Bortezomib induced reversible left ventricular systolic dysfunction: a case report and review of literature.
Bortezomib is a reversible proteasome inhibitor, currently approved by US FDA for use in multiple myeloma and mantle cell lymphoma. It has been shown to cause new onset and exacerbation of underlying congestive cardiac failure (CHF) in some case reports. Although the exact mechanism of bortezomib induced congestive cardiac failure is unknown, studies have shown dysregulation of ubiquitin proteasome system (UPS) in human cardiac tissues in end stage heart failure (1-3). Furthermore, a study in rats has shown reduced left ventricular contractility after bortezomib administration, which was attributed to reduced ATP synthesis in mitochondria of cardiac myocytes (4). Our case demonstrates new onset severe reversible left ventricular systolic dysfunction after 4 cycles of bortezomib in a 58 year old female with multiple myeloma. It highlights the importance of monitoring cardiac function in patients receiving bortezomib.
A 58 year old female with past medical history of well controlled hypertension presented with severe low back pain, anorexia and unintentional weight loss of around 20 pounds over a period of 3 months in medical clinic. On evaluation of her routine laboratory tests, she was found to have haemoglobin of 6.5 g/dl, haematocrit of 19.9%, white blood cell (WBC) count of 3.9 x [10.sup.3]/cc, red blood cell (RBC) count of 2.18 x [10.sup.6]/cc and platelet count of 1.52 x [10.sup.5]/cc. Her blood urea nitrogen and creatinine was 10 mg/dl and 0.7 mg/dl respectively and corrected calcium level was 10g/dl. On liver function test, her total protein was 12.4 g/dl and albumin level was 2.8 g/dl. X-ray of lumbosacral spine revealed a compression fracture at the level of T12and L2 vertebra. Bone survey confirmed diffuse osteopenia, severe collapse of the body of T12 and partial collapse of L2 and L3. Due to the presence of severe anaemia and compression fractures, multiple myeloma was suspected. Urine protein electrophoresis showed two monoclonal protein bands with concentration of 46.8% and 4.8% and urine immunofixation showed two intact monoclonal IgA-Kappa immunoglobulin bands. Beta-2 microglobulin level was 5.49. Bone marrow aspiration and biopsy confirmed the diagnosis of multiple myeloma. Patient was staged as IIIA according to Durie-Salmon staging system.
Subsequently, patient was planned to be treated with eight cycles of bortezomib and dexamethasone, with bortezomib being given on day 1, 4, 8 and 11 of each cycle at a dose of 1.3 mg/[m.sup.2] body surface area. Prior to initiation of chemotherapy, she received radiotherapy to spine as well. However, after completing the fourth cycle of bortezomib/dexamethasone, she was admitted to the hospital with generalized weakness, nausea and vomiting. Chest X ray revealed possible right lower lobe infiltrate or effusion along with increased bronchovascular markings and she was treated with antibiotics for suspected community acquired pneumonia. However, an echocardiogram was obtained due to bilateral crackles on physical exam and increased bronchovascular markings on chest X ray, which revealed dilation of left ventricle with left ventricular ejection fraction of 30-35%, diffuse hypo kinesis of left ventricle, mild mitral and tricuspid regurgitation and diastolic dysfunction with abnormal relaxation(Tajik grade I). Left ventricular septal and posterior wall thickness was 0.8 cm. Infiltrative Cardiomyopathy in the setting of multiple myeloma was unlikely due to the absence of bi-atrial enlargement, pericardial effusion and thick bright myocardium on echocardiogram. Cardiology consultation was sought and their impression was new onset left ventricular dysfunction due to bortezomib therapy.
Patient did not receive any further cycles of chemotherapy due to cardiotoxicity and was on optimal medical management for heart failure with lisinopril, carvedilol and isosorbide dinitrate. An echocardiogram was repeated four months after discontinuation of bortezomib, which revealed normal left ventricular contractility with global left ventricular ejection fraction of 55% and trace mitral regurgitation.
Currently, at 2 year follow up, her echocardiogram shows global left ventricular ejection fraction of 65%, trace mitral and tricuspid regurgitation and diastolic dysfunction with abnormal relaxation(Tajik grade I).
