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Chronic Myeloid Leukemia in Children: Challenges and Opportunities

Based on 7th Dr. I. C. Verma Excellence Award for Young Pediatricians Delivered as Oration on 29th Sept. 2019

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Abstract

Treatment with tyrosine kinase inhibitors (TKI) is an effective therapy for children and adolescents with chronic phase of chronic myeloid leukemia (CML). For the majority of patients with CML in low- and middle-income countries (LMIC), imatinib is the TKI of choice for reasons of cost, availability, and experience. Children are exposed to therapy for a greater proportion of their lifetime as compared to adults. The adverse effects of prolonged administration of TKI is a subject of ongoing research, as more experience is collected. Therapy with TKI is currently considered to be life-long. Trials on stopping treatment are ongoing to explore if it may be feasible in selected patients, as reported in adults. Growth-failure is a concerning adverse effect. Currently, it seems unclear if the final height attained is within the expected range of the mid-parenteral height and growth standards. Whether the children will achieve a normal height at the end of their growth potential or remain below the predicted range is critical to decide if therapeutic interventions (E.g., growth hormone therapy, or interruption in TKI) should be considered during the period of growth potential. Research on CML in children is at a relatively slow pace, largely due to the rarity of the disease. This provides a unique opportunity for research in population-dense LMICs, as several tertiary centers tend to have a sizable cohort of children and adolescents with CML on follow-up. This narrative summarises the challenges and opportunities in dealing with CML in children, particularly in reference to a center in LMIC.

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References

  1. Hijiya N, Millot F, Suttorp M. Chronic myeloid leukemia in children: clinical findings, management, and unanswered questions. Pediatr Clin N Am. 2015;62:107–19.

    Google Scholar 

  2. Athale U, Hijiya N, Patterson BC, et al. Management of chronic myeloid leukemia in children and adolescents: recommendations from the Children’s Oncology Group CML Working Group. Pediatr Blood Cancer. 2019;66:e27827.

  3. Krumbholz M, Karl M, Tauer JT, et al. Genomic BCR-ABL1 breakpoints in pediatric chronic myeloid leukemia. Genes Chromosomes Cancer. 2012;51:1045–53.

    CAS  PubMed  Google Scholar 

  4. Tahlan A, Varma N, Naseem S, et al. Comparative study of clinico-hematological features. Molecular spectrum and response to imatinib in chronic myelogenous leukemia patients: pediatric and adolescent versus adults. Indian J Hematol Blood Transfus. 2018;34:19–24.

    PubMed  Google Scholar 

  5. Marwaha RK, Bansal D, Trehan A, Varma N. Profile and survival patterns in children with adult-variety chronic myeloid leukemia, treated with conventional chemotherapy. PHO Bull. 2005;2:10–4.

    Google Scholar 

  6. Malhotra H, Radich J, Garcia-Gonzalez P. Meeting the needs of CML patients in resource-poor countries. Hematology Am Soc Hematol Educ Program. 2019;2019:433–42.

    PubMed  Google Scholar 

  7. Totadri S, Mahajan A, Gupta V, et al. Treatment and outcome of chronic myeloid leukemia in children and adolescents: The Indian Pediatric Oncology Group (INPOG) CML-16-01 multicentric study. Pediatr Blood Cancer. 2019:66:e27989 (Abstract: V224 SIOP19–0090).

  8. Kumar S, Bansal D, Prakash M, Sharma P. Avascular necrosis of femoral head as the initial manifestation of CML. Pediatr Hematol Oncol. 2014;31:568–73.

    CAS  PubMed  Google Scholar 

  9. Hijiya N, Schultz KR, Metzler M, Millot F, Suttorp M. Pediatric chronic myeloid leukemia is a unique disease that requires a different approach. Blood. 2016;127:392–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Sokal JE, Gomez GA, Baccarani M, et al. Prognostic significance of additional cytogenetic abnormalities at diagnosis of Philadelphia chromosome-positive chronic granulocytic leukemia. Blood. 1988;72:294–8.

