Clinical and Biological Features at Diagnosis in 40 Children With Chronic Myeloid Leukemia
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《小儿科》
Department of Oncology Hematology, University Hospital, Poitiers, France
Department of Pediatrics, University Hospital, Lille, France
Department of Pediatrics, St Louis Hospital, Paris, France
Department of Pediatrics, Trousseau Hospital, Paris, France
Department of Pediatrics, University Hospital, Grenoble, France
Department of Pediatrics, University Hospital, Lyon, France
Department of Pediatrics, University Hospital, Nancy, France
ABSTRACT
Objective. The purpose of this study was to determine the clinical and biological characteristics at diagnosis in children and adolescents with chronic myelogenous leukemia (CML) in contemporary practice.
Methods. Analysis was conducted on data from 3 prospective trials conducted in children and adolescents with CML. Forty pediatric patients were evaluated in 16 French pediatric oncology units between 1991 and 2003.
Results. The disease predominately affected children who were older than 10 years (67% of the patients), with a higher prevalence in boys than girls (gender ratio: 1.5). Approximately 20% of cases were diagnosed incidentally. The main presenting symptoms were asthenia, weight loss, and complaints related to splenomegaly. Occasional patients presented with signs evocative of leukostasis. Symptoms were more common in patients with splenic enlargement, which was present in 70% of patients, and higher leukocyte counts. Markedly raised leukocyte counts were common (median white blood cell count: 242 x 109/L). The age and the gender of the patients had no effect on the leukocyte count, the hemoglobin level, or the platelet count. A predominance of b3a2 transcript was observed in the 16 children who were studied for the type of chimeric BCR-ABL mRNA.
Conclusions. This is largest reported series of CML at diagnosis in children and adolescents. It shows that the characteristics of CML seem to differ in children compared with previously published adult series; in particular, the presenting leukocyte counts are often higher in children.
Key Words: children leukostasis chronic myelogenous leukemia
Abbreviations: CML, chronic myelogenous leukemia WBC, white blood cell
Chronic myelogenous leukemia (CML) is a very rare disease in children, accounting for 2% to 3% of leukemias in children and adolescents with an annual incidence of 1 case per million children in Western countries.1–3 For this reason, presenting features of this myeloproliferative disease in the pediatric population are based on studies of a limited number of patients or on reports published several decades ago. The aim of this study was to determine the main presenting features of CML in children and adolescents in modern clinical practice.
METHODS
We reviewed the records of 40 children and adolescents who were treated for CML in 16 French centers. Among them, 12 consecutive children were included in the randomized trial LMC 91 protocol between January 1991 and May 1996 comparing interferon- alone and interferon- in combination with cytarabine in patients with CML in first chronic phase.4,5 Twenty-eight consecutive children at various stages of the disease were treated with interferon-–based therapy or imatinib mesylate or received a transplant between September 2000 and March 2003.6,7 The diagnosis of CML was confirmed by the presence of the BCR-ABL translocation by cytogenetic analysis, fluorescence in situ hybridization analysis, or molecular analysis as previously reported.8–10 The symptoms, physical signs, and peripheral blood and bone marrow analysis at initial diagnosis of CML were recorded. Stage of the disease (chronic phase, accelerated phase, or blastic crisis) was classified according to the criteria of the International Bone Marrow Transplant Registry.11 Anemia was diagnosed when the hemoglobin level was <11 g/dL in children who were between 0 and 6 years of age, <13 g/dL in boys who were >6 years of age, and <12 g/dL in girls who were >6 years of age. Thrombocytosis was diagnosed when the platelet count was >450 x 109/L, and thrombocytopenia was diagnosed when the platelet count was <150 x 109/L.
Statistical Analysis
Comparisons between groups were made with the use of Fisher's exact test for categorical variables, the Wilcoxon rank-sum test, and Kruskal-Wallis test for continuous variables. The significance of the correlation between 2 independent parameters was determined by the Spearman test. All statistical tests of significance were 2-tailed with a type I error of .05. Analyses were performed by using SAS statistical software (SAS Institute, Cary, NC).
