Response to Tyrosine Kinase Inhibitors in Patients with BCR-ABL1 Positive Chronic Myeloid Leukemia; 13.5 Years’ Experience at Patan Hospital, Nepal
International Blood Research & Reviews, Volume 14, Issue 2,
Background: Since the advent of Tyrosine Kinase Inhibitor (TKI), well controlled studies in developed world have shown that the life expectancy of patients with CML is comparable to normal people without the disease. But long-term follow up studies are lacking in resource poor setting.
Methods: This is a retrospective follow up study looking at the molecular response and resistance to Tyrosine Kinase Inhibitors (TKI) in patients enrolled in the Max Access Program since February 2003 till March 2017. Patients with two or more BCR-ABL1 levels by Karyotyping/ fluorescent in situ hybridization (FISH) / reverse transcriptase polymerase chain reaction (RT-PCR) were included. At baseline, complete blood count (CBC), renal function test (RFT), and liver function test (LFT) were evaluated. Bone marrow aspiration and biopsy for morphology, cytogenetic analysis by Karyotyping/FISH and/or molecular analysis by RT-PCR were also done if these tests were not performed earlier. FISH or RT-PCR was done on peripheral blood every 3–12 months as necessary if the patient could afford. Patients with warning response/failure underwent BCR-ABL1 Resistance Mutation Analysis (IRMA).
Results: Three hundred and forty six (346) patients had two or more BCR-ABL1 monitoring tests done. Optimal response was seen in 49.42%. Similarly, suboptimal response and failure were seen in 16.5% and 34% respectively. Overall Survival is 89.6% (at 1.8 -165 months, mean 62 months) . If only CML related events is considered survival is 95.9%. Seventy seven (77) patients with a total of 80 BCR-ABL1 domain Imatinib Resistance Mutation Analyses (IRMA) showed 19 different types of mutations with the most common being T315I mutation (8 and 19.5%). About 22.25% of the total patients showed resistance to Glivec out of which 10.98% showed mutations. Nine patients underwent trial for treatment free response (TFR) and 5 of them relapsed between 2-8 months.
Conclusions: Despite all the odds of having financial problem, accessibility problem due to distances, transportation, etc. and difficulty monitoring with routine BCR-ABL1 and IRMA, our findings show that the outcome of TKI therapy in our CML patients is comparable to well controlled studies done elsewhere. Overall survival, molecular and cytogenetic responses and mutations in our patients who developed resistance as well as TFR are also similar to other studies. The resistance rate of 22.25% is slightly higher compared to other studies in developed world. This is mainly because of poor monitoring due to unavailability of the test including IRMA in our country and affordability until 2012. It proves that TKI is very effective in CML even in a resource-poor, developing country.
- Chronic myeloid leukemia
- CML in Nepal
- tyrosine kinase inhibitors
- TKI in Nepal
- response to TKI in CML patients
- resistance to TKI
How to Cite
Janet Davison Rowley, Geoff Watts. February 01,14 Available:https://doi.org/10.1016/S0140-6736(14)60142-2
Seong D, et al. Analysis of Philadelphia chromosome-negative BCR-ABL1-positive chronic myelogenous leukemia by hypermetaphase fluorescence in situ hybridization. Ann Oncol. 1999;10(8): 955-9.
Richard E. Clark, Jane F. Apperley, Mhairi Copland, Silvia Cicconi. Additional chromosomal abnormalities at chronic myeloid leukemia diagnosis predict an increased risk of progression. Blood Advances. 2021;5(4). DOI 10.1182/bloodadvances.2020003570
Wei Wang, et al. Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Blood. 2016;127(22):2742-50. DOI: 10.1182/blood-2016-01-690230.
Access on 2016 Mar 22
Hasford J1, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, Alimena G, Steegmann JL, Ansari H. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst. 1998;90(11):850-8.
Shafaq Maqsood, Fatima Ali, Abdul Hameed, Neelam Siddiqui. Chromosomal aberrations in chronic myeloid leukemia: Response to conventional TKIs and risk of blastic transformation. Asian Pac J Cancer Care. 6(1):35-39. DOI:10.31557/APJCC.2021.6.1.35
Mariam IS, et al. Differential prognostic impact of stratified additional chromosome abnormalities on disease progression among Malaysian chronic myeloid leukemia patients undergoing treatment with imatinib mesylate Front. Oncol., Sec. Cancer Genetics. 2022;12. Available:https://doi.org/10.3389/fonc.2022.720845
Mahon FX, et al. Discontinuation of imatinib in patients with chronic myeloid leukemia who have maintained complete molecular remission for at least 2 years: The prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11(11): 1029-35. DOI: 10.1016/S1470-2045(10)70233-3.
