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Thrombotic microangiopathies and antineoplastic agents
Ne´phrologie & The´rapeutique 13S (2017) S109–S113
Available online at
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Oncology
Thrombotic microangiopathies and antineoplastic agents Steven Grange´ a,b, Paul Coppo b,c,d,e,*, Centre de re´fe´rence des microangiopathies thrombotiques (CNR-MAT)b,1 a
Service de re´animation, CHU Charles-Nicolle, 1, rue de Germont, 76000 Rouen, France Centre de re´fe´rence des microangiopathies thrombotiques (CNR-MAT), AP–HP, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France c Service d’he´matologie, hoˆpital Saint-Antoine, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France d Universite´ Pierre-et-Marie-Curie, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France e Inserm 1170, institut Gustave-Roussy, 114, rue E´douard-Vaillant, 94800 Villejuif, France b
A R T I C L E I N F O
A B S T R A C T
Keywords: Thrombotic microangiopathy Antineoplastic drug Vascular endothelial growth factor Gemcitabine Complement system Eculizumab
Thrombotic microangiopathy is a well-described complication of cancer treatment. Its incidence has increased these last decades, as a result of a better awareness of this complication in cancer patients in one hand, but also of a larger array of therapeutic compounds including anti-vascular endothelium growth factor (VEGF) drugs. It is therefore mandatory to recognize these conditions since they have a significant impact in thrombotic microangiopathies management and prognosis. Practitioners should be aware of the more classical antineoplastic agents associated with thrombotic microangiopathies, the mechanisms by which they induce them, and the resulting management and prognosis. Since malignancy itself can induce thrombotic microangiopathies, it is also mandatory to know how to distinguish rapidly those caused by antineoplastic agents from those associated with cancer, for an adapted management. Thrombotic microangiopathies associated with chemotherapy remain of dismal prognosis. A better understanding of pathophysiology in these forms of thrombotic microangiopathies, in association with a more empirical approach through the use of new therapeutic agents that can also help in the understanding on new mechanisms a posteriori, should improve their prognosis. The preliminary encouraging results reported with complement blockers in this field could represent a convincing example.
C 2017 Socie ´ te´ francophone de ne´phrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction The diseases collectively termed the thrombotic microangiopathies are various life-threatening disorders characterized by microangiopathic hemolytic anemia, peripheral thrombocytopenia, and organ failure of variable severity caused by microvascular occlusion. In thrombotic thrombocytopenic purpura, the systemic microvascular aggregation of platelets causes ischemia in the brain, kidneys, heart, and other organs. In hemolytic-uremic syndrome, fibrin-rich thrombi predominantly occlude the renal circulation. A thrombotic microangiopathy can also be typically observed in patients with the hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome, disseminated cancer, or a
* Corresponding author. Service d’he´matologie, hoˆpital Saint-Antoine, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France. E-mail address: [email protected] (P. Coppo). 1 Members of the CNR-MAT are listed in Appendix A.
human immunodeficiency virus infection and within the context of chemotherapy or transplantation. Thrombotic microangiopathy is a well-described complication of cancer treatment. Its incidence has increased these last decades, as a result of a better awareness of this complication in cancer patients in one hand, but also of a larger array of therapeutic compounds including anti-vascular endothelial growth factor (VEGF) drugs. It can sometimes be difficult to establish a causal relationship between a specific chemotherapeutic agent and thrombotic microangiopathy given that malignancy itself can induce thrombotic microangiopathy. Moreover, many patients are treated with multiple chemotherapeutic agents, which can lead to difficulty indicting a particular drug. Practitioners should be aware of the more classical antineoplastic agents associated with thrombotic microangiopathy, the mechanisms by which they induce it, and the resulting management and prognosis. It is also mandatory to know how to distinguish rapidly thrombotic microangiopathies caused by antineoplastic agents from those associated with cancer for an adapted management. Recognition of
http://dx.doi.org/10.1016/j.nephro.2017.01.016 C 2017 Socie ´ te´ francophone de ne´phrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved. 1769-7255/
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an antineoplastic drug-etiology in a patient with thrombotic microangiopathy is also critical to avoid re-exposure and recurrent illness. This review addresses these goals. 2. Mitomycin C and gemcitabine-associated thrombotic microangiopathy The most classical antineoplastic agents associated with thrombotic microangiopathies include mitomycin C and gemcitabine (Table 1). Pathophysiology still remains unclear, and may involve a direct damage of renal endothelial cells resulting in the formation of platelet aggregates. Mitomycin C also causes decreased prostacyclin production in human endothelial cell cultures, which may participate to platelet aggregation. Plasma levels of thrombomodulin, tissue plasminogen activator and plasminogen activator inhibitor-1 are elevated in patients with mitomycin C-induced thrombotic microangiopathy that are similar to those observed in patients with idiopathic thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome [1]. The onset of outcome is delayed, and ranges from 6 to 12 months after treatment initiation. Thrombotic microangiopathy results from a dose-dependent toxicity and is cumulative. Hematologic manifestations are usually present. Hypertension, acute renal failure, pulmonary edema and acute respiratory distress syndrome are common. Microthrombi involve both glomerular capillaries and arterioles. Clinical features are typically permanent and irreversible, and respond poorly to therapeutic plasma exchange. 2.1. Mitomycin C-associated thrombotic microangiopathy Mitomycin C is an antitumor alkylating agent isolated from Streptomyces caespitosus that has been in use since 1958. It is an active agent in salvage combination chemotherapy regimens for adenocarcinoma of the breast, lung, stomach, pancreas, rectum, and head and neck. It is one of the primary agents for anal carcinoma. Thrombotic microangiopathy usually occurs 4 to 8 weeks after the last dose of mitomycin C, with most cases occurring after 6 to 12 months of chemotherapy. The threshold total cumulative dose of 40 to 60 mg is associated with the development of thrombotic microangiopathy. In the largest registry of mitomycin C-associated thrombotic microangiopathy, 83 (99%) of 84 patients received a cumulative dose of 40 mg or more, and all but nine received a cumulative dose greater than 60 mg. Pulmonary edema, generally noncardiogenic, developed in 65% of patients, often after blood product transfusion. In a series of 142 patients with gastrointestinal cancer treated with combination chemotherapy including mitomycin C, ten patients developed renal failure, and five of the ten also developed microangiopathic hemolytic anemia. The ten patients received a total cumulative Table 1 Antineoplastic agents associated with thrombotic microangiopathies. Chemotherapy
Anti-VEGF therapy
Other targeted therapies
Mitomycin C Gemcitabine Platinum salts Pegylated liposomal doxorubicin
Ligands Bevacizumab Afilbercept
Other tyrosine kinase inhibitors Imatinib mesylate Dasatinib
Tyrosine kinase inhibitors Sunitinib Sorafenib Cediranib Brivanib Pazopranib Lucitanib
Immunotoxins Targeting typically CD22 or IL-2 Other immunotherapies Apolizumab
VEGF: vascular endothelial growth factor; IL-2: interleukin-2.