RESULTS
Patients
Characteristics of the children are reported in Table 1. There was a male preponderance with a gender ratio of 1.5. The median age was 12.5 years (range: 1–18). Most of the patients were >10 years of age and received their diagnosis in the chronic phase. Three children were between 1 and 2 years of age at initial diagnosis of CML.
An incidental diagnosis of CML was made in 9 children for reasons including routine blood testing in patients with trauma or in those who underwent investigations for allergy or chronic cough. The median duration of symptoms before the diagnosis of CML was 1 month (range: 0–5.5 months). The main presenting symptoms are reported in Table 2. Asthenia was the most common symptom followed by splenic discomfort and weight loss. Bleeding, such as menorrhagia or epistaxis, was seen in 7 patients, 3 of whom had a normal platelet count and 4 of whom had thrombocytosis. Occasional patients presented with signs evocative of leukostasis, such as headache, dizziness, and hearing and visual disturbances. Priapism was the primary complaint in 1 boy with marked splenomegaly, leukocytosis (320 x 109/L), and thrombocytosis (643 x 109/L) counts. The nature of the symptoms and their duration before the diagnosis of CML did not differ between boys and girls.
The physical signs at diagnosis are reported in Table 1. Splenomegaly was the predominant abnormality, occurring in 70% of patients with a median size of 13 cm (range: 2–32 cm) below the costal margin. In 40% of these patients, the spleen extended >10 cm below the costal margin. The presence of a splenomegaly was significantly more frequent in patients with symptoms (Fischer's exact test, P = .027), especially in those with asthenia (Fischer's exact test, P = .034) than in asymptomatic patients. Hepatomegaly and enlarged lymph nodes were unusual. The clinical signs did not differ between boys and girls.
The hematologic findings are reported in Table 2. A white blood cell (WBC) count >10 x 109/L was observed in all of our patients. A higher presenting WBC count was associated with symptoms at diagnosis (Kruskal-Wallis test, P < .01) and splenomegaly at diagnosis (P < .01). The median percentage of peripheral blood granulocyte precursors (blasts, promyelocytes, and myelocytes) was 33.5% (range: 0–76%), and the percentage of granulocyte precursor was significantly higher in children with splenomegaly at diagnosis (Kruskal-Wallis test, P < .01). Sixty-five percent of our patients presented with anemia. The level of hemoglobin was significantly lower in children with asthenia and in those with splenomegaly at diagnosis (Kruskal-Wallis test, P = .01 and P = .03, respectively). The hemoglobin concentration also correlated with the size of the spleen (Spearman, P = .004). Sixty percent of our patients presented with thrombocytosis. The platelet count was significantly lower in children with splenomegaly at diagnosis (Kruskal-Wallis test, P = .04). There was no influence of age or gender on the WBC count, the hemoglobin level, or the platelet count.
Molecular analysis was performed in 28 children. In these patients, the break occurred in major breakpoint cluster region of the BCR gene on chromosome 22. Among them, 16 children were studied for the type of chimeric BCR-ABL mRNA using reverse transcription and the polymerase chain reaction: in 6 children, the major breakpoint cluster region (Mbcr) 2 was joined to ABL II (b2 a2 transcript), and in 10 children, Mbcr 3 was joined to ABL II (b3a2 transcript) on chromosome 9.
DISCUSSION
To our knowledge, 9 studies have reported clinical and biological data in patients who were younger than 20 years and had CML12–20 (Table 3). However, the numbers of children in most of these reports were small, and they were published between 1962 and 1992, leading to possible confusion between CML and juvenile myelomonocytic leukemia. Some descriptive studies in adults have also enrolled children and adolescents, but the data about the younger patients were not described separately.21–23
A slight male preponderance, as in our study, has been reported both in pediatric cases24 and in adult series.22 CML remains extremely rare in very young children; >60% of children in our study were older than 10 years at diagnosis, as previously reported,24 and the incidence rises with increasing age. A recent Japanese study found that CML represented 0.2% of leukemias between 1 and 4 years of age, 2.2% between 5 and 9 years, 3.7% between 10 and 14 years, and 8.3% between 15 and 19 years.3 In our study, the lower-than-expected number of patients in the 15- to 18-year age group is likely to be attributable to the tendency of this age group to be cared for in adult departments.