    CAS  PubMed  Google Scholar 

  11. Hasford J, Baccarani M, Hoffmann V, 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.

    CAS  PubMed  Google Scholar 

  12. Hasford J, Pfirrmann M, Hehlmann R, et al; Writing Committee for the Collaborative CML Prognostic Factors Project Group. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. J Natl Cancer Inst. 1998;90:850–8.

  13. Bansal D, Munikoty V, Trehan A, Naseem S, Bhatia P, Varma N. Prognostic scoring systems validated for CML in adult’s, correlate poorly with survival in paediatric patients treated with imatinib. Pediatr Blood Cancer. 2016:63:S5–6 (Abstract: O-015).

  14. Gurrea Salas D, 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.

    PubMed  Google Scholar 

  15. Millot F, Guilhot J, Suttorp M, et al. Prognostic discrimination based on the EUTOS long-term survival score within the International Registry for Chronic Myeloid Leukemia in children and adolescents. Haematologica. 2017;102:1704–8.

  16. Quintás-Cardama A, Cortes J. Molecular biology of bcr-abl1–positive chronic myeloid leukemia. Blood. 2009;113:1619–30.

    PubMed  PubMed Central  Google Scholar 

  17. Abou Dalle I, Kantarjian H, Burger J, et al. Efficacy and safety of generic imatinib after switching from original imatinib in patients treated for chronic myeloid leukemia in the United States. Cancer Med. 2019;8:6559–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Bonifacio M, Scaffidi L, Binotto G, et al. Safety and efficacy of switching from branded to generic imatinib in chronic phase chronic myeloid leukemia patients treated in Italy. Leuk Res. 2018;74:75–9.

    CAS  PubMed  Google Scholar 

  19. Suttorp M, Metzler M, Millot F, et al. Generic formulations of imatinib for treatment of Philadelphia chromosome-positive leukemia in pediatric patients. Pediatr Blood Cancer. 2018;65:e27431.

    PubMed  Google Scholar 

  20. Shanmuganathan N, Hughes TP. Early management of CML. Curr Hematol Malig Rep. 2019;14:480–91.

    PubMed  Google Scholar 

  21. Chai-Adisaksopha C, Lam W, Hillis C. Major arterial events in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a meta-analysis. Leuk Lymphoma. 2016;57:1300–10.

    CAS  PubMed  Google Scholar 

  22. Douxfils J, Haguet H, Mullier F, Chatelain C, Graux C, Dogne JM. Association between BCR-ABL tyrosine kinase inhibitors for chronic myeloid leukemia and cardiovascular events, major molecular response, and overall survival: a systematic review and metaanalysis. JAMA Oncol. 2016;2:625–32.

    PubMed  Google Scholar 

  23. Fox LC, Cummins KD, Costello B, et al. The incidence and natural history of dasatinib complications in the treatment of chronic myeloid leukemia. Blood Adv. 2017;1:802–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naïve chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34:2333–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Clark RE. Tyrosine kinase inhibitor therapy discontinuation for patients with chronic myeloid leukaemia in clinical practice. Curr Hematol Malig Rep. 2019;14:507–14.

    PubMed  PubMed Central  Google Scholar 

  26. NCCN. NCCN Clinical Practice Guidelines in Oncology; Chronic Myelogenous Leukemia, Version 1.2019: National Comprehensive Cancer Network. 2018.

  27. De la Fuente J, Baruchel A, Biondi A, et al. Recommendations for the management of CML in children and young people up to the age of 18 years. Br J Haematol. 2014;167:33–47.

    PubMed  Google Scholar 

  28. Millot F, Guilhot J, Suttorp M, et al. Advanced phases at diagnosis of childhood chronic myeloid leukemia: the experience of the International Registry for Chronic Myeloid Leukemia (CML) in Children and Adolescents (I-CML-Ped Study).[Abstract]. Blood. 2017;130 Abstract 316.

