No dose reductions were performed for any grade of anemia. During imatinib mesylate therapy, donor lymphocyte infusions (DLI) were allowed in patients included for relapse after SCT.
Assessment and monitoring of the patients
Physical examination was performed three times a week during the 1st month of treatment, once a week from the 2nd to the 4th month, twice a month during the 5th and 6th month and monthly thereafter. During the first 6 months of the study, a complete blood count was performed three times a week during the 1st month, every week for the next 2 months and every other week thereafter. Serum chemistry was performed weekly during the first 4 months and thereafter at the same time when blood count was performed. Bone marrow studies, including morphologic, cytogenetic or fluorescent in situ hybridization (FISH) analysis were perfomed monthly during the first 3 months and at the end of the first 6 months of the treatment. Blood counts and serum chemistry were performed monthly and bone marrow analysis every 3 months thereafter. Information about all adverse events were collected and recorded on the Adverse Event Case Report Form and followed as appropriate. A complete hematologic response was defined as disappearance of all signs and symptoms of the disease, normalization of white blood cell counts to less than 10 × 109/l with normal differential and normalization of the platelet counts for more than 4 weeks. A partial hematologic response was based on the same criteria used for complete hematologic response but allowed persistent palpable splenomegaly (however, spleen size had to have been reduced at least by 50%), thrombocytosis and/or the presence of a few immature cells (no blasts or promyelocytes, 5% or fewer myelocytes plus metamyelocytes). A minimum of 20 metaphases was required for cytogenetic analysis and 200 interphases for FISH analysis. Response in terms of the percentage of Ph-positive cells was defined as follows : complete (0%), partial (1–35%), minor (36–95%) and failure (>95%). The bcr-abl transcript was determined by conventional polymerase chain reaction (PCR) at inclusion. Molecular response was assessed in each center using real-time quantitative competitive assays in blood or marrow samples collected in patients who achieved complete cytogenetic response. bcr-abl transcripts were detected by real-time quantitative reverse transcriptase-PCR analysis and negative results (i.e., undetectable transcript) were confirmed by nested PCR as previously reported.12 The lower limit of detection in the nested PCR assay is approximately one bcr-abl-expressing cell per 100 000. Ratios of bcr-abl transcript level were carried out by comparison with the level of abl transcript.
Survival and time to events were calculated from the date of start of imatinib mesylate. Overall survival distribution was estimated by the Kaplan–Meir method. Time to response was estimated by the cumulative incidence method. Analysis of overall survival and response were performed in an intention to treat basis first; then patients were censored at the date of transplant. Analysis were performed using SAS statistical software (SAS Institute, Cary, NC, USA).
From August 2001 until April 2003, 30 children with Ph chromosome-positive CML were recruited in 23 centers from eight European countries. The current analysis is based on data collected up to January 1, 2005. Characteristics of the patients are summarized in Table 1. There was a male preponderance with a gender ratio of 1.3 and the median age was 13 years (range: 1–17.5). In all, 26 patients were pretreated with an IFN-containing regimen (13 patients) or were in relapse after allogeneic SCT (13 patients) and four patients were in de novo accelerated phase at inclusion. In all, eight patients were included in advanced phase (five in accelerated phase and three in blastic crisis) and 22 in chronic phase of the disease (12 of them were in hematologic remission at inclusion). Median time from diagnosis to the start of imatinib mesylate therapy was 13 months (range, 1 week–9 years). Among the 13 patients in relapse after SCT, four patients received 2–6 (median, 2) DLI after starting treatment with imatinib mesylate.
Doses and duration of treatment
The median starting dose of imatinib mesylate was 292 mg/m2 (range, 241–333). The dose was escalated in one patient (included in chronic phase with hematological resistance to IFN) because of progression of the disease. Five patients had the dose reduced for hematologic toxicity (four patients included in chronic phase) or nonhematologic toxicity (one patient included in accelerated phase). At last follow-up all of these five patients are alive and well with minimal residual disease in four of them and minor cytogenetic response in the other one. Of the 30 children and adolescents, 17 (including 11 patients enrolled in chronic phase) discontinued treatment after a median time of 6 months (range, 1–27) from the start of imatinib mesylate therapy. The reasons for discontinuation were the following: (a) initiation of SCT in eight patients who progressed to accelerated phase (one patient included in chronic phase) or who achieved a complete or a partial hematologic response (seven patients of whom four were included in the study in accelerated or blastic phase; median time of discontinuation 6 months after the start of imatinib mesylate, range 1–27 months), (b) disease progression for two adolescents included in chronic phase or blastic crisis post-SCT and occurrence of cerebral aspergillosis in one patient included in blastic phase after SCT, (c) undetectable transcript (five patients) or no Ph chromosome detected by FISH (one patient) in six patients included in chronic phase (discontinuation 1.5–22 months after the start of imatinib). At the time of analysis, 13 patients were still receiving imatinib mesylate for a median time of 34 months (range, 25–38). The median dose administered in the 30 patients was 300 mg (range, 100–580) per day corresponding to 290 mg/m2 (range, 240–330) per day, including six patients who temporarily stopped imatinib mesylate according to the rules of the trial.