An incidental diagnosis of CML was made in 23% of our patients. This frequency is similar to that reported in adults22 and slightly higher than the 15% reported in a previous French pediatric study published in 1962,13 probably because of the increased use of routine blood counts in contemporary practice. A very small number of our patients received their diagnoses in advanced phases of CML, but this probably reflects that being in the first chronic phase of the disease was 1 of the inclusion criteria for 2 of the 3 trials from which our patients are derived.
In our study, asthenia and symptoms caused by splenomegaly were the most common presenting symptoms, as in a previous pediatric study13 and in adults.22 Children with symptoms at diagnosis had higher leukocyte counts and lower hemoglobin levels than those without symptoms, as reported in adults.22 Hepatomegaly was uncommon in our patients in comparison with a previous pediatric study (15% vs 33%), which included a higher number of children with advanced-phase disease.14 Mild hemorrhage was common in our patients; as in adults,22 this was not associated with thrombocytopenia and may have been attributable to platelet dysfunction.25 The type of BCR-ABL transcript was investigated in 16 of the children in our study: approximately two thirds of the children had b3a2 transcripts, as previously reported in adults with CML.26 Our data contrast with 2 previous pediatric studies in which only 4 (24%) of the total of 17 children studied had the b3a2 transcript.12,16
The main difference in CML at presentation between the children in our study and adults with CML was the higher leukocyte count in the children (median: 242 x 109/L) than reported in several adult studies (median: 12–174 x 109/L).22,27–30 There was no influence of gender on leukocyte count, unlike the observation of higher leukocyte counts in men than women reported in 1 large adult study.22 Despite the high median leukocyte count in our study, leukostasis was evident in only a few of our patients, in contrast to a review in 1984 that suggested that leukostasis was more common in children.19
This retrospective study represents the largest series of children in which the clinical signs and biology of CML have been reported. The main difference that we have identified between the children in this study and previous reports in adults is the higher leukocyte count at diagnosis. A prospective analysis of a larger cohort of children and adolescents with CML is needed to determine the biological and clinical significance of this observation and to identify prognostic factors in this age group.
ACKNOWLEDGMENTS
In addition to the authors, the following physicians participated in this study: Jean-Pierre Lamagnère (Pediatrics, University Hospital, Tours, France), Anne Notz (Pediatrics, University Hospital, Bordeaux, France), Frédéric Bernard (Pediatrics, University Hospital, Montpellier, France), Claire Berger (Pediatrics, University Hospital, Saint Etienne, France), Franoise Mazingue (Pediatrics, University Hospital, Lille, France), Karima Yacouben (Pediatrics, Robert Debre Hospital, Paris, France), Catherine Béhar (Pediatrics, University Hospital Reims, France), Antoine Thyss (Oncology, Lacassagne Center, France), Virginie Gandemer (Pediatrics, University Hospital, Rennes, France), and Guy Cornu (Pediatrics, St Luc Hospital, Brussels, Belgium).
We gratefully acknowledge Professor Irene Roberts (Hematology, Imperial College, London) for helpful comments on the manuscript.
FOOTNOTES
Accepted Jan 20, 2005.
No conflict of interest declared.
