Safety of trastuzumab after trastuzumab emtansine-induced nodular regenerative hyperplasia: A case report

Introduction

Trastuzumab emtansine (T-DM1) is composed of trastuzumab, a monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER2), which is bound to emtansine (known as DM1), a microtubule inhibitor. ¹ In monotherapy, this conjugate drug-antibody has been shown to improve median progression-free survival and overall survival in patients with metastatic breast cancer (MBC) who progressed after at least one HER2-targeted therapy and one chemotherapy.^1,2 For these patients, T-DM1 is the preferred choice in second-line after progression with a combination of pertuzumab, trastuzumab and a taxane. Unlike trastuzumab, T-DM1 frequently causes thrombocytopenia and elevated transaminases usually without other hepatic problems.^3–5

There are seven T-DM1-induced nodular regenerative hyperplasia (NRH) cases described in the literature (Table 1).^6–9 NRH usually presents itself with a mild elevation of transaminases occurring over several months, followed by clinical signs of portal hypertension such as ascites, hypersplenism and variceal bleeding. ¹⁰ Mildly elevated transaminases usually do not require an interruption of therapy, but unaddressed NRH can lead to severe hepatic damage with one case of death from liver failure reported in the literature.^6,8 Hence, T-DM1-induced NRH normally requires a definitive interruption of the therapy. ⁸ It is still unclear if trastuzumab therapy can be reintroduced after NRH induced by T-DM1, depriving the patient of a HER2-targeted therapy. There was only one reported case where trastuzumab was reintroduced following the diagnosis of NRH and was continued for one month until metastatic progression. ⁹ In this case report, we present one case where trastuzumab was reintroduced without any complications for a long extent following T-DM1-associated NRH.

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Table 1.

Cases of T-DM1-induced NRH in the literature.^6–9

Patient and age at presentation of NRH	Manifestation of NRH	Time from T-DM1 therapy to diagnosis of NRH	Outcome (lived/died from adverse event)	Symptoms that resolved
61 years old (our patient)	↑ liver transaminasesThrombocytopeniaStellate angiomas and variceal system in the lower mesenteric veins	27 months (39 cycles)	Lived	Liver test abnormalitiesStellate angiomas
No information 6	Clinical or radiographic signs of portal hypertension	2 months (3 cycles)	Lived	No information
No information 6	Clinical or radiographic signs of portal hypertension	14 months (20 cycles)	Lived	No information
No information 6	Clinical or radiographic signs of portal hypertension	19 months (27 cycles)	Died
66 years old 7	↑ liver transaminasesThrombocytopeniaAscitesEsophageal varicesHepatic encephalopathyPortal vein thrombosis	15 months (23 cycles)	Lived	Liver test abnormalitiesAscitesHepatic encephalopathy
50 years old 7	↑ liver transaminasesThrombocytopeniaEsophageal varices	17 months (22 cycles)	Lived	↑ liver transaminasesThrombocytopenia
73 years old 8	↑ liver transaminasesThrombocytopeniaSplenomegalyEsophageal varices	15 months (21 cycles)	Lived	Liver test abnormalities
48 years old 9	Hepatosplenomegaly ↑ liver transaminases	12 months (16 cycles)	Lived	Liver test abnormalities

NRH: nodular regenerative hyperplasia; T-DM1:  trastuzumab emtansine.

Case report

A 61-year-old woman was diagnosed with an invasive ductal carcinoma in 2003, stage pT1cN0M0 with hormonal receptors and HER2 positive treated with neoadjuvant chemotherapy (gemcitabine, epirubicin and paclitaxel) and radical modified mastectomy of left breast followed by radiotherapy and tamoxifen. In October 2006, a bone metastasis was found which was treated with local radiotherapy followed by tamoxifen and trastuzumab for 22 months until November 2009. Between January 2010 and October 2012, capecitabine-lapatinib was started because the right occipital condyle metastasis was worsening. After the discovery of a small metastasis in her 8th left rib, she was switched to T-DM1 3.6 mg/kg every three weeks (according to the Emilia trial’s research protocol) and received 39 cycles over more than two years. ²

During her treatment with T-DM1, the patient had progressive stellate angiomas. Multiple abdominal CT-scans were done during her treatment period, and they showed a stable hypodensity lesion in segment IV-A with a small element of steatosis without portal thrombosis nor hepatic metastasis. However, there was a sign of portal hypertension presented as a variceal system in the lower mesenteric veins on the CT-scan of April 2014, which was after cycle 24 of T-DM1. The portal hypertension was not clinically significant and no ascites was present. The liver was otherwise of normal morphology. The elevation in transaminase enzymes and reduction in platelet count were apparent over several months during the T-DM1 therapy (Figure 1). The highest values for AST and ALT were seen before cycle 9, which represents a modest increase of approximately twice the upper normal value (normal values between 13 and 39 units/L). In December 2014, a liver biopsy was done since stellate angiomas were increasing. Initial cirrhosis evaluation, which included the viral hepatitis B and C, antimitochondrial antibodies, anti-smooth muscle antibodies, antiparietal cell antibodies, ferritin and alpha-1 antitrypsin, was negative. The histological diagnostic of NRH was confirmed on January 2015 which led to the permanent discontinuation of T-DM1 therapy as required by the research protocol. ² Up to this point, the patient had had no cancer progression under T-DM1. The patient previously had a good response on trastuzumab, hence this therapy was restarted together with exemestane in March 2015. Three months after the discontinuation of T-DM1, the patient had significant improvement of her stellate angiomas and the abdominal CT-scan showed no evidence of progression of the hypodensity lesion previously identified. Liver enzymes reached normalization six months after T-DM1 discontinuation (Figure 1). In total, the patient received 22 cycles of trastuzumab between March 2015 and May 2016 before dying from cancer progression a month later.

