Imatinib Efficacy, Safety and Resistance in Iranian Patients with Chronic Myeloid Leukemia: A Review of Literature
Background: Imatinib is the gold standard in the treatment of chronic myeloid leukemia (CML) patients. Resistance to imatinib is interfering with patients’ responses and their survival.
Materials and Methods: We designed a systematic search to find relevant studies by applying appropriate keywords in PubMed, Web of Science, Scopus, Ovid, ProQuest, Science Direct, and Google scholar for English studies. We also investigated the aforementioned terms’ correspondence in Magiran, Scientific information database (SID), and Google scholar for Persian articles.
Results: 25 studies were selected for final analysis. Reported hematologic responses from adult studies ranged 86-99% and major molecular responses were estimated in 38.84% of our patients within 12 months of treatment. The most frequently reported adverse drug reactions (ADRs) were edema (n=5 studies, 100%) and fatigue and nausea (n=4 studies, 80%); ADR per capita ratio was 1.46. Only one study informed ADRs in pediatrics demonstrating 93% of patients experienced ADRs after receiving imatinib. Most of the Studies (n=4, 67% from 7 studies) considered BCR/ABL point mutation as the main reason for imatinib resistance. Drug-binding sites and P-loop regions were two common sites for BCR/ABL point mutation.
Conclusion: Imatinib as the first-line treatment for CML has been associated with proper and durable responses in Iranian adults and children CML patients. Moreover, Imatinib life-threatening adverse effects were reported as uncommon. Various responses to modified regimens have been reported in resistant patients; therefore, individualized treatment based on mutation type could be recommended.
2. Olivieri A, Manzione L. Dasatinib: a new step in molecular target therapy. Ann Oncol .2007 Jun;18 Suppl 6:vi42-6.
3. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med . 2001;344(14):1031-7.
4. Graham SM, Jørgensen HG, Allan E, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood; 2002. 99 (1): 319-25.
5. Ottmann OG, Pfeifer H. First-line treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia in adults. Curr Opin Oncol. 2009; 21 Suppl 1:S43-6.
6. Branford S, Rudzki Z, Walsh S, et al. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood. 2002; 99 (9): 3472-5.
7. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009; 27 (35): 6041-51.
8. Hughes TP, Hochhaus A, Branford S, et al. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood; 2010. 116 (19): 3758-65.
9. Shah NP. Loss of response to imatinib: mechanisms and management. Hematology Am Soc Hematol Educ Program. 2005. 183-7.
10. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362 (24): 2260-70.
11. Mitra D, Trask PC, 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):263-73.
12. Henk HJ, Woloj M, Shapiro M, et al. Real-world analysis of tyrosine kinase inhibitor treatment patterns among patients with chronic myeloid leukemia in the United States. Clin Ther . 2015;37(1):124-33.
13. Thanopoulou E, Judson I. The safety profile of imatinib in CML and GIST: long-term considerations. Arch Toxicol . 2012;86(1):1-12.
14. Zhu Y, Qian S-X. Clinical efficacy and safety of imatinib in the management of Ph+ chronic myeloid or acute lymphoblastic leukemia in Chinese patients. Onco Targets Ther . 2014;7:395-404.
15. Daroudi R, Mirzania M, Nikravanfard N, et al. Estimation of the prevalence and direct medical costs of chronic myeloid leukemia in the IR of Iran in the era of tyrosine kinase inhibitors. Asia Pac J Clin Oncol . 2017;13(5):e416-e422
16. Mathews V. Generic imatinib: the real-deal or just a deal? Leuk Lymphoma . 2014;55(12):2678-80
17. Navidi GR, Rezvan H, Samiei S, et al. A preliminary study on the effect of two therapeutic procedures on the expression of BCR-ABL gene in CML patients. Blood Journal. 2005; 2 (5): 151-6.
18. Yousefi P, Rostami S, Alizadeh Ghandfurosh N, et al. Study of STAT3 Expression in Different Phases of Patients with Chronic Myeloid Leukemia. Payavard. 2019; 13. (2): 101-9.
19. Moshfeghi K, Nazemzadeh N, Mehrzad V, et al. Comparison of effectiveness and safety of Iranian-made vs. Indian-made imatinib in treatment of chronic myeloid leukemia. Adv Biomed Res . 2013; 2:17
20. Bahoush G, Albouyeh M, Vossough P. Imatinib Mesylate (Glivec) in Pediatric Chronic Myelogenous Leukemia. Int J Hematol Oncol Stem Cell Res. 2009;3 (3): 8-13.
21. Golabchifar A-A, Rezaee S, Ghavamzadeh A, et al. Population pharmacokinetics of imatinib in Iranian patients with chronic-phase chronic myeloid leukemia. Cancer Chemother Pharmacol . 2014;74(1):85-93
22. Mohajeri E, Kalantari-Khandani B, Pardakhty A, et al. Comparative pharmacokinetic evaluation and bioequivalence study of three different formulations of Imatinib Mesylate in CML patients. Int J Hematol Oncol Stem Cell Res. 2015; 9 (4): 165-72.