REFERENCES
Jakab Z, Balogh E, Kiss C, et al. Epidemiologic studies in a population-based childhood cancer registry in northeast Hungary. Med Pediatr Oncol.2002; 38 :338 –344
Ries LAG, Smith MA, Gurney JG, et al. Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995. SEER Pediatr Monogr.1999; 99 :46 –49
Horibe K, Tsukimoto I, Ohno R. Clinicopathologic characteristics of leukemia in Japanese children and young adults. Leukemia.2001; 15 :1256 –1261
Guilhot F, Chastang C, Michallet M, et al. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N Engl J Med.1997; 337 :223 –229
Millot F, Brice P, Philippe N, et al. -Interferon in combination with cytarabine in children with Philadelphia chromosome-positive chronic myeloid leukemia. J Pediatr Hematol Oncol.2002; 24 :18 –21
Millot F, Guilhot J, Nelken B, et al. Results of the Glivec (STI571)-CML-Ped Phase II trial testing Imatinib Mesylate (GleevecTM) in children with chronic myelogenous leukemia in advanced phase, resistant or intolerant to interferon or in relapse after stem cell transplantation . Blood.2003; 102 :183a
Millot F, Guilhot J, Nelken B, et al. Results of a phase II trial testing interferon alpha 2b and cytarabine in children with chronic myelogenous leukemia . Blood.2003; 102 :225
Morse HG, Humbert JR, Hutter JJ, Robinson A. Karyotyping of bone marrow cells in hematologic disease. Hum Genet.1977; 37 :33 –39
Bentz JM, Cabot G, Moos M, et al. Detection of chimeric BCR-ABL genes on bone marrow samples and blood smears in chronic myeloid and acute lymphoblastic leukaemia by in situ hybridisation. Blood.1994; 83 :1922 –1928
Zaccaria A, Martinelli G, Buzzi M, et al. The type of BCR/ABL junction does not predict the survival of patients with Ph1-positive chronic myeloid leukaemia. Br J Haematol.1993; 84 :265 –268
Speck B, Bortin MM, Champlin R. Allogeneic bone marrow transplantation for chronic myelogenous leukemia. Lancet.1984; 1 :665 –668
Auer I, Butturini A, Gale RP. BCR-ABL rearrangements in children with Philadelphia chromosome-positive chronic myelogenous leukaemia. Blood.1991; 78 :2407 –2410
Bernard J, Seligmann M, Acar J. [Chronic myeloid leukemia in the child (study of 20 cases).] Arch Fr Pediatr.1962; 19 :881 –894
Castro-Malaspina H, Schaison G, Briere J, et al. Philadelphia chromosome-positive chronic myelocytic leukemia in children. Cancer.1983; 52 :721 –727
Dow LW, Raimondi SC, Culbert SJ, et al. Response to alpha-interferon in children with Philadelphia-positive chronic myelocytic leukemia. Cancer.1991; 68 :1678 –1684
Fioretos T, Heim S, Garwicz S, Ludvigsson J, Mitelman F. Molecular analysis of Philadelphia-positive childhood chronic myeloid leukemia. Leukemia.1992; 6 :723 –725
Hardisty RM, Speed DE, Till M. Granulocytic leukemia in childhood. Br J Haematol.1964; 10 :551 –566
Hays T, Morse H, Peakman D, Rose B, Robinson A. Cytogenetic studies of chronic myelocytic leukemia in children and adolescents. Cancer.1979; 44 :210 –214
Rowe JM, Lichtman MA. Hyperleukocytosis and leucostasis: common features of childhood chronic myelogenous leukemia. Blood.1984; 63 :1230 –1234
Smith KL, Johnson W. Classification of chronic myelocytic leukaemia in children. Cancer.1974; 34 :670 –679
Prabhu M, Kochupillai V, Sharma S, et al. Prognostic assessment of various parameters in chronic myeloid leukemia. Cancer.1986; 58 :1357 –1369
Savage D, Szydlo R, Goldman J. Clinical features at diagnosis in 430 patients with chronic myeloid leukaemia seen at a referral centre over a 16-year period. Br J Haematol.1997; 96 :111 –116
Sokal JE, Baccarani M, Tura S, Fiacchini M, Cervantes F, Rozman C. Prognostic discrimination among younger patients with chronic granulocytic leukemia: relevance to bone marrow transplantation. Blood.1985; 66 :1352 –1357
Marin T, Butturini A, Kantarjian H, Sokal J, Mickey MR, Gale RP. Survival of children with chronic myeloid leukemia. Am J Pediatr Hematol Oncol.1992; 14 :229 –232
Cardamone JM, Edson JR, McArthur JR, Jacobs HS. Abnormalities of platelet function in the myeloproliferative disorders. JAMA.1972; 221 :270 –278
Eisenberg A, Silver R, Soper L, et al. The location of breakpoints within the breakpoint cluster region (bcr) of chromosome 22 in chronic myeloid leukemia. Leukemia.1988; 2 :642 –647
Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med.2002; 346 :645 –652
Hehlmann R, Heimpel H, Hasford J, et al. Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. Blood.1994; 84 :4064 –4077
