Ixazomib-induced thrombotic microangiopathy
Authors: Jennifer C. Yui, Angela Dispenzieri, Nelson Leung
Journal: American Journal of Hematology (2017)

Thrombotic microangiopathy (TMA) is a group of hematologic syndromes that presents with microangiopathic hemolytic anemia and thrombocytopenia, either as a result or a cause of endothelial injury and microvascular thrombosis.1 Many etiologies have been described ranging from inhibition of ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type I motifs 13) to defects in complement regulation. One of the more common causes is drug-induced TMA (DITMA).1 Recent case reports have described DITMA attributed to proteasome inhibitors (PI) carfilzomib and bortezomib in patients with multiple myeloma (MM). In our recent review of PI-associated TMA, we review the literature and present 11 new cases of DITMA attributed to bortezomib or carfilzomib.2 Evidence suggests this may be a class effect which can occur with any PI. Ixazomib is the first oral PI and was approved by the FDA in 2015.3 Similar to bortezomib, ixazomib is a boronic acid-based PI that reversibly inhibits the chymotrypsin-like activity of the 20S proteasome, suppressing tumor growth, tumor spread, and angiogenesis.4 In phase 1 trials of ixazomib, the most common adverse effect was thrombocytopenia, affecting 43% of patients, with 33% experiencing grade 3-4 thrombocytopenia.4, 5 Other adverse effects included diarrhea, nausea, and fatigue. There was one case of acute renal failure, attributed to a pre-renal etiology. No mention of TMA was made in these reports. Below, we present, to the best our knowledge, the first case of ixazomib-associated TMA. The patient was a 75-year-old woman initially diagnosed with IgG kappa MM in January 2009. She was treated with three cycles of lenalidomide and dexamethasone and achieved a partial response. An autologous hematopoietic stem cell transplant (HSCT) was performed in August 2009 and she was in a complete response until December 2011 when screening revealed a biochemical relapse with M-spike 0.7 g/dL. Repeat bone marrow biopsy revealed 10%-15% involvement of plasma cells, and she was initiated on a clinical trial with single agent ixazomib. Ixazomib was given on a 28-day cycle at 5.5 mg administered on days 1, 8, and 15. She was given her initial dose of ixazomib on March 26, 2012. Laboratory tests were checked on April 9, on day 15 cycle 1. On April 11, 2012, she developed significant nausea, vomiting, and diarrhea. She was noted to have acute kidney injury as well as significant decreases in her hemoglobin and platelet count (Table 1). Peripheral smear demonstrated schistocytes, and LDH was significantly elevated at 2355 U L−1. Given the concern for TMA, daily plasma exchange (PLEX) was initiated. ADAMTS13 level was 59%, and PLEX was tapered to three sessions weekly. Given persistent cytopenias and hemolysis, she also received four weekly doses of rituximab. Roughly one month later, PLEX was discontinued, and her laboratory values remained stable without further intervention. Her MM was subsequently treated with a repeat course of cyclophosphamide and prednisone, and then later with lenalidomide and dexamethasone. Her clinical course was complicated by herpes zoster infection with severe post-herpetic neuralgia and a lower extremity deep vein thrombosis. She had no other exposure to any other PI, and she died in November 2014. Two major criteria for DITMA have been described: an immune-mediated mechanism and a dose-dependent toxicity mechanism.1 Evidence for immune-mediated reactions includes onset of symptoms within 21 days of initiating a medication or onset within 24 h of administration of an intermittently-dosed medication. Patients who do not meet these criteria are assigned the toxicity mechanism.1 Moore and Romeril suggest that the mechanism of immune-mediated toxicities for PI may be due to the abundant pro-inflammatory cytokines (IL-6 and TNF-α), creating a microvascular milieu which allows for the formation of drug-dependent antibodies.6 However, while platelet-directed drug-dependent antibodies have been detected in some immune-mediated DITMA, with the greatest evidence for quinine- or ticlopidine-dependent antibodies, to date no such antibodies have been detected in PI-associated TMA.1 Certainly, this does not preclude their existence, but this proposed mechanism remains to be substantiated. With regard to the dose-mediated toxicity, one proposed mechanism involves VEGF inhibition leading to microvascular injury, particularly to glomerular capillaries. This patient's presentation was consistent with presentations seen in other cases of PI-associated TMA. Her TMA presented 17 days after initiation of PI therapy, consistent with the 50% of previously described PI-associated TMA presenting within 21 days of drug initiation.2 ADAMTS13 was nondeficient as in all other cases, and the anemia, thrombocytopenia, renal dysfunction, and LDH were all within previously described ranges. This patient was treated with PLEX, corticosteroids, and rituximab, without rapid improvement with any of these interventions. PLEX and rituximab may be effective treatments when DITMA is caused by autoantibodies or drug-dependent antibodies. The lack of response to these therapies may support a dose-dependent toxicity. In DITMA, the most important intervention or treatment is the discontinuation of the offending agent. Thus, given the demonstration of TMA with bortezomib, carfilzomib, and now ixazomib, providers should be vigilant for development of DITMA in patients receiving any PI, including new PIs such as marizomib. In patients treated with PI who develop thrombocytopenia, microangiopathic hemolytic anemia, and renal injury, providers should maintain a high index of suspicion for PI-associated TMA and should initially discontinue the PI while evaluating all potentially etiologies of TMA. Nothing to report.