23. Chahardouli B, Zaker F, Mousavi SA, et al. Evaluation of T315I mutation frequency in chronic myeloid leukemia patients after imatinib resistance. Hematology. 2013. 18 (3): 158-62.
24. Chahardouli B, Zaker F, Mousavi SA, et al. Detection of BCR-ABL kinase domain mutations in patients with chronic myeloid leukemia on imatinib. Hematology. 2013;18(6): 328-33.
25. Valizadeh N. Imatinib Induced Facial Skin Hyperpigmentation in a Case of Chronic Myelogenous Leukemia. Shiraz e med j (Online). 2011;12 (3):162-4.
26. Mozaheb Z, Javani M. Regional Evaluation of Tolerability and Efficacy of Imatinib Mesylate in Patients with Chronic Phase CML in Mashhad (Iran, Southwest Asia). Health. 2014; 6(6): 900-7.
27. Salimizand H, Amini S, Abdi M, et al. Concurrent effects of ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp genetic polymorphisms with risk of cancer, clinical output, and response to treatment with imatinib mesylate in patients with chronic myeloid leukemia. Tumour Biol. 2016. 37 (1): 791-8.
28. Safaei A, Monabati A, Safavi M, et al. Additional cytogenetic aberrations in chronic myeloid leukemia: a single-center experience in the Middle East. Blood Res. 2018; 53(1): 49-52.
29. Solali S, Kaviani S, Movassaghpour A, et al. Real-Time Polymerase Chain Reaction Testing for Quantitative Evaluation of hOCT1 and MDR1 Expression in Patients with Chronic Myeloid Leukemia Resistant to Imatinib. Lab Med.2013; 44(1): 13-9.
30. Rejali L, Poopak B, Hasanzad M, et al. Characterizing of Four Common BCR-ABL Kinase Domain Mutations (T315I, Y253H, M351T and E255K) in Iranian Chronic Myelogenous Leukemia Patients With Imatinib Resistance. Iran J Cancer Prev . 2015;8(3):e2334.
31. Razmkhah F, Razavi M, Zaker F, et al. Hematologic and molecular responses to generic imatinib in patients with chronic myeloid leukemia. Lab Med. 2010; 41 (9): 547-50.
32. Vatanmakanian M, Tavallaie M, Ghadami S. Imatinib independent aberrant methylation of NOV/CCN3 in chronic myelogenous leukemia patients: a mechanism upstream of BCR-ABL1 function? Cell Commun Signa. 2019; 17 (1): 38.
33. Rostami G, Hamid M, Jalaeikhoo H. Impact of the BCR-ABL1 fusion transcripts on different responses to Imatinib and disease recurrence in Iranian patients with Chronic Myeloid Leukemia. Gene. 2017; 627: 202-6.
34. Vatanmakanian M, Tavallaie M, Ghadami S. Imatinib independent aberrant methylation of NOV/CCN3 in chronic myelogenous leukemia patients: a mechanism upstream of BCR-ABL1 function? Cell Commun Signal. 2019; 17 (1): 38.
35. Payandeh M, Aeinfar M, Yari S, et al. Molecular monitoring of Chronic Myeloid Leukemia in Chronic Phase (CML-CP). Asian Pac J Cance Care. 2018; 4(1): 1-5.
36. Nekoohesh L, Rostami S, Nikbakht M, et al. Evaluation of molecular response to imatinib mesylate treatment in Iranian patients with chronic myeloid leukemia Evaluation of molecular response to generic Imatinib treatment in Iranian patients with chronic myeloid leukemia. Clin Lymphoma Myeloma Leuk . 2020; 20(1):e1-e10.
37. Jalaeikhoo H, Ahmadzadeh A, Toogeh G, et al. Six-year follow up of imatinib therapy for newly diagnosed chronic myeloid leukemia in Iranian patients. Arch Iran Med . 2011;14(6):378-80
38. Rostami G, Hamid M, Yaran M, et al. Incidence and clinical importance of BCR-ABL1 mutations in Iranian patients with chronic myeloid leukemia on imatinib. J Hum Genet. 2015; 60 (5): 253-8.
39. Payandeh M, Sadeghi E, Sadeghi M. Non-hematological Adverse Events of Imatinib in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP). J Appl Pharm Sci. 2015; 5(2):87-90.
40. Hamidieh AA, Ansari S, Darbandi B, et al. The treatment of children suffering from chronic myelogenous leukemia: a comparison of the result of treatment with imatinib mesylate and allogeneic hematopoietic stem cell transplantation. Pediatr Transplant . 2013;17(4):380-6.
41. Payandeh M, Sadeghi M, Sadeghi E. Treatment and survival in patients with chronic myeloid leukemia in a chronic phase in West Iran. Asian Pac J Cancer Prev. 2015; 16 (17): 7555-9.
42. Abbasian S, Ghotaslou A, Ghasemi A, et al. Analysis of Expression Of SIRT1 Gene In Patients With Chronic Myeloid Leukemia Resistant To Imatinib Mesylate. Iran J Blood Cancer. 2015; 7 (4): 184-90.
43. Höglund M, Sandin F, Simonsson B. Epidemiology of chronic myeloid leukaemia: an update. Ann Hematol. 2015; 94 Suppl 2. S241-7.
