Chronic myeloid leukemia in children: Clinical findings, management, and unanswered questions

Pediatric Clinics of North America

Volumn 62, Issue 1, 2015, Pages 107-119

  Hijiya, Nobuko ^a,b   Millot, Frederic ^c   Suttorp, Meinolf ^d  

^a CHILDREN'S MEMORIAL HOSPITAL   (United States)

^b NORTHWESTERN UNIVERSITY   (United States)

^c POITIERS UNIVERSITY HOSPITAL   (France)

^d UNIVERSITY HOSPITAL CARL GUSTAV CARUS   (Germany)

Author keywords

BCR ABL1; Chronic myeloid leukemia; Hematopoietic stem cell transplant; Tyrosine kinase inhibitor

Indexed keywords

BOSUTINIB; DASATINIB; IMATINIB; NILOTINIB; PONATINIB; PROTEIN TYROSINE KINASE INHIBITOR; PROTEIN KINASE INHIBITOR;

AGE; CANCER INHIBITION; CANCER PROGNOSIS; CARDIOTOXICITY; CHRONIC MYELOID LEUKEMIA; CLINICAL FEATURE; DISEASE COURSE; DRUG SAFETY; GROWTH DISORDER; GROWTH HORMONE DEFICIENCY; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMAN; LIFE EXPECTANCY; LIVER TOXICITY; MANAGED CARE; MORBIDITY; NONHUMAN; PATIENT MONITORING; PRACTICE GUIDELINE; REVIEW; RISK ASSESSMENT; THYROID DISEASE; TREATMENT DURATION; ADULT; CHILD; DIFFERENTIAL DIAGNOSIS; LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE;

ADULT; CHILD; DIAGNOSIS, DIFFERENTIAL; GUIDELINES AS TOPIC; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMANS; LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE; PROTEIN KINASE INHIBITORS;

EID: 84915758765     PISSN: 00313955     EISSN: 15578240     Source Type: Journal    
DOI: 10.1016/j.pcl.2014.09.008     Document Type: Review

References (86)