dose of 75 to 180 mg of mitomycin C, with a correlation between the prevalence of renal toxicity and the total cumulative dose. Dyspnea, caused typically by pulmonary edema, is the most common presenting symptom of mitomycin C-associated thrombotic microangiopathy; it can progress to the adult respiratory distress syndrome. Progressive renal failure is present in almost all patients. Neurologic abnormalities are less common. Treatment consists mainly in the interruption of mitomycin C immediately with diagnosis of thrombotic microangiopathy. As opposed to thrombotic thrombocytopenic purpura, response to therapeutic plasma exchange is typically poor, although some reports suggested a role for staphylococcal protein A immunopheresis. Acute mortality is elevated, approaching 75% at 4 months [2]. 2.2. Gemcitabine-associated thrombotic microangiopathy As for mitomycin C, gemcitabine-associated thrombotic microangiopathy is typically chronic with cumulative dose dependence. Gemcitabine was approved by the US Food and Drug Administration (FDA) in 1996 for the treatment of metastatic pancreatic cancers and is currently used for the treatment of malignancies such as lymphomas, lung, bladder and breast cancers. The incidence of gemcitabine-associated thrombotic microangiopathy was initially estimated to be of 0.015%. However, more recent works reported incidences as high as 0.4% [3,4], which could result from an increasing recognition of milder forms due to a better awareness of practitioners about this complication. Given the possible clinically silent presentation of gemcitabine-associated thrombotic microangiopathy, its clinical features should be sought before each new cycle of treatment. From a series of 56 cases, the mean duration between the initiation of gemcitabine and thrombotic microangiopathy occurrence was reported to be 7.5 months, although the range was wide (0.5 to 19 months). The median cumulative dose of gemcitabine was 22.5 g 14 g (range 2–70 g). A mild proteinuria and a microscopic hematuria could be observed in two-third of cases. A de novo arterial hypertension or the worsening of a preexisting arterial hypertension was observed in 75% of patients [3]. Patients were managed with a plasma-based therapy and/or steroids although this approach has never proved its efficacy. Although patients may improve hematological findings, renal prognosis is usually poor and patients maintain chronic renal failure in 70% of cases. Median survival was 16.5 months [3]. Physiopathology of gemcitabine-induced thrombotic microangiopathy is still poorly understood. Gemcitabine was suggested to have direct endothelial toxicity with a concomitant activation of the coagulation cascade. Histological data obtained from renal biopsies suggest a possible role of complement activation: a thickening of capillary walls, fibrin thrombi, necrotic endothelial cells, and granular deposits of immunoglobulins and C3 in the wall of small arteries and arterioles, and in glomeruli [5]. The hypothesis that complement could be involved in gemcitabineinduced thrombotic microangiopathy physiopathology and the unmet need with current treatments led to propose eculizumab to patients with such condition. Eculizumab is a monoclonal antibody targeting the C5 fraction of the terminal complement pathway and provided remarkable benefit in atypical hemolytic-uremic syndrome. To date six patients were treated with eculizumab for gemcitabine-induced-thrombotic microangiopathy that did not improve despite chemotherapy discontinuation [5–7]. Eculizumab was started 3 to 5 weeks after thrombotic microangiopathy diagnosis, with a median total dose of 6 g (range 3.6–9.6 g). Eculizumab was associated with hematological improvement and afforded a partial renal response. Four patients still had chronic renal failure with an estimated glomerular filtration rate (GFR) below 60 mL/min/1.73 m2 at last follow-up (median of 4 months
S. Grange´, P. Coppo / Ne´phrologie & The´rapeutique 13S (2017) S109–S113
[range 3–5 months]). Our group has performed an observational, retrospective, multicentric study from ten patients with gemcitabine-induced thrombotic microangiopathy treated with eculizumab in France between 2011 and 2016. Complete hematological remission was achieved in most patients and blood transfusion significantly decreased after only one injection of eculizumab. Renal function also improved. These preliminary results open promising perspectives on the role of complement cascade in the pathophysiology of gemcitabine-associated thrombotic microangiopathy, and deserve further studies to confirm the efficacy of complement blockers on this indication. Other strategies including rituximab and recombinant thrombomoduline were reported anecdotally and their efficacy remains uncertain. 3. Thrombotic microangiopathy associated with anti-VEGF agents Among antineoplastic drugs associated with thrombotic microangiopathy, those that inhibit VEGF pathway are the most widely studied (Table 1). Inhibition of VEGF, either by antibodymediated binding of the ligand (bevacizumab, aflibercept) or small-molecule inhibition of the VEGF receptor (tyrosine kinase inhibitors, sunitinib, sorafenib, pazopanib, axitinib and vandetanib) has demonstrated clinically relevant benefits in solid tumors. All these agents have been linked to the development of a syndrome characterized by new-onset hypertension (or exacerbation of a preexisting hypertension), proteinuria, severe hypertension, and/or acute kidney injury with histopathologic evidence of kidney thrombotic microangiopathy, suggesting a potential classwide effect [8]. These thrombotic microangiopathy occur with a variable range of time after anti-VEGF initiation (from 1 day after treatment initiation to more than 2 years), they are not doserelated, and there is a high likelihood of recovery after interruption. Hematologic manifestations are only observed in half of patients, whereas hypertension and proteinuria are typical features. Microthrombi involve exclusively glomerular capillaries and renal failure occurs rarely. Prognosis is good after treatment cessation, effective blood pressure control with renin angiotensin inhibitors and other symptomatic measures including hemodialysis in the more severe cases. Reintroducing the drug at lower dose levels may be a strategy to avoid recurrent thrombotic microangiopathy, while allowing for continued treatment. On the opposite, combination therapy of bevacizumab and sunitinib results in a more severe form of thrombotic microangiopathy, with the development of extrarenal complications [9]. The efficacy of plasma exchange with steroids is unclear in this form of thrombotic microangiopathy, but these procedures are usually proposed in patients with a severe presentation and/or lack of improvement following drug withdrawal. In a large series of patients with biopsy-proven kidney damage during anti-VEGF therapy, intraglomerular thrombotic microangiopathy occurred preferentially with VEGF-ligand exposure, whereas tyrosine kinase inhibitors provided more often podocytopathies such as minimal change nephropathy/collapsing focal glomerulosclerosis. Additionally, 31% of patients with thrombotic microangiopathy had proteinuria with protein excretion up to 1 g/24 h. Half the thrombotic microangiopathy cases were kidney limited without microangiopathic hemolytic anemia or thrombocytopenia. Pathologic thrombotic microangiopathy features limited to the glomerular structures differentiate anti-VEGF-induced thrombotic microangiopathy from other causes, including those secondary to gemcitabine. Kidney function could be preserved with a combination of blood pressure control and withdrawal of the anti-VEGF drug and hypertension and proteinuria could both resolve with these measures [9]. Another group reported the association of anti-VEGF therapies with a ‘‘pre-eclampsia-like
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syndrome’’ from 22 patients. Almost all patients had hypertension. There were mild or no biological signs of thrombotic microangiopathy and the mean proteinuria in the 22 patients was 2.97 2.0 g/day and the mean serum creatinine 134 117 mmol/L. Renal biopsies were performed in all patients and showed microangiopathy lesions of variable importance in all glomeruli, sometimes associated with acute tubular necrosis (18% of cases). In all biopsies was observed a mild to strong expression of proteins involved in the integrity and the physiology of the glomerular basement membrane: nephrin, podocin and synaptopodin [10]. In a pathophysiological point of view, Eremina et al. described six biopsy-documented cases of thrombotic microangiopathy resembling hemolytic-uremic syndrome following bevacizumab administration [11]. All of the patients described developed proteinuria or increased serum creatinine following the initiation of bevacizumab, ultimately leading to renal biopsy. Following discontinuation of bevacizumab, improvement in renal function was noted, suggesting at least partial reversibility. In this work, the authors provided a detailed proposal for a mechanism of VEGFinduced thrombotic microangiopathy from an elegant animal model in which the renal podocytes were electively deprived of the VEGF gene. In this model, the knockout mice developed features consistent with bevacizumab-associated thrombotic microangiopathy. From these results, the authors proposed that inhibition of VEGF in the glomerular microvasculature prevents the formation and maintenance of healthy, fenestrated endothelium. Without active VEGF signaling, the endothelium is compromised, along with the filtration barrier of the glomerulus (Fig. 1). These results underline the importance of regular cardiovascular and renal checking during all anti-VEGF therapies for cancer for early detection of renal dysfunction, which implies a close collaboration between oncologists and nephrologists. 4. Thrombotic microangiopathy associated with proteasome inhibitors Proteasome inhibitors represent a therapeutic class of drugs developed in multiple myeloma for more than 10 years that are now used as a standard of care in this disease. Bortezomib (Velcade1) was the first agent of this class. More recently, the new proteasome inhibitor carfilzomib (Kyprolis1) and an oral form of bortezomib (Ixazomib1) also enriched the therapeutic arsenal of multiple myeloma. As these drugs are increasingly prescribed, thrombotic microangiopathies were reported in association with carfilzomib and bortezomib. Thrombotic microangiopathy typically occurs 3 weeks following medication initiation (range 5 days– 17 months). Patients typically present with microangiopathic hemolytic anemia, thrombocytopenia and renal failure. ADAMTS13 activity is normal or mildly decreased. The outcome is usually favorable with medication withdrawal and symptomatic measures. Rarely, laboratory values remain stable with poor improvement. Paradoxically, bortezomib was also recently reported efficient in refractory forms of acquired thrombotic thrombocytopenic purpura [12]. 5. Other antineoplastic agents Features reminiscent of thrombotic microangiopathy have been reported in patients treated with oxaliplatin [9]; however, others suggested that anemia and thrombocytopenia could result from oxaliplatin-dependent antibodies against erythrocytes and platelets [13]. Therefore, the clear role of oxaliplatin in the occurrence of thrombotic microangiopathy remains uncertain. On the other hand, cisplatin could be associated with clear features of thrombotic microangiopathy suggestive of hemolytic-uremic syndrome [9].
