DISCLAIMER: This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken tao verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Overview

Imatinib is a protein-tyrosine kinase inhibitor indicated for the treatment of chronic myeloid leukaemia, gastrointestinal stromal tumours, Philadelphia chromosome active acute lymphoblastic leukaemia, myelodysplastic/myeloproliferative diseases and etc.¹ It potently inhibits the activity of the breakpoint cluster region-Abelson (BCR-ABL) tyrosine kinase (TK) and other receptor TKs, including those for platelet-derived growth factor (PDGF_R) TK, thereby disrupting cellular events mediated by their activation. In Malaysia, there are currently 24 products containing imatinib registered with the Drug Control Authority (DCA).²

Thrombotic microangiopathy (TMA) encompasses a diverse group of disorders defined by the presence of haemolytic anaemia, thrombocytopenia, and potentially fatal end-organ damage, that stems from occlusive microvascular thrombosis.^3-6 Manifestations of TMA include thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS), atypical haemolytic uraemic syndrome (aHUS), and complications of other systemic illnesses or certain medications.⁶ The evaluation of ADAMTS13 (a protease responsible for cleaving von Willebrand factor) activity and inhibitor level may provide important diagnostic and prognostic information for appropriate TMA management.^4,6-7 Most TMA cases in Malaysia were attributed to secondary aetiologies (42.5%), such as systemic lupus erythematosus (SLE) and infections, with drug-induced causes accounting for 3% of secondary TMA cases.⁶

Background of the Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) learned through its global safety signal monitoring activity that the Japan Pharmaceuticals and Medical Devices Agency (PMDA) had requested all product registration holders for imatinib-containing products to update package inserts with the risk of TMA.⁸ Following a review of the post-marketing adverse reaction reports in Japan and globally, the PMDA considered that there is at least a reasonably possible causal relationship between imatinib and TMA.

The specific mechanisms involved in imatinib-induced TMA remain elusive.^4,7,9 Two (2) broad mechanisms are postulated to underlie drug-induced TMA: immune-mediated mechanism and direct endothelial toxicity. Irrespective of the specific trigger, drug-induced endothelial injury is considered the initiating event.^4-5 Multi-kinase inhibitors like imatinib inhibit PDGF TK, but the effects of PDGF inhibition on endothelial cells in human clinical settings are still unclear.⁹ Other possible mechanisms contributing to endothelial injury include complement activation and ADAMTS13 deficiency.^5,10

According to literature reviews and case reports, TMA following imatinib administration may occur at any time, with reported time-to-onset ranging from four days to several years.^4,5,9,11,12 Notably, one (1) patient who developed TMA after 12 years of imatinib therapy presented several risk factors for endothelial damage, including older age, long-term hypertension, obesity, and a history of heavy smoking and cardiovascular diseases.⁹ 

As reported in the literature, kidney involvement is predominant in cancer drug-induced TMA.⁵ Other than the clinical symptoms and signs mentioned above, acute kidney injury (AKI), progressive renal dysfunction, massive proteinuria, anuria, dyspnoea, metabolic acidosis, and hyperkalaemia were reported in the literature cases.^9,11-12 Reported renal outcomes following discontinuation of imatinib varied across cases, encompassing recovery to baseline function, withdrawal from haemodialysis but renal dysfunction persisted, haemodialysis dependence without recovery, and persistent renal dysfunction with subsequent improvement 2.5 years later.

Adverse Drug Reaction Reports¹³

Till date, the NPRA has received 2,316 reports with 3,767 adverse events suspected to be related to imatinib-containing products. The most reported adverse events are drug resistance (559), death (331), and drug intolerance (235). Thus far, no local reports of TMA have been received.

Advice for Healthcare Professionals

• Be aware that BCR-ABL tyrosine kinase inhibitors (TKIs), including imatinib, have been associated with thrombotic microangiopathy (TMA).
• Early recognition and treatment of this rare but potentially life-threatening TMA are crucial to minimise its burden and prevent complications, such as dialysis-dependent chronic kidney disease (CKD).
• Consider strict monitoring of renal function, platelet count and screen for signs of non-autoimmune haemolytic anaemia of a patient on treatment with imatinib.
• Advise patients to promptly seek medical attention if they experience signs of blood vessel damage, such as bruising, bleeding, fever, fatigue and confusion, even after a prolonged use of imatinib.
• If patients receiving imatibinb exhibit laboratory or clinical signs suggestive of TMA, consider discontinuing imatinib. A thorough evaluation for TMA is necessary to make a more accurate diagnosis and determine the appropriate management.
• Report all suspected adverse events associated with imatinib-containing products to the NPRA.

