Profile of Pediatric Chronic Myeloid Leukemia in the Era of Imatinib: A Study from South India
CC BY-NC-ND 4.0 ? Indian J Med Paediatr Oncol 2019; 40(S 01): S77-S81
DOI: DOI: 10.4103/ijmpo.ijmpo_234_17
Abstract
Introduction:?Chronic myeloid leukemia (CML), a chronic hematologic malignancy, is rare in pediatric patients. Studies of the tyrosine kinase inhibitor imatinib are required so that uniform guidelines may focus on disease therapy and follow-up for children. We analyzed the clinicohematologic features of the disease, treatment response to imatinib, follow-up measures, and the impact of the disease on the patients and their family.?Materials and Methods:?All pediatric patients diagnosed with CML and treated and followed-up were studied regarding demographics, clinical features at presentation, and diagnostic profile, including laboratory parameters, peripheral blood smear test, fluorescent?in situ?hybridization and karyotyping, and reverse-transcriptase polymerase chain reaction for the BCR-ABL fusion gene. Treatment modalities, adverse reactions, remedial measures, assessment at every follow-up visit, patient?s education, parents? socioeconomic status, and economic and psychological stresses were also evaluated.?Results:?Six patients were administered upfront therapy with a standard dose of imatinib. Hematological and biochemical parameters were monitored after the drug administration. We assessed the treatment response using molecular detection of the BCR-ABL transcripts. All patients who complied with drug therapy showed a complete molecular response and minimal toxic symptoms. However, parents found it difficult to cope socially and economically.?Conclusion:?Imatinib mesylate is effective and has a good molecular response, minimal toxicity, and good patient compliance. However, due to its cost, families reacquire financial debt, and the disease creates uncertainty about the child?s future, thereby necessitating psychosocioeconomic support for parents. Changes in the policies of cancer support groups are urgently needed to provide lifelong, lifesaving drugs free of cost.
Publication History
Article published online:
24 May 2021
? 2019. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
Abstract
Introduction:?Chronic myeloid leukemia (CML), a chronic hematologic malignancy, is rare in pediatric patients. Studies of the tyrosine kinase inhibitor imatinib are required so that uniform guidelines may focus on disease therapy and follow-up for children. We analyzed the clinicohematologic features of the disease, treatment response to imatinib, follow-up measures, and the impact of the disease on the patients and their family.?Materials and Methods:?All pediatric patients diagnosed with CML and treated and followed-up were studied regarding demographics, clinical features at presentation, and diagnostic profile, including laboratory parameters, peripheral blood smear test, fluorescent?in situ?hybridization and karyotyping, and reverse-transcriptase polymerase chain reaction for the BCR-ABL fusion gene. Treatment modalities, adverse reactions, remedial measures, assessment at every follow-up visit, patient?s education, parents? socioeconomic status, and economic and psychological stresses were also evaluated.?Results:?Six patients were administered upfront therapy with a standard dose of imatinib. Hematological and biochemical parameters were monitored after the drug administration. We assessed the treatment response using molecular detection of the BCR-ABL transcripts. All patients who complied with drug therapy showed a complete molecular response and minimal toxic symptoms. However, parents found it difficult to cope socially and economically.?Conclusion:?Imatinib mesylate is effective and has a good molecular response, minimal toxicity, and good patient compliance. However, due to its cost, families reacquire financial debt, and the disease creates uncertainty about the child?s future, thereby necessitating psychosocioeconomic support for parents. Changes in the policies of cancer support groups are urgently needed to provide lifelong, lifesaving drugs free of cost.
