Ethnic Differences in Hematologic Toxicity from Imatinib in Patients with Gastrointestinal Stromal Cell Tumor (GIST): Coincidence or a Real Phenomenon
Objectives: There is a wide variability in the pharmacokinetics, pharmacodynamics and tolerance of anticancer drugs based on ethnicity. GIST is a rare cancer, (~1% of GI cancers). Imatinib is used in the neo-adjuvant, adjuvant and metastatic setting. The purpose of this study was to report the difference in hematologic toxicities to imatinib among different ethnicities when treated for GIST either in the adjuvant or metastatic setting. Methods: We performed a retrospective study to collect data on patients with GIST (in any stage), who were on imatinib and presenting with grade 2 or more anemia, neutropenia and/or thrombocytopenia from July 1, 2005 to January 31, 2018. The degree of cytopenia was graded as per National Cancer Institute Common Toxicity criteria; version 4.0. We collected included age, gender, ethnicity, pathology, adverse effects-hematologic and non-hematologic, management of toxicities including dose modifications and administration of pegfilgrastim. Results: Among 57 patients (median age 61 years, M: F=41:16 (F); ethnicities: White 65%, African-American (AA 19%, Asian 12% and Hispanic 4%), neutropenia (Grade 3 & 4) was seen in 6 patients (10%): 5 AA and 1 Asian. 45% of all AA patients developed neutropenia. Median absolute neutrophil count (ANC) nadir was 700/µL, median duration on drug prior to onset of neutropenia was 4.5 weeks and median duration of neutropenia was 4 weeks. One patient developed febrile neutropenia. Dose interruptions were needed in 3, dose-reductions in all patients, and 3 patients required pegfilgrastim. One patient had to discontinue imatinib, while one patient was escalated back to 400mg daily dose. Conclusion: This is the first study to examine ethnic variations in myelosuppression following imatinib in patients with GIST.
Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB. Effects of a selective inhibi-tor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996;2:561–6. [CrossRef]
2. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031–7. [CrossRef]
3. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472–480. [CrossRef]
4. Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schütte J, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA 2012;307:1265–72. [CrossRef]
5. Paul TR, Uppin SG, Uppin MS, Jacob RT, Rao DR, Rajappa SJ. Evaluation of Cytopenias Occurring in Imatinib Treated Chronic Myeloid Leukemia (CML) Patients. Indian J Hematol Blood Transfus 2010;26:56–61. [CrossRef]
6. Guilhot F. Indications for imatinib mesylate therapy and clinical management. Oncologist 2004;9:271–281. [CrossRef]
7. Sneed TB, Kantarjian HM, Talpaz M, O’Brien S, Rios MB, Bekele BN, et al. The significance of myelosuppression during therapy with imatinib mesylate in patients with chronic myelogenous leukemia in chronic phase. Cancer. 2004;100:116–121. [CrossRef]
8. Okeshwar N, Kumar L, Kumari M. Severe bone marrow aplasia following imatinib mesylate in a patient with chronic myelogenous leukemia. Leuk Lymphoma 2005;46:781–4. [CrossRef]
9. Srinivas U, Pillai LS, Kumar R, Pati HP, Saxena R. Bone marrow aplasia–a rare complication of imatinib therapy in CML patients. Am J Hematol 2007;82:314–6. [CrossRef]
10. Khan KA, Junaid A, Siddiqui NS, Mukhtar K. Siddiqui S Imatinib-related bone marrow aplasia after complete cytogenetic response in chronic myeloid leukemia. J Coll Physicians Surg Pak 2008;18:176–8.
11. Ram R, Gafter-Gvili A, Okon E, Pazgal I, Shpilberg O, Raanani P. Gelatinous transformation of bone marrow in chronic myeloid leukemia during treatment with imatinib mesylate: a disease or a drug effect? Acta Haematol 2008;119:104–7.
12. Braziel RM, Launder TM, Druker BJ, Olson SB, Magenis RE, Mauro MJ, et al. Hematopathologic and cytogenetic findings in imatinib mesylate-treated chronic myelogenous leukemia patients: 14 months’ experience. Blood 2002;100:435–41.
13. Kovitz C, Kantarjian H, Garcia-Manero G, Abruzzo LV, Cortes J. Myelodysplastic syndromes and acute leukemia developing after imatinib mesylate therapy for chronic myeloid leukemia. Blood 2006;108:2811–3. [CrossRef]
14. Charles BA, Hsieh MM, Adeyemo AA, et al. Analyses of genome wide association data, cytokines, and gene expression in African-Americans with benign ethnic neutropenia. PLoS One 2018;13:e0194400. [CrossRef]