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S. Grange´, P. Coppo / Ne´phrologie & The´rapeutique 13S (2017) S109–S113 Table 2 Typical distinctive features between cancer-associated or chemotherapy-associated thrombotic microangiopathies.
Disseminated cancer Renal involvement Disseminated intravascular coagulopathy Circulating erythroblasts Clinical presentation
Treatment
Cancer-associated thrombotic microangiopathy
Chemotherapy-associated thrombotic microangiopathy
Yes Mild/absent Present
No Mild/severe Absent
Present Thrombotic thrombocytopenic purpura-like disease Chemotherapy
Absent Hemolytic-uremic syndrome-like disease Stop chemotherapy Supportive care Specific treatments
90% of patients with cancer-associated thrombotic microangiopathy have metastatic disease, whereas patients with antineoplastic drug-associated thrombotic microangiopathy have little or no detectable malignancy. Kidney involvement is uncommon in cancer-associated thrombotic microangiopathy, whereas chemotherapy-associated thrombotic microangiopathy is a more localized kidney disease and typically mimics hemolytic-uremic syndrome. Patients with cancer-associated thrombotic microangiopathy typically present with disseminated intravascular coagulopathy in up to 30% of cases and circulating erythroblasts are observed in most cases. ADAMTS13 activity is not discriminant since it is detectable in a majority of cases in both conditions [15] (Table 2). 7. Conclusion – future directions
Fig. 1. Role of VEGF/VEGFR pathway in vascular relaxation and involvement of VEGF/ VEGFR blockers in thrombotic microangiopathy pathophysiology. MoAb: monoclonal antibody; VEGF: vascular-endothelium growth factor; VEGF-R: VEGFreceptor; ITK: inhibitor of tyrosine kinase; HELLP: hemolysis, elevated liver enzymes, low platelet count; PLC: phospholipase C; mTOR: major target of rapamycin; COX: cyclo-oxygenase; NO: nitric oxide; eNOS: endothelial NO synthase; PGI2: prostaglandin-I2; GC: guanyl cyclase; GMP: guanosine monophosphate.
Other antineoplastic agents and targeted therapies have been associated with thrombotic microangiopathy, although more anecdotally: tyrosine kinase inhibitors (imatinib mesylate, dasatinib), immunotoxins (targeting typically CD22 or interleukin-2), and apolizumab (humanized monoclonal antibody targeting 1D10, an antigen on the b chain of HLA-DR) [9,14]. The drug pegylated liposomal doxorubicin is commonly used to treat recurrent ovarian cancer. A thrombotic microangiopathy was reported in association with this drug in patients who received high cumulative doses (880–1445 mg/m2) of pegylated liposomal doxorubicin after several years of therapy. Renal biopsy-proven thrombotic microangiopathy consisted in increased serum creatinine levels, hypertension, and non-nephrotic range proteinuria, which improved partially upon drug withdrawal. Notably, no patient had thrombocytopenia or hemolytic anemia [9]. 6. How to distinguish antineoplastic drug-associated or cancer-associated thrombotic microangiopathy? The distinction between cancer-associated or antineoplastic drug-associated thrombotic microangiopathy is mandatory for an appropriate management. This distinction may be challenging in some cases. However, both conditions have specific features. Up to
Thrombotic microangiopathy is a potentially severe complication of antineoplastic drugs that should be considered in any patient with cancer therapy who presents with microangiopathic hemolytic anemia, thrombocytopenia, neurologic changes, proteinuria, hypertension or renal failure. Clinicians need to differentiate chemotherapy-associated thrombotic microangiopathy from a cancer-induced thrombotic microangiopathy for an appropriate management. Treatment of chemotherapy-associated thrombotic microangiopathy still remains a challenge and prognosis is usually dismal. A better understanding of pathophysiology in these forms of thrombotic microangiopathy, in association with a more empirical approach through the use of new therapeutic agents that can also help in the understanding on new mechanisms a posteriori, should improve their prognosis. The preliminary encouraging results reported with complement blockers in this field could represent a convincing example. Disclosure of interest PC: member of the Clinical Advisory Board for Alexion, Ablynx and Octapharma; financings from Roche Pharma. The other authors have not supplied their declaration of competing interest. Acknowledgements We thank S. Thouzeau, S. Savigny, S. Capdenat (laboratoire d’he´matologie, hoˆpital Lariboisie`re, Paris) and S. Malot (centre de re´fe´rence des microangiopathies thrombotiques, hoˆpital SaintAntoine, AP–HP, Paris) for technical assistance. Work of the CNRMAT are also supported by the national plan for rare diseases of the French ministry of health (Direction ge´ne´rale de l’offre de soin [DGOS]).