O'Brien S, Guilhot F, Larson RA, et al. The IRIS study: International Randomized Study of Interferon and low dose cytarabine versus STI571 (imatinib mesylate) in patients with newly diagnosed chronic phase chronic myeloid leukemia. N Engl J Med.2003; 348 :994 –1004
Gardembas M, Rousselot P, Tulliez M, et al. Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase. Blood.2003; 102 :4298 –4305(Frédéric Millot, MD, Phil)
Department of Pediatrics, University Hospital, Lille, France
Department of Pediatrics, St Louis Hospital, Paris, France
Department of Pediatrics, Trousseau Hospital, Paris, France
Department of Pediatrics, University Hospital, Grenoble, France
Department of Pediatrics, University Hospital, Lyon, France
Department of Pediatrics, University Hospital, Nancy, France
ABSTRACT
Objective. The purpose of this study was to determine the clinical and biological characteristics at diagnosis in children and adolescents with chronic myelogenous leukemia (CML) in contemporary practice.
Methods. Analysis was conducted on data from 3 prospective trials conducted in children and adolescents with CML. Forty pediatric patients were evaluated in 16 French pediatric oncology units between 1991 and 2003.
Results. The disease predominately affected children who were older than 10 years (67% of the patients), with a higher prevalence in boys than girls (gender ratio: 1.5). Approximately 20% of cases were diagnosed incidentally. The main presenting symptoms were asthenia, weight loss, and complaints related to splenomegaly. Occasional patients presented with signs evocative of leukostasis. Symptoms were more common in patients with splenic enlargement, which was present in 70% of patients, and higher leukocyte counts. Markedly raised leukocyte counts were common (median white blood cell count: 242 x 109/L). The age and the gender of the patients had no effect on the leukocyte count, the hemoglobin level, or the platelet count. A predominance of b3a2 transcript was observed in the 16 children who were studied for the type of chimeric BCR-ABL mRNA.
Conclusions. This is largest reported series of CML at diagnosis in children and adolescents. It shows that the characteristics of CML seem to differ in children compared with previously published adult series; in particular, the presenting leukocyte counts are often higher in children.
Key Words: children leukostasis chronic myelogenous leukemia
Abbreviations: CML, chronic myelogenous leukemia WBC, white blood cell
Chronic myelogenous leukemia (CML) is a very rare disease in children, accounting for 2% to 3% of leukemias in children and adolescents with an annual incidence of 1 case per million children in Western countries.1–3 For this reason, presenting features of this myeloproliferative disease in the pediatric population are based on studies of a limited number of patients or on reports published several decades ago. The aim of this study was to determine the main presenting features of CML in children and adolescents in modern clinical practice.
METHODS
We reviewed the records of 40 children and adolescents who were treated for CML in 16 French centers. Among them, 12 consecutive children were included in the randomized trial LMC 91 protocol between January 1991 and May 1996 comparing interferon- alone and interferon- in combination with cytarabine in patients with CML in first chronic phase.4,5 Twenty-eight consecutive children at various stages of the disease were treated with interferon-–based therapy or imatinib mesylate or received a transplant between September 2000 and March 2003.6,7 The diagnosis of CML was confirmed by the presence of the BCR-ABL translocation by cytogenetic analysis, fluorescence in situ hybridization analysis, or molecular analysis as previously reported.8–10 The symptoms, physical signs, and peripheral blood and bone marrow analysis at initial diagnosis of CML were recorded. Stage of the disease (chronic phase, accelerated phase, or blastic crisis) was classified according to the criteria of the International Bone Marrow Transplant Registry.11 Anemia was diagnosed when the hemoglobin level was <11 g/dL in children who were between 0 and 6 years of age, <13 g/dL in boys who were >6 years of age, and <12 g/dL in girls who were >6 years of age. Thrombocytosis was diagnosed when the platelet count was >450 x 109/L, and thrombocytopenia was diagnosed when the platelet count was <150 x 109/L.
