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Year : 2023  |  Volume : 66  |  Issue : 3  |  Page : 560-563
Pediatric and adolescent chronic myeloid leukemia: A follow-up study in Western India

Department of Oncopathology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India

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Date of Submission10-May-2021
Date of Acceptance20-Jul-2021
Date of Web Publication07-Jun-2022


Background: Chronic myeloid leukemia (CML) is relatively rare in pediatric and adolescent age groups. The purpose of this study was to evaluate the clinical, hematopathological, and biochemical parameters of CML in pediatric and adolescent age groups, along with an assessment of the treatment response with first-line tyrosine kinase inhibitors (TKI) and its correlation with the prognostic scoring systems of adults. Materials and Methods: A retrospective study of 44 Breakpoint Cluster Region-Abelson leukemia virus (BCR-ABL1)-positive pediatric and adolescent CML cases registered at our hospital was done. The clinical and laboratory parameters were evaluated using hospital software. The treatment response was monitored and scoring was performed using mathematical calculations. Results: The mean age was 11.6 (±4.7) years. The median hemoglobin was 8.4 g/dL and 63.6% of the cases showed white blood cell (WBC) counts >250,000/μL. The average follow-up was 21 months. A total of 97.7 and 78.1% cases achieved complete hematological response (CHR) and molecular response, respectively, during the treatment course. The maximum number of patients had low Sokal and European treatment and Outcomes Study (EUTOS) scores. Seventy-five per cent of the cases achieved CHR at 3 months, while 73.6 and 78.6% CML-Chronic phase (CP) cases with low Sokal and EUTOS scores achieved CHR at 3 months, respectively. Conclusion: This study revealed that the CML cases in pediatric and adolescent age groups are normally present with higher WBC counts at the time of diagnosis. The association of the prognostic scoring system with treatment response was statistically insignificant. However, a larger cohort study is needed to determine the treatment response of TKI in children and adolescent CML and its correlation with the prognostic scoring systems.

Keywords: Child chronic myeloid leukemia, EUTOS score, Sokal score, treatment response, tyrosine kinase inhibitors

How to cite this article:
Vanik SA, Jetly D, Parikh B, Dhandapani K, Bezbaruah R. Pediatric and adolescent chronic myeloid leukemia: A follow-up study in Western India. Indian J Pathol Microbiol 2023;66:560-3

How to cite this URL:
Vanik SA, Jetly D, Parikh B, Dhandapani K, Bezbaruah R. Pediatric and adolescent chronic myeloid leukemia: A follow-up study in Western India. Indian J Pathol Microbiol [serial online] 2023 [cited 2023 Sep 23];66:560-3. Available from:

   Introduction Top

The incidence of chronic myeloid leukemia (CML) in pediatric and adolescent age groups is very rare and it primarily affects the adult population.[1] The pediatric CML accounts for only 2–3% of all leukemias in this age group with an annual incidence of one case per million children in the western countries (Surveillance, Epidemiology, and End Results [SEER]).[1] CML arises from reciprocal translocation of genes on chromosomes 9 and 22, results in the juxtaposition of the Breakpoint Cluster Region (BCR) gene on chromosome 22 with the Abelson leukemia virus (ABL) gene and formation of the BCR-ABL1 fusion gene which has an enhanced tyrosine kinase activity resulting in enhanced myeloid proliferation and differentiation.[2],[3]

Evidence-based recommendations have been established in adults for the treatment of CML with tyrosine kinase inhibitors (TKIs).[4] But due to the rarity of the disease in the pediatric age group, the development of similar recommendations is challenging. Imatinib was approved for the treatment of pediatric CML in 2003.[4] In addition to this, the second-generation TKIs dasatinib and nilotinib were recently approved for use in pediatric CML, expanding the therapeutic options, and pushing the allogeneic stem cell transplantation to a third-line treatment in most cases.[4] There are many validated adult scoring systems available to assess the treatment response and none of them has been specifically validated in the pediatric population.[5]

The aim of this study is to describe and compare the clinical, hematopathological, and biochemical parameters of the pediatric and adult CML cases and to study the association between the prognostic scoring system with treatment response.

