Severe thrombocytopaenia caused by trastuzumab emtansine in a patient with breast cancer: A case report

Abstract

We present the case of a 48-year-old woman with human epidermal growth factor receptor 2- and hormone receptor-positive left early breast cancer who developed severe thrombocytopaenia and moderate liver dysfunction after administration of trastuzumab emtansine as an adjuvant therapy. Briefly, she experienced grade 2 subcutaneous bleeding, decreased platelet count (18,000/µL), and elevated aspartate aminotransferase/alanine aminotransferase levels (254/193 IU), resulting in admission to the emergency room. Although thrombocytopaenia is a well-known adverse event associated with trastuzumab emtansine, we observed it immediately after trastuzumab emtansine administration in our patient. Based on the literature survey, we hypothesised that trastuzumab emtansine may have affected mature platelets in our patient. In addition, moderate hepatotoxicity may be partially explained based on the pharmacological mechanisms of trastuzumab emtansine action involving microtubule disorganisation in hepatocytes via cytoskeleton-associated protein 5 on the cell surface by emtansine. We discuss the mechanism of the development of thrombocytopaenia and liver dysfunction.

Introduction

Breast cancer has the highest incidence rate among Japanese women. Over 20% of breast cancer patients were reported to overexpress human epidermal growth factor receptor 2 (HER2). ¹ Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate that combines the anti-HER2 antibody, trastuzumab (Tmab), and the tubulin polymerisation inhibitor, emtansine (DM-1), via a linker. ¹ Because of the attached DM-1, a cytotoxic agent, T-DM1 has more potential for adverse events than Tmab.

In August 2020, T-DM1 was approved in japan as an additional postoperative drug therapy for patients with HER2-positive early breast cancer who have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. ² The population treated with T-DM1 is expected to steadily increase with time, warranting a detailed assessment of its adverse events. Information on the clinical course of T-DM1-induced adverse events is scarce, despite dose-limiting toxicity for thrombocytopaenia and hepatotoxicity. Here, we present a case of typical adverse events of thrombocytopaenia and hepatotoxicity and discuss the timing of thrombocytopaenia caused by T-DM1 administration. Written informed consent for this report was obtained from the patient.

Case presentation

A 48-year-old woman started receiving neoadjuvant therapy for HER2- and hormone-receptor-positive left early breast cancer. Four courses of 90 mg/m² epirubicin hydrochloride and 600 mg/m² cyclophosphamide and four of a loading fixed dose of 840 mg/kg body weight, followed by a fixed dose of 420 mg/kg body weight of pertuzumab, a loading dose of 8 mg/kg body weight and 6 mg/kg body weight trastuzumab, and 75 mg/m² docetaxel were administered intravenously every 3 weeks.

Probiotics, rabeprazole sodium and furosemide were prescribed to ameliorate diarrhoea, heartburn and oedema caused by docetaxel administration. Clinical response was partial according to Response Evaluation Criteria in Solid Tumours. She underwent a left partial mastectomy and sentinel lymph node biopsy. Pathological diagnosis revealed residual invasive ductal carcinoma, 15 mm in size, with negative surgical margins. Sentinel lymph node biopsy was negative. The results of immunological staining were oestrogen receptor negative, progesterone receptor negative, HER2 positive and Ki 67 20%–30%. Therefore, we changed the adjuvant therapy to 14 courses of T-DM1 3.6 mg/kg every 3 weeks.

Two days after T-DM1 administration, she developed a grade 2 rash, and subcutaneous bleeding appeared in the knee area (Figure 1). On day 5, she was admitted to our hospital with low platelet count (18,000/µL) and increased liver transaminase levels (aspartate aminotransferase (AST)/alanine aminotransferase (ALT), 254/193 IU; total bilirubin (T-bil), 1.3 mg/dL). Notably, her platelet count (59,000/µL) and normal range of liver function (AST/ALT, 21/13 IU; T-bil, 0.8 mg/dL) before T-DM1 administration were grade 2 according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (US Department of Health and Human Services, National Institutes of Health, National Cancer Institute).