1. Surveillance Research Program NCI. Fast Stats: An interactive tool for access to SEER cancer statistics. 2013. Available at: Accessed November 1, 2013. http://seer.cancer.gov/faststats/.
2. Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995 1999, National Cancer Institute, SEER Program, Bethesda, MD, NIH Pub. No. 99-4649.
3. Childhood acute myeloid leukemia/other myeloid malignancies treatment (PDQ®). 2014. Available at: Accessed June 22, 2014. http://www.cancer.gov/cancertopics/pdq/treatment/childAML/HealthProfessional/page1#Reference1.3.
4. Druker B.J., Sawyers C.L., Kantarjian H., et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. NEngl J Med 2001, 344(14):1038-1042.
5. Champagne M.A., Fu C.H., Chang M., et al. Higher dose imatinib for children with de novo chronic phase chronic myelogenous leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 2011, 57(1):56-62.
6. Millot F., Baruchel A., Guilhot J., 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. JClin Oncol 2011, 29(20):2827-2832.
7. Mahon F.X., Rea D., Guilhot J., et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 2010, 11(11):1029-1035.
8. Hasford J., Pfirrmann M., Hehlmann R., et al. Anew prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. JNatl Cancer Inst 1998, 90(11):850-858.
9. Bonifazi F., de Vivo A., Rosti G., et al. Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders. Blood 2001, 98(10):3074-3081.
10. Lindoerfer D., Hoffmann V., Rosti G., et al. The EUTOS population-based registry; evaluation of baseline characteristics and first treatment choices of 2983 newly diagnosed chronic myeloid leukemia (CML) patients from 20 European countries. Haematologica 2014, 99(s1):238.
11. Millot F., Suttorp M., Guilhot J., et al. The International Registry for Chronic Myeloid Leukemia (CML) in Children and Adolescents (I-CML-Ped-Study): Objectives and preliminary results. Blood 2012, 120:3741.
12. Kalmanti L., Saussele S., Lauseker M., et al. Younger patients with chronic myeloid leukemia do well in spite of poor prognostic indicators: results from the randomized CML study IV. Ann Hematol 2013, 93(1):71-80.
13. Pemmaraju N., Kantarjian H., Shan J., et al. Analysis of outcomes in adolescents and young adults with chronic myelogenous leukemia treated with upfront tyrosine kinase inhibitor therapy. Haematologica 2012, 97(7):1029-1035.
14. Savage D.G., Szydlo R.M., Goldman J.M. 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(1):111-116.
15. Millot F., Traore P., Guilhot J., et al. Clinical and biological features at diagnosis in 40 children with chronic myeloid leukemia. Pediatrics 2005, 116(1):140-143.
16. Suttorp M., Millot F. Treatment of pediatric chronic myeloid leukemia in the year 2010: use of tyrosine kinase inhibitors and stem-cell transplantation. Hematology Am Soc Hematol Educ Program 2010, 2010:368-376.
17. Mitra D., Trask P.C., Iyer S., et al. Patient characteristics and treatment patterns in chronic myeloid leukemia: evidence from a multi-country retrospective medical record chart review study. Int J Hematol 2012, 95(3):263-273.
18. Krumbholz M., Karl M., Tauer J.T., et al. Genomic BCR-ABL1 breakpoints in pediatric chronic myeloid leukemia. Genes Chromosomes Cancer 2012, 51(11):1045-1053.
19. Network NCC. NCCN Clinical practice guidelines in oncology; chronic myelogenous leukemia. Version 1.2015. Available at: 2013. Accessed October 19, 2014. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#cml.
20. Baccarani M., Deininger M.W., Rosti G., et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia. Blood 2013, 122(6):872-884.
21. Sokal J.E., Cox E.B., Baccarani M., et al. Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood 1984, 63(4):789-799.
22. 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(3):686-692.
23. Suttorp M.G., Salas D.G., Tauer J.T., et al. Scoring systems for predicting outcome of chronic myeloid leukemia in adults are poorly informative in pediatric patients treated with imatinib. Blood 2013, 122(21):2725.
24. Sokal J.E., Baccarani M., Tura S., et al. Prognostic discrimination among younger patients with chronic granulocytic leukemia: relevance to bone marrow transplantation. Blood 1985, 66(6):1352-1357.
25. Branford S., Yeung D.T., Parker W.T., et al. Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood 2014, 124(4):511-518.
26. Marin D., Ibrahim A.R., Lucas C., et al. Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. JClin Oncol 2012, 30(3):232-238.
27. Goldman J., Gordon M. Why do chronic myelogenous leukemia stem cells survive allogeneic stem cell transplantation or imatinib: does it really matter?. Leuk Lymphoma 2006, 47(1):1-7.
28. Ross D.M., Hughes T.P. How I determine if and when to recommend stopping tyrosine kinase inhibitor treatment for chronic myeloid leukaemia. Br J Haematol 2014, 166(1):3-11.
29. Reaman G.H., Bonfiglio J., Krailo M., et al. Cancer in adolescents and young adults. Cancer 1993, 71(Suppl 10):3206-3209.