[TAG:2]Materials and Methods[/TAG:2]

The present study is a retrospective study of 44 newly diagnosed BCR-ABL1-positive and/or Philadelphia (Ph) chromosome-positive CML cases in the pediatric and adolescent population (≤18 years) from 2016 to 2019 in the department of Oncopathology at a tertiary care center in western India. The demographic and clinical data were retrieved from the patients' clinical files. The patients with no follow-up were excluded from the study. All the parameters were compared with 44 adult CML patients.

The diagnosis and stage of CML were reported according to the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues, 2016.[6] The diagnosis and stage were given on morphology of the peripheral blood, bone marrow aspiration, and trephine biopsy. The flow cytometry was done only in cases presented with blast crisis (BC). At the time of diagnosis, Fluorescence in situ hybridization (FISH) using dual color fusion probes labeled with ABL gene (orange signal) and BCR gene (green signal) was performed on the bone marrow/peripheral blood sample. A minimum of 200 cells was counted in each case and single orange, single green, and double or single yellow signals were considered as positive for fusion. For monitoring of the treatment response, quantitative real time-polymerase chain reaction (qRT-PCR) was performed on the peripheral blood sample/bone marrow at 3, 6, and 12 months and a normalized copy number of BCR-ABL1 copies was given. A complete hematological response (CHR) is defined as no blast or myeloid precursors in the peripheral blood and normal spleen size. A major molecular response (MMR) is a 3 log or less reduction in the BCR-ABL1 levels or less than or 0.1% of the cells that have the BCR-ABL1 gene. A complete molecular response (CMR) is an undetectable BCR-ABL1 gene copy number.[7],[8] The CHR was studied in all the 44 patients while the molecular response was studied in only 32 patients due to the low socioeconomical status of many of the patients.

The calculation of various prognostic scoring systems like Sokal and European treatment and Outcomes Study (EUTOS) scores were assessed using mathematical equations including the following parameters: Age, spleen size, platelets count, and blast cells percentage in the blood for the Sokal score; spleen size and basophils percentage in the blood for the EUTOS score at the time of the diagnosis.[9],[10] Based on the calculated score, the children were categorized into low-risk, intermediate-risk, or high-risk groups for the Sokal score and low risk or high risk for the EUTOS score.[9],[10]

At the time of the presentation, the patients with WBC counts >100,000/μL were admitted and started on hydroxyurea. All the investigations were done and after the diagnosis of CML, imatinib was started at a dose of 340 mg/m2/day after consent from the parent/guardian. The patients with imatinib resistance or intolerance were shifted to nilotinib. All the patients were followed up for response to TKI. The response to TKI is the most important prognostic factor. Currently, there are no pediatric-specific response criteria available; the National Comprehensive Cancer Network (NCCN) guidelines or European LeukemiaNet (ELN) criteria may be used in a pediatric patient.[4],[7] The responses to TKI are defined as “optimal” or “failure” and intermediate zone that is “warning.” The optimal response is associated with good long-term outcomes.

Statistical analysis

The IBM SPSS statistic software version 20, Armonk, NY, United States, was used for various statistical analyses. All hematopathological and biochemical parameters of the pediatric and adult age groups were compared using paired t-test, and for the association between the scoring system and treatment response, Fisher's exact test was used, and P value < 0.05 was considered as statistically significant.

   Results Top

Patient characteristics

A total of 44 patients age ≤18 years were included in this study. The median age was 12 (1–18) years and M: F ratio was 1.09:1. All the patients were positive for the BCR-ABL1 fusion gene by FISH analysis; 8 also showed variant BCR-ABL 1 fusion gene-positive. All clinical and prognostic scoring system parameters are listed in [Table 1]. The hematopathological and biochemical parameters of the pediatric and adult CML cases are compared in [Table 2].
Table 1: Baseline clinical profile of paediatric and adolescent (≤18 years) with chronic myeloid leukemia (n=44)

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Table 2: Baseline characteristics and comparison of hematopathological and biochemical parameters of pediatric and adult CML cases

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Flow cytometry was performed on four cases with CML-BC at the time of diagnosis and all show B cell lymphoblastic crisis. Three of these cases also showed aberrant expression of myeloid markers, i.e., CD13 and CD33 along with B cell markers. Two patients of these CML-BC had cerebrospinal fluid (CSF) involvement. Apart from these four cases, one case of CML-Chronic phase (CP) progressed to BC (myeloblastic) and showed extramedullary blast proliferation (myeloid sarcoma) after 2 years of CHR and MMR to TKI therapy.