Chronic phase CML patients
Main results are reported in Table 2. Complete hematologic response was achieved in eight of 10 (80%) patients assessable for the hematologic response (12 patients were recruited into the study being still in hematologic remission). The median interval to complete hematologic response was 4 weeks (range, 3–6) after starting imatinib mesylate. For the 20 patients in complete hematologic response, the median duration of hematologic response was 26 months (range, 1–37). Among the two patients who failed to achieve a complete hematologic response (Table 1, patient nos. 03 and 07) a partial hematologic response was observed in one of them. Evaluation of the presence of Ph chromosome was performed in 20 patients (two children (Table 1, patient nos. 21 and 22) were still in complete cytogenetic remission at inclusion) using karyotyping on metaphase spreads (10 patients) or using bcr-abl interphase FISH (10 patients) performed on bone marrow sample. Complete cytogenetic response or FISH negativity was observed in 12 (60%) patients with a median time of 5 months (range, 1–15 months). One patient (Table 1, patient no. 14) lost his complete cytogenetic response (23 months after complete cytogenetic response was obtained) while receiving imatinib mesylate. Six children had reduction of their residual disease to less than 1 × 10−4 and five patients had undetectable transcript 1–33 months (median, 5 months) after the start of imatinib. Among the six patients (Table 1, patient nos.12, 13, 15, 19, 21 and 22) who discontinued imatinib mesylate because of undetectable transcript or FISH negativity, five patients are in persistent molecular remission 8–24.5 months (median, 9 months) after discontinuation while one patient (Table 1, patient no. 13) developed an hematologic relapse 12 months after discontinuation of imatinib mesylate. Three patients died of complications of SCT performed in children (two patients, no. 02 and 08,) who achieved an hematologic response to imatinib mesylate or of failure to achieve complete hematologic response with imatinib mesylate (one patient, no. 07). Probability of survival at 12 months was 95% (95% CI, 87–100%). When patients were censored at transplant, probability of survival at 12 months was similar.
Advanced phase CML patients
Complete hematologic response was achieved in six (75%) of the eight patients (Table 2). The median interval to a complete hematologic response was 4 weeks (range, 2 weeks–3 months) after starting imatinib mesylate. The median duration of hematologic response was 30 months (range, 3 weeks–36 months). Among the two patients who failed to achieve a complete hematologic response (Table 1, patient nos. 25 and 28), a partial hematologic response was observed in one of them. One patient (Table 1, patient no. 30) lost his complete hematologic response 1 month after complete hematologic response was obtained. Complete cytogenetic response was observed in two (29%) patients included in accelerated phase, 3 and 6 months after the start of imatinib mesylate, respectively. None of these patients (Table 1, patient nos. 23 and 24) had reduction of their residual disease to less than 1 × 10−4. Three patients died; the reasons for death were: complications of SCT performed in one child (Table 1, patient no. 28) who achieved a partial hematologic response to imatinib mesylate, loss of complete hematologic response and progression of the disease (Table 1, patient no. 30) and cerebral aspergillosis in one patient (Table 1, patient no. 29) who received imatinib mesylate and two infusions of DLI for blastic crisis occurring after SCT. Probability of survival at 12 months was 75% (95% CI, 45–100%). When patients were censored at transplant, probability of survival at 12 months was 71% (95% CI, 38–100%).
Hematologic and nonhematologic adverse events are listed in Table 3. Adverse events were mostly grade 1 or 2. Grade 3 or 4 neutropenia or thrombocytopenia was observed exclusively in patients included in chronic phase. Three of these patients experienced more than one episode of severe neutropenia and one patient more than one episode of severe thrombocytopenia. Five patients (four included in chronic phase and one in accelerated phase) required temporary interruption of therapy (1–4 weeks on two occasions in two of them and 1–2 weeks one time in the remainder) because of neutropenia or thrombopenia but these hematologic abnormalities quickly resolved and treatment was resumed. Granulocyte colony-stimulating factor was not used in any children who developed neutropenia induced by imatinib mesylate. Grade 3 or 4 nonhematologic toxicity was observed exclusively in two patients included in advanced phase (reversible grade 3 liver transaminase elevation in one patient and severe infection in the other). Signs of fluid retention such as edema were observed in one patient included in chronic phase.
The median duration of follow-up is 28 months (range, 2–48). Six patients have died of causes described above. Among the eight children who proceeded to allogeneic SCT immediately after imatinib therapy, five were alive with no evidence of disease with a median follow-up of 23 months (range, 17–35 months) after transplantation.