30. Millot F., Claviez A., Leverger G., et al. Imatinib cessation in children and adolescents with chronic myeloid leukemia in chronic phase. Pediatr Blood Cancer 2014, 61(2):355-357.
31. Dusetzina S.B., Winn A.N., Abel G.A., et al. Cost sharing and adherence to tyrosine kinase inhibitors for patients with chronic myeloid leukemia. JClin Oncol 2014, 32(4):306-311.
32. Efficace F., Baccarani M., Breccia M., et al. Health-related quality of life in chronic myeloid leukemia patients receiving long-term therapy with imatinib compared with the general population. Blood 2011, 118(17):4554-4560.
33. Ross D.M., Branford S., Seymour J.F., et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood 2013, 122(4):515-522.
34. Rea D., Rousselot P., Guilhot F. Discontinuation of second generation (2G) tyrosine kinase inhibitors (TKI) in chronic phase (CP)-chronic myeloid leukemia (CML) patients with stable undetectable BCR-ABL transcripts. Blood 2012, 120:916.
35. Moser O., Krumbholz M., Thiede C., et al. Sustained complete molecular remission after imatinib discontinuation in children with chronic myeloid leukemia. Pediatr Blood Cancer 2014, 61(11):2080-2082.
36. Ross D.M., Branford S., Seymour J.F., et al. Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR. Leukemia 2010, 24(10):1719-1724.
37. La Rosee P., Martiat P., Leitner A., et al. Improved tolerability by a modified intermittent treatment schedule of dasatinib for patients with chronic myeloid leukemia resistant or intolerant to imatinib. Ann Hematol 2013, 92(10):1345-1350.
38. Russo D., Martinelli G., Malagola M., et al. Effects and outcome of a policy of intermittent imatinib treatment in elderly patients with chronic myeloid leukemia. Blood 2013, 121(26):5138-5144.
39. Talpaz M., Hehlmann R., Quintas-Cardama A., et al. Re-emergence of interferon-alpha in the treatment of chronic myeloid leukemia. Leukemia 2013, 27(4):803-812.
40. Warsch W., Walz C., Sexl V. JAK of all trades: JAK2-STAT5 as novel therapeutic targets in BCR-ABL1+ chronic myeloid leukemia. Blood 2013, 122(13):2167-2175.
41. Kinstrie R., Copland M. Targeting chronic myeloid leukemia stem cells. Curr Hematol Malig Rep 2013, 8(1):14-21.
42. Bocchia M., Defina M., Aprile L., et al. Complete molecular response in CML after p210 BCR-ABL1-derived peptide vaccination. Nat Rev Clin Oncol 2010, 7(10):600-603.
43. Smahel M. Antigens in chronic myeloid leukemia: implications for vaccine development. Cancer Immunol Immunother 2011, 60(12):1655-1668.
44. Muramatsu H., Kojima S., Yoshimi A., 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(2):231-238.
45. Suttorp M., Claviez A., Bader P., et al. Allogeneic stem cell transplantation for pediatric and adolescent patients with CML: results from the prospective trial CML-paed I. Klin Padiatr 2009, 221(6):351-357.
46. Cwynarski K., Roberts I.A., Iacobelli S., et al. Stem cell transplantation for chronic myeloid leukemia in children. Blood 2003, 102(4):1224-1231.
47. Goldman J.M., Majhail N.S., Klein J.P., et al. Relapse and late mortality in 5-year survivors of myeloablative allogeneic hematopoietic cell transplantation for chronic myeloid leukemia in first chronic phase. JClin Oncol 2010, 28(11):1888-1895.
48. Warlick E., Ahn K.W., Pedersen T.L., et al. Reduced intensity conditioning is superior to nonmyeloablative conditioning for older chronic myelogenous leukemia patients undergoing hematopoietic cell transplant during the tyrosine kinase inhibitor era. Blood 2012, 119(17):4083-4090.
49. Shami P.J., Deininger M. Evolving treatment strategies for patients newly diagnosed with chronic myeloid leukemia: the role of second-generation BCR-ABL inhibitors as first-line therapy. Leukemia 2012, 26(2):214-224.
50. Vandyke K., Fitter S., Dewar A.L., et al. Dysregulation of bone remodeling by imatinib mesylate. Blood 2010, 115(4):766-774.
51. Rastogi M.V., Stork L., Druker B., et al. Imatinib mesylate causes growth deceleration in pediatric patients with chronic myelogenous leukemia. Pediatr Blood Cancer 2012, 59(5):840-845.
52. Hobernicht S.L., Schweiger B., Zeitler P., et al. Acquired growth hormone deficiency in a girl with chronic myelogenous leukemia treated with tyrosine kinase inhibitor therapy. Pediatr Blood Cancer 2011, 56(4):671-673.
53. Bansal D., Shava U., Varma N., et al. Imatinib has adverse effect on growth in children with chronic myeloid leukemia. Pediatr Blood Cancer 2012, 59(3):481-484.
54. Schmid H., Jaeger B.A., Lohse J., et al. Longitudinal growth retardation in a prepuberal girl with chronic myeloid leukemia on long-term treatment with imatinib. Haematologica 2009, 94(8):1177-1179.
55. Mariani S., Giona F., Basciani S., et al. Low bone density and decreased inhibin-B/FSH ratio in a boy treated with imatinib during puberty. Lancet 2008, 372(9633):111-112.
56. Kimoto T., Inoue M., Kawa K. Growth deceleration in a girl treated with imatinib. Int J Hematol 2009, 89(2):251-252.