Discussion and Review of Literature
Botezomib is a novel proteasome inhibitor which acts by inducing bcl-2 phosphorylation and cleavage, resulting in G2M cell cycle phase arrest and apoptosis (5). US Food and Drug Administration (FDA) have approved bortezomib for use in multiple myeloma and mantle cell lymphoma. The common adverse effects of bortezomib observed in clinical trials and post marketing surveillance include thrombocytopenia, neutropenia, hypotension, asthenia, peripheral neuropathy and nausea. US package insert for bortezomib states that acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction and it is recommended to closely monitor patients with risk factor for, or existing heart disease.
The role of ubiquitin proteasome system (UPS) in heart failure has been studied extensively in recent years. Two studies by Hein et al and Weekes et al in 2003 have shown presence of increased amount of ubiquitinated proteins and substrates in cardiac tissues of heart failure patients, indicating reduced activity of UPS in end stage heart failure (1-3). Another study has shown impaired proteasome activity in hypertrophic and dilated cardiomyopathy likely secondary to post translational modification of proteasome (6). However, in early stage heart failure, there is increased activity of UPS, resulting in remodelling and high cardiac output (2). Bortezomib, by inhibiting UPS, would lead to accumulation of ubiquitinated proteins in cardiac myocytes, similar to that seen in end stage heart failure. A study in rats exposed to bortezomib alone showed development of left ventricular systolic dysfunction by echocardiography and reduced synthesis of ATP was observed in the mitochondria of cardiac myocytes (4). However, the exact mechanism of bortezomib induced systolic dysfunction in humans is not clear.
There have been a few reported cases of bortezomib induced congestive cardiac failure in literature (Table 1). The amount of bortezomib administered before development of symptoms of heart failure was 20.8 mg/[m.sup.2] in four patients, 3 mg/[m.sup.2] in one patient and 10.4mg/[m.sup.2] in one patient. Three of them have received prior anthracycline based chemotherapy. Complete reversibility of heart failure after discontinuation of bortezomib was documented only in two cases by follow up echocardiograms and brain natriuretic peptide levels (7, 8). The patient described in our index case had well controlled hypertension and no additional cardiac risk factors at baseline. She developed non-specific symptoms, including weakness, nausea and vomiting after the fourth cycle of chemotherapy and was admitted to the hospital for community acquired pneumonia. However, an echocardiogram was obtained due to pulmonary congestion, which uncovered the diagnosis of left ventricular systolic failure. The two echocardiograms obtained at a follow up of 4 months and 2 years showed gradual improvement in ejection fraction to 55% and 65% respectively from 15% after chemotherapy with bortezomib.
We did a review of major clinical trials of bortezomib in patients with multiple myeloma, Waldenstrom's macroglobulinemia and plasma cell leukaemia (Table 2) to investigate the incidence of congestive cardiac failure reported after administration of bortezomib. In APEX trial, the incidence of congestive cardiac failure was 2% in both bortezomib and high dose dexamethasone group (11). In a study on melphalan refractory multiple myeloma by Hjorth et al, 3 cases of congestive cardiac failure was reported in bortezomib-dexamethasone group and 2 cases were reported in thalidomidedexamethasone group (12). Another study evaluating the safety of prolonged therapy with bortezomib by Berenson et al reported 1 case of cardiomegaly and 1 case of pulmonary edema (13). However, further studies are needed to specifically evaluate the incidence of congestive cardiac failure with bortezomib therapy.
In summary, our case and review highlights the importance of maintaining a high level of suspicion for development of congestive cardiac failure after therapy with bortezomib. Given the widespread use of bortezomib and new generation proteasome inhibitors in multiple myeloma, there might be increased incidence of new onset and exacerbation of underlying congestive cardiac failure in future. Currently, there is no guideline for routine evaluation and monitoring of cardiac function in all patients during the course of bortezomib therapy. Furthermore, it is unclear whether the severity of congestive cardiac failure is proportional to the cumulative dosage of bortezomib administration and also, if there is any correlation between onsets of congestive cardiac failure with the timing of bortezomib therapy. Further studies are required in future to address these issues.
CHF is an infrequent but serious adverse effect of bortezomib. Cardiac function should be closely monitored in patients receiving bortezomib, as case reports have shown that these patients might present with non-specific symptoms like weakness and fatigue. Further studies are required to establish the frequency and mode of monitoring of cardiac function during and after bortezomib therapy.
RAJSHEKHAR CHAKRABORTY, MD, Queens Hospital Center(Affiliated to Icahn School of Medicine at Mount Sinai), New York, USA. SHIVA KUMAR R. MUKKAMALLA, MD, Queens Hospital Center(Affiliated to Icahn School of Medicine at Mount Sinai), New York, USA. NATALIA CALDERON, MD, Queens Hospital Center(Affiliated to Icahn School of Medicine at Mount Sinai), New York, USA.
