|Year : 2018 | Volume
| Issue : 2 | Page : 142-145
The biology of chronic myelogenous leukemia in childhood and young adolescents: An indian perspective
Dinesh Chandra, Jasdeep Singh, Roopam Deka, Richa Chauhan, Sudha Sazwal, Pravas Mishra, Tulika Seth, Manoranjan Mahapatra, Renu Saxena
Department of Hematology, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||21-Mar-2018|
Dr. Tulika Seth
Department of Hematology, AIIMS, New Delhi
Source of Support: None, Conflict of Interest: None
Objective: The purpose of this study was to determine the clinical, biological, and molecular characteristics at diagnosis in children and adolescents with chronic myelogenous leukemia (CML) in the Indian scenario at our tertiary patient care center. Subjects and Methods: We evaluated 51 children and adolescents with CML registered at our clinic, from January 2007 to December 2015. The mean and median of various parameters were calculated using a Microsoft excel sheet and SPSS software version 16. Results: The median age of presentation in children was 16 years; 92.2% of them were older than 10 years, with a higher prevalence in boys than girls (gender ratio 2.6:1). The symptoms at presentation were fatigue, fever, awareness of mass due to splenomegaly, and bleeding manifestations. One patient presented with Bell's palsy. Markedly raised leukocyte counts were present in 29.4% patients (median white blood cell count >400 × 109/L). Most of the patients presented in the chronic phase of the disease, four each were in accelerated phase and blast crisis, respectively. Majority of patients were categorized as intermediate risk as per Sokal and Hansford score. About 60.7% of these pediatric patients fell in low-risk category as per European Treatment and Outcome Study score at baseline. A predominance of transcript P210-b3a2 (68%) was observed in the children who were studied for the type of chimeric BCR-ABL mRNA. Conclusions: This is one of the most recent reported series of CML in children and adolescents from India highlighting the difference in presentation from adults; mainly hepatomegaly, bleeding manifestations, and higher leukocyte count. Presence of b3a3 transcript of p210 breakpoint of BCR-ABL was more common in children (68%) than b2a2 transcript (32%) when compared to adults as recently described in a study from India, which may explain the differences at presentation.
Keywords: BCR-ABL transcripts, chronic myelogenous leukemia, clinical presentation, pediatric
|How to cite this article:|
Chandra D, Singh J, Deka R, Chauhan R, Sazwal S, Mishra P, Seth T, Mahapatra M, Saxena R. The biology of chronic myelogenous leukemia in childhood and young adolescents: An indian perspective. Indian J Med Paediatr Oncol 2018;39:142-5
|How to cite this URL:|
Chandra D, Singh J, Deka R, Chauhan R, Sazwal S, Mishra P, Seth T, Mahapatra M, Saxena R. The biology of chronic myelogenous leukemia in childhood and young adolescents: An indian perspective. Indian J Med Paediatr Oncol [serial online] 2018 [cited 2018 Dec 15];39:142-5. Available from: http://www.ijmpo.org/text.asp?2018/39/2/142/228101
| Introduction|| |
Chronic myelogenous leukemia (CML) is primarily an adult disease and its incidence is rare in children and adolescents, accounting for only 2% to 3% of all leukemias in this age group with an annual incidence of 1 case per million children in Western countries (Surveillance, Epidemiology, and End Results [SEER]). Although the age-adjusted rates for CML in pediatric and young adults are slightly higher in India than in SEER registries, the characteristic features of this myeloproliferative disease in the younger population are based on studies of a limited number of patients. The aim of this study was to determine the main presenting features of CML in children and adolescents in the Indian population as well as to characterize the molecular subtype of the BCR-ABL transcript, as the studies pertaining to this entity are sparse.
| Subjects and Methods|| |
We reviewed the records of 51 children and adolescents who were treated for CML at this center over a period of 9 years, between January 2007 to December 2015. The diagnosis of CML was confirmed by the presence of the BCR-ABL translocation by reverse transcription polymerase chain reaction (RT-PCR). The symptoms, physical signs, peripheral blood, and bone marrow analysis at initial diagnosis were recorded. Stage of the disease (chronic phase, accelerated phase, or blast crisis) was classified according to the WHO 2008 criteria. Anemia was diagnosed when the hemoglobin level was <110 g/L in children who were between 0 and 6 years of age, <130 g/L in boys who were >6 years of age, and <120 g/L in girls who were >6 years of age. Thrombocytosis was diagnosed when the platelet count was >450 × 109/L, and thrombocytopenia was diagnosed when the platelet count was <150 × 109/L. The BCR-ABL fusion gene was analyzed in all patients and the type of fusion transcript was determined in 25 patients. The Sokal, European Treatment and Outcome Study (EUTOS) scores were evaluated for patients.