Introduction
Chronic myeloid leukemia (CML) is a chronic hematologic malignancy involving the myeloid cells due to translocation t(9; 22) causing the formation of BCR-ABL fusion gene. This disease is rare in pediatric patients.[1] Allogeneic stem cell transplantation (SCT) is the only treatment modality for children, but it is beyond the reach of almost all people in developing countries.[2] With the advent and approval of the tyrosine kinase inhibitor imatinib, an oral drug, there is hope for children who are affected by this chronic malignant disease. Few clinical trial reports and single-center experiences are available because the disease is rare and the patient population is small, especially in developing countries and in children. Imatinib mesylate must be used during a patient?s lifetime. However, due to its associated costs and lack of financial support, it has increased abandonment rates. Long-term medications, drug toxicity and monitoring, long-term follow-up of outcomes, growth, education of children, family support, and the psycho-socioeconomic impact of the disease on the family must be analyzed and documented. More studies are required, especially in developing countries, so that a consensus can be reached regarding treatment and so that uniform guidelines may be created to address disease therapy and follow-up. We analyzed the clinico-hematologic features of and treatment response to imatinib, the follow-up measures, and the impact of the disease on patients and their families.
Materials and Methods
This prospective, descriptive study was performed at the departments of pathology and paediatric hematologic oncology at our institution. The Institutional Ethics Committee approved the study and informed consent was obtained from the parents of the patients. All pediatric patients diagnosed with CML between 2011 and 2016 were included in the study. The patients? medical records were thoroughly read, and we interviewed the patients and parents when they attended a review clinic. The demographics and clinical features at presentation were recorded. The diagnostic profile, which included laboratory parameters, peripheral blood smear test results, fluorescent?in situ?hybridization (FISH), karyotyping, and reverse-transcriptase polymerase chain reaction (RT-PCR) for the BCR-ABL gene, were recorded.
Treatment modalities, adverse reactions, and remedial measures performed were recorded on data sheets. Patients were assessed at every follow-up visit and the treatment response was recorded. Treatment responses were assessed as the complete hematologic response (CHR) (white blood cell count [WBC] <10 xss=removed>3/?l, platelet count <450 xss=removed>3/?l, myelocytes and metamyelocytes <5>3-log reduction in transcripts).[3] [4] The response criterion for imatinib according to the timeline was defined as an optimal or suboptimal response, and failure was defined according to the European LeukemiaNet panel.[3] [4]
Patients were interviewed regarding their education. The socioeconomic status of the parents was assessed using the modified Kuppuswamy?s socioeconomic status scale.[5] A questionnaire was developed after extensive research of the literature, and it was validated by experienced pediatric hemato-oncologists from three other institutions. It consisted of 15 questions and was composed of variables such as economic and psychological stresses due to chronicity of the disease and frequent hospital visits, social stigma, and funding sources. The questionnaire was prepared according to the situations that typically occur in developing countries and was validated.[6] Parents were asked to complete the questionnaire at a semi-structured, scheduled interview. The data were tabulated and a descriptive analysis was performed.
Results
Between 2011 and 2016, seven patients were diagnosed with CML. At our center, 3.6% of pediatric patients had leukemia and 9% had CML. Among these seven patients, one patient opted out of treatment. The six remaining patients were followed up.
Among these six patients, four were male and two were female. Three (50%) of these patients were between 15 and 19 years old, 2 (33.3%) were between 10 and 14 years old, and 1 (16.7%) was between 5 and 9 years old. Four patients were classified as lower-middle class, one was classified as upper-middle class, and one was classified as upper class.
The hematological findings at presentation are shown in [Table 1]. Three patients (50%) had hyperleukocytosis with more than 100 ? 103/?l WBC in the peripheral blood.[7] Among these patients, 2 (33.3%) had a low red blood cell count and hemoglobin. Only one patient had thrombocytopenia. Splenomegaly was not noted in two patients (33.3%). Hepatomegaly was not observed.