CORRESSPONDENCE: DR RAJSHEKHAR CHAKRAB O RTY, Queens Hospital Center, Dept. of Internal Medicine, 82-68, 164th street, Jamaica, NY 11432. USA. Email: firstname.lastname@example.org
(1.) Hein S, Arnon E, Kostin S, et al. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: Structural deterioration and compensatory mechanisms. Circulation. 2003; 107(7):984-991.
(2.) Powell SR, Herrmann J, Lerman A, Patterson C, Wang X. The ubiquitin-proteasome system and cardiovascular disease. Prog Mol Biol Transl Sci. 2012;109:295-346. doi: 10.1016/B978-0-12-3978639.00009-2; 10.1016/B978-0-12-397863-9.00009-2.
(3.) Weekes J, Morrison K, Mullen A, Wait R, Barton P, Dunn MJ. Hyperubiquitination of proteins in dilated cardiomyopathy. Proteomics. 2003;3(2):208-216. doi: 10.1002/pmic.200390029.
(4.) Nowis D, Maczewski M, Mackiewicz U, et al. Cardiotoxicity of the anticancer therapeutic agent bortezomib. Am J Pathol. 2010;176(6):2658-2668. doi: 10.2353/ajpath.2010.090690; 10.2353/ajpath.2010.090690.
(5.) Ling YH, Liebes L, Ng B, et al. PS-341, a novel proteasome inhibitor, induces bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis. Mol Cancer Ther. 2002;1(10):841-849.
(6.) Predmore JM, Wang P, Davis F, et al. Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies. Circulation. 2010;121(8):997-1004. doi: 10.1161/CIRCULATIONAHA.109.904557; 10.1161/CIRCULATIONAHA.109.904557.
(7.) Voortman J, Giaccone G. Severe reversible cardiac failure after bortezomib treatment combined with chemotherapy in a non-small cell lung cancer patient: A case report. BMC Cancer. 2006;6:129. doi: 10.1186/1471-2407-6-129.
(8.) Bockorny M, Chakravarty S, Schulman P, Bockorny B, Bona R. Severe heart failure after bortezomib treatment in a patient with multiple myeloma: A case report and review of the literature. Acta Haematol. 2012;128(4):244-247. doi: 10.1159/000340050; 10.1159/000340050.
(9.) Enrico O, Gabriele B, Nadia C, et al. Unexpected cardiotoxicity in haematological bortezomib treated patients. Br J Haematol. 2007;138(3):396-397. doi: 10.1111/j.1365-2141.2007.06659.x.
(10.) Hacihanefioglu A, Tarkun P, Gonullu E. Acute severe cardiac failure in a myeloma patient due to proteasome inhibitor bortezomib. Int J Hematol. 2008;88(2):219-222. doi: 10.1007/s12185-008-0139-7; 10.1007/s12185-008-0139-7.
(11.) Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352(24):2487-2498. doi: 10.1056/NEJMoa043445.
(12.) Hjorth M, Hjertner O, Knudsen LM, et al. Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma: A randomized study. Eur J Haematol. 2012;88(6):485-496. doi: 10.1111/j.1600-0609.2012.01775.x; 10.1111/j.1600-0609.2012.01775.x.
(13.) Berenson JR, Jagannath S, Barlogie B, et al. Safety of prolonged therapy with bortezomib in relapsed or refractory multiple myeloma. Cancer. 2005;104(10):2141-2148. doi: 10.1002/cncr.21427.
(14.) Chen CI, Kouroukis CT, White D, et al. Bortezomib is active in patients with untreated or relapsed waldenstrom's macroglobulinemia: A phase II study of the national cancer institute of canada clinical trials group. J Clin Oncol. 2007;25(12):1570-1575. doi: 10.1200/JCO.2006.07.8659.
(15.) D'Arena G, Valentini CG, Pietrantuono G, et al. Frontline chemotherapy with bortezomib-containing combinations improves response rate and survival in primary plasma cell leukemia: A retrospective study from GIMEMA multiple myeloma working party. Ann Oncol. 2012;23(6):1499-1502. doi: 10.1093/annonc/mdr480; 10.1093/annonc/mdr480.
