Different Patterns of Platelet Count Fluctuation in Response to Various Anticancer Chemotherapies among Patient with Bladder Cancer

Platelet count is a crucial biomarker in patients with cancer undergoing treatment with anticancer agents to ensure patient safety. Our previous study highlighted gemcitabine-induced thrombocytopenia, followed by thrombocytosis, in patient with bladder cancer [1]. This case underscores the transient increase and dramatic alteration in platelet count, as well as the persistent decrease in platelet count during ongoing anticancer therapy involving gemcitabine. In this case report, we present distinct forms of thrombocytosis triggered by gemcitabine followed by pembrolizumab as part of an anticancer therapy regimen.

A 47-year-old man (weight, 75 kg; height, 169 cm; body surface area: 1.80 m²) experienced urinary retention in March 2021. He underwent placement of a urinary catheter and received tamsulosin 0.2 mg/day, dutasteride 0.5 mg/day, and bethanechol 50 mg/day. Despite these treatments, gross hematuria persisted even as urinary retention improved. Three urine cytology examinations were performed, yielded no evidence of bladder cancer. In July 2021, he was admitted to Showa University Koto-Toyosu Hospital in Japan for further evaluation of hematuria.

Following diagnostic imaging, including a computed tomography scan and magnetic resonance imaging, we diagnosed the patient with invasive urothelial carcinoma (high grade) of the bladder at stage IV (T3N0M1) with lung metastasis, as confirmed by transurethral resection of bladder tumor and by the results of subsequent pathology. The cancer mass extended to cover both ureteral orifices, but there was no hydronephrosis and no renal dysfunction. To initiate prompt action, we initiated Gemcitabine and Cisplatin (GC) therapy (gemcitabine: 1,000 mg/m², cisplatin: 70 mg/m², every 4 weeks). Following the first course, his platelet count increased from 275 × 10⁹/L to 609 × 10⁹/L. In the second course, his platelet count exhibited substantial fluctuations, ranging from 187 × 10⁹/L to 787 × 10⁹/L, in response to the GC therapy (Fig. 1). However, after the second course of GC therapy, we observed the progression of the cancer mass and node metastases. On day 65 after the initiation of chemotherapy, the patient was switched to sole treatment with pembrolizumab (200 mg/body every 3 weeks). The patient’s platelet count remained high after pembrolizumab treatment was initiated. At the 17th course of pembrolizumab therapy, his platelet count increased to 628 × 10⁹/L, at the 21st course, to 724 × 10⁹/L. Until at the 28th course of pembrolizumab therapy, his average platelet counts after starting pembrolizumab was 560 × 10⁹/L (shown in Fig. 1). His cancer treatment efficacy assessment showed progressive disease after the 23rd course. The patient discontinued the pembrolizumab therapy because of cancer progression.

Herein, we report the significant and distinct fluctuations in platelet counts observed during anticancer chemotherapy. Previously, we reported gemcitabine-induced thrombocytopenia, followed by thrombocytosis, following GC therapy [1]. Notably, platelet counts increase as a rebound during recovery after thrombocytopenia, followed by a decrease accompanied by the accumulation of chemotherapy-induced toxicities.

In the present case, the patient received GC therapy, which is associated with fluctuations in platelet count. The platelet count fluctuations aligned logically with the timing of GC therapy, indicating a possible association. Subsequently, an increase in platelet count was observed following pembrolizumab monotherapy. To our knowledge, there are no typical case reports of pembrolizumab-induced thrombocytosis. Therefore, we present a case of thrombocytosis due to a response to cancer and a potential reaction to pembrolizumab.

Generally, thrombocytosis is prevalent in patients with cancer, and increased platelet counts have been observed in 10–57% of patients with cancer. Tumor-derived factors, such as thrombopoietin-like activity and growth factors, platelet-derived microparticles, factors secreted from bone marrow endothelial cells, and growth factors released by megakaryocytes (acting through an autocrine loop), have been hypothesized as the mechanisms through which thrombocytosis occurs [2]. In this case, the increase in platelet count was associated with cancer progression.

Pembrolizumab is effective in patients with essential thrombocythemia and is thought to have a platelet-lowering effect [3]. Therefore, if pembrolizumab has a thrombocytopenic effect like bone marrow suppression, similar to that of GC, reactive thrombocytosis may occur as a rebound during the recovery period after myelosuppression. However, immune checkpoint inhibitors, such as pembrolizumab, generally exhibit distinct adverse reaction patterns compared with conventional cytotoxic chemotherapy agents. Thus, the immune status of patients treated with immune checkpoint inhibitors is affected by an excessive autoimmune reaction that activates the immune response of normal cells. Immune-related adverse events associated with platelet count include immune thrombocytopenic purpura, in which antibodies are produced and platelets are destroyed.

In such cases, platelet counts are decreased, in contrast to thrombocytosis. In addition, we considered iron-deficiency anemia a factor affecting an increase in platelet count. However, the platelet count trend was not parallel, although the anemia improved with iron administration, suggesting that thrombocytosis during pembrolizumab administration was due to cancer progression.

In conclusion, we present a unique platelet count pattern in patients with bladder cancer who underwent GC therapy and pembrolizumab monotherapy, in conjunction with cancer progression. Previous studies have demonstrated a correlation between elevated platelet counts in patient with cancer and lower survival rates [4‒7]. Conversely, information for the effects of increasing platelet counts coinciding with the introduction of pembrolizumab requires further investigations. These temporal dynamics are inherent to patients with cancer. This case underscores the need for a diverse perspective on platelet behavior in clinical settings. 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/10.1159/000541679).

We are grateful to Dr. Yuka Kashiwabara for helpful discussions.

Ethical approval for this study protocol was determined not to be necessary by the Showa University Research Ethics Review Committee. We obtained written informed consent from the patient for publication of this report.

The Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, received funds from Ono for a contract research project in accordance with a collaborative research agreement. As potential conflicts of interest, Hospital Pharmaceutics received research grants from Daiichi Sankyo, Mochida, Shionogi, Ono, Taiho, Nippon-Kayaku, and Bayer. TN received an honorarium fee for presentations from Sanofi. KM received an honorarium from AbbVie, Eisai, Sawai, and Nippon-Kayaku for his presentation. The other authors declare no conflicts of interest associated with this manuscript.

The funder had no role. This study was not supported by any sponsor or funder.

A.W.: study conception and manuscript drafting; data collection. Y.O.: supervision of the conduct of this study; M.S. and T.N.: data collection; M.M.: supervision of the conduct of this study. K.M.: study conception and manuscript drafting.

All information in this case is included in this published article. Further inquiries can be directed to the corresponding author.