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Figure 1.

Evolution of ALT, AST and platelet count during T-DM1 treatment.

Discussion

We report the case of a patient who developed NRH, that was histologically confirmed, during her 27-months course on T-DM1 therapy for MBC, who recovered six months after discontinuation of T-DM1 therapy while trastuzumab was restarted.

Drug-induced NRH is often reported in the literature as overt noncirrhotic portal hypertension with ascites and variceal bleed.^10,11 NRH is usually not diagnosed rapidly, as there is often a latent phase of asymptomatic liver damage without significant elevation in transaminases and a possible mild decrease in platelet count linked to splenic sequestration. ¹⁰ After this phase, NRH is usually diagnosed when complications of portal hypertension are seen without other cause of liver damage. Sinusoidal obstruction syndrome (SOS) induced by T-DM1 was recently reported in three patients.^12,13 The clinical presentation of SOS is more severe than NRH and included symptoms such as hyperbilirubinemia, development of right upper-quadrant pain and tender hepatomegaly, ascites and unexplained weight gain. ¹⁴ Liver biopsy is necessary to differentiate NRH from SOS.

The most likely hypothesis for the pathogenesis of NRH is that it is caused by the emtansine (DM1) part of the T-DM1. After binding to HER2 receptor, T-DM1 is internalized into human hepatocytes and DM1-containing moieties are then released into the hepatocytes which disorganizes the microtubule network, causing a halt in cell mitosis and apoptosis. ¹⁵ In mouse subjects, T-DM1 induces a dose-dependent inflammation and necrosis of liver tissue associated with the upregulation of tumor necrosis factor alpha (TNFɑ) which seems to be related to T-DM1 and not with trastuzumab nor with placebo. ¹⁵ According to this information, trastuzumab could be reintroduced in a patient with NRH induced by T-DM1.

Except for T-DM1, the patient was not exposed to other hepatotoxic medication while on chemotherapy. Extrahepatic metastatic cancer has been reported to cause NRH by mechanical obstruction of the portal vein. ¹⁰ This differential diagnosis was ruled out since the patient presented no organ metastasis on the CT-scans. The extensive cirrhosis evaluation, the timing of the hepatic injury and the absence of other drug-related causes make T-DM1 the most likely explanation for the NRH in our patient. The Naranjo scale is a tool that can help evaluate the probability that the adverse drug reaction is actually due to one drug rather than other factors. ¹⁶ A score of 7 was obtained on the Naranjo scale indicating a probable association between the NRH and T-DM1. ¹⁶

The published cases of NRH caused by T-DM1 have reported clinical or radiographic signs of portal hypertension with either ascites or esophageal varices as overt signs of portal hypertension, which occurred after a median of 15 months after the initiation of T-DM1 (interval 2 to 26 months).^6–9 Only one patient (13%) presented an early presentation of NRH two months after T-DM1 therapy, while all other cases occurred after a minimum of 12 months. Therefore, NRH may be suspected after one year of T-DM1 treatment in patients with signs of portal hypertension without cirrhosis. Our patient presented no clinically significant signs of portal hypertension, but instead had stellate angiomas that were increasing in numbers after 24 months on T-DM1. Transaminases elevation was present in every case of NRH, including ours.^7–9 The extent of the augmentation was variable but stayed below three times the normal upper limit.^7,8 Including our case, thrombocytopenia was present in half of the reported cases with the lowest reported value being 99 × 10⁹/L.^7,8 The platelet count was not stated in the other cases (Table 1).^6,9 However, since T-DM1 is known to cause thrombocytopenia in 31% of the patients, this adverse event might not be directly related to NRH but could be a hematological toxicity from T-DM1. Hence, our case had a similar presentation as the other cases reported in the literature in terms of laboratory abnormalities (transaminases and platelet count) and in terms of delay before presentation of NRH (Figure 1 and Table 1).

Re-introduction of trastuzumab after T-DM1-induced NRH has not been described well in the literature. To our knowledge, only one recent article reported having given trastuzumab in this situation but it was stopped after one month due to metastatic progression. ⁹ Our case received trastuzumab for 15 months (22 cycles) after discontinuation of T-DM1, and still had normalisation of her liver enzymes and improvement of her stellate angiomas, which occurred 6 months after T-DM1 was stopped. This is consistent with the other reported cases in which the normalisation occurred a few months after discontinuation of T-DM1.^7–9 This is important for clinicians because it gives us light on the adequate time to do a follow-up for NRH induced by T-DM1.

Conclusion

We presented a case of NRH induced by T-DM1 in a patient who had stellate angiomas as main clinical sign of liver damage. Remission from NRH was obtained several months after discontinuation of T-DM1 while the patient was on trastuzumab therapy. Therefore, even if T-DM1 is the cause of NRH, we hypothesize that the use of trastuzumab may be both safe and efficient as demonstrated by our particular case in which prolonged cancer remission was achieved.