Cabazitaxel Induced Thrombotic Microangiopathy in a Patient with Prostate Cancer

Cancer-associated thrombotic microangiopathy (TMA) refers to a group of disorders characterized by microangiopathic haemolytic anemia, thrombocytopenia, and ischemic organ damage. TMA manifestations can be induced by cancer or by chemotherapy. We report the case of a 64-year-old man with metastatic prostate cancer who experienced a Cabazitaxel-induced TMA manifestation. TMA responds to conservative therapy, dialysis without plasmaphoresis, with progressive recovered renal function.


Introduction
rombotic microangiopathy (TMA) is a clinical association of thrombocytopenia, microangiopathic haemolytic anaemia and organ dysfunction related to microvascular thrombosis [1,2]. TMA is associated with significant mortality and morbidity including acute renal failure [3], a common feature caused by high susceptibility of renal vessels to endothelial damage [3]. In the course of cancer, TMA can be secondary to malignancy or to direct chemotherapy toxicity [4]. Al-Nouri et al. have established a list of anti-cancer agents associated with TMA with evidence of definitive causality, including a taxane drug, Docetaxel [5]. We report a case of TMA induced by Cabazitaxel, a newly integrated taxane drug in the treatment of advanced prostate cancer.

Case Report
A 64-year-old male, is treated since 2005 for metastatic (spine and sub-diaphragmatic lymph nodes) and hormone-resistant prostate cancer. e patient was previously treated with Docetaxel and currently with Cabazitaxel every 3 weeks since 13 th june 2018. e level of Prostate-specific antigen (PSA) in March 2019 was 25.00 ng/mL for free PSA, and 898 ng/mL for total PSA. e patient who had previously received 18 cycles of Cabazitaxel at 25 mg/m 2 (50 mg) and blood samples on 28 th January 2019 showed a thrombocytopenia at 82 G/L and an elevated creatinine up to 328 mol/L with spontaneous normalization of creatinine and platelet count 7 weeks later a er its discontinuation (Hb 9 g/dL, platelets 439G/L, creatinine 77 μmol/L). Another injection of Cabazitaxel at lower dose (40 mg) was given on 21 th march 2019, with appearance 24 hours later of oliguria and asthenia. e file chart doesn't mention acute kidney injury (AKI) at the moment of reinjection.
e clinical examination was unremarkable except for moderate hypertension at 150/90 mmHg. Blood samples on 26 th march showed an anemia with haemoglobin at 5 g/dL, thrombocytopenia at 17 G/L, schizocytes at more than 15% on blood smear, LDH at 4597 IU/L, haptoglobin <0.1 g/L, and normal INR at 1.14. e Coombs test was negative and there was renal insufficiency with creatinine at 1022 mol/L, urea 62 mmol/L. e profile of this renal failure was parenchymal with urinary sodium-potassium ratio >1. An ultrasound ruled out a post-renal AKI. e serum potassium was 5.7 mmol/L. Etiological investigations of this thrombotic microangiopathy showed 75% ADAMST13 activity, C4 at 0.45 g/L (0.10-0.40), C3 at 1.60 g/L (0.9-1.8), CH50 141% (70-130), 137% of factor H (65-140) and 180% factor I (60-130). e anti-factor H antibody was negative. e TMA aetiology looks as if associated with Cabazitaxel and chronologically compatible. Simultaneously to drug interruption, the patient had six dialysis sessions without plasmaphoresis. e evolution was characterized by progressive disappearance of biological signs of haemolysis and improvement of renal function (Figure 1). On May 3, 2019, haemoglobin level was 8.6 g/dL without schizocytes, platelets count at 209 G/L, creatinine at 137 mol/L, urea at 9 mmol/L, LDH at 661 IU/L and haptoglobin at 2.5 g/L. In this context, renal biopsy was not performed. e patient survived to the AKI KDIGO 3 episode with creatinine at 95 mol/L (eGFR 73 ml/min/1.73 m 2 ) at 6 month.

Discussion
In a cancer patient, it is o en difficult to distinguish chemotherapy-induced TMA from TMA caused by cancer [6]. Tumor-related TMA occurs in poorly controlled carcinomas, whereas chemotherapy-associated TMA is more common in disease remission or in minimal tumoral burden [7]. TMA induced by chemotherapy occurs by two main mechanisms: an immune-mediated reaction involving the development of drug-dependent antibodies or a direct endothelial damage [5,6]. Direct toxicity is dose dependent in case of acute toxicity [5,8]. e main anticancer agents associated with TMA are bleomycin, and mitomycin C [9,10,11]. In a systematic review, AL-Nouri et al. reported 22 drugs that had evidences for association with TMA, including Docetaxel, a taxane class molecule [5]. ey defined the typical clinical manifestations of an immune reaction by the onset of symptoms within 21 days for a drug administered daily or in the hours following exposure (within 24 hours) for a drug taken intermittently [5]. Direct toxicity was defined either by the acute onset of symptoms a er exposure to the offending drug or by the progressive development of toxicity in the form of acute renal failure [5]. Cabazitaxel is used for prostatic cancer [12] in combination with prednisolone. Renal insufficiency following treatment with Cabazitaxel is very rare, but cases of nephrotoxicity in patients have been reported [13]. Most of the cases of renal insufficiency described are associated with sepsis, dehydration or obstructive uropathy, without evidence for a direct nephrotoxicity [13]. Tumma et al. reported a case of TMA, 48 hours a er the first dose of Cabazitaxel, with a fatal renal failure [7]. In our case, the occurrence a er 18 cycles of Cabazitaxel and the regression of TMA a er withdrawal of the treatment suggests a cumulative dose nephrotoxicity of this new treatment. e taxanes have significant antiangiogenic properties in vitro and in vivo [14]. ey inhibits endothelial function and angiogenesis and shows a dose-dependent vascular toxicity [14]. In this context, taxane can impair renal vasculature and cause TMA. Our patient had already received 18 injections of Cabazitaxel with a first episode suggesting TMA in January 2019 (platelets at 82 G/L and creatinine at 328 mol/L with normalization in February, at distance from injections). e current episode was following an injection on march 21, 2019 (haemoglobin 9 g/dL, platelet 439 G/L, creatinine 77 mol/L before the injection).

Conclusion
We report a case of thrombotic microangiopathy due to Cabazitaxel, a toxoid used in the treatment of advanced prostate cancer.

Consent
Informed consent was obtained from the patient.

Conflicts of Interest
e authors declare that they have no conflicts of interest.