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Appendix A. The members of the Reference Center for Thrombotic Microangiopathies (CNR-MAT) are: E´lie Azoulay (service de re´animation me´dicale, hoˆpital Saint-Louis, Paris), Virginie Barbay (laboratoire d’he´matologie, CHU Charles-Nicolle, Rouen), Guy Bonmarchand (service de re´animation, CHU Charles-Nicolle, Rouen), Dominique Bordessoule (service d’he´matologie, hoˆpital Dupuytren, Limoges), Christophe Charasse (service de ne´phrologie, centre hospitalier de Saint-Brieuc), Dominique Chauveau (de´partement de ne´phrologie et transplantation d’organes, CHU Rangueil, Toulouse), Gabriel Choukroun (service de ne´phrologie, hoˆpital Sud, Amiens), JeanPhilippe Coindre (service de ne´phrologie, CH Le Mans), Paul Coppo (service d’he´matologie, hoˆpital Saint-Antoine, Paris), E´lise Corre (service d’he´matologie, hoˆpital Saint-Antoine, Paris), Yahsou Delmas (service de ne´phrologie, hoˆpital Pellegrin, Bordeaux), Georges Descheˆnes (service de ne´phrologie pe´diatrique, hoˆpital Robert-Debre´, Paris), Alain Devidas (service d’he´matologie, hoˆpital Sud-Francilien, Corbeil-Essonnes), Olivier Fain (service de me´decine interne, hoˆpital Saint-Antoine, Paris), Ve´ronique Fre´meauxBacchi (laboratoire d’immunologie, hoˆpital europe´en GeorgesPompidou, Paris), Lionel Galicier (service d’immunopathologie, hoˆpital Saint-Louis, Paris), Steven Grange´ (service de re´animation, CHU Charles-Nicolle, Rouen), Bertrand Guidet (service de re´animation me´dicale, hoˆpital Saint-Antoine, Paris), Jean-Michel Halimi (service de ne´phrologie pe´diatrique, hoˆpital Bretonneau, Tours), Mohamed Hamidou (service de me´decine interne, Hoˆtel-Dieu, Nantes), Raoul Herbrecht (service d’oncologie et d’he´matologie, hoˆpital de Hautepierre, Strasbourg), Fre´de´ric Jacobs (service de re´animation me´dicale, hoˆpital Antoine-Be´cle`re, Clamart), Be´range`re Joly (service d’he´matologie biologique, hoˆpital Lariboisie`re, Paris), Tarik Kanouni (unite´ d’he´maphre`se, service d’he´matologie, CHU de Montpellier), Alexandre Lautrette (service de ne´phrologie pe´diatrique B, hoˆpital Hoˆtel-Dieu, Clermont-Ferrand), Ve´ronique Le Guern (unite´ d’he´maphe´re`se, service de me´decine interne, hoˆpital Cochin, Paris), Chantal Loirat (service de ne´phrologie pe´diatrique, hoˆpital Robert-Debre´, Paris), Jean-Paul Mira (service de re´animation me´dicale, hoˆpital Cochin), Bruno Moulin (service de ne´phrologie, hoˆpital Civil, Strasbourg), Christiane Mousson (service de ne´phrologie, CHU de Dijon), Mario Ojeda Uribe (service d’he´matologie, hoˆpital E´mile-Muller, Mulhouse), Abdelkader Ouchenir (service de re´animation, hoˆpital Louis-Pasteur, Le Coudray), Nathalie Parquet (unite´ de clinique transfusionnelle, hoˆpital Cochin, Paris), Julie Peltier (urgences ne´phrologiques et transplantation re´nale, hoˆpital Tenon, Paris), Pierre Perez (service de re´animation polyvalente, CHU de Nancy), Pascale Poullin (service d’he´maphe´re`se et d’autotransfusion, hoˆpital la Conception, Marseille), Claire Pouteil-Noble (service de ne´phrologie, CHU Lyon-Sud, Lyon), Claire Presne (service de ne´phrologie, hoˆpital Nord, Amiens), Franc¸ois Provoˆt (service de ne´phrologie, hoˆpital Albert-Calmette, Lille), Jean-Antoine Ribeil (service de the´rapie
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cellulaire, hoˆpital Necker-Enfants Malades, Paris), E´ric Rondeau (urgences ne´phrologiques et transplantation re´nale, hoˆpital Tenon, Paris), Samir Saheb (unite´ d’he´maphe´re`se, hoˆpital la Pitie´Salpeˆtrie`re, Paris), Benoıˆt Schlemmer (service de re´animation me´dicale, hoˆpital Saint-Louis, Paris), Ame´lie Seguin (service de re´animation me´dicale, CHU de Caen), Alain Ste´panian (laboratoire d’he´matologie, hoˆpital Lariboisie`re, Paris), Jean-Paul Vernant (service d’he´matologie, hoˆpital la Pitie´-Salpeˆtrie`re, Paris), Agne`s Veyradier (service d’he´matologie biologique, hoˆpital Lariboisie`re, Paris), Ce´cile Vigneau (service de ne´phrologie, hoˆpital Pontchaillou, Rennes), Alain Wynckel (service de ne´phrologie, hoˆpital Maison-Blanche, Reims), Patricia Zunic (service d’he´matologie, groupe hospitalier Sud-Re´union, la Re´union). References [1] Medina PJ, Sipols JM, George JN. Drug-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Curr Opin Hematol 2001;8: 286–93. [2] Lesesne JB, Rothschild N, Erickson B, Korec S, Sisk R, Keller J, et al. Cancerassociated hemolytic-uremic syndrome: analysis of 85 cases from a national registry. J Clin Oncol 1989;7:781–9. [3] Izzedine H, Isnard-Bagnis C, Launay-Vacher V, Mercadal L, Tostivint I, Rixe O, et al. Gemcitabine-induced thrombotic microangiopathy: a systematic review. Nephrol Dial Transplant 2006;21:3038–45. [4] Zupancic M, Shah PC, Shah-Khan F. Gemcitabine-associated thrombotic thrombocytopenic purpura. Lancet Oncol 2007;8:634–41. [5] Al Ustwani O, Lohr J, Dy G, Levea C, Connolly C, Arora P, et al. Eculizumab therapy for gemcitabine induced hemolytic uremic syndrome: case series and concise review. J Gastrointest Oncol 2014;5:E30–3. [6] Starck M, Wendtner CM. Use of eculizumab in refractory gemcitabineinduced thrombotic microangiopathy. Br J Haematol 2014;164:894–6. http://dx.doi.org/10.1111/bjh.12686. [7] Rogier T, Gerfaud-Valentin M, Pouteil-Noble C, Taleb A, Guillet M, Noel A, et al. [Clinical efficacy of eculizumab as treatment of gemcitabine-induced thrombotic microangiopathy: a case report]. Rev Med Interne 2016;37:701–4. [8] Izzedine H, Escudier B, Lhomme C, Pautier P, Rouvier P, Gueutin V, et al. Kidney diseases associated with anti-vascular endothelial growth factor (VEGF): an 8year observational study at a single center. Medicine (Baltimore) 2014;93: 333–9. [9] Izzedine H, Perazella MA. Thrombotic microangiopathy, cancer, and cancer drugs. Am J Kidney Dis 2015;66:857–68. [10] Vigneau C, Lorcy N, Dolley-Hitze T, Jouan F, Arlot-Bonnemains Y, Laguerre B, et al. All anti-vascular endothelial growth factor drugs can induce ‘‘preeclampsia-like syndrome’’: a RARe study. Nephrol Dial Transplant 2013;29: 325–32. [11] Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 2008;358:1129–36. [12] Yui JC, Van Keer J, Weiss BM, Waxman AJ, Palmer MB, D’Agati VD, et al. Proteasome inhibitor associated thrombotic microangiopathy. Am J Hematol 2016;91:E348–52. [13] Phan NT, Heng AE, Lautrette A, Kemeny JL, Souweine B. Oxaliplatin-induced acute renal failure presenting clinically as thrombotic microangiopathy: think of acute tubular necrosis. NDT Plus 2009;2:254–6. [14] Martino S, Daguindau E, Ferrand C, Bamoulid J, Hayette S, Nicolini FE, et al. A successful renal transplantation for renal failure after dasatinib-induced thrombotic thrombocytopenic purpura in a patient with imatinib-resistant chronic myelogenous leukaemia on nilotinib. Leuk Res Rep 2013;2:29–31. [15] Oberic L, Buffet M, Schwarzinger M, Veyradier A, Clabault K, Malot S, et al. Cancer awareness in atypical thrombotic microangiopathies. Oncologist 2009;14:769–79.
