Proteasome inhibitor associated thrombotic microangiopathy

Abstract

A variety of medications have been implicated in the causation of thrombotic microangiopathy (TMA). Recently, a few case reports have emerged of TMA attributed to the proteasome inhibitors (PI) bortezomib and carfilzomib in patients with multiple myeloma. The aim of this case series was to better characterize the role of PI in the etiology of drug‐induced TMA. We describe eleven patients from six medical centers from around the world who developed TMA while being treated with PI. The median time between medication initiation and diagnosis of TMA was 21 days (range 5 days to 17 months). Median laboratory values at diagnosis included hemoglobin—7.5 g dL−1, platelet count—20 × 109/L, LDH—698 U L−1, creatinine—3.12 mg dL−1. No patient had any other cause of TMA, including ADAMTS13 inhibition, other malignancy or use of any other medication previously associated with TMA. Nine patients had resolution of TMA without evidence of hemolysis after withdrawal of PI. Two patients had stabilization of laboratory values but persistent evidence of hemolysis despite medication withdrawal. One patient had recurrence of TMA with rechallenge of PI. There is a strong level of evidence that PI can cause DITMA. In evaluating patients with suspected TMA, PI use should be recognized as a potential etiology, and these medications should be discontinued promptly if thought to be the cause of TMA. Am. J. Hematol. 91:E348–E352, 2016. © 2016 Wiley Periodicals, Inc.

None of the above: thrombotic microangiopathy beyond TTP and HUS

“…Proof of drug-dependent antibodies can confirm the cause, but the absence of these does not rule it out, 29 as was the case of a recently reported DI-TMA caused by proteasome inhibitors carfilzomib and bortezumib. 34,35 Patients with immunemediated DI-TMA will usually have a relevant history of exposure to a drug known to cause this condition. They will present with systemic symptoms and acute kidney injury on their first exposure to the suspected drug.…”

Therapy for Relapsed Multiple Myeloma

“…There are rare reports of thrombotic microangiopathy with PI, and therefore clinicians need to be aware of this problem, especially in patients who develop hypertension and thrombocytopenia during therapy. 72 Proteasome inhibitors may be associated with an increased risk of cardiotoxicity, and this potential complication has to be kept in mind when patients present with symptoms of congestive heart failure. 73 …”

Carfilzomib‐induced hemolysis is noticeably common but rarely shows features of thrombotic microangiopathy: A retrospective study

“…One patient had undergone an allogeneic stem cell transplantation (SCT), whereas 15 of 24 (63%) had undergone autologous SCT. CFZ was given intravenously, together with oral dexamethasone, on days 1, 2, 8,9,15, and 16 of a 28-day cycle.…”

“…(MAHA) as the hallmark of thrombotic microangiopathy (TMA) has been described in single patients treated with CFZ [4][5][6][7] and in case series, [8][9][10][11] the latter also including patients treated with bortezomib. 9 Besides MAHA, CFZ-induced TMA presented commonly with renal failure and hypertension in addition to thrombocytopenia. [4][5][6][7][8][9][10][11] Recently, mostly well-compensated hemolysis was observed in 8 of 10 patients treated with CFZ in a single center.…”

“…9 Besides MAHA, CFZ-induced TMA presented commonly with renal failure and hypertension in addition to thrombocytopenia. [4][5][6][7][8][9][10][11] Recently, mostly well-compensated hemolysis was observed in 8 of 10 patients treated with CFZ in a single center. 12 The most sensitive and specific hemolysis parameter is a decreased plasma level of the heme scavenger protein haptoglobin (Hp).…”