Severe Thrombocytopenia from Trastuzumab and Pertuzumab Combination Therapy in a Patient with HER2-Positive Metastatic Rectal Cancer

In recent years, human epidermal growth factor receptor type 2 (HER2)-targeted therapies have been introduced into clinical practice for various solid tumors, including breast cancer [1], gastric cancer [2], and lung adenocarcinoma [3]. Meanwhile, in approximately 2–6% of patients with colorectal cancer, HER2 expression is positive [4, 5]. The effectiveness of trastuzumab and pertuzumab combination therapy as a salvage line for HER2-positive colorectal cancer has been demonstrated in the TRIUMPH and MyPathway trials [4, 5]. Therefore, anti-HER2 antibody therapies have been incorporated into the management of colorectal cancer over the past few years. No cases of severe thrombocytopenia were reported in either trial, and the frequency of severe thrombocytopenia due to anti-HER2 treatment in other types of cancer remains unclear, with certain reports for breast cancer [6‒9] and gastric cancer [10] documented. While these reports are related to thrombocytopenia induced by trastuzumab treatment, no reports of thrombocytopenia caused by the combination therapy of trastuzumab and pertuzumab have been identified for any type of cancer. Several patients reported to have severe thrombocytopenia recovered after discontinuation of anti-HER2 treatment and corticosteroid administration. However, the patient with metastatic rectal cancer in the present case exhibited persistent thrombocytopenia after the discontinuation of anti-HER2 treatment and administration of corticosteroids.

A 76-year-old man presented with rectal cancer with multiple liver and para-aortic lymph node metastases. His medical history included hypertension, diabetes mellitus, and glaucoma. Molecular biological diagnostics showed a microsatellite-stable tumor, which was RAS and BRAF wild type, and immunohistochemical staining revealed a HER2 score of 3+ (HER2-positive). In July 2021, the patient received the mFOLFOX plus panitumumab regimen as first-line treatment and completed four cycles before treatment was discontinued owing to port infection. The chemotherapy regimen was switched to capecitabine, oxaliplatin, and bevacizumab for four cycles, but disease progression was observed. From November 2022, 12 cycles of capecitabine, irinotecan, and bevacizumab were administered; however, disease progression was observed. Trastuzumab and pertuzumab therapy was started as fourth-line treatment (four weekly cycles: trastuzumab 8 mg/kg and pertuzumab 840 mg/body) in August 2023. After the first cycle, on the 29th day before starting the 2nd cycle, oral hemorrhage and petechiae on both lower legs were observed and a blood test revealed severe thrombocytopenia, leading to emergency hospitalization on the same day.

Laboratory tests showed that the platelet count was low (0.1 × 10⁴/µL) and the immature platelet fraction high (18.5%). No anemia or leukopenia was observed, and PT, APTT, and ATIII levels were within the normal ranges. A mild elevation in D-dimer levels was noted at 1.5 μg/dL. Tests for antiplatelet antibodies, Helicobacter pylori antibodies, and anti-HLA antibodies were negative. Platelet-associated IgG levels were elevated at 1,720 ng/10⁷ cells. Drug-induced lymphocyte stimulation tests for trastuzumab and pertuzumab were negative. No other abnormalities were observed during the assessment. Bone marrow examination revealed that the number of megakaryocytes did not markedly increase or decrease. No atypical cells or abnormalities were found in the granulocytes or erythroblasts. These findings indicated enhanced platelet consumption, ruling out myelosuppression, hemophagocytic syndrome, disseminated intravascular coagulation, or thrombotic thrombocytopenic purpura. Abdominal computed tomography revealed no bleeding or splenomegaly (Fig. 1).

The patient received a transfusion of 20 units of platelets on day 1 because of his low platelet count of 0.1 × 10⁴/µL. However, the platelet count on day 2 was only elevated to 0.3 × 10⁴/µL, prompting an additional transfusion of 10 units of platelets. Despite these interventions, the platelet count did not show considerable improvement, and daily platelet transfusions were administered. Because severe drug (anti-HER2 antibody)-induced immune thrombocytopenia (DITP) was suspected, methylprednisolone (500 mg/day) was administered from days 3 to 5, after which the platelet count improved to 5 × 10⁴/μL; therefore, the treatment was switched to oral prednisolone (0.5 mg/kg/day) on day 6. However, the platelet count showed a decreasing trend, indicating a transfusion-dependent state. Steroid pulse therapy (methylprednisolone, 1,000 mg/day) was administered from days 13 to 15. Subsequently, the platelet count increased, and treatment was switched to oral prednisolone (1 mg/kg/day) on day 16. After the steroid dose was tapered, the platelet count decreased to 3 × 10⁴/μL, necessitating further platelet transfusions. The patient’s thrombocytopenia was refractory to steroid pulse therapy, and no spontaneous remission was observed over a month with frequent platelet transfusions. Hence, we considered that the patient presented with a condition similar to immune thrombocytopenic purpura (ITP), and treatment with a thrombopoietin receptor agonist (Revolade^®; eltrombopag olamine tablets 12.5 mg/day) was initiated on day 33. Subsequently, the platelet count increased, and the patient was discharged on day 43 with a platelet count of 24 × 10⁴/μL (Fig. 2). During the treatment course, in addition to subcutaneous bleeding, no serious hemorrhagic complications, such as massive bleeding or intracranial hemorrhage, were observed.