  29. Hijiya N, Suttorp M. How I treat chronic myeloid leukemia in children and adolescents. Blood. 2019;133:2374–84.

    CAS  PubMed  Google Scholar 

  30. Saußele S, Silver RT. Management of chronic myeloid leukemia in blast crisis. Ann Hematol. 2015;94:S159–65.

    PubMed  Google Scholar 

  31. Bansal D, Shava U, Varma N, Trehan A, Marwaha RK. Imatinib has adverse effect on growth in children with chronic myeloid leukemia. Pediatr Blood Cancer. 2012;59:481–4.

    PubMed  Google Scholar 

  32. Boddu D, Thankamony P, Guruprasad CS, Nair M, Rajeswari B, Seetharam S. Effect of imatinib on growth in children with chronic myeloid leukemia. Pediatr Hematol Oncol. 2019;36:189–97.

    CAS  PubMed  Google Scholar 

  33. Samis J, Lee P, Zimmerman D, Suttorp M, Hijiya N. The complexity of growth failure in children receiving tyrosine kinase inhibitor therapy for chronic myelogenous leukemia. Pediatr Blood Cancer. 2017;64:e26703.

    Google Scholar 

  34. Narayanan KR, Bansal D, Walia R, et al. Growth failure in children with chronic myeloid leukemia receiving imatinib is due to disruption of GH/IGF-1 axis. Pediatr Blood Cancer. 2013;60:1148–53.

    CAS  PubMed  Google Scholar 

  35. Walia R, Aggarwal A, Bhansali A, et al. Acquired neuro-secretory defect in growth hormone secretion due to imatinib mesylate and the efficacy of growth hormone therapy in children with chronic myeloid leukemia. Pediatr Hematol Oncol. 2019;20:1–10 [Epub ahead of print].

    Google Scholar 

  36. Shima H, Tokuyama M, Tanizawa A, 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.

    CAS  PubMed  Google Scholar 

  37. Rajala HLM, Missiry ME, Ruusila A, et al. Tyrosine kinase inhibitor therapy-induced changes in humoral immunity in patients with chronic myeloid leukemia. J Cancer Res Clin Oncol. 2017;143:1543–54.

    CAS  PubMed  Google Scholar 

  38. Santachiara R, Maffei R, Martinelli S, et al. Development of hypogammaglobulinemia in patients treated with imatinib for chronic myeloid leukemia or gastrointestinal stromal tumor. Haematologica. 2008;93:1252–5.

    CAS  PubMed  Google Scholar 

  39. Totadri S, Thipparapu S, Aggarwal R, et al. Imatinib induced hypogammaglobulinemia in children with chronic myeloid leukemia. Pediatr Blood Cancer. 2019;66:e27989 (Abstract: V225 SIOP19–0325).

    Google Scholar 

  40. García-Ferrer M, Wojnicz A, Mejía G, Koller D, Zubiaur P, Abad-Santos F. Utility of therapeutic drug monitoring of imatinib, nilotinib, and dasatinib in chronic myeloid leukemia: a systematic review and meta-analysis. Clin Ther. 2019;41:2558–70.e7.

    PubMed  Google Scholar 

  41. Shankar T, Attri SV, Patial A, et al. Drug level of imatinib and its correlation with dose and molecular remission in children with chronic myeloid leukemia (CML). Pediatr Blood Cancer. 2018;65:e27455 (Abstract: PO-178).

    Google Scholar 

  42. Hughes TP, Ross DM. Moving treatment-free remission into mainstream clinical practice in CML. Blood. 2016;128:17–23.

    CAS  PubMed  Google Scholar 

  43. de Bruijn CMA, Millot F, Suttorp M, et al. Discontinuation of imatinib in children with chronic myeloid leukaemia in sustained deep molecular remission: results of the STOP IMAPED study. Br J Haematol. 2019;185:718–24.