There are scant data regarding imatinib mesylate therapy in children with CML. The Children's Oncology Group reported the results of a phase 1 study concerning 31 patients under the age of 22 years with Ph-positive leukemia (including 20 patients with CML) treated with imatinib mesylate.11 The treatment was found to be safe and complete cytogenetic response was documented in 12 of these patients. In another cohort of four consecutive children with CML receiving imatinib mesylate, none of the patients had Ph-positive cells detected by cytogenetics or RT-PCR with a median of 198 and 287 days of imatinib therapy, respectively.13
In our trial, the dose range of 260–340 mg/m2 was selected on the basis of the pediatric phase 1 study indicating that these doses are associated with drug exposures similar to the doses of 400–600 mg used in adult studies.11 It was reported that doses of 400 mg or higher are required for a maximal pharmacodynamic effect in adults.14
In the current study, we report significant responses to imatinib mesylate with acceptable toxicity in an heterogeneous cohort of children with CML who were in advanced phase of the disease or who had failed to respond to IFN-based therapy or in relapse after allogeneic SCT. However, four children in relapse after allogeneic SCT received a combination of DLI and imatinib mesylate making it difficult to attribute efficiency to one or the other therapy in these four cases.
Our results indicate that in pretreated children with Ph-positive chronic phase CML, imatinib mesylate induced sustained hematologic response and disappearance of Ph chromosome in bone marrow cells in 80 and 60% of them, respectively, with an estimated 12-month overall survival rate of 95%. The results reported here obtained in children compare favorably with those reported in adults. In adults in whom previous therapy with IFN had failed, imatinib mesylate induced complete hematologic and cytogenetic responses in 60 and 41% of the patients, respectively, with an overall survival of 95% at 18 months.15 In patients receiving imatinib mesylate for relapse after allogeneic SCT for CML, complete hematologic response and complete cytogenetic remission were achieved in 71 and 42% of the patients respectively, with estimated 2-year survival rate of 65%.15 In addition to hematologic and cytogenetic response, our study revealed that 50% of the children enrolled in chronic phase receiving imatinib mesylate achieved very low levels of bcr-abl transcript, including 27% with undetectable transcripts. This significant reduction in the amount of residual disease compares favorably with the molecular response to imatinib mesylate reported in adults in late chronic-phase of CML or in relapse after SCT.16, 17 The degree of molecular response predicts disease progression in adults receiving imatinib mesylate but such an effect remains to be determined in children.18 Interestingly, in five of our six patients included for relapse after SCT, molecular remission was induced by imatinib mesylate followed by long-lasting molecular remission after discontinuation of the drug. However, two of them received additional therapy with DLI which could also contribute to an allogeneic graft-versus-leukemia reaction.
The present study indicates that imatinib mesylate induced complete hematologic response lasting at least 1 month in six of eight children with Ph-positive advanced phase CML, two of whom achieved a complete cytogenetic response. In adults with CML in accelerated or blastic phase, imatinib mesylate induced complete hematologic response in 34 and 15% of the patients, complete cytogenetic response in 17 and 7% and estimated 12-months overall survival was 74 and 32%, respectively.9, 10
In our trial, a daily dose of imatinib mesylate equivalent to 400–600 mg in adults induced side effects of similar types to those observed in adults. However, the rate of grade 3 or 4 hematologic toxicities and fluid retention observed in our patients seems to be less frequent than that reported in adults receiving imatinib mesylate for advanced phase of CML or relapse after SCT.9, 10, 16, 19 Interestingly, none of our patients required permanent discontinuation of therapy for toxicity. One patient developed cerebral aspergillosis. However, this highly immunosuppressed patient received a combination of imatinib mesylate and DLI for hematologic relapse after SCT making difficult to attribute the occurrence of this infection to imatinib mesylate.
There is no broad consensus on the use of imatinib mesylate in children with CML according to a recent editorial.20 In spite of significant cytogenetic and molecular responses, there is no evidence that imatinib mesylate is curative and long-term side effects of this drug remain to be determined in children. Imatinib mesylate is well tolerated and cytogenetic and molecular remissions can be achieved in a significant percentage of children and adolescents with advanced phases of CML. However, the long-term tolerability and the durability of responses must be evaluated. Studies are under way to evaluate activity of imatinib mesylate in children and adolescent with CML in first chronic phase.
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Preliminary data were presented at the 45th annual meeting of the American Society of Hematology, San Diego, CA, December 6–9, 2003.
In addition to the authors, the following investigators participated in this trial: Claire Berger, Saint Etienne, France; Françoise Mazingue, Lille, France; Guy Leverger, Paris, France; Frédéric Bernard, Montpellier, France; Dominique Plantaz, Grenoble, France; Yves Bertrand, Lyon, France; Virginie Gandemer, Rennes, France.
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Millot, F., Guilhot, J., Nelken, B. et al. Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase and in relapse after stem cell transplantation. Leukemia 20, 187–192 (2006). https://doi.org/10.1038/sj.leu.2404051
- chronic myelogenous leukemia
- imatinib mesylate
- hematopoietic stem cell transplantation
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