57. Hijiya N., Broglie L., Chaudhury S., et al. Survival after hematopoietic stem cell transplantation (HSCT) or tyrosine kinase inhibitors (TKI) in children with chronic myeloid leukemia (CML) in chronic phase; a single institution experience. May 9-12. Ped Blood Cancer 2012, 58(7):1049.
58. 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. JPediatr 2011, 159(4):676-681.
59. Giona F., Mariani S., Gnessi L., et al. Bone metabolism, growth rate and pubertal development in children with chronic myeloid leukemia treated with imatinib during puberty. Haematologica 2013, 98(3):e25-e27.
60. Ulmer A., Tauer J.T., Suttorp M. Impact of treatment with tyrosine kinase inhibitors (TKIs) on blood levels of growth hormone-related parameters, testosterone, and inhibin B in juvenile rats and pediatric patients with chronic myeloid leukemia (CML). Blood 2012, 120:3752.
61. Pye S.M., Cortes J., Ault P., et al. The effects of imatinib on pregnancy outcome. Blood 2008, 111(12):5505-5508.
62. Berveiller P., Andreoli A., Mir O., et al. Adramatic fetal outcome following transplacental transfer of dasatinib. Anticancer Drugs 2012, 23(7):754-757.
63. Apperley J. CML in pregnancy and childhood. Best Pract Res Clin Haematol 2009, 22(3):455-474.
64. Schultheis B., Nijmeijer B.A., Yin H., et al. Imatinib mesylate at therapeutic doses has no impact on folliculogenesis or spermatogenesis in a leukaemic mouse model. Leuk Res 2012, 36(3):271-274.
65. Seshadri T., Seymour J.F., McArthur G.A. Oligospermia in a patient receiving imatinib therapy for the hypereosinophilic syndrome. NEngl J Med 2004, 351(20):2134-2135.
66. Christopoulos C., Dimakopoulou V., Rotas E. Primary ovarian insufficiency associated with imatinib therapy. NEngl J Med 2008, 358(10):1079-1080.
67. Kim T.D., Schwarz M., Nogai H., et al. Thyroid dysfunction caused by second-generation tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia. Thyroid 2010, 20(11):1209-1214.
68. Fallahi P., Ferrari S.M., Vita R., et al. Thyroid dysfunctions induced by tyrosine kinase inhibitors. Expert Opin Drug Saf 2014, 13(6):723-733.
69. Atallah E. Nilotinib cardiac toxicity: should we still be concerned?. Leuk Res 2011, 35(5):577-578.
70. Giles F.J., Mauro M.J., Hong F., et al. Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. Leukemia 2013, 27(6):1310-1315.
71. de la Fuente J., Baruchel A., Biondi A., et al. Managing children with chronic myeloid leukaemia (CML): recommendations for the management of CML in children and young people up to the age of 18 years. Br J Haematol 2014, 167(1):33-47.
72. Champagne M.A., Capdeville R., Krailo 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(9):2655-2660.
73. Kantarjian H.M., Shah N.P., Cortes J.E., et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 2012, 119(5):1123-1129.
74. Jabbour E., Kantarjian H.M., Saglio G., et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 2014, 123(4):494-500.
75. Larson R.A., Hochhaus A., Hughes T.P., et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia 2012, 26(10):2197-2203.
76. Zwaan C.M., Rizzari C., Mechinaud F., et al. Dasatinib in children and adolescents with relapsed or refractory leukemia: results of the CA180-018 phase I dose-escalation study of the Innovative Therapies for Children with Cancer Consortium. JClin Oncol 2013, 31(19):2460-2468.
77. Aplenc R., Blaney S.M., Strauss L.C., et al. Pediatric phase I trial and pharmacokinetic study of dasatinib: a report from the children's oncology group phase I consortium. JClin Oncol 2011, 29(7):839-844.
78. Cortes J.E., Kim D.W., Kantarjian H.M., et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. JClin Oncol 2012, 30(28):3486-3492.
79. Cortes J.E., Kim D.W., Pinilla-Ibarz J., et al. Aphase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. NEngl J Med 2013, 369(19):1783-1796.
80. Cortes J., Digumarti R., Parikh P.M., et al. Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol 2013, 88(5):350-354.
81. Kantarjian H.M., Hochhaus A., Saglio G., et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 2011, 12(9):841-851.
82. Larson RA, Saglio G, Kim DW, etal. Nilotinib versus imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd 4-year (y) update. Paper presented at: American Society of Clinical Oncology (ASCO) Annual '13 meeting. Chicago, 2013. J Clin Oncol 2013;31 (suppl; abstr 7052).
83. Soverini S., Hochhaus A., Nicolini F.E., et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 2011, 118(5):1208-1215.
84. de Lavallade H., Khoder A., Hart M., et al. Tyrosine kinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling. Blood 2013, 122(2):227-238.
85. de Lavallade H., Garland P., Sekine T., et al. Repeated vaccination is required to optimize seroprotection against H1N1 in the immunocompromised host. Haematologica 2011, 96(2):307-314.
86. Luthy K.E., Tiedeman M.E., Beckstrand R.L., et al. Safety of live-virus vaccines for children with immune deficiency. JAm Acad Nurse Pract 2006, 18(10):494-503.