Figure 1.

Clinical course for the present case.

We discontinued tamoxifen and administered glycyrrhizin (40 mg) injection and 10 units of concentrated platelets for 2 days according to the Serious Adverse Drug Reactions Disease-Specific Manual for Treatment of Drug-Induced Liver Injury ³ from the Ministry of Health, Labour and Welfare in Japan. ⁴ On day 6, her platelet count (35,000/µL) and liver function (AST/ALT, 138/123 IU; T-bil, 1.1 mg/dL) began to improve. On day 7, the patient was discharged because her platelet count (59,000/µL) and liver function (AST/ALT, 89/88 IU; T-bil, 0.9 mg/dL) were in the normal range. Subcutaneous bleeding peaked on days 6–7 and recovered on day 10.

Patient follow-up

The patient finally completed one course of T-DM1 and underwent radiation therapy (42 Gy/16 fractions) for the left breast. Thereafter, we changed from T-DM1 to Tmab alone. Finally, she completed the adjuvant therapy.

Discussion

We present a case of T-DM1-induced thrombocytopaenia and liver dysfunction in the adjuvant setting for breast cancer. To our knowledge, this is the first clinical case report to detail the time course of T-DM1-induced thrombocytopaenia.

Prothrombin time (PT) and activated partial thromboplastin time (APTT) were measured twice. The first measurement (PT: 99 s; APTT: 33.5 s) was made immediately before mastectomy and the second measurement (PT: over 100 s; APTT: 32.4 s) was made immediately before EC chemotherapy. The patient did not have a history of bleeding-related diseases. Based on the results of laboratory tests and disease history, we rule out bleeding disorders in the patient.

We also observed a mild hepatocytotoxic reaction. DM-1 binds to cytoskeleton-associated protein 5 on the cell surface and induces microtubule disorganisation in hepatocytes, ⁵ which might have caused the hepatocytotoxic reaction in this case.

Bender et al. observed the lowest platelet counts approximately 8 days after T-DM1 administration. ⁶ By contrast, in our case, bleeding due to thrombocytopaenia was observed 2 days after, and a low platelet count was observed 5 days after T-DM1 administration, which was earlier than in previous reports.

The timing of T-DM1-induced thrombocytopaenia is related to the timing of (1) megakaryocyte differentiation and (2) platelet maturation process.^7,8 In general, it takes 7 days for haematopoietic stem cells to differentiate into megakaryocytes and mature into platelets. Therefore, the mechanism underlying thrombocytopaenia in this case may have been different. One possible hypothesis is that T-DM1 may have affected the mature platelets in our case. Diéras V et al. reported that grade 3/4 thrombocytopaenia is more frequent in Asians than in non-Asian breast cancer patients treated with T-DM1 (44.4% vs. 10.6%). ⁹ They hypothesised that the mechanisms for the ethnic differences are (1) higher activity of target-dependent uptake-pathway for T-DM1 via the Fc receptor in Asians, and (2) target-independent pathways such as endocytosis-mediated thrombocytopaenia. ¹⁰ We may, therefore, need to consider the adverse events of T-DM1, especially in Asian patients, due to the higher toxicity.

Previously, a patient assigned to the T-DM1 group in a clinical trial (KATHERINE) died of intracranial haemorrhage associated with a fall and grade 2 thrombocytopaenia. ² Considering this result, physicians and pharmacists should consider changing the medication from T-DM1 to another anti-cancer drug for patients with severe thrombocytopaenia. However, this is a conservative approach, and in practice, the requirements of each patient should be considered individually.

Our case study had several limitations. First, although thrombocytopaenia observed on day 2 after administration of T-DM1 is a rational time course, her platelet count was at a lower level (59000/µL) immediately before T-DM1 administration. There was no history of bleeding-related disorders, unknown genetic factors and other specific conditions. Second, the mechanisms underlying adverse events proposed by us are based on the literature survey.

Conclusion

Our case suggests that clinicians should be aware of the importance of carefully monitoring platelet counts and liver function, particularly after the first dose of T-DM1.