The patient was followed up on an outpatient basis, and eltrombopag olamine (12.5 mg/day) and prednisolone (15 mg/day) were continued after discharge. On day 57, following admission, the platelet count had increased to 5.7 × 10⁴/μL, resulting in the disappearance of oral hemorrhage and petechiae. Considering the potential risk of intestinal obstruction due to primary lesion growth, we performed an ostomy on day 69. The platelet count had increased to 22.4 × 10⁴/μL on day 78, with no subsequent decrease observed.

Herein, we report a case of DITP suspected to be caused by anti-HER2 antibodies. Despite the discontinuation of anti-HER2 treatment and administration of corticosteroids, the patient’s condition did not improve, necessitating 250 units of platelet transfusion over 43 days. Owing to steroid resistance, the patient ultimately required treatment consistent with ITP, where a thrombopoietin receptor agonist was administered, resulting in increased platelet count. The American Society of Hematology 2019 guidelines for immune thrombocytopenia recommend that platelet transfusions in ITP patients are limited to situations involving life-threatening bleeding or invasive surgeries [11]. Although this case did not involve life-threatening bleeding, there was a clear tendency for bleeding, such as continuous oral hemorrhage and petechiae. The prognosis for improvement was uncertain, and an observation period was necessary to assess the response to steroid treatment. Consequently, frequent transfusions were required owing to the ongoing risk of bleeding.

DITP can arise from immunological mechanisms or drug-induced bone marrow suppression. In this case, bone marrow examination showed no increase or a marked decrease in the number of megakaryocytes. Furthermore, an elevated number of young platelets and the need for frequent transfusions suggested a reduced platelet lifespan. These findings indicated that the underlying cause was likely related to an immunological mechanism, rather than pharmacological myelosuppression. The mechanisms of immunologically mediated DITP include (1) drug-dependent antibodies causing structural changes in platelet membrane proteins, exposing new antigens; (2) natural antibodies to these new antigens, leading to rapid thrombocytopenia after administration; and (3) drugs impairing platelet production, as observed with certain antibody preparations, such as interferon and infliximab [12]. In this case, thrombocytopenia was identified 29 days after administration; however, the exact day of onset was unclear. The onset of symptoms, such as petechiae, coincided with the examination date, suggesting that the first mechanism was likely.

In previous cases reporting thrombocytopenia associated with HER2 antibodies, many patients showed improvement after discontinuing the medication or receiving steroid treatment [6‒10]. Miyake et al. [13] reported a case of severe thrombocytopenia caused by trastuzumab. Despite administering 90 units of platelet transfusion and discontinuing trastuzumab, the platelet count did not recover sufficiently. However, after administering steroids, the platelet count started to increase. Moreover, they summarized 9 cases of thrombocytopenia caused by trastuzumab, including their own case, reporting that on average, thrombocytopenia improved within 11 days after discontinuation of the anti-HER2 antibody. In this case, the thrombocytopenia was resolved 106 days after administration. It was refractory to steroid pulse therapy, and the platelet levels did not improve even after a significant observation period following the cessation of anti-HER2 treatment. Hence, we considered that the patient presented with a condition similar to ITP.

Several therapeutic strategies have been considered for the management of ITP refractory to steroid pulse therapy, including (1) eradication of H. pylori, (2) administration of a thrombopoietin receptor agonist, (3) treatment with rituximab (an anti-CD20 monoclonal antibody), and (4) splenectomy [14]. In the present case, the absence of H. pylori antibodies negated the first treatment option. Considering the patient’s age while undergoing palliative chemotherapy, the third and fourth options were unsuitable. Therefore, thrombopoietin receptor agonist therapy was recommended. This intervention improved the patient’s platelet count within a few days.

In previous reports, cases where anti-HER2 treatment was readministered after improvement of thrombocytopenia have been documented; however, thrombocytopenia recurred in all instances [6‒8]. In the current case, trastuzumab and pertuzumab combination therapy was not readministered. This decision was made because of severe and prolonged thrombocytopenia, and a decline in performance status caused by tumor progression.

The number of cases registered in the TRIUMPH and MyPathway trials was small (30 and 57 participants, respectively); therefore, low-prevalence side effects were possibly not observed during the trials. This case was negative for drug-induced lymphocyte stimulation test, and whether trastuzumab or pertuzumab was the cause is unclear; however, severe prolonged thrombocytopenia developed after the initiation of this treatment regimen. Numerous reported cases of severe thrombocytopenia showed improvement after the discontinuation of anti-HER2 therapy, administration of corticosteroids, and frequent platelet transfusions. The patient reported herein was steroid resistant and presented significant treatment challenges. Ultimately, a treatment approach in accordance with ITP led to improvements, making this rare case worth reporting.

To the best of our knowledge, this is the first report of severe thrombocytopenia following the administration of trastuzumab and pertuzumab combination therapy in HER2-positive metastatic rectal cancer. When persistent thrombocytopenia is observed despite treatment discontinuation and administration of corticosteroids, considering treatment in accordance with ITP is important. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000540980).

This study was conducted in accordance with the Declaration of Helsinki of the World Medical Association. Ethical approval in accordance with local and national guidelines was not required because the patient data were reviewed retrospectively. Written informed consent was obtained from the patient for the publication of the details of their medical case and any accompanying images.

The authors have no conflicts of interest to declare.

No research support was obtained for this report.

D.O. wrote the manuscript. T.Y., M.Y., T.K., H.Y., E.F., and H.N. provided critical feedback and reviewed the data. All the authors have read and approved the final version of this manuscript.

The research data supporting this study are not available in a specific repository. For data access, please contact the corresponding author directly. The data that support the findings of this study are not publicly available due to containing information that could compromise the privacy of research participants but are available from the coauthor T.Y. upon reasonable request.