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Oncology
Thrombotic microangiopathies and antineoplastic agents Steven Grange´ a,b, Paul Coppo b,c,d,e,*, Centre de re´fe´rence des microangiopathies thrombotiques (CNR-MAT)b,1 a
Service de re´animation, CHU Charles-Nicolle, 1, rue de Germont, 76000 Rouen, France Centre de re´fe´rence des microangiopathies thrombotiques (CNR-MAT), AP–HP, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France c Service d’he´matologie, hoˆpital Saint-Antoine, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France d Universite´ Pierre-et-Marie-Curie, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France e Inserm 1170, institut Gustave-Roussy, 114, rue E´douard-Vaillant, 94800 Villejuif, France b
A R T I C L E I N F O
A B S T R A C T
Keywords: Thrombotic microangiopathy Antineoplastic drug Vascular endothelial growth factor Gemcitabine Complement system Eculizumab
Thrombotic microangiopathy is a well-described complication of cancer treatment. Its incidence has increased these last decades, as a result of a better awareness of this complication in cancer patients in one hand, but also of a larger array of therapeutic compounds including anti-vascular endothelium growth factor (VEGF) drugs. It is therefore mandatory to recognize these conditions since they have a significant impact in thrombotic microangiopathies management and prognosis. Practitioners should be aware of the more classical antineoplastic agents associated with thrombotic microangiopathies, the mechanisms by which they induce them, and the resulting management and prognosis. Since malignancy itself can induce thrombotic microangiopathies, it is also mandatory to know how to distinguish rapidly those caused by antineoplastic agents from those associated with cancer, for an adapted management. Thrombotic microangiopathies associated with chemotherapy remain of dismal prognosis. A better understanding of pathophysiology in these forms of thrombotic microangiopathies, in association with a more empirical approach through the use of new therapeutic agents that can also help in the understanding on new mechanisms a posteriori, should improve their prognosis. The preliminary encouraging results reported with complement blockers in this field could represent a convincing example.
C 2017 Socie ´ te´ francophone de ne´phrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction The diseases collectively termed the thrombotic microangiopathies are various life-threatening disorders characterized by microangiopathic hemolytic anemia, peripheral thrombocytopenia, and organ failure of variable severity caused by microvascular occlusion. In thrombotic thrombocytopenic purpura, the systemic microvascular aggregation of platelets causes ischemia in the brain, kidneys, heart, and other organs. In hemolytic-uremic syndrome, fibrin-rich thrombi predominantly occlude the renal circulation. A thrombotic microangiopathy can also be typically observed in patients with the hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome, disseminated cancer, or a
* Corresponding author. Service d’he´matologie, hoˆpital Saint-Antoine, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France. E-mail address: [email protected] (P. Coppo). 1 Members of the CNR-MAT are listed in Appendix A.
human immunodeficiency virus infection and within the context of chemotherapy or transplantation. Thrombotic microangiopathy is a well-described complication of cancer treatment. Its incidence has increased these last decades, as a result of a better awareness of this complication in cancer patients in one hand, but also of a larger array of therapeutic compounds including anti-vascular endothelial growth factor (VEGF) drugs. It can sometimes be difficult to establish a causal relationship between a specific chemotherapeutic agent and thrombotic microangiopathy given that malignancy itself can induce thrombotic microangiopathy. Moreover, many patients are treated with multiple chemotherapeutic agents, which can lead to difficulty indicting a particular drug. Practitioners should be aware of the more classical antineoplastic agents associated with thrombotic microangiopathy, the mechanisms by which they induce it, and the resulting management and prognosis. It is also mandatory to know how to distinguish rapidly thrombotic microangiopathies caused by antineoplastic agents from those associated with cancer for an adapted management. Recognition of
http://dx.doi.org/10.1016/j.nephro.2017.01.016 C 2017 Socie ´ te´ francophone de ne´phrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved. 1769-7255/
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an antineoplastic drug-etiology in a patient with thrombotic microangiopathy is also critical to avoid re-exposure and recurrent illness. This review addresses these goals. 2. Mitomycin C and gemcitabine-associated thrombotic microangiopathy The most classical antineoplastic agents associated with thrombotic microangiopathies include mitomycin C and gemcitabine (Table 1). Pathophysiology still remains unclear, and may involve a direct damage of renal endothelial cells resulting in the formation of platelet aggregates. Mitomycin C also causes decreased prostacyclin production in human endothelial cell cultures, which may participate to platelet aggregation. Plasma levels of thrombomodulin, tissue plasminogen activator and plasminogen activator inhibitor-1 are elevated in patients with mitomycin C-induced thrombotic microangiopathy that are similar to those observed in patients with idiopathic thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome [1]. The onset of outcome is delayed, and ranges from 6 to 12 months after treatment initiation. Thrombotic microangiopathy results from a dose-dependent toxicity and is cumulative. Hematologic manifestations are usually present. Hypertension, acute renal failure, pulmonary edema and acute respiratory distress syndrome are common. Microthrombi involve both glomerular capillaries and arterioles. Clinical features are typically permanent and irreversible, and respond poorly to therapeutic plasma exchange. 2.1. Mitomycin C-associated thrombotic microangiopathy Mitomycin C is an antitumor alkylating agent isolated from Streptomyces caespitosus that has been in use since 1958. It is an active agent in salvage combination chemotherapy regimens for adenocarcinoma of the breast, lung, stomach, pancreas, rectum, and head and neck. It is one of the primary agents for anal carcinoma. Thrombotic microangiopathy usually occurs 4 to 8 weeks after the last dose of mitomycin C, with most cases occurring after 6 to 12 months of chemotherapy. The threshold total cumulative dose of 40 to 60 mg is associated with the development of thrombotic microangiopathy. In the largest registry of mitomycin C-associated thrombotic microangiopathy, 83 (99%) of 84 patients received a cumulative dose of 40 mg or more, and all but nine received a cumulative dose greater than 60 mg. Pulmonary edema, generally noncardiogenic, developed in 65% of patients, often after blood product transfusion. In a series of 142 patients with gastrointestinal cancer treated with combination chemotherapy including mitomycin C, ten patients developed renal failure, and five of the ten also developed microangiopathic hemolytic anemia. The ten patients received a total cumulative Table 1 Antineoplastic agents associated with thrombotic microangiopathies. Chemotherapy
Anti-VEGF therapy
Other targeted therapies
Mitomycin C Gemcitabine Platinum salts Pegylated liposomal doxorubicin
Ligands Bevacizumab Afilbercept
Other tyrosine kinase inhibitors Imatinib mesylate Dasatinib
Tyrosine kinase inhibitors Sunitinib Sorafenib Cediranib Brivanib Pazopranib Lucitanib
Immunotoxins Targeting typically CD22 or IL-2 Other immunotherapies Apolizumab
VEGF: vascular endothelial growth factor; IL-2: interleukin-2.
