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Bortezomib induced reversible left ventricular systolic dysfunction: a case report and review of literature.

Introduction

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.

Case Report

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.

Conclusion

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.

Competing Interests

None.

Author Details

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: rajshekhar.ucms@gmail.com

REFERENCES

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(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
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Title Annotation:Case Report
Author:Chakraborty, Rajshekhar; Mukkamalla, Shiva Kumar R.; Calderon, Natalia
Publication:British Journal of Medical Practitioners
Article Type:Clinical report
Geographic Code:4EUUK
Date:Dec 1, 2013
Words:3360
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