(16.) Jagannath S, Barlogie B, Berenson J, et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004;127(2):165-172. doi: 10.1111/j.1365-2141.2004.05188.x.
(17.) Jagannath S, Durie BG, Wolf JL, et al. Extended follow-up of a phase 2 trial of bortezomib alone and in combination with dexamethasone for the frontline treatment of multiple myeloma. Br J Haematol. 2009;146(6):619-626. doi: 10.1111/j.1365-2141.2009.07803.x; 10.1111/j.1365-2141.2009.07803.x.
(18.) Kobayashi T, Kuroda J, Shimura K, et al. Bortezomib plus dexamethasone for relapsed or treatment refractory multiple myeloma: The collaborative study at six institutes in kyoto and osaka. Int J Hematol. 2010;92(4):579-586. doi: 10.1007/s12185-010-0696-4; 10.1007/s12185-010-0696-4.
(19.) Mikhael JR, Belch AR, Prince HM, et al. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: Results of a global phase 3b expanded access program. Br J Haematol. 2009;144(2):169-175. doi: 10.1111/j.1365-2141.2008.07409.x; 10.1111/j.1365 2141.2008.07409.x.
(20.) Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348(26):2609-2617. doi: 10.1056/NEJMoa030288.
(21.) Rosinol L, Oriol A, Mateos MV, et al. Phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem-cell transplantation in younger patients with multiple myeloma: Efficacy and clinical implications of tumor response kinetics. J Clin Oncol. 2007;25(28):4452-4458. doi: 10.1200/JCO.2007.12.3323.
(22.) Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: Results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012;30(24):2946-2955. doi: 10.1200/JCO.2011.39.6820; 10.1200/JCO.2011.39.6820.
(23.) Yuan ZG, Jin J, Huang XJ, et al. Different dose combinations of bortezomib and dexamethasone in the treatment of relapsed or refractory myeloma: An open-label, observational, multi-center study in china. Chin Med J (Engl). 2011;124(19):2969-2974.
(24.) Suvannasankha A, Smith GG, Juliar BE, Abonour R. Weekly bortezomib/methylprednisolone is effective and well tolerated in relapsed multiple myeloma. Clin Lymphoma Myeloma. 2006;7(2):131-134. doi: 10.3816/CLM.2006.n.050.
Table 1: Review of cases of bortezomib induced congestive cardiac failure reported so far. Author Age/sex Prior cardiac history and risk factors Voortman et al (7) 53/M 36 pack years of smoking and COPD Orciuolo et al (9) 73/M NK * Orcioulo et al (9) 61/F NK Orciuolo et al (9) 80/F NK Hasihanefioglu et al (10) 47/M None Bockorny et al (8) 56/F Hypertension, well controlled INDEX CASE 58/F Hypertension, well controlled Author Baseline Number of cardiac Bortezomib function containing cycles Voortman et al (7) Echo not 4 available; NT-Pro BNP 1389 ng/l Orciuolo et al (9) NK 6 Orcioulo et al (9) NK 4 Orciuolo et al (9) NK 4 Hasihanefioglu et al (10) EF 70% and 2 normal Bockorny et al (8) NK 4 INDEX CASE NK 4 Author Exposure Amount of to other Bortezomib cardiotoxic received medications before onset of cardiac symptoms Voortman et al (7) Gemcitabine 3 mg/[m.sup.2] Orciuolo et al (9) 1 Anthracycline 20.8 mg/[m.sup.2] containing regimen Orcioulo et al (9) 2 Anthracycline 20.8 mg/[m.sup.2] containing regimens Orciuolo et al (9) 1 prior non 20.8 mg/[m.sup.2] anthracycline chemotherapy regimen received Hasihanefioglu et al (10) 1 cycle of 10.4 mg/[m.sup.2] Vincristine, Doxorubicin and Dexamethasone Bockorny et al (8) None 20.8 mg/[m.sup.2] INDEX CASE None 20.8 mg/[m.sup.2] Author Lowest EF on EF ** after follow Bortezomib up visits administration Voortman et al (7) 10-15% on 45% on Echo after MUGA 4 cycles scan at 6 months Orciuolo et al (9) EF 25% NK Orcioulo et al (9) EF 20% NK Orciuolo et al (9) EF 35% NK Hasihanefioglu et al (10) EF 10% EF 20% at 6 month follow up Bockorny et al (8) EF 20-25% EF 5560% INDEX CASE EF 30-35% EF 55% at 4 month and 65% at 2 year follow up. * NK: Not