dose of 75 to 180 mg of mitomycin C, with a correlation between the prevalence of renal toxicity and the total cumulative dose. Dyspnea, caused typically by pulmonary edema, is the most common presenting symptom of mitomycin C-associated thrombotic microangiopathy; it can progress to the adult respiratory distress syndrome. Progressive renal failure is present in almost all patients. Neurologic abnormalities are less common. Treatment consists mainly in the interruption of mitomycin C immediately with diagnosis of thrombotic microangiopathy. As opposed to thrombotic thrombocytopenic purpura, response to therapeutic plasma exchange is typically poor, although some reports suggested a role for staphylococcal protein A immunopheresis. Acute mortality is elevated, approaching 75% at 4 months [2]. 2.2. Gemcitabine-associated thrombotic microangiopathy As for mitomycin C, gemcitabine-associated thrombotic microangiopathy is typically chronic with cumulative dose dependence. Gemcitabine was approved by the US Food and Drug Administration (FDA) in 1996 for the treatment of metastatic pancreatic cancers and is currently used for the treatment of malignancies such as lymphomas, lung, bladder and breast cancers. The incidence of gemcitabine-associated thrombotic microangiopathy was initially estimated to be of 0.015%. However, more recent works reported incidences as high as 0.4% [3,4], which could result from an increasing recognition of milder forms due to a better awareness of practitioners about this complication. Given the possible clinically silent presentation of gemcitabine-associated thrombotic microangiopathy, its clinical features should be sought before each new cycle of treatment. From a series of 56 cases, the mean duration between the initiation of gemcitabine and thrombotic microangiopathy occurrence was reported to be 7.5 months, although the range was wide (0.5 to 19 months). The median cumulative dose of gemcitabine was 22.5 g 14 g (range 2–70 g). A mild proteinuria and a microscopic hematuria could be observed in two-third of cases. A de novo arterial hypertension or the worsening of a preexisting arterial hypertension was observed in 75% of patients [3]. Patients were managed with a plasma-based therapy and/or steroids although this approach has never proved its efficacy. Although patients may improve hematological findings, renal prognosis is usually poor and patients maintain chronic renal failure in 70% of cases. Median survival was 16.5 months [3]. Physiopathology of gemcitabine-induced thrombotic microangiopathy is still poorly understood. Gemcitabine was suggested to have direct endothelial toxicity with a concomitant activation of the coagulation cascade. Histological data obtained from renal biopsies suggest a possible role of complement activation: a thickening of capillary walls, fibrin thrombi, necrotic endothelial cells, and granular deposits of immunoglobulins and C3 in the wall of small arteries and arterioles, and in glomeruli [5]. The hypothesis that complement could be involved in gemcitabineinduced thrombotic microangiopathy physiopathology and the unmet need with current treatments led to propose eculizumab to patients with such condition. Eculizumab is a monoclonal antibody targeting the C5 fraction of the terminal complement pathway and provided remarkable benefit in atypical hemolytic-uremic syndrome. To date six patients were treated with eculizumab for gemcitabine-induced-thrombotic microangiopathy that did not improve despite chemotherapy discontinuation [5–7]. Eculizumab was started 3 to 5 weeks after thrombotic microangiopathy diagnosis, with a median total dose of 6 g (range 3.6–9.6 g). Eculizumab was associated with hematological improvement and afforded a partial renal response. Four patients still had chronic renal failure with an estimated glomerular filtration rate (GFR) below 60 mL/min/1.73 m2 at last follow-up (median of 4 months
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[range 3–5 months]). Our group has performed an observational, retrospective, multicentric study from ten patients with gemcitabine-induced thrombotic microangiopathy treated with eculizumab in France between 2011 and 2016. Complete hematological remission was achieved in most patients and blood transfusion significantly decreased after only one injection of eculizumab. Renal function also improved. These preliminary results open promising perspectives on the role of complement cascade in the pathophysiology of gemcitabine-associated thrombotic microangiopathy, and deserve further studies to confirm the efficacy of complement blockers on this indication. Other strategies including rituximab and recombinant thrombomoduline were reported anecdotally and their efficacy remains uncertain. 3. Thrombotic microangiopathy associated with anti-VEGF agents Among antineoplastic drugs associated with thrombotic microangiopathy, those that inhibit VEGF pathway are the most widely studied (Table 1). Inhibition of VEGF, either by antibodymediated binding of the ligand (bevacizumab, aflibercept) or small-molecule inhibition of the VEGF receptor (tyrosine kinase inhibitors, sunitinib, sorafenib, pazopanib, axitinib and vandetanib) has demonstrated clinically relevant benefits in solid tumors. All these agents have been linked to the development of a syndrome characterized by new-onset hypertension (or exacerbation of a preexisting hypertension), proteinuria, severe hypertension, and/or acute kidney injury with histopathologic evidence of kidney thrombotic microangiopathy, suggesting a potential classwide effect [8]. These thrombotic microangiopathy occur with a variable range of time after anti-VEGF initiation (from 1 day after treatment initiation to more than 2 years), they are not doserelated, and there is a high likelihood of recovery after interruption. Hematologic manifestations are only observed in half of patients, whereas hypertension and proteinuria are typical features. Microthrombi involve exclusively glomerular capillaries and renal failure occurs rarely. Prognosis is good after treatment cessation, effective blood pressure control with renin angiotensin inhibitors and other symptomatic measures including hemodialysis in the more severe cases. Reintroducing the drug at lower dose levels may be a strategy to avoid recurrent thrombotic microangiopathy, while allowing for continued treatment. On the opposite, combination therapy of bevacizumab and sunitinib results in a more severe form of thrombotic microangiopathy, with the development of extrarenal complications [9]. The efficacy of plasma exchange with steroids is unclear in this form of thrombotic microangiopathy, but these procedures are usually proposed in patients with a severe presentation and/or lack of improvement following drug withdrawal. In a large series of patients with biopsy-proven kidney damage during anti-VEGF therapy, intraglomerular thrombotic microangiopathy occurred preferentially with VEGF-ligand exposure, whereas tyrosine kinase inhibitors provided more often podocytopathies such as minimal change nephropathy/collapsing focal glomerulosclerosis. Additionally, 31% of patients with thrombotic microangiopathy had proteinuria with protein excretion up to 1 g/24 h. Half the thrombotic microangiopathy cases were kidney limited without microangiopathic hemolytic anemia or thrombocytopenia. Pathologic thrombotic microangiopathy features limited to the glomerular structures differentiate anti-VEGF-induced thrombotic microangiopathy from other causes, including those secondary to gemcitabine. Kidney function could be preserved with a combination of blood pressure control and withdrawal of the anti-VEGF drug and hypertension and proteinuria could both resolve with these measures [9]. Another group reported the association of anti-VEGF therapies with a ‘‘pre-eclampsia-like
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syndrome’’ from 22 patients. Almost all patients had hypertension. There were mild or no biological signs of thrombotic microangiopathy and the mean proteinuria in the 22 patients was 2.97 2.0 g/day and the mean serum creatinine 134 117 mmol/L. Renal biopsies were performed in all patients and showed microangiopathy lesions of variable importance in all glomeruli, sometimes associated with acute tubular necrosis (18% of cases). In all biopsies was observed a mild to strong expression of proteins involved in the integrity and the physiology of the glomerular basement membrane: nephrin, podocin and synaptopodin [10]. In a pathophysiological point of view, Eremina et al. described six biopsy-documented cases of thrombotic microangiopathy resembling hemolytic-uremic syndrome following bevacizumab administration [11]. All of the patients described developed proteinuria or increased serum creatinine following the initiation of bevacizumab, ultimately leading to renal biopsy. Following discontinuation of bevacizumab, improvement in renal function was noted, suggesting at least partial reversibility. In this work, the authors provided a detailed proposal for a mechanism of VEGFinduced thrombotic microangiopathy from an elegant animal model in which the renal podocytes were electively deprived of the VEGF gene. In this model, the knockout mice developed features consistent with bevacizumab-associated thrombotic microangiopathy. From these results, the authors proposed that inhibition of VEGF in the glomerular microvasculature prevents the formation and maintenance of healthy, fenestrated endothelium. Without active VEGF signaling, the endothelium is compromised, along with the filtration barrier of the glomerulus (Fig. 1). These results underline the importance of regular cardiovascular and renal checking during all anti-VEGF therapies for cancer for early detection of renal dysfunction, which implies a close collaboration between oncologists and nephrologists. 4. Thrombotic microangiopathy associated with proteasome inhibitors Proteasome inhibitors represent a therapeutic class of drugs developed in multiple myeloma for more than 10 years that are now used as a standard of care in this disease. Bortezomib (Velcade1) was the first agent of this class. More recently, the new proteasome inhibitor carfilzomib (Kyprolis1) and an oral form of bortezomib (Ixazomib1) also enriched the therapeutic arsenal of multiple myeloma. As these drugs are increasingly prescribed, thrombotic microangiopathies were reported in association with carfilzomib and bortezomib. Thrombotic microangiopathy typically occurs 3 weeks following medication initiation (range 5 days– 17 months). Patients typically present with microangiopathic hemolytic anemia, thrombocytopenia and renal failure. ADAMTS13 activity is normal or mildly decreased. The outcome is usually favorable with medication withdrawal and symptomatic measures. Rarely, laboratory values remain stable with poor improvement. Paradoxically, bortezomib was also recently reported efficient in refractory forms of acquired thrombotic thrombocytopenic purpura [12]. 5. Other antineoplastic agents Features reminiscent of thrombotic microangiopathy have been reported in patients treated with oxaliplatin [9]; however, others suggested that anemia and thrombocytopenia could result from oxaliplatin-dependent antibodies against erythrocytes and platelets [13]. Therefore, the clear role of oxaliplatin in the occurrence of thrombotic microangiopathy remains uncertain. On the other hand, cisplatin could be associated with clear features of thrombotic microangiopathy suggestive of hemolytic-uremic syndrome [9].
