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Bortezomib-Associated severe orthostatic hypotension and hyponatremia / Bortezomib Ilsjili Ortostatik Hipotansiyon ve Hiponatremi.

To the Editor,

The most frequent side effects of bortezomib are fatigue, hematologic toxicity with cytopenias, and peripheral neuropathy, whereas postural hypotension and hypo-natremia are less common late side effects (1), (2). Hypo-natremia is a potentially fatal complication that has been reported in 3%-22% of patients treated with bortezomib, and has been attributed to direct bortezomib toxicity and syndrome of inappropriate anti-diuretic hormone secretion (SIADH) (3). The direct toxicity of bortezomib might be dose dependent Ill; however; there is insufficient evidence to support this mode of action. We think hyponatre-mia in the presented patient was due to direct bortezomib toxicity, as it resolved following cessation of bortezomib and saline infusion.

A 68-year-old male with lgG kappa multiple myeloma had undergone autologous hematopoetic stem cell transplantation (ASCT). The disease progressed despite posttransplantation, thalidomide maintenance. Cyclophosphamide and dexamethasone (CD) was commenced 6 months post-transplantation; however, disease progression continued and 2 years post ASCT bortezomib monotherapy was started at the dose of 1.3 mg [m.sub.-2] on d 1, 4, 8, and 11, every 3 weeks. The first 2 courses of bortezomib were uneventful; however, on d 7 of the third cycle the patient was admitted to hospital due to dizziness and a syncope episode. Physical examination showed severe orthostatic hypotension in the absence of compensatory tachycardia, with blood pressure or 120/80 mmHg in the supine position and 60/50 mmHg while standing. He was not clinically dehydrated and there were no signs of infection or edema. Laboratory investigations showed isolated hypo-natremia without any other electrolyte abnormality (Na:1.26 mmol [L.sub.-1]; K: 3.5 mmol [L.sub.-1]; 98 mmol [L.sub.-1]). Serumbiochemistry, including the renal profile, was normal. A written consent was obtained from the patient about the treatments and use of data in his file.

Bortezomib was withdrawn and isotonic saline infusion was commenced. Sodium returned to normal without requiring fluid restriction; however, there was no improvement in orthostatic hypotension, despite normal cardiac findings. Holier electrocardiography, echocardiography, and carotid Doppler ultrasound were also normal, which excluded the possibility of cardiac etiology. Neurologic examination was suspicious for peripheral sensorial neuropathy, which was confirmed electromyography. Pregabalin 75 mg b.i.d. was started and the Close was increased to 150 mg b.i.d. 7 days later The patient's clinical condition improved 2 weeks after starting prega-balin treatment, without a recurrent syncope and with decreased dizziness.

Postural hypotension occurs in 10% of patients treated with bortezomib and is associated with dehydration, concomitant anti-hypertensive treatment, and/or autonomic neuropathy 141. The presented patient had no signs of dehydration and postural hypotension did not improve with saline infusion. Moreover, the presence of widespread peripheral neuropathy and the absence of compensatory tachycardia suggested that autonomic neuropathy was the cause of orthostatic hypotension.

As the number of myeloma patients treated with bortezomib increases, so is awareness of bortezomib-related side effects. Orthostatic hypotension associated with autonomic neuropathy and hyponatremia seems to be reversible with cessation of bortezomib and use of pregabalin. In conclusion, orthostatic hypotension and hyponatremia should be included in the differential diagnosis of treatment-related toxicity in myeloma patients treated with bortezomib.

Conflicts of Interest Statement

None of the authors of this letter have any conflicts of interest, including specific financial interests, relationships, and/or affiliations, relevant to the subject matter or materials included.

Address for Correspondence: Elif SUYANI, M.D.,

Gazi Universitesi Hastanesi, Eriskin Hematoloji, Besevler 06500 Ankara, Turkey Phone: +90 312 202 63 17 E-mail: eli.elifsuyani@hotmailcom

Reccived/Geli tarihi: May 24, 2011

Accepted/Kabul tarihi: February 21, 2012


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(2.) O'Connor OA, Wright. J, Moskowitz C, Muzzy J, MacGregor-Cortelli B, Stubblefield M, Straus D, Portlock C, P, Choi E, Dumetrescu 0, Esseltine D, Trehu E, Adams J, Schenkein D, Zelenetz AD. Phase 11 clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol 2005; 23 (4): 676-684

(3.) Brodmann 5, Gyr Klaas E., Cathomas R, Girardi V, von Moos R. Severe hyponatremia in a patient with mantle cell lymphoma treated with bortezomib: A case report and review of the literature. Onkologie 2007;30 (12): 651-654

(4.) Rajkumar SV, Richardson PG, Hideshima T, Anderson KC. Proteasome inhibition as a novel therapeutic target in human cancer. 3 Clin Oncol 2005; 23 (3): 630-639-

Elif Suyam (1), Zeynep Aki (1) Arzu Yegin (1), Gulsan Turkoz Sucak (1) (1) Gazi University, School of Medicine, Department of Hematology, Ankara, Turkey
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Author:Suyam, Elif; Aki, Zeynep; Yegin Zeynep Arzu; Sucak, Gulsan Turkoz
Publication:Turkish Journal of Hematology
Article Type:Case study
Geographic Code:7TURK
Date:Sep 1, 2012
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