44. Breccia M, Tiribelli M, Alimena G. Tyrosine kinase inhibitors for elderly chronic myeloid leukemia patients: a systematic review of efficacy and safety data. Crit Rev Oncol Hematol. 2012; 84 (1): 93-100.
45. Hochhaus A, Kreil S, Corbin AS, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002; 16 (11): 2190-6.
46. Kim SH, Kim D, Kim DW, et al. Analysis of Bcr-Abl kinase domain mutations in Korean chronic myeloid leukaemia patients: poor clinical outcome of P-loop and T315I mutation is disease phase dependent. Hematol Oncol. 2009; 27 (4): 190-7.
47. Talati C, Ontiveros EP, Griffiths EA, et al. How we will treat chronic myeloid leukemia in 2016. Blood Rev. 2015; 29 (2): 137-42.
48. Pulsipher MA. Treatment of CML in pediatric patients: Should imatinib mesylate (STI‐571, Gleevec) or allogeneic hematopoietic cell transplant be front‐line therapy? Pediatr Blood Cancer . 2004;43(5):523-33.
49. Druker BJ, Guilhot F, O'brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med . 2006;355(23):2408-17.
50. Hochhaus A, O'brien S, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009; 23 (6): 1054-61.
51. Sánchez-Guijo FM, Durán S, Galende J, et al. Evaluation of tolerability and efficacy of imatinib mesylate in elderly patients with chronic phase CML: ELDERGLI study. Leukemia Res. 2011; 35 (9): 1184-7.
52. Mealing S, Barcena L, Hawkins N, et al. The relative efficacy of imatinib, dasatinib and nilotinib for newly diagnosed chronic myeloid leukemia: a systematic review and network meta-analysis. Exp Hematol Oncol . 2013;2(1):5.
53. O'brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med . 2003;348(11):994-1004.
54. Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood. 2002; 99 (6): 1928-37.
55. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346 (9): 645-52.
56. Kodama Y, Morozumi R, Matsumura T, et al. Increased financial burden among patients with chronic myelogenous leukaemia receiving imatinib in Japan: a retrospective survey. BMC Cancer. 2012; 12: 152.
57. Cheng M-y, 鄭文瑛. Prescribing pattern of imatinib among chronic phase chronic myeloid leukaemia (CML) patients and its financial impact on Hong Kong. HKU Theses Online (HKUTO); 2013.
58. Druker BJ. Imatinib and chronic myeloid leukemia: validating the promise of molecularly targeted therapy. Eur J Cancer . 2002;38 Suppl 5:S70-6.
59. Au WY, Caguioa PB, Chuah C, et al. Chronic myeloid leukemia in Asia. Int J Hematol . 2009; 89(1):14-23.
60. 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;2010:368-76
61. 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. J Clin Oncol . 2011;29(20):2827-32.
62. Muramatsu H, Takahashi Y, Sakaguchi H, et al. Excellent outcomes of children with CML treated with imatinib mesylate compared to that in pre-imatinib era. Int J Hematol . 2011;93(2):186-191.
63. Millot F, Guilhot J, Nelken B, 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 (2): 187-92.
64. Redaelli S, Piazza R, Rostagno R, et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol. 2009; 27 (3): 469-71.
65. Kang HY, Hwang JY, Kim SH, et al. Comparison of allele specific oligonucleotide-polymerase chain reaction and direct sequencing for high throughput screening of ABL kinase domain mutations in chronic myeloid leukemia resistant to imatinib. Haematologica. 2006; 91 (5): 659-62.
66. Yousefi P, Rostami S, Alizadeh Ghandfurosh N, et al. Study of STAT3 Expression in Different Phases of Patients with Chronic Myeloid Leukemia. Payavard. 2019; 13 (2): 101-9.
67. Iqbal Z, Aleem A, Iqbal M, et al. Sensitive detection of pre-existing BCR-ABL kinase domain mutations in CD34+ cells of newly diagnosed chronic-phase chronic myeloid leukemia patients is associated with imatinib resistance: implications in the post-imatinib era. PLoS One. 2013; 8 (2): e55717.
68. Qin Y, Chen S, Jiang B, et al. Characteristics of BCR-ABL kinase domain point mutations in Chinese imatinib-resistant chronic myeloid leukemia patients. Ann Hematol. 2011;90(1): 47-52.
69. Jabbour E, Cortes J, Kantarjian H. Treatment selection after imatinib resistance in chronic myeloid leukemia. Target Oncol. 2009; 4 (1): 3-10.
70. Kantarjian HM, Talpaz M, O'Brien S, et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood. 2003;101 (2): 473-5.
71. Bixby D, Talpaz M. Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia. Leukemia. 2011; 25 (1): 7-22.
72. Nicolini FE, Corm S, Le QH, et al. Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP). Leukemia. 2006; 20 (6): 1061-6.
|Issue||Vol 15, No 2 (2021)|
|Imatinib mesylate; Treatment outcome; Antineoplastic agent resistance; Chronic myeloid leukemia; Adverse drug event|
|Rights and permissions|
|This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.|