Parameter |
n (%) |
---|---|
FISH ? Fluorescent in situ hybridization; RT-PCR ? Reverse-transcriptase polymerase chain reaction; CML ? Chronic myeloid leukemia; WBC ? White blood cell; RBC ? Red blood cell |
|
WBC (?103/?l) |
|
40-60 |
2 (33.3) |
60-80 |
2 (33.3) |
>200->300 |
1 (16.6) |
>400-<500> |
1 (16.6) |
Hemoglobin (g/dl) |
|
<8> |
1 (16.6) |
8.12 |
4 (66.6) |
>12 |
1 (16.6) |
RBC (?103/?l) |
|
<3> |
1 (16.6) |
<3> |
5 (83.3) |
Genetics |
|
FISH t(9;22) |
6 (100) |
Karyotyping |
6 (100) |
RT-PCR (BCR-ABL) |
6 (100) |
Platelet (103/?l) |
|
150-450 |
4 (66.6) |
450-600 |
1 (16.6) |
>600 |
1 (16.6) |
Diagnostic phase |
|
Chronic phase CML |
6(100) |
Toxicity |
n (%) |
---|---|
GI ? Gastrointestinal |
|
GI intolerance |
4 (66.6) |
Skin rash |
2 (33.3) |
Hypopigmentation |
2 (33.3) |
Bone pain |
2 (33.3) |
Myalgia |
1 (16.6) |
Cramps |
1 (16.6) |
Necessity to reduce dose |
1 (16.6) |
Patient number |
3 months |
6 months |
12?1 months |
18?1 months |
Within 3 months of last follow-up |
Duration of follow-up |
Treatment response |
---|---|---|---|---|---|---|---|
CCyR ? Complete cytogenetic response; MMR ? Major molecular response; CHR ? Complete hematological response; CMR ? Complete molecular response |
|||||||
1 |
CCyR |
MMR |
MMR |
CMR |
CMR |
6 years 5 months |
Optimal |
2 |
CHR |
CCyR |
MMR |
CMR |
CMR |
2 year 6 months |
Optimal |
3 |
CHR |
CHR |
CHR |
- |
< MMR> |
3 years 4 months |
Suboptimal/failure (due to lack of compliance and irregular follow-up) |
4 |
CHR |
CCyR |
MMR |
CMR |
CMR |
5 years 4 months |
Optimal |
5 |
CCyR |
CCyR |
MMR |
MMR |
CMR |
3 years 2 months |
Optimal |
6 |
CHR |
CCyR |
CMR |
CMR |
CMR |
5 years 6 months |
Optimal |
Variable |
Percentage |
---|---|
Guilt |
33 |
Depression |
50 |
Worried about the future |
50 |
Difficulty in coping with the chronic disease |
50 |
Burdened |
50 |
Stigmatized |
17 |
Neglected |
17 |
Worried about the worsening economic status |
33 |
- Raut LS.?Chronic myeloid leukemia in children: A brief review. Clin Cancer Investing J 2014; 6: 467-71
- Druker BJ, Sawyers CL, Capdeville R, Ford JM, Baccarani M, Goldman JM. et al.?Chronic myelogenous leukemia. Hematology Am Soc Hematol Educ Program 2001; 2001: 87-112
- 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
- Goldman JM.?How I treat chronic myeloid leukemia in the imatinib era. Blood 2007; 110: 2828-37
- Kumar N.?Kuppuswamy?s socioeconomic status scale-updating for 2007. Indian J Pediatri 2007; 74: 1131-2
- Han HR, Cho EJ, Kim D, Kim J.?The report of coping strategies and psychosocial adjustment in Korean mothers of children with cancer. Psychooncology 2009; 18: 956-64
- R?llig C, Ehninger G.?How I treat hyperleukocytosis in acute myeloid leukemia. Blood 2015; 125: 3246-52
- Champagne MA, Capdeville R, Krailo M, Qu W, Peng B, Rosamilia M. et al.?Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: Results from a children?s oncology group phase 1 study. Blood 2004; 104: 2655-60
- Millot F, Guilhot J, Nelken B, Leblanc T, De Bont ES, B?kassy AN. 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 2006; 20: 187-92
- Kolb EA, Pan Q, Ladanyi M, Steinherz PG.?Imatinib mesylate in Philadelphia chromosome-positive leukemia of childhood. Cancer 2003; 98: 2643-50
- Andolina JR, Neudorf SM, Corey SJ.?How I treat childhood CML. Blood 2012; 119: 1821-30
- Bansal S, Prabhash K, Parikh P.?Chronic myeloid leukemia data from India. Indian J Med Paediatr Oncol 2013; 34: 154-8
- Suttorp M.?Innovative approaches of targeted therapy for CML of childhood in combination with paediatric haematopoietic SCT. Bone Marrow Transplant 2008; 42 (02) Suppl S40-6