Statistical Analysis
Comparisons between groups were made with the use of Fisher's exact test for categorical variables, the Wilcoxon rank-sum test, and Kruskal-Wallis test for continuous variables. The significance of the correlation between 2 independent parameters was determined by the Spearman test. All statistical tests of significance were 2-tailed with a type I error of .05. Analyses were performed by using SAS statistical software (SAS Institute, Cary, NC).
RESULTS
Patients
Characteristics of the children are reported in Table 1. There was a male preponderance with a gender ratio of 1.5. The median age was 12.5 years (range: 1–18). Most of the patients were >10 years of age and received their diagnosis in the chronic phase. Three children were between 1 and 2 years of age at initial diagnosis of CML.
An incidental diagnosis of CML was made in 9 children for reasons including routine blood testing in patients with trauma or in those who underwent investigations for allergy or chronic cough. The median duration of symptoms before the diagnosis of CML was 1 month (range: 0–5.5 months). The main presenting symptoms are reported in Table 2. Asthenia was the most common symptom followed by splenic discomfort and weight loss. Bleeding, such as menorrhagia or epistaxis, was seen in 7 patients, 3 of whom had a normal platelet count and 4 of whom had thrombocytosis. Occasional patients presented with signs evocative of leukostasis, such as headache, dizziness, and hearing and visual disturbances. Priapism was the primary complaint in 1 boy with marked splenomegaly, leukocytosis (320 x 109/L), and thrombocytosis (643 x 109/L) counts. The nature of the symptoms and their duration before the diagnosis of CML did not differ between boys and girls.
The physical signs at diagnosis are reported in Table 1. Splenomegaly was the predominant abnormality, occurring in 70% of patients with a median size of 13 cm (range: 2–32 cm) below the costal margin. In 40% of these patients, the spleen extended >10 cm below the costal margin. The presence of a splenomegaly was significantly more frequent in patients with symptoms (Fischer's exact test, P = .027), especially in those with asthenia (Fischer's exact test, P = .034) than in asymptomatic patients. Hepatomegaly and enlarged lymph nodes were unusual. The clinical signs did not differ between boys and girls.
The hematologic findings are reported in Table 2. A white blood cell (WBC) count >10 x 109/L was observed in all of our patients. A higher presenting WBC count was associated with symptoms at diagnosis (Kruskal-Wallis test, P < .01) and splenomegaly at diagnosis (P < .01). The median percentage of peripheral blood granulocyte precursors (blasts, promyelocytes, and myelocytes) was 33.5% (range: 0–76%), and the percentage of granulocyte precursor was significantly higher in children with splenomegaly at diagnosis (Kruskal-Wallis test, P < .01). Sixty-five percent of our patients presented with anemia. The level of hemoglobin was significantly lower in children with asthenia and in those with splenomegaly at diagnosis (Kruskal-Wallis test, P = .01 and P = .03, respectively). The hemoglobin concentration also correlated with the size of the spleen (Spearman, P = .004). Sixty percent of our patients presented with thrombocytosis. The platelet count was significantly lower in children with splenomegaly at diagnosis (Kruskal-Wallis test, P = .04). There was no influence of age or gender on the WBC count, the hemoglobin level, or the platelet count.
Molecular analysis was performed in 28 children. In these patients, the break occurred in major breakpoint cluster region of the BCR gene on chromosome 22. Among them, 16 children were studied for the type of chimeric BCR-ABL mRNA using reverse transcription and the polymerase chain reaction: in 6 children, the major breakpoint cluster region (Mbcr) 2 was joined to ABL II (b2 a2 transcript), and in 10 children, Mbcr 3 was joined to ABL II (b3a2 transcript) on chromosome 9.