Treatment response assessment

The average follow-up was 21 months with a range of 4–43 months with the median duration for the achievement of CHR being 5.14 weeks and a total of 97.7% cases had achieved CHR. At 3 months, 33 (75%) patients achieved CHR, at 6 months, 7 (15.9%) more patients achieved CHR, at 12 months, 3 (6.8%) more patients achieved CHR, while 1 (2.3%) patient did not achieve CHR even after 12 months. During the further treatment course, 10 (22.7%) patients showed loss of CHR. Three cases out of five who presented with accelerated phase showed CHR at 3 months and two cases at 6 months. During the further treatment course, three of these cases showed loss of CHR.

The molecular response was studied on 32 patients. Only two patients achieved CMR after 18 months of TKI therapy. The response milestone for TKI therapy is listed in [Table 3].
Table 3: Response to tyrosine kinase inhibitor therapy

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In our study, a total of 17 (73.9%), 8 (88.9%) and 8 (66.7%) cases with low, intermediate, and high Sokal scores achieved CHR, respectively, at 3 months, while 29 (80.6%) and 4 (50.0%) with low and high EUTOS scores achieved CHR, respectively, at 3 months. However, these results were statistically insignificant (P-values 0.524 and 0.092, respectively). The association between the treatment response and scoring system are assessed in [Table 4].
Table 4: Outcome among risk group

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   Discussion Top

Limited studies of pediatric and adolescent CML are available. The maximum number of patients in our study were in the age group 11–15 years (36.4%) with a slight male preponderance and the M: F ratio was 1.09:1. A study by Millot[11] showed male predominance and also the maximum number of their patients belonged to the 10–14 (47%) years age group which is concordant with our study. Abdominal pain and abdominal distension were predominant symptoms and splenomegaly was the predominant sign in this study. These findings are similar to the studies conducted by Chandra[12] and Millot.[11] Hepatomegaly was more in our study compared to the other pediatric studies by Raut[13] (69.5% vs. 14%) and Chandra[12] (69.5% vs. 35%). Out of the 44 cases, 35 (79.5%) cases were in the CP of the disease which was concordant with the study by Chandra[12] and Raut.[13]

The median of the WBC count, platelets count, and hemoglobin in this study was similar to the study conducted by Millot11. In our study, the mean WBC count at the time of presentation was higher than that of the adult CML cases which is consistent with the study by Chandra.[12]

In this study, the mean of lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) was 1124.11 and 150.50 U/L, respectively, which is associated with a higher WBC count. In the study by Hasan,[14] the mean of ALP was 122.6 U/L and LDH was 813.6 IU/L which was slightly lower than our study. The median of the uric acid was 5.8 mg/dL with a range of 2–10 mg/dL which was higher than the reference value for the age.[15] However, the uric acid level was not associated with a higher WBC count.

Tyrosine kinase inhibitor is the gold standard treatment for pediatric as well as adult CML cases. Various risk scores in the adult CML predict the treatment response but there is no defined risk score system developed in the pediatric population. In a study by Salas and Johnson,[16] 62, 16 and 22% of the cases had low-, intermediate- and high-risk Sokal scores while the EUTOS low- and high-risk scores were 81 and 19%, respectively, which is concordant with our study. A study by Ganta[5] showed 90, 97 and 83% of the cases with low, intermediate, and high Sokal scores, respectively, and 94 and 86% with low and high EUTOS scores, respectively, achieved CHR at 3 months which was higher than our study. While another study by Ganta[17] showed that 95 and 79% of the cases with low and high EUTOS scores, respectively, achieved molecular response during treatment which was also not concordant with our study.

