Ado-trastuzamab emtansine associated hyponatremia and intracranial hemorrhage

Ado-trastuzamab emtansine (T-DM1) is an anti-body-drug conjugate (ADC) approved for the sec-ond-line treatment of HER2-positive (HER2 ) metastatic breast cancer. This agent is in clinical trials for use in ﬁ rst-line metastatic disease, adjuvant and neoadjuvant treatment due to the superior efﬁ cacy with reduced toxicity demonstrated in the pivotal trial [1]. The mechanisms of action involve binding of the monoclonal antibody to HER2 on the cell surface to inhibit HER2 receptor signaling, HER2 shedding and triggering of the antibody-de-pendent cell-mediated cytotoxicity (ADCC) immune response. Once bound, the compound is internalized via endocytosis and is degraded inside the tumor to release emtansine or DM1, which binds to microtu-bules and inhibits polymerization causing cell-cycle arrest and death [2 – 4]. The most common adverse drug reactions (ADR) in early clinical trials of T-DM1 were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation [1]. Additionally, hepatoxicity, cardiotoxicity with reduc-tions in left ventricular ejection fractions, interstitial lung disease including pneumonitis, infusion-related reactions, and peripheral neuropathy was reported [5]. Recently, Roche released a Direct Healthcare Professional Communication about severe hemor-rhage in patients receiving T-DM1 advising caution in patients with thrombocytopenia. A recent report [6] describes a radiation recall phenomenon with increased brain edema in patients treated with T-DM1 having previous stereotactic radiosurgery. This study described edema and necrosis at tumor sites that was posited to be due to enhanced cell death and inﬂ ammation elicited by T-DM1 in HER2 upregulated glial cells at the edematous sites. Here we describe a case involving previously irradiated brain metastasis of HER2 cancer leading to both hyponatremia and intracra-nial hemorrhage despite an adequate platelet count after T-DM1 treatment. A patient with a 13-year history of metastatic breast cancer to lung and bone and three-year his-tory of brain metastases initiated treatment with T-DM1 3.6 mg/kg given every 21 days. Complica-tions requiring hospitalization occurred a total of three times over six cycles. She had previously been treated with ovarian suppression, tamoxifen, vinore-lbine and trastuzumab, exemestane, whole brain irradiation (external beam intensity modulated radiotherapy 39.8 Gy in 1.8 Gy/fraction, 3 years prior to T-DM1), capecitabine and lapatinib, ste-reotactic radiosurgery (8 lesions were treated with 1750 cGy per lesion using 11 isocenters, 2 years prior to T-DM1), and trastuzumab and lapatinib prior to initiating T-DM1. The patient was ﬁ rst admitted one week after the ﬁ rst treatment of ado-trastuzamab for increasing episodes of partial seizures and confusion. Labora-tory results upon arrival showed a sodium level of 118 mmol/L (previous week ’ s baseline was 131 mmol/L). The hyponatremia was treated with nor-mal saline, which raised her sodium level. The cause of the hyponatremia was thought to be mainly poor oral intake and dehydration with cerebral salt wast-ing. Dexamethasone was started to decrease cerebral edema, thought to be most likely related to necrotic