The mean and median of various parameters were calculated using a Microsoft excel sheet and IBM SPSS statistic software version 16, Armonk, New York, United States.
| Results|| |
Patient characteristics of the children and adolescents are reported in [Table 1]. There was a male preponderance with male to female ratio of 2.6:1. The median age at diagnosis was 16 years (range: 7–17 years). Most of the patients were >10 years of age (92.2%) and were diagnosed in the chronic phase (84.4%). The median duration of symptoms before the diagnosis of CML was 2 months (range: 10 days to 48 months). The main presenting symptoms are reported in [Table 1]. Generalized weakness was the most common symptom followed by fever and abdominal discomfort or awareness of mass. Bleeding such as menorrhagia or epistaxis was seen in 8 patients, of whom 7 had normal platelet count and one had thrombocytosis. The nature of the symptoms and their duration before the diagnosis of CML did not differ between boys and girls. One of the patients with Bell's palsy was detected to have blast crisis.
|Table 1: Baseline clinical profile of children and adolescents (n=51) with chronic myelogenous leukemia|
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The physical signs at diagnosis are reported in [Table 1]. Splenomegaly was the predominant abnormality detected in 90.2% of patients with a median spleen size of 12 cm (range: 1–28 cm) below the costal margin, of these 67.4% of patients had massive splenomegaly (spleen size >8 cm below the costal margin). The presence of a splenomegaly was significantly more frequent in symptomatic (Fischer's exact test, P < 0.05) than in asymptomatic patients. Hepatomegaly was also present in 35.3% of the patients, while lymphadenopathy was unusual. The physical signs did not differ between boys and girls.
A white blood cell (WBC) count >10 × 109/L was observed in all of our patients [Table 2]. A higher presenting WBC count was associated with symptoms at diagnosis (Kruskal–Wallis test, P < 0.01) and splenomegaly at diagnosis (P< 0.01). About 92.1% of our patients presented with anemia. The level of hemoglobin was significantly lower in children with splenomegaly at diagnosis (Kruskal–Wallis test, P = 0.01). Nearly, 27.4% of our patients presented with thrombocytosis. There was no influence of age or gender on the WBC count, the hemoglobin level, or the platelet count.
|Table 2: Baseline laboratory parameters of children and adolescents (n=51) with chronic myelogenous leukemia|
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About 27.5% and 25.5% of our patients were categorized as low risk as per Sokal and Hasford scoring system, respectively, and 60.7% fell in the low risk category as per EUTOS score at baseline [Table 3].
|Table 3: Prognostic scores of children and adolescents (n=51) with chronic myelogenous leukemia|
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Molecular analysis of BCR-ABL mutation was done using reverse transcription and the RT-PCR in our patients [Table 4]. Majority of the patients (50) were positive for p210 and 1 patient was positive for p230. None of the patients were positive for p190. BCR-ABL p210 transcripts had been analyzed in 25 patients. These patients were studied for the type of chimeric BCR-ABL mRNA, of which b3a2 was positive in 17 and b2a2 was positive in 8 patients. The most common transcript was b3a2 in our patients.
| Discussion|| |
Till date, the major focus of studies on reported clinical and biological data has been in adults with CML with pediatric CML as an incidental part; similarly, at our center, adult CML data of 20 years was published in 2013.
However, the numbers of children in most of these reports were small and were published between 1990–2010.,,,, Earlier studies before 2002 may have included patients with juvenile myelomonocytic leukemia as there was a diagnostic dilemma between these two entities.,, The earlier studies from AIIMS have presented data up to 2010 but without the molecular transcript data. We, in our study, have retrieved data from the last 9 years and correlated it along with the molecular transcript data available.
Our data show male preponderance; this has been reported both in pediatric cases by the French group and in our adult series. CML remains extremely rare in very young children; more than 90% of children in our study were older than 10 years at diagnosis, as previously reported; this can be ascribed to the fact that the incidence of CML rises with increasing age. Similar trend of rising incidence with age in the pediatric patients has been seen in the SEER data and Asian studies including Indian and Japanese group.,,, The Japanese group 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. The Asian group diagnosed CML in 0.3% in age group 0–4 years, 1.2% in 5–9 years, 2.7% in 10–14 years, 5.1% in 15–19 years. Only the French multicenter study has shown more patients in the younger age group which may be due to a separate adult CML clinic. However, in the present study, the majority of our pediatric and adolescent population with CML were diagnosed in the age group >10 years. Out of these 43 were diagnosed in chronic phase and 4 in accelerated phase and 4 in blast crisis. The rate of detection of CML in aggressive phase is higher than reported by earlier studies, which may be ascribed to the delay in initiating therapy or confirming diagnosis.
Generalized weakness, fever, distress caused by splenomegaly, and bleeding were the most common presenting symptoms, which was different from previous pediatric studies by the French group and Raut et al., where bleeding manifestations were seen in rare cases., Children with symptoms at diagnosis had higher leukocyte counts and lower hemoglobin levels than those without symptoms, as reported in adults in data published by our institution.
Hepatomegaly was more common in our patients in comparison with a previous pediatric study by Raut (35% vs. 14%). Hepatomegaly may be related to adverse prognosis as previously reported by some older studies, and these patients will require greater follow-up to monitor response to therapy before a definitive conclusion can be drawn. Mild hemorrhage was common in our patients, as in adult patients of our institution. This was not associated with thrombocytopenia and may have been attributable to platelet dysfunction.