Regulatory Action

NPRA had completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13(33) Jld.1] had been issued for all registration holders of products containing imatinib to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). GLIVEC 100 and 400mg Film-Coated Tablets [Package Insert]. 2023 Mar [Cited 2023 Nov 29]. The Malaysian Product Registration Database (QUEST). Available from: https://www.npra.gov.my
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2023 [Cited 2023 Nov 29]. Available from: https://www.npra.gov.my
3. Blake-Haskins JA, Lechleider RJ, Kreitman RJ. Thrombotic microangiopathy with targeted cancer agents. Clin Cancer Res. 2011 Sep 15;17(18):5858-66. Available from: https://doi.org/10.1158%2F1078-0432.CCR-11-0804
4. Valério P, Barreto JP, Ferreira H, Chuva T, Paiva A, Costa JM. Thrombotic microangiopathy in oncology - a review. Transl Oncol. 2021 Jul;14(7):101081. Available from: https://doi.org/10.1016/j.tranon.2021.101081
5. Izzedine H, Perazella MA. Thrombotic microangiopathy, cancer, and cancer drugs. Am J Kidney Dis. 2015 Nov;66(5):857-68. Available from: https://doi.org/10.1053/j.ajkd.2015.02.340
6. Yap YY, Sathar J, Law KB, Zulkurnain PAB, Edmund SC, Chang KM, Baker R. Clinical characteristics and outcomes of thrombotic microangiopathy in Malaysia. Blood Res. 2018 Jun;53(2):130-137. Available from: https://doi.org/10.5045%2Fbr.2018.53.2.130
7. Masias C, Vasu S, Cataland SR. None of the above: thrombotic microangiopathy beyond TTP and HUS. Blood. 2017 May 25;129(21):2857-2863. doi: 10.1182/blood-2016-11-743104. Epub 2017 Apr 17. PMID: 28416509. Available from: https://doi.org/10.1182/blood-2016-11-743104
8. Pharmaceuticals and Medical Devices Agency (PMDA). Summary of Investigation Results: Imatinib mesilate [Internet]. 2022 Nov 16 [cited 2023 Nov 29]. Available from: https://www.pmda.go.jp/files/000249192.pdf
9. Morita N, Ozaki T, Yokota S, Sasaki H, Watanabe M, Takahashi K, Himuro N, Ito K, Yasuno T, Miyake K, Nawata A, Nakayama T, Uesugi N, Masutani K. Focal segmental glomerulosclerosis and concurrent glomerular microangiopathy after long-term imatinib administration. CEN Case Rep. 2022 Feb;11(1):134-140. Available from: https://doi.org/10.1007/s13730-021-00622-w
10. Chatzikonstantinou T, Gavriilaki M, Anagnostopoulos A, Gavriilaki E. An Update in Drug-Induced Thrombotic Microangiopathy. Front Med (Lausanne). 2020 May 22;7:212. Available from: https://doi.org/10.3389/fmed.2020.00212
11. Al Aly Z, Philoctête Ashley JM, Gellens ME, González EA. Thrombotic thrombocytopenic purpura in a patient treated with imatinib mesylate: true association or mere coincidence? Am J Kidney Dis. 2005 Apr;45(4):762-8. Available from: https://doi.org/10.1053/j.ajkd.2004.12.017
12. Ojeda-Uribe M, Merieau S, Guillon M, Aujoulat O, Hinschberger O, Eisenmann JC, Kenizou D, Debliquis A, Veyradier A, Chantrel F. Secondary thrombotic microangiopathy in two patients with Philadelphia-positive hematological malignancies treated with imatinib mesylate. J Oncol Pharm Pract. 2016 Apr;22(2):361-70. Available from: https://doi.org/10.1177/1078155214568580
13. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2023 [Cited on 2023 Oct 23]. Available from: https://www.npra.gov.my (access restricted)

Written by: Wang Khee Ing
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Norleen Mohamed Ali