Development of thrombotic thrombocytopenic purpura during lenalidomide therapy: three new cases and review of literature

Abstract

Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy (TMA) syndrome (Kremer et al. 2017). TTP typically includes severe thrombocytopenia, microangiopathic hemolytic anemia (MAHA) with schistocytes and organ manifestations secondary to microvascular thrombosis (neurological symptoms, acute kidney injury (AKI), myocardial infarction), associated with severe functional deficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) (Joly et al, 2019). The majority of acquired TTP in adults are related to an auto-immune disorder where anti-ADAMTS13 antibodies cause that deficiency and subsequent platelet adhesion and aggregation.Bacterial infections, autoimmune diseases, pregnancy, drugs, HIV infection, cancers, organ or HSC transplantation are the most frequent clinical conditions associated with TTP (Joly et al, 2019).Lenalidomide, an immunomodulatory drug, is a treatment of multiple myeloma (MM), myelodysplastic syndromes. Most frequent adverse effects are cytopenias, infections and thrombosis. We report 3 new cases of acquired autoimmune TTP in patients treated with Lenalidomide. A 69-year-old female, with a 10-year history of MM (multiple myeloma) IgG kappa, received lenalidomide (10 mg daily) plus dexamethasone (20 mg weekly) for a second relapse. In April 2017, while in partial response after five months of treatment, she developed dizziness, ataxia, visual field abnormalities and left upper limb dyskinesia. She presented with haemoglobin 80 g/l, platelets 4 × 109/l, high reticulocyte count 180 × 109/l, elevated LDH 1200 UI/l, decreased haptoglobin, no schistocytes on blood smears and a creatinine level of 11 mg/l. A direct antiglobulin test was negative and complement (C3, C4 and CH50) levels were normal. A brain MRI showed several cortical and non-cortical cerebrovascular infarctions. ADAMTS13 activity was undetectable at <5%, with presence of anti-ADAMTS13 IgG (>100 U/ml). Lenalidomide was stopped and the patient benefited from 16 therapeutic plasma exchanges (TPE), with methylprednisolone 1 mg/kg daily, tapered over a month, resulting in a rise of the platelet count till 70 × 109/l, and a normalisation of LDH levels ‒ neurological symptoms progressively disappeared. Ten months later, the platelet count remained stable at 67 × 109/l with a normal ADAMTS13 activity (88%). She is currently treated with bortezomib, cyclophosphamide and dexamethasone in a partial haematological response. A 70-year-old woman was treated with lenalidomide (10 mg daily) from June 2014 for refractory anaemia, 5q-syndrome. After three months of treatment, she presented with fever, abdominal pain and right upper limb paresis, haemoglobin 40 g/l, platelets 2 × 109/l, high LDH levels (1560 U/l), low haptoglobin, the presence of schistocytes on blood smear, oliguric AKI (17 mg/l), and a high level of troponin. ADAMTS13 activity was undetectable at <5%, associated with anti-ADAMTS13 IgG (190 U/ml). CT scans revealed multiple ischemic events: infarctions of cerebrum, cerebellum and brainstem, renal, splenic and colic infarctions. A total of 15 TPE were performed and after the fourth the patient experienced improved motor function. She also received methylprednisolone initially of 1 mg/kg, tapering over two weeks after TPE discontinuation, and four infusions of rituximab 375 mg/m2. After 12 months, ADAMTS13 activity was at 61%, with 165 × 109/l platelets. The patient then developed secondary myelofibrosis and died from its complications. A 71-year-old male with a five-year history of IgG lambda MM, who underwent an autologous stem cell transplant in 2013, experienced a first relapse in October 2016 and was treated with lenalidomide 25 mg/day and dexamethasone weekly with a very good partial response. After 17 months of treatment, the patient presented with hypothermia, dyspnea, dizziness, diarrhoea and bone pain. He had 77 g/l haemoglobin with 9 × 109/l platelets and the presence of