Known; ** EF: Ejection Fraction Table 2: Review of cases of congestive cardiac failure reported in clinical trials with bortezomib in multiple myeloma, Waldenstrom's Macroglobulinemia and plasma cell leukaemia. Authors (ref) Study Study population Berenson, J.R. et Safety of prolonged 63 patients with al. 2005 (13) therapy with relapsed and/or bortezomib in refractory MM relapsed or refractory multiple myeloma Chen, C.I. et al. Bortezomib in 27 patients with 2007 (14) Waldenstrom's untreated or Macroglobulinemia relapsed WM D'Arena, G. et al. Frontline 29 patients with 2012 (15) chemotherapy with untreated PPCL bortezomib- containing combinations improves response rate and survival in primary plasma cell leukaemia Hjorth, M. et al. Thal-Dex vs. 131 patients with 2012 (12) Bort-Dex in Melphalan refractory refractory myeloma MM Jagannath, S. et al Bortezomib for 54 patients with 2009 (16) Relapsed or relapsed or Refractory Multiple refractory MM Myeloma Jagannath, S. et al Extended follow-up 49 patients with 2010 (17) of Frontline untreated MM Bortezomib [+ or -] Dexamethasone for MM Kobayashi, T. et al. Bortezomib plus 88 patients with 2010 (18) dexamethasone for relapse/refractory relapsed or MM treatment refractory multiple myeloma Mikhael, J.R. et al. High response rate 638 patients with 2009 (19) to bortezomib with refractory or or without relapsed MM dexamethasone in patients with relapsed or refractory multiple myeloma Richardson, P.G. et A Phase 2 Study of 202 patients with al. 2003 (20) Bortezomib in relapsed MM Relapsed, Refractory Myeloma Richardson, P.G. et Bortezomib or 669 patients with al. 2005 (11) High-Dose relapsed MM Dexamethasone for Relapsed Multiple Myeloma(APEX trial) Rosino, L. et al. Phase II PETHEMA 40 patients with 2007 (21) Trial of Alternating newly diagnosed MM Bortezomib and Dexamethasone As Induction Regimen Before Autologous Stem-Cell Transplantation in Younger Patients With Multiple Myeloma Sonneveld, P. et al. Bortezomib Induction 827 patients with 2012 (22) and Maintenance newly diagnosed MM Treatment in Patients With Newly Diagnosed Multiple Myeloma Yuan, Z.G. et al. Different dose 168 patients with 2011 (23) combinations of relapsed MM bortezomib and dexamethasone in the treatment of relapsed or refractory myeloma Suvannasankha et al Weekly bortezomib/ 29 patients with 2006 (24) methylprednisolone relapsed multiple in relapsed multiple myeloma myeloma Authors (ref) Significant Cardiac events (n) Berenson, J.R. et Cardiomegaly (1) MI, al. 2005 (13) SVT, Pulmonary oedema (1) Complete AV block (1) Chen, C.I. et al. Congestive Heart 2007 (14) Failure (1) D'Arena, G. et al. None reported 2012 (15) Hjorth, M. et al. 2 cases of cardiac 2012 (12) failure in Thal-Dex group and 3 in Bort- dex group Jagannath, S. et al None reported 2009 (16) Jagannath, S. et al None reported 2010 (17) Kobayashi, T. et al. None reported 2010 (18) Mikhael, J.R. et al. None reported 2009 (19) Richardson, P.G. et None reported al. 2003 (20) Richardson, P.G. et Congestive cardiac al. 2005 (11) failure in 2% of each arm. Rosino, L. et al. None reported 2007 (21) Sonneveld, P. et al. Cardiac Disorders in 2012 (22) 5% of patient in VAD group vs. 8% of patients in PAD group. Yuan, Z.G. et al. None reported 2011 (23) Suvannasankha et al 1 case of congestive 2006 (24) cardiac failure
|Printer friendly Cite/link Email Feedback|
|Title Annotation:||Case Report|
|Author:||Chakraborty, Rajshekhar; Mukkamalla, Shiva Kumar R.; Calderon, Natalia|
|Publication:||British Journal of Medical Practitioners|
|Article Type:||Clinical report|
|Date:||Dec 1, 2013|
|Previous Article:||Biologies in dermatology: a brief review.|
|Next Article:||Aggression and homicidal thoughts in a patient with primary hyperparathyroidism: a case report.|