Severe thrombocytopenia after trastuzumab in a patient with HER2-positive serous endometrial cancer

Background

Uterine cancer is the most common gynecologic malignancy in the USA. Uterine serous carcinoma is an aggressive subtype of uterine cancer, with approximately 70% of cases being diagnosed at stage III or IV, although it only accounts for 10% of all types of uterine cancer.1 2 Uterine serous cancer is traditionally treated with surgical staging and platinum/taxol combination chemotherapy.3 However, initial response rate to platinum/taxol combination has been cited as low as 10%–15% in recurrent disease.4

In recent years, studies have investigated the utility of trastuzumab both as a single agent and in combination with other chemotherapy agents for recurrent or advanced stage uterine serous cancer. Trastuzumab is a humanised monoclonal antibody directed against the human epidermal growth factor receptor 2 (HER2). The HER2 receptors are proteins embedded in the cell membrane that regulate cell growth and survival, and are overexpressed in 30% of uterine serous carcinoma. Trastuzumab in combination with other chemotherapy agents has been shown to increase progression free survival in patients with advanced stage or recurrent uterine serous carcinoma and the combination chemotherapy is now considered the standard of care for patients with stage III/IV HER2-positive uterine serous carcinoma.3 5

Furthermore, endometrial cancer classification has been expanded to include molecular characterisation: polymerase epsilon ultra-mutated, microsatellite instability hypermutated, copy-number (CN) low and CN high.6 Many recent and ongoing studies have investigated the utility of this molecular classification and analysis to refine therapeutic management with immunotherapy, especially in advanced/metastatic endometrial cancers.7 8 With the transition to more specific-targeted therapies, trastuzumab continues to be a mainstay treatment for certain endometrial cancers as per the updated National Comprehensive Cancer Network guidelines.3 Limited new studies have demonstrated that p53-aberrant endometrial cancers may also be HER2 amplified, with these patients benefiting from addition of trastuzumab.9 10

Trastuzumab can cause hypersensitivity reactions and cardiac dysfunction over long-term treatment, but rarely causes myelosuppression. Nevertheless, there have been 13 cases of trastuzumab-related thrombocytopenia reported in the literature to date.11 Among the reported cases, none have been reported in gynecologic cancer patients. We report a patient with stage IV serous endometrial carcinoma and severe thrombocytopenia, likely related to trastuzumab infusion.

Case presentation

A woman in her 70s first presented to a general gynaecology clinic with 4 months of abdominal pain and vaginal bleeding. She underwent an endometrial biopsy which showed endometrial serous adenocarcinoma with intact mismatch repair proteins and positive for HER2 expression. Furthermore, imaging showed multifocal mesenteric and retroperitoneal lymphadenopathy, bone lesions and solid pulmonary nodules, classifying the patient with radiologic stage IVB disease. The patient was started on first-line chemotherapy consisting of carboplatin/paclitaxel/trastuzumab, with a loading dose of 8 mg/kg of trastuzumab. Her complete blood count was within normal limits until cycle 1 day 7, when she had an episode of vaginal bleeding and outpatient laboratories were significant for platelets <5×10³/uL. She was transferred to the nearest emergency room for expedited management of grade 4 thrombocytopenia. In the emergency room, the patient was noted to have heavy vaginal bleeding, melena, bruising around her port site and a petechial rash on her lower extremities and abdomen. Her platelets were 0×10³/uL with a haemoglobin of 11.7 g/L (figures 1 and 2) and she was admitted to the hospital. Disseminated intravascular coagulation was excluded based on normal levels of fibrinogen, fibrin degradation products and the cross-linked fragment, D-dimer. Haemolysis was also excluded given normal peripheral smear and normal lactate dehydrogenase level. She was transferred to the ICU on hospital day 2, given that her platelets remained at 3×10³/uL and haemoglobin had dropped to 6.1 g/L, even after 4 units of platelets and 2 units of packed red blood cells. Haematology was consulted and recommended empiric treatment for drug-induced immune thrombocytopenia (ITP) with high-dose immune globulin (1 g/kg daily for two doses) and high-dose steroids with dexamethasone 40 mg IV daily for 2 days followed by 20 mg daily for 2 days. Gastroenterology was consulted for management of melena, and recommended supportive care with outpatient follow-up, given the inability to perform inpatient colonoscopy/esophagogastroduodenoscopy (EGD) with severe anaemia and thrombocytopenia. She was downgraded from the ICU on hospital day 4, with her platelet count slowly improving. On hospital day 6, the patient had received in total 6 units of platelets and 3 units of packed red blood cells, her vaginal and rectal bleeding had stopped, her platelets had recovered to 52×10³/uL and her haemoglobin improved to 7.2 g/L. She was discharged home on hospital day 6 and was continued on a dose-reduced chemotherapy regimen with trastuzumab (4 mg/kg) for subsequent cycles. On day 1 of her second cycle of chemotherapy, her platelets were in the normal range of 153×10³/uL. One week after her second cycle, her platelets dropped to 105×10³/uL, and the patient was asymptomatic.

Outcome and follow-up

The patient is currently continuing the dose-adjusted chemotherapy and has not had a readmission to the hospital to date. She has had normal platelet counts throughout her treatment and is tolerating her chemotherapy well. She is currently receiving cycle 8 of multiagent chemotherapy with excellent treatment response noted on imaging after four cycles.