schistocytes on blood smear; LDH levels were high (655 U/l), with a low haptoglobin and creatinine level of 11 mg/l. Shigatoxin research in stools was negative, ADAMTS13 activity was undetectable at <5% with positive anti-ADAMTS13 IgG (>100 U/ml). The brain MRI was normal. The patient underwent 10 TPE with methylprednisolone of 1 mg/kg and one injection of rituximab with rapid clinical and biological improvement. Six months later, ADAMTS13 activity was 49% and platelet count was normal (246 × 109/l). The patient is currently being treated with bortezomib, cyclophosphamide and dexamethasone in partial response. These three cases of TTP occurred during lenalidomide therapy (Table 1)‒ there was nothing that can usually be associated with thrombotic microangiopathy ‒ no infectious trigger, no association with other autoimmune disorders, and no drugs intake. The PLASMIC score (Upadhyay et al., 2019) has stratified our three cases in the intermediate and high risk group for severe ADAMTS13 deficiency. To the best of our knowledge, only two other cases of TTP and treatment with lenalidomide in MM have been reported in literature (Hofmeister et al., 2010; Cheah et al., 2015). All five cases had a creatinine level under 23 mg/l (200 µmol/l) and platelet count under 30 × 109/l, which are predicting features of severe acquired ADAMTS13 deficiency on diagnosis (Coppo et al., 2010). Two mechanisms for drug-induced TTP have been proposed: immune-mediated reaction and dose-related toxicity (Al-Nouri et al., 2015). For our patients, the presence of anti-ADAMTS13 antibodies in each case and the efficacy of TPE and/or rituximab therapies imply an immune-mediated reaction. Montefusco et al. (2014) described six autoimmune diseases after lenalidomide administration to 140 patients (4·3%): three autoimmune cytopenias and three organ-specific autoimmune disorders, occurring mostly in the first months of treatment. In the first case, ADAMTS13 activity (which was tested on frozen serum samples), was normal five years prior to lenalidomide initiation and decreased to <5% one month after its initiation. This strongly suggests the emergence of anti-ADAMTS13 antibodies after lenalidomide initiation. After lenalidomide discontinuation, the patients were not rechallenged with the drug. Dose-related toxicity cannot be ruled out. Lu et al. (2009) showed in vitro that lenalidomide inhibits VEGF-induced endothelial cell cord formation in a dose-dependent manner, and it was also demonstrated in hepatocellular carcinoma cells that lenalidomide inhibits angiogenesis via a VEGF pathway (Qu et al., 2016). Local reduction of VEGF within the kidney has been proved sufficient to trigger microvascular injury, particularly to glomerular capillaries and renal podocytes, leading to TMA (Eremina et al., 2008). This supports the concept that local production of VEGF plays a critical protective role in the pathogenesis of microangiopathic processes. Also, in the first months of treatment, immunomodulators induce a transitory rise of factors VIII and vWF, an acquired resistance to the activated protein C, and a reduction of the soluble thrombomodulin rate: favourable conditions for thrombosis (Boyle et al., 2012). The physiopathology needs to be clarified but one can make several hypotheses: lenalidomide could induce development of anti-ADAMTS13 antibodies leading to TTP; it could also facilitate endothelial lesions (via a VEGF inhibition), leading to TMA and promoting a pro-thrombotic environment. Although rare, if bicytopenia occurs with high LDH levels when treating patients with lenalidomide, this could imply TTP and we suggest considering its early discontinuation. DE, AT, NL, SH, LG, AA, SR, EA, BR, BA have taken care of patients, collected clinical and laboratory information and gave therapeutic advice. DE, AT, BR and BA wrote the letter. DE, AT, NL, SH, LG, AA, SR, EA, PC BR, BA carefully read and critically reviewed the letter. AV and BJ performed the ADAMTS13 analysis. None of the authors has a relevant conflict of interest.