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S. Grange´, P. Coppo / Ne´phrologie & The´rapeutique 13S (2017) S109–S113 Table 2 Typical distinctive features between cancer-associated or chemotherapy-associated thrombotic microangiopathies.
Disseminated cancer Renal involvement Disseminated intravascular coagulopathy Circulating erythroblasts Clinical presentation
Treatment
Cancer-associated thrombotic microangiopathy
Chemotherapy-associated thrombotic microangiopathy
Yes Mild/absent Present
No Mild/severe Absent
Present Thrombotic thrombocytopenic purpura-like disease Chemotherapy
Absent Hemolytic-uremic syndrome-like disease Stop chemotherapy Supportive care Specific treatments
90% of patients with cancer-associated thrombotic microangiopathy have metastatic disease, whereas patients with antineoplastic drug-associated thrombotic microangiopathy have little or no detectable malignancy. Kidney involvement is uncommon in cancer-associated thrombotic microangiopathy, whereas chemotherapy-associated thrombotic microangiopathy is a more localized kidney disease and typically mimics hemolytic-uremic syndrome. Patients with cancer-associated thrombotic microangiopathy typically present with disseminated intravascular coagulopathy in up to 30% of cases and circulating erythroblasts are observed in most cases. ADAMTS13 activity is not discriminant since it is detectable in a majority of cases in both conditions [15] (Table 2). 7. Conclusion – future directions
Fig. 1. Role of VEGF/VEGFR pathway in vascular relaxation and involvement of VEGF/ VEGFR blockers in thrombotic microangiopathy pathophysiology. MoAb: monoclonal antibody; VEGF: vascular-endothelium growth factor; VEGF-R: VEGFreceptor; ITK: inhibitor of tyrosine kinase; HELLP: hemolysis, elevated liver enzymes, low platelet count; PLC: phospholipase C; mTOR: major target of rapamycin; COX: cyclo-oxygenase; NO: nitric oxide; eNOS: endothelial NO synthase; PGI2: prostaglandin-I2; GC: guanyl cyclase; GMP: guanosine monophosphate.
Other antineoplastic agents and targeted therapies have been associated with thrombotic microangiopathy, although more anecdotally: tyrosine kinase inhibitors (imatinib mesylate, dasatinib), immunotoxins (targeting typically CD22 or interleukin-2), and apolizumab (humanized monoclonal antibody targeting 1D10, an antigen on the b chain of HLA-DR) [9,14]. The drug pegylated liposomal doxorubicin is commonly used to treat recurrent ovarian cancer. A thrombotic microangiopathy was reported in association with this drug in patients who received high cumulative doses (880–1445 mg/m2) of pegylated liposomal doxorubicin after several years of therapy. Renal biopsy-proven thrombotic microangiopathy consisted in increased serum creatinine levels, hypertension, and non-nephrotic range proteinuria, which improved partially upon drug withdrawal. Notably, no patient had thrombocytopenia or hemolytic anemia [9]. 6. How to distinguish antineoplastic drug-associated or cancer-associated thrombotic microangiopathy? The distinction between cancer-associated or antineoplastic drug-associated thrombotic microangiopathy is mandatory for an appropriate management. This distinction may be challenging in some cases. However, both conditions have specific features. Up to
Thrombotic microangiopathy is a potentially severe complication of antineoplastic drugs that should be considered in any patient with cancer therapy who presents with microangiopathic hemolytic anemia, thrombocytopenia, neurologic changes, proteinuria, hypertension or renal failure. Clinicians need to differentiate chemotherapy-associated thrombotic microangiopathy from a cancer-induced thrombotic microangiopathy for an appropriate management. Treatment of chemotherapy-associated thrombotic microangiopathy still remains a challenge and prognosis is usually dismal. A better understanding of pathophysiology in these forms of thrombotic microangiopathy, in association with a more empirical approach through the use of new therapeutic agents that can also help in the understanding on new mechanisms a posteriori, should improve their prognosis. The preliminary encouraging results reported with complement blockers in this field could represent a convincing example. Disclosure of interest PC: member of the Clinical Advisory Board for Alexion, Ablynx and Octapharma; financings from Roche Pharma. The other authors have not supplied their declaration of competing interest. Acknowledgements We thank S. Thouzeau, S. Savigny, S. Capdenat (laboratoire d’he´matologie, hoˆpital Lariboisie`re, Paris) and S. Malot (centre de re´fe´rence des microangiopathies thrombotiques, hoˆpital SaintAntoine, AP–HP, Paris) for technical assistance. Work of the CNRMAT are also supported by the national plan for rare diseases of the French ministry of health (Direction ge´ne´rale de l’offre de soin [DGOS]).