- Ray SS, Chakrabarti P, Nath U, Chaudhuri U.?A single centre experience of treating CML in a tertiary care centre at Eastern India. 51st National Conference of Indian Society of Hematology and Transfusion Medicine 2010. 18th-21st November. 2010. Kolkata, India: Springer; 2010 129-81
- Burke MJ.?Profile of imatinib in pediatric leukemia. Pediatri Health Med Ther 2014; 5: 1-7
- Vardiman JW.?Chronic myelogenous leukemia, BCR-ABL1+. Am J Clin Pathol 2009; 132: 250-60
- Cwynarski K, Roberts IA, Iacobelli S, van Biezen A, Brand R, Devergie A. et al.?Stem cell transplantation for chronic myeloid leukemia in children. Blood 2003; 102: 1224-31
- Raut LS.?Chronic myeloid leukemia in children. A brief review. Clin Cancer Investig J 2014; 3: 467-71
- Muramatsu H, Kojima S, Yoshimi A, Atsuta Y, Kato K, Nagatoshi Y. et al.?Outcome of 125 children with chronic myelogenous leukemia who received transplants from unrelated donors: The Japan Marrow Donor Program. Biol Blood Marrow Transplant 2010; 16: 231-8
- Millot F, Baruchel A, Guilhot J, Petit A, Leblanc T, Bertrand Y. et al.?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
- 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
- Linga VG, Ganta RR, Kalpathi KI, Gundeti S, Rajappa SJ, Digumarti R. et al.?Response to imatinib mesylate in childhood chronic myeloid leukemia in chronic phase. South Asian J Cancer 2014; 3: 203-5
- Ghadyalpatil N, Banawali S, Kurkure P, Arora B, Bansal S, Amare P.?Efficacy and tolerability of imatinib mesylate in pediatric chronic myeloid leukemia in a large cohort: Results from a tertiary care referral centre in India. J Clin Oncol 2009; 27: 15s
- Shima H, Tokuyama M, Tanizawa A, Tono C, Hamamoto K, Muramatsu H. et al.?Distinct impact of imatinib on growth at prepubertal and pubertal ages of children with chronic myeloid leukemia. J Pediatr 2011; 159: 676-81
- Ganesan P, Rajendranath R, Kandakumar V, Sagar TG.?Treatment of chronic phase chronic myeloid leukemia with imatinib. Indian J Pediatr 2015; 82: 235-9
- Rao GP, Malhotra S, Marwaha RK.?Psychosocial study of leukemic children and their parents. Indian Pediatr 1992; 29: 985-90
- Bayat M, Erdem E, G?l Kuzucu E.?Depression, anxiety, hopelessness, and social support levels of the parents of children with cancer. J Pediatr Oncol Nurs 2008; 25: 247-53
- Kohlsdorf M, Junior ALC.?Psychosocial impact of pediatric cancer on parents: A literature review. Paideia 2012; 22: 119-29
- Klassen AF, Klaassen R, Dix D, Pritchard S, Yanofsky R, O?Donnell M. et al.?Impact of caring for a child with cancer on parents? health-related quality of life. J Clin Oncol 2008; 26: 5884-9
Address for correspondence
Publication History
Article published online:
24 May 2021
? 2019. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
References
- Raut LS.?Chronic myeloid leukemia in children: A brief review. Clin Cancer Investing J 2014; 6: 467-71
- Druker BJ, Sawyers CL, Capdeville R, Ford JM, Baccarani M, Goldman JM. et al.?Chronic myelogenous leukemia. Hematology Am Soc Hematol Educ Program 2001; 2001: 87-112
- 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
- Goldman JM.?How I treat chronic myeloid leukemia in the imatinib era. Blood 2007; 110: 2828-37
- Kumar N.?Kuppuswamy?s socioeconomic status scale-updating for 2007. Indian J Pediatri 2007; 74: 1131-2
- Han HR, Cho EJ, Kim D, Kim J.?The report of coping strategies and psychosocial adjustment in Korean mothers of children with cancer. Psychooncology 2009; 18: 956-64