DISCUSSION
To our knowledge, 9 studies have reported clinical and biological data in patients who were younger than 20 years and had CML12–20 (Table 3). However, the numbers of children in most of these reports were small, and they were published between 1962 and 1992, leading to possible confusion between CML and juvenile myelomonocytic leukemia. Some descriptive studies in adults have also enrolled children and adolescents, but the data about the younger patients were not described separately.21–23
A slight male preponderance, as in our study, has been reported both in pediatric cases24 and in adult series.22 CML remains extremely rare in very young children; >60% of children in our study were older than 10 years at diagnosis, as previously reported,24 and the incidence rises with increasing age. A recent Japanese study found that CML represented 0.2% of leukemias between 1 and 4 years of age, 2.2% between 5 and 9 years, 3.7% between 10 and 14 years, and 8.3% between 15 and 19 years.3 In our study, the lower-than-expected number of patients in the 15- to 18-year age group is likely to be attributable to the tendency of this age group to be cared for in adult departments.
An incidental diagnosis of CML was made in 23% of our patients. This frequency is similar to that reported in adults22 and slightly higher than the 15% reported in a previous French pediatric study published in 1962,13 probably because of the increased use of routine blood counts in contemporary practice. A very small number of our patients received their diagnoses in advanced phases of CML, but this probably reflects that being in the first chronic phase of the disease was 1 of the inclusion criteria for 2 of the 3 trials from which our patients are derived.
In our study, asthenia and symptoms caused by splenomegaly were the most common presenting symptoms, as in a previous pediatric study13 and in adults.22 Children with symptoms at diagnosis had higher leukocyte counts and lower hemoglobin levels than those without symptoms, as reported in adults.22 Hepatomegaly was uncommon in our patients in comparison with a previous pediatric study (15% vs 33%), which included a higher number of children with advanced-phase disease.14 Mild hemorrhage was common in our patients; as in adults,22 this was not associated with thrombocytopenia and may have been attributable to platelet dysfunction.25 The type of BCR-ABL transcript was investigated in 16 of the children in our study: approximately two thirds of the children had b3a2 transcripts, as previously reported in adults with CML.26 Our data contrast with 2 previous pediatric studies in which only 4 (24%) of the total of 17 children studied had the b3a2 transcript.12,16
The main difference in CML at presentation between the children in our study and adults with CML was the higher leukocyte count in the children (median: 242 x 109/L) than reported in several adult studies (median: 12–174 x 109/L).22,27–30 There was no influence of gender on leukocyte count, unlike the observation of higher leukocyte counts in men than women reported in 1 large adult study.22 Despite the high median leukocyte count in our study, leukostasis was evident in only a few of our patients, in contrast to a review in 1984 that suggested that leukostasis was more common in children.19
This retrospective study represents the largest series of children in which the clinical signs and biology of CML have been reported. The main difference that we have identified between the children in this study and previous reports in adults is the higher leukocyte count at diagnosis. A prospective analysis of a larger cohort of children and adolescents with CML is needed to determine the biological and clinical significance of this observation and to identify prognostic factors in this age group.
ACKNOWLEDGMENTS
In addition to the authors, the following physicians participated in this study: Jean-Pierre Lamagnère (Pediatrics, University Hospital, Tours, France), Anne Notz (Pediatrics, University Hospital, Bordeaux, France), Frédéric Bernard (Pediatrics, University Hospital, Montpellier, France), Claire Berger (Pediatrics, University Hospital, Saint Etienne, France), Franoise Mazingue (Pediatrics, University Hospital, Lille, France), Karima Yacouben (Pediatrics, Robert Debre Hospital, Paris, France), Catherine Béhar (Pediatrics, University Hospital Reims, France), Antoine Thyss (Oncology, Lacassagne Center, France), Virginie Gandemer (Pediatrics, University Hospital, Rennes, France), and Guy Cornu (Pediatrics, St Luc Hospital, Brussels, Belgium).