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Appendix A. The members of the Reference Center for Thrombotic Microangiopathies (CNR-MAT) are: E´lie Azoulay (service de re´animation me´dicale, hoˆpital Saint-Louis, Paris), Virginie Barbay (laboratoire d’he´matologie, CHU Charles-Nicolle, Rouen), Guy Bonmarchand (service de re´animation, CHU Charles-Nicolle, Rouen), Dominique Bordessoule (service d’he´matologie, hoˆpital Dupuytren, Limoges), Christophe Charasse (service de ne´phrologie, centre hospitalier de Saint-Brieuc), Dominique Chauveau (de´partement de ne´phrologie et transplantation d’organes, CHU Rangueil, Toulouse), Gabriel Choukroun (service de ne´phrologie, hoˆpital Sud, Amiens), JeanPhilippe Coindre (service de ne´phrologie, CH Le Mans), Paul Coppo (service d’he´matologie, hoˆpital Saint-Antoine, Paris), E´lise Corre (service d’he´matologie, hoˆpital Saint-Antoine, Paris), Yahsou Delmas (service de ne´phrologie, hoˆpital Pellegrin, Bordeaux), Georges Descheˆnes (service de ne´phrologie pe´diatrique, hoˆpital Robert-Debre´, Paris), Alain Devidas (service d’he´matologie, hoˆpital Sud-Francilien, Corbeil-Essonnes), Olivier Fain (service de me´decine interne, hoˆpital Saint-Antoine, Paris), Ve´ronique Fre´meauxBacchi (laboratoire d’immunologie, hoˆpital europe´en GeorgesPompidou, Paris), Lionel Galicier (service d’immunopathologie, hoˆpital Saint-Louis, Paris), Steven Grange´ (service de re´animation, CHU Charles-Nicolle, Rouen), Bertrand Guidet (service de re´animation me´dicale, hoˆpital Saint-Antoine, Paris), Jean-Michel Halimi (service de ne´phrologie pe´diatrique, hoˆpital Bretonneau, Tours), Mohamed Hamidou (service de me´decine interne, Hoˆtel-Dieu, Nantes), Raoul Herbrecht (service d’oncologie et d’he´matologie, hoˆpital de Hautepierre, Strasbourg), Fre´de´ric Jacobs (service de re´animation me´dicale, hoˆpital Antoine-Be´cle`re, Clamart), Be´range`re Joly (service d’he´matologie biologique, hoˆpital Lariboisie`re, Paris), Tarik Kanouni (unite´ d’he´maphre`se, service d’he´matologie, CHU de Montpellier), Alexandre Lautrette (service de ne´phrologie pe´diatrique B, hoˆpital Hoˆtel-Dieu, Clermont-Ferrand), Ve´ronique Le Guern (unite´ d’he´maphe´re`se, service de me´decine interne, hoˆpital Cochin, Paris), Chantal Loirat (service de ne´phrologie pe´diatrique, hoˆpital Robert-Debre´, Paris), Jean-Paul Mira (service de re´animation me´dicale, hoˆpital Cochin), Bruno Moulin (service de ne´phrologie, hoˆpital Civil, Strasbourg), Christiane Mousson (service de ne´phrologie, CHU de Dijon), Mario Ojeda Uribe (service d’he´matologie, hoˆpital E´mile-Muller, Mulhouse), Abdelkader Ouchenir (service de re´animation, hoˆpital Louis-Pasteur, Le Coudray), Nathalie Parquet (unite´ de clinique transfusionnelle, hoˆpital Cochin, Paris), Julie Peltier (urgences ne´phrologiques et transplantation re´nale, hoˆpital Tenon, Paris), Pierre Perez (service de re´animation polyvalente, CHU de Nancy), Pascale Poullin (service d’he´maphe´re`se et d’autotransfusion, hoˆpital la Conception, Marseille), Claire Pouteil-Noble (service de ne´phrologie, CHU Lyon-Sud, Lyon), Claire Presne (service de ne´phrologie, hoˆpital Nord, Amiens), Franc¸ois Provoˆt (service de ne´phrologie, hoˆpital Albert-Calmette, Lille), Jean-Antoine Ribeil (service de the´rapie
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cellulaire, hoˆpital Necker-Enfants Malades, Paris), E´ric Rondeau (urgences ne´phrologiques et transplantation re´nale, hoˆpital Tenon, Paris), Samir Saheb (unite´ d’he´maphe´re`se, hoˆpital la Pitie´Salpeˆtrie`re, Paris), Benoıˆt Schlemmer (service de re´animation me´dicale, hoˆpital Saint-Louis, Paris), Ame´lie Seguin (service de re´animation me´dicale, CHU de Caen), Alain Ste´panian (laboratoire d’he´matologie, hoˆpital Lariboisie`re, Paris), Jean-Paul Vernant (service d’he´matologie, hoˆpital la Pitie´-Salpeˆtrie`re, Paris), Agne`s Veyradier (service d’he´matologie biologique, hoˆpital Lariboisie`re, Paris), Ce´cile Vigneau (service de ne´phrologie, hoˆpital Pontchaillou, Rennes), Alain Wynckel (service de ne´phrologie, hoˆpital Maison-Blanche, Reims), Patricia Zunic (service d’he´matologie, groupe hospitalier Sud-Re´union, la Re´union). References [1] Medina PJ, Sipols JM, George JN. Drug-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Curr Opin Hematol 2001;8: 286–93. [2] Lesesne JB, Rothschild N, Erickson B, Korec S, Sisk R, Keller J, et al. Cancerassociated hemolytic-uremic syndrome: analysis of 85 cases from a national registry. J Clin Oncol 1989;7:781–9. [3] Izzedine H, Isnard-Bagnis C, Launay-Vacher V, Mercadal L, Tostivint I, Rixe O, et al. Gemcitabine-induced thrombotic microangiopathy: a systematic review. Nephrol Dial Transplant 2006;21:3038–45. [4] Zupancic M, Shah PC, Shah-Khan F. Gemcitabine-associated thrombotic thrombocytopenic purpura. Lancet Oncol 2007;8:634–41. [5] Al Ustwani O, Lohr J, Dy G, Levea C, Connolly C, Arora P, et al. Eculizumab therapy for gemcitabine induced hemolytic uremic syndrome: case series and concise review. J Gastrointest Oncol 2014;5:E30–3. [6] Starck M, Wendtner CM. Use of eculizumab in refractory gemcitabineinduced thrombotic microangiopathy. Br J Haematol 2014;164:894–6. http://dx.doi.org/10.1111/bjh.12686. [7] Rogier T, Gerfaud-Valentin M, Pouteil-Noble C, Taleb A, Guillet M, Noel A, et al. [Clinical efficacy of eculizumab as treatment of gemcitabine-induced thrombotic microangiopathy: a case report]. Rev Med Interne 2016;37:701–4. [8] Izzedine H, Escudier B, Lhomme C, Pautier P, Rouvier P, Gueutin V, et al. Kidney diseases associated with anti-vascular endothelial growth factor (VEGF): an 8year observational study at a single center. Medicine (Baltimore) 2014;93: 333–9. [9] Izzedine H, Perazella MA. Thrombotic microangiopathy, cancer, and cancer drugs. Am J Kidney Dis 2015;66:857–68. [10] Vigneau C, Lorcy N, Dolley-Hitze T, Jouan F, Arlot-Bonnemains Y, Laguerre B, et al. All anti-vascular endothelial growth factor drugs can induce ‘‘preeclampsia-like syndrome’’: a RARe study. Nephrol Dial Transplant 2013;29: 325–32. [11] Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 2008;358:1129–36. [12] Yui JC, Van Keer J, Weiss BM, Waxman AJ, Palmer MB, D’Agati VD, et al. Proteasome inhibitor associated thrombotic microangiopathy. Am J Hematol 2016;91:E348–52. [13] Phan NT, Heng AE, Lautrette A, Kemeny JL, Souweine B. Oxaliplatin-induced acute renal failure presenting clinically as thrombotic microangiopathy: think of acute tubular necrosis. NDT Plus 2009;2:254–6. [14] Martino S, Daguindau E, Ferrand C, Bamoulid J, Hayette S, Nicolini FE, et al. A successful renal transplantation for renal failure after dasatinib-induced thrombotic thrombocytopenic purpura in a patient with imatinib-resistant chronic myelogenous leukaemia on nilotinib. Leuk Res Rep 2013;2:29–31. [15] Oberic L, Buffet M, Schwarzinger M, Veyradier A, Clabault K, Malot S, et al. Cancer awareness in atypical thrombotic microangiopathies. Oncologist 2009;14:769–79.