The type of BCR-ABL transcript was investigated in 25 of the children in our study: two-thirds of these had b3a2 transcript of p210, as compared to adults where b2a2 transcripts are more common as reported in a recent study and data published from our center in the past. This may explain the presence of higher leukocyte count at presentation in pediatric CML.,
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: 170 × 109/L) than reported in several adult studies, which can be explained by two-thirds of patients having b3a2 transcripts , [Table 5]. Despite the high median leukocyte count in our study, leukostasis was evident in only a few of our patients which has also been seen in the French group study; this finding is in contrast to older reviews in which leukostasis was more common in children. Bleeding manifestations were also more common in our study than previously published series. Hepatomegaly was also present in many of our patients which are in contrast to published data by the French group. The most common BCR-ABL transcript was b3a2 in our study which is higher (41%) than as reported in a recent study in this part of the world.
|Table 5: Comparison between adult and pediatric chronic myelogenous leukemia patients|
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| Conclusions|| |
This retrospective study represents the largest series of children and adolescents in which the clinical signs and biology of CML have been reported from South Asian part of the subcontinent. The main differences that we have identified between the children and adolescents in this study are the higher leukocyte count at diagnosis, presence of hepatomegaly, bleeding manifestations at presentation, presence of b3a3 transcript of p210 breakpoint of BCR-ABL being more common in our patients. A prospective analysis of a larger cohort is needed to determine the clinical significance of these observations and also to identify if these factors affect response to tyrosine kinase inhibitor therapy or have any prognostic significance.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ries LAG, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, et al
. Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995, National Cancer Institute, SEER Program. NIH Pub. No. 99-4649. Bethesda, MD, 1999.
Dikshit RP, Nagrani R, Yeole B, Koyande S, Banawali S. Changing trends of chronic myeloid leukemia in greater Mumbai, India over a period of 30 years. Indian J Med Paediatr Oncol 2011;32:96-100.
] [Full text]
Vardiman JW, Melo JV, Baccarani M, Thiele J. Chronic myelogenous leukaemia, BCR-ABL1 positive. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al
., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th
ed. Lyon: IARC; 2008. p. 32-7.
Mishra P, Seth T, Mahapatra M, Saxena R. Report of chronic myeloid leukemia in chronic phase from all India Institute of Medical Sciences, 1990-2010. Indian J Med Paediatr Oncol 2013;34:159-63.
] [Full text]
Marin T, Butturini A, Kantarjian H, Sokal J, Mickey MR, Gale R, et al.
Survival of children with chronic myeloid leukemia. Am J Pediatr Hematol Oncol 1992;14:229-32.
Savage DG, Szydlo RM, Goldman JM. 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;96:111-6.
Jakab Z, Balogh E, Kiss C, Oláh E. Epidemiologic studies in a population-based childhood cancer registry in Northeast Hungary. Med Pediatr Oncol 2002;38:338-44.
Millot F, Traore P, Guilhot J, Nelken B, Leblanc T, Leverger G, et al.
Clinical and biological features at diagnosis in 40 children with chronic myeloid leukemia. Pediatrics 2005;116:140-3.
Raut L, Bohara VV, Ray SS, Chakrabarti P, Chaudhuri U. Chronic myeloid leukemia in children and adolescents: A single center experience from Eastern India. South Asian J Cancer 2013;2:260-4.
] [Full text]
Smith KL, Johnson W. Classification of chronic myelocytic leukemia in children. Cancer 1974;34:670-9.
Mendizabal AM, Garcia-Gonzalez P, Levine PH. Regional variations in age at diagnosis and overall survival among patients with chronic myeloid leukemia from low and middle income countries. Cancer Epidemiol 2013;37:247-54.
Horibe K, Tsukimoto I, Ohno R. Clinicopathologic characteristics of leukemia in Japanese children and young adults. Leukemia 2001;15:1256-61.
Cardamone JM, Edson JR, McArthur JR, Jacob HS. Abnormalities of platelet function in the myeloproliferative disorders. JAMA 1972;221:270-3.
Hasan SK, Sazawal S, Kumar B, Chaubey R, Mishra P, Mir R, et al.
Childhood CML in India: B2a2 transcript is more common than b3a2. Cancer Genet Cytogenet 2006;169:76-7.
Jain P, Kantarjian H, Patel KP, Gonzalez GN, Luthra R, Kanagal Shamanna R, et al.
Impact of BCR-ABL transcript type on outcome in patients with chronic-phase CML treated with tyrosine kinase inhibitors. Blood 2016;127:1269-75.
Hanfstein B, Lauseker M, Hehlmann R, Saussele S, Erben P, Dietz C, et al.
Distinct characteristics of e13a2 versus e14a2 BCR-ABL1 driven chronic myeloid leukemia under first-line therapy with Imatinib. Haematologica 2014;99:1441-7.
Rowe JM, Lichtman MA. Hyperleukocytosis and leukostasis: Common features of childhood chronic myelogenous leukemia. Blood 1984;63:1230-4.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]