In a study trial by Suttorp,[18] the treatment of pediatric CML (n = 50) with imatinib as a first-line had shown that in the CP, 96% of the cases achieved CHR and 69% complete cytogenetic response (CCyR) at 12 months, which was higher than in our study. In the French study (n = 44), 86% of the cases achieved CHR at 3 months, 62% CCyR at 12 months and 31% achieved MMR at 12 months with a median follow-up being 31 months,[19] which was concordant with our study.

   Conclusion Top

The studies on pediatric and adolescent CML are very limited. In the present study, we identified that pediatric and adolescent CML patients present with a higher WBC count compared to adult CML. While the association between the prognostic scoring systems and treatment response was statistically insignificant in the present study, larger prospective studies should be undertaken for monitoring of the treatment responses. There is also a need to develop a new prognostic scoring system for the pediatric age group to assess the treatment response.

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Conflicts of interest

There are no conflicts of interest.

   References Top

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Cortes J, Deininger. BCR-ABL as a molecular target. In: Deininger M, editor. Chronic Myeloid Leukemia. 1st ed. New York: Informa Healthcare; 2006. p. 27-45.  Back to cited text no. 2
Sawyers CL. Chronic myeloid leukemia. N Engl J Med 1999;340:1330-40.  Back to cited text no. 3
Hijiya N, Suttorp M. How I treat chronic myeloid leukemia in children and adolescents. Blood 2019;133:2374-84.  Back to cited text no. 4
Ganta RR, Nasaka S, Linga VG, Gundeti S, Maddali LS, Digumarti RR. Effectiveness of three prognostic scoring systems in predicting the response and outcome in pediatric chronic myeloid leukemia CP on frontline imatinib. Indian J Med Paediatr Oncol 2017;38:282-6.  Back to cited text no. 5
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Swerdlow SH. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. Revised 4th ed. Lyon: International Agency for Research on Cancer; 2017.  Back to cited text no. 6
Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, et al. Evolving concepts in the management of chronic myeloid leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006;108:1809-20.  Back to cited text no. 7
Goldman JM. How I treat chronic myeloid leukemia in the imatinib era. Blood 2007;110:2828-37.  Back to cited text no. 8
Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood 1984;63:789-99.  Back to cited text no. 9
Hasford J, Baccarani M, Hoffmann V, Guilhot J, Saussele S, Rosti G, et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood 2011;118:686-92.  Back to cited text no. 10
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.  Back to cited text no. 11
Chandra D, Singh J, Deka R, Chauhan R, Sazwal S, Mishra P, et al. The biology of chronic myelogenous leukemia in childhood and young adolescents: An Indian perspective. Indian J Med Paediatr Oncol 2018;39:142-5.  Back to cited text no. 12
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Hasan KM. Evaluation of chronic myeloid leukemia patients and their molecular responses to tyrosine kinase inhibitors in Erbil city, Iraq. Iraqi J Hematol 2018;7:1-7.  Back to cited text no. 14
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Kubota M., Nagai A, Tang L, Tokuda M. Investigation on hyperuricemia in children with obesity or various pediatric disorders, “nucleosides, nucleotides and nucleic acid. 2011;30:1051-9.  Back to cited text no. 15
Salas GD, Glauche I, Tauer JT, Thiede C, Suttorp M. Can prognostic scoring systems for chronic myeloid leukemia as established in adults be applied to pediatric patients? Ann Hematol 2015;94:1363-71.  Back to cited text no. 16
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Suttorp M, Thiede C, Tauer JT, Roettgers S, Sedlacek P, Harbott J, et al. Chronic myeloid leukemia in pediatrics – first results from study CML-PAED II. 2009. Blood. 2009;114:342.  Back to cited text no. 18
Millot F, Baruchel A, Guilhot J, Petit A, Leblanc T, Bertrand Y. Imatinib is effective in children with previously untreated chronic myelogenous leukemia in early chronic phase: Results of the French national phase IV trial. J Clin Oncol 2011;29: 2827-32.  Back to cited text no. 19

Correspondence Address:
Dhaval Jetly
The Gujarat Cancer and Research Institute, Ahmedabad - 380 016, Gujarat
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_462_21

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