We gratefully acknowledge Professor Irene Roberts (Hematology, Imperial College, London) for helpful comments on the manuscript.
FOOTNOTES
Accepted Jan 20, 2005.
No conflict of interest declared.
REFERENCES
Jakab Z, Balogh E, Kiss C, et al. Epidemiologic studies in a population-based childhood cancer registry in northeast Hungary. Med Pediatr Oncol.2002; 38 :338 –344
Ries LAG, Smith MA, Gurney JG, et al. Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995. SEER Pediatr Monogr.1999; 99 :46 –49
Horibe K, Tsukimoto I, Ohno R. Clinicopathologic characteristics of leukemia in Japanese children and young adults. Leukemia.2001; 15 :1256 –1261
Guilhot F, Chastang C, Michallet M, et al. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N Engl J Med.1997; 337 :223 –229
Millot F, Brice P, Philippe N, et al. -Interferon in combination with cytarabine in children with Philadelphia chromosome-positive chronic myeloid leukemia. J Pediatr Hematol Oncol.2002; 24 :18 –21
Millot F, Guilhot J, Nelken B, et al. Results of the Glivec (STI571)-CML-Ped Phase II trial testing Imatinib Mesylate (GleevecTM) in children with chronic myelogenous leukemia in advanced phase, resistant or intolerant to interferon or in relapse after stem cell transplantation . Blood.2003; 102 :183a
Millot F, Guilhot J, Nelken B, et al. Results of a phase II trial testing interferon alpha 2b and cytarabine in children with chronic myelogenous leukemia . Blood.2003; 102 :225
Morse HG, Humbert JR, Hutter JJ, Robinson A. Karyotyping of bone marrow cells in hematologic disease. Hum Genet.1977; 37 :33 –39
Bentz JM, Cabot G, Moos M, et al. Detection of chimeric BCR-ABL genes on bone marrow samples and blood smears in chronic myeloid and acute lymphoblastic leukaemia by in situ hybridisation. Blood.1994; 83 :1922 –1928
Zaccaria A, Martinelli G, Buzzi M, et al. The type of BCR/ABL junction does not predict the survival of patients with Ph1-positive chronic myeloid leukaemia. Br J Haematol.1993; 84 :265 –268
Speck B, Bortin MM, Champlin R. Allogeneic bone marrow transplantation for chronic myelogenous leukemia. Lancet.1984; 1 :665 –668
Auer I, Butturini A, Gale RP. BCR-ABL rearrangements in children with Philadelphia chromosome-positive chronic myelogenous leukaemia. Blood.1991; 78 :2407 –2410
Bernard J, Seligmann M, Acar J. [Chronic myeloid leukemia in the child (study of 20 cases).] Arch Fr Pediatr.1962; 19 :881 –894
Castro-Malaspina H, Schaison G, Briere J, et al. Philadelphia chromosome-positive chronic myelocytic leukemia in children. Cancer.1983; 52 :721 –727
Dow LW, Raimondi SC, Culbert SJ, et al. Response to alpha-interferon in children with Philadelphia-positive chronic myelocytic leukemia. Cancer.1991; 68 :1678 –1684
Fioretos T, Heim S, Garwicz S, Ludvigsson J, Mitelman F. Molecular analysis of Philadelphia-positive childhood chronic myeloid leukemia. Leukemia.1992; 6 :723 –725
Hardisty RM, Speed DE, Till M. Granulocytic leukemia in childhood. Br J Haematol.1964; 10 :551 –566
Hays T, Morse H, Peakman D, Rose B, Robinson A. Cytogenetic studies of chronic myelocytic leukemia in children and adolescents. Cancer.1979; 44 :210 –214
Rowe JM, Lichtman MA. Hyperleukocytosis and leucostasis: common features of childhood chronic myelogenous leukemia. Blood.1984; 63 :1230 –1234
Smith KL, Johnson W. Classification of chronic myelocytic leukaemia in children. Cancer.1974; 34 :670 –679
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