    PubMed  Google Scholar 

  44. Shima H, Kada A, Tanizawa A, et al. Discontinuation of tyrosine kinase inhibitor in children with chronic myeloid leukemia (JPLSG STKI-14 study). Blood. 2019;134:25. https://doi.org/10.1182/blood-2019-122623.

    Article  Google Scholar 

  45. Malaspina F, Putti MC, Santopietro M, et al. Intermittent imatinib mesylate in children with chronic myeloid leukemia: results and outcome. Blood. 2018;132:4256.

    Google Scholar 

  46. Stopping tyrosine kinase inhibitors in affecting treatment-free remission in patients with chronic phase chronic myeloid leukemia. Available at: https://clinicaltrials.gov/ct2/show/NCT03817398. Accessed 30 Dec 2019.

  47. Radich JP, Deininger M, Abboud CN, et al. Chronic myeloid leukemia, version 1.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2018;16:1108–35.

    Google Scholar 

  48. Pye SM, Cortes J, Ault P, et al. The effects of imatinib on pregnancy outcome. Blood. 2008;111:5505–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Ault P, Kantarjian H, O'Brien S, et al. Pregnancy among patients with chronic myeloid leukemia treated with imatinib. J Clin Oncol. 2006;24:1204–8.

    CAS  PubMed  Google Scholar 

  50. Berman E, Druker BJ, Burwick R. Chronic myelogenous leukemia: pregnancy in the era of stopping tyrosine kinase inhibitor therapy. J Clin Oncol. 2018;36:1250–6.

    CAS  PubMed  Google Scholar 

  51. Bansal D, Davidson A, Supriyadi E, Njuguna F, Ribeiro RC. Kaspers GJL. SIOP PODC adapted risk stratification and treatment guidelines: recommendations for acute myeloid leukemia in resource-limited settings. Pediatr Blood Cancer. 2019:e28087.

  52. Vaishnavi K, Bansal D, Trehan A, Jain R, Attri SV. Improving the safety of high-dose methotrexate for children with hematologic cancers in settings without access to MTX levels using extended hydration and additional leucovorin. Pediatr Blood Cancer. 2018;65:e27241.

    PubMed  Google Scholar 

  53. Gomez-de-León A, Gómez-Almaguer D, Ruiz-Delgado GJ, Ruiz-Arguelles GJ. Insights into the management of chronic myeloid leukemia in resource-poor settings: a Mexican perspective. Expert Rev Hematol. 2017;10:809–19.

    PubMed  Google Scholar 

  54. de Jong M, van der Worp HB, van der Graaf Y, Visseren FLJ, Westerink J. Pioglitazone and the secondary prevention of cardiovascular disease. A meta-analysis of randomized-controlled trials Cardiovasc Diabetol. 2017;16:134.

    PubMed  Google Scholar 

  55. Capano L, Dupuis A, Brian J, et al. A pilot dose finding study of pioglitazone in autistic children. Mol Autism. 2018;9:59.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Rousselot P, Prost S, Guilhot J, et al. French CML group. Pioglitazone together with imatinib in chronic myeloid leukemia: a proof of concept study. Cancer. 2017;123:1791–9.

    CAS  PubMed  Google Scholar 

  57. Schoepf AM, Salcher S, Obexer P, Gust R. Overcoming imatinib resistance in chronic myelogenous leukemia cells using non-cytotoxic cell death modulators. Eur J Med Chem. 2020;185:111748.

    CAS  PubMed  Google Scholar 

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  1. Hematology-Oncology Unit, Department of Pediatrics, Advanced Pediatrics Center, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    Deepak Bansal

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  1. Deepak Bansal
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Bansal, D. Chronic Myeloid Leukemia in Children: Challenges and Opportunities. Indian J Pediatr 87, 443–450 (2020). https://doi.org/10.1007/s12098-020-03234-x

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