- R?llig C, Ehninger G.?How I treat hyperleukocytosis in acute myeloid leukemia. Blood 2015; 125: 3246-52
- Champagne MA, Capdeville R, Krailo M, Qu W, Peng B, Rosamilia M. et al.?Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: Results from a children?s oncology group phase 1 study. Blood 2004; 104: 2655-60
- Millot F, Guilhot J, Nelken B, Leblanc T, De Bont ES, B?kassy AN. 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 2006; 20: 187-92
- Kolb EA, Pan Q, Ladanyi M, Steinherz PG.?Imatinib mesylate in Philadelphia chromosome-positive leukemia of childhood. Cancer 2003; 98: 2643-50
- Andolina JR, Neudorf SM, Corey SJ.?How I treat childhood CML. Blood 2012; 119: 1821-30
- Bansal S, Prabhash K, Parikh P.?Chronic myeloid leukemia data from India. Indian J Med Paediatr Oncol 2013; 34: 154-8
- Suttorp M.?Innovative approaches of targeted therapy for CML of childhood in combination with paediatric haematopoietic SCT. Bone Marrow Transplant 2008; 42 (02) Suppl S40-6
- Ray SS, Chakrabarti P, Nath U, Chaudhuri U.?A single centre experience of treating CML in a tertiary care centre at Eastern India. 51st National Conference of Indian Society of Hematology and Transfusion Medicine 2010. 18th-21st November. 2010. Kolkata, India: Springer; 2010 129-81
- Burke MJ.?Profile of imatinib in pediatric leukemia. Pediatri Health Med Ther 2014; 5: 1-7
- Vardiman JW.?Chronic myelogenous leukemia, BCR-ABL1+. Am J Clin Pathol 2009; 132: 250-60
- Cwynarski K, Roberts IA, Iacobelli S, van Biezen A, Brand R, Devergie A. et al.?Stem cell transplantation for chronic myeloid leukemia in children. Blood 2003; 102: 1224-31
- Raut LS.?Chronic myeloid leukemia in children. A brief review. Clin Cancer Investig J 2014; 3: 467-71
- Muramatsu H, Kojima S, Yoshimi A, Atsuta Y, Kato K, Nagatoshi Y. et al.?Outcome of 125 children with chronic myelogenous leukemia who received transplants from unrelated donors: The Japan Marrow Donor Program. Biol Blood Marrow Transplant 2010; 16: 231-8
- Millot F, Baruchel A, Guilhot J, Petit A, Leblanc T, Bertrand Y. et al.?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
- 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
- Linga VG, Ganta RR, Kalpathi KI, Gundeti S, Rajappa SJ, Digumarti R. et al.?Response to imatinib mesylate in childhood chronic myeloid leukemia in chronic phase. South Asian J Cancer 2014; 3: 203-5
- Ghadyalpatil N, Banawali S, Kurkure P, Arora B, Bansal S, Amare P.?Efficacy and tolerability of imatinib mesylate in pediatric chronic myeloid leukemia in a large cohort: Results from a tertiary care referral centre in India. J Clin Oncol 2009; 27: 15s
- Shima H, Tokuyama M, Tanizawa A, Tono C, Hamamoto K, Muramatsu H. et al.?Distinct impact of imatinib on growth at prepubertal and pubertal ages of children with chronic myeloid leukemia. J Pediatr 2011; 159: 676-81
- Ganesan P, Rajendranath R, Kandakumar V, Sagar TG.?Treatment of chronic phase chronic myeloid leukemia with imatinib. Indian J Pediatr 2015; 82: 235-9
- Rao GP, Malhotra S, Marwaha RK.?Psychosocial study of leukemic children and their parents. Indian Pediatr 1992; 29: 985-90
- Bayat M, Erdem E, G?l Kuzucu E.?Depression, anxiety, hopelessness, and social support levels of the parents of children with cancer. J Pediatr Oncol Nurs 2008; 25: 247-53
- Kohlsdorf M, Junior ALC.?Psychosocial impact of pediatric cancer on parents: A literature review. Paideia 2012; 22: 119-29
- Klassen AF, Klaassen R, Dix D, Pritchard S, Yanofsky R, O?Donnell M. et al.?Impact of caring for a child with cancer on parents? health-related quality of life. J Clin Oncol 2008; 26: 5884-9