Access on 2010 Oct 19
Mahon FX. Treatment-free remission in CML: Who, how, and why? Hematology Am Soc Hematol Educ Program. 2017;2017:102–9.
Hughes TP, et al. Moving treatment- free remission into mainstream clinical practice in CML. Blood. 2016;128: 17–23.
Saussele S, et al. The concept of treatment-free remission in chronic myeloid leukemia. Leukemia. 2016;30: 1638–47.
Ilander M, et al. NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia. Leukemia. 2017;31(5):1108-1116. DOI: 10.1038/leu.2016.360. Access on 2016 Nov 28
Kayastha GK, et al. Patan hospital experience in treating philadelphia chromosome/BCR-ABL1 positive chronic myeloid leukemia patients with gleevec (imatinib mesylate); the first generation specific tyrosine kinase inhibitor. BMC Blood Disord. 2010;10:8. DOI: 10.1186/1471-2326-10-8.
Gyan K. Kayastha, et al. Treating philadelphia chromosome/BCR-ABL1 positive patients with glivec (imatinib mesylate): 10 years’ experience at Patan Hospital, Nepal. British Journal of Haematology. 2017;177:991–999. DOI: 10.1111/bjh.14645
Gyan K. Kayastha, et al. The use of imatinib resistance mutation analysis to direct therapy in philadelphia chromosome/BCR-ABL1 positive chronic myeloid leukemia patients failing BCR-ABL1 treatment, in Patan Hospital, Nepal. British Journal of Haematology. 2017;177: 1000–1007.
Nora Ranjitkar Manandhar et al. Dasatinib tyrosine kinase inhibitor as second and third line therapy in chronic myeloid leukemia: Outcome of a Nepalese study. Journal of Patan Academy of Health Sciences. 2018;5(1):47-56.
Michael J. Mauro, defining and managing imatinib resistance. ASH Education Book. 2006;2006(1):219-225. DOI: 10.1182/asheducation-2006.1.219
Druker BJ, Guilhot F, O’Brien S, et al. Long-term benefits of imatinib (IM) for patients newly diagnosed with Chronic Myelogenous Leukemia in Chronic Phase (CML-CP): The 5-year update from the IRIS study [abstract]. J Clin Oncol. 2006;24:338s
Druker BJ, Guilhot F, O’Brien SG, et al. IRIS investigators five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006; 355:2408–17.
Deininger M, O’Brien SG, Guilhot F, et al. International randomized study of interferon vs. STI571 (IRIS) 8-year follow up: Sustained survival and low risk for progression or events in patients with newly diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) treated with imatinib. 51st ASH Annual Meeting and Exposition. Oral and Poster Abstracts. Poster Session: Chronic Myeloid Leukemia - Therapy Poster.
Julian Borrow. Guidelines for mutation analysis of BCR/ABL kinase domain: Interpreting TKI-resistance mutations in CML patients West Midlands Regional Genetics Laboratory; 2007.
Franck E. Nicolini, et al. Overall survival with ponatinib versus allogeneic stem cell transplantation in philadelphia chromosome-positive leukemias with the T315I mutation. DOI: 10.1002/cncr.30558
Cortes JE, et al. A phase 2 trial of ponatinib in philadelphia chromosome–positive Leukemias. November 7, 2013. N Engl J Med. 2013;369:1783-1796
Susanne Saussele, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukemia (EURO-SKI): A prespecified interim analysis of a prospective, multicentre, non-randomised. Trial Lancet Oncol. 2018;19(6):747-757. DOI: 10.1016/S1470-2045(18)30192-X Access on 2018 May 4
Sheena Bhalla, et. al. Discontinuing tyrosine kinase inhibitor therapy in chronic myelogenous leukemia: Current understanding and future directions. Clin Lymphoma Myeloma Leuk. 2016;16(9): 488-494. DOI: 10.1016/j.clml.2016.06.012. Access on 2016 Jun 16
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