Journal of Cardiology Cases 10 (2014) 200–203

Case Report

Myopericarditis in a pregnant woman with acute promyelocyticleukemia

Andrew Oehler (MD)a,*, Shimoli Shah (MD)b

a OHSU Internal Medicine, Portland, OR, USAb OHSU Knight Cardiovascular Institute, Portland, OR, USA

A R T I C L E I N F O

Article history:

Received 8 April 2014

Received in revised form 16 June 2014

Accepted 15 July 2014

Keywords:

Pregnancy

Acute promyelocytic leukemia

Differentiation syndrome

Myopericarditis

A B S T R A C T

Acute promyelocytic leukemia (APL) is a form of acute leukemia with a characteristic translocation,

t(15;17), and is considered a hematologic emergency, typically treated with all-trans retinoic acid and an

anthracycline. We present the case of a young, gravid woman who was diagnosed with APL in the third

trimester, initiated typical treatment, and suffered uncommon cardiac complications.

<Learning objective: Myopericarditis is not a side effect often encountered in the management of acute

promyelocytic leukemia with alpha t-retinoic acid, and its mechanism is incompletely understood but

possibly related to the differentiation syndrome. This complication can be effectively treated with

systemic glucocorticoids, supportive care, and withdrawal of the offending agent, even in the pregnant

population.>

� 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Contents lists available at ScienceDirect

Journal of Cardiology Cases

jo u rn al ho m epag e: ww w.els evier . c om / lo cat e/ jcc as e

Introduction

Acute promyelocytic leukemia (APL) is an M3 form of acuteleukemia with a characteristic translocation t(15;17) and isconsidered a hematologic emergency. Leukemia generally affects1 in 70,000 pregnancies, a subset at higher risk of morbidity andmortality by virtue of underlying physiologic stress and potentialplacental transfer of chemotherapeutics. APL presents morecommonly relative to other myeloid leukemias in pregnancydue to its higher prevalence in younger populations [1,2]. Amongtreated, non-pregnant APL patients in the general population,survival rates exceed 70% [3]. Similar outcome data in pregnantpatients with treated APL are not available, but case reports ofsuccessful therapy have been published. Management of APL inpregnancy varies by trimester at diagnosis [1,4]. The mostcommonly used regimens involve high-dose all-trans retinoicacid (ATRA) along with an anthracycline both of which can havesignificant cardiotoxic effects. The case that follows is of a young,gravid woman who was diagnosed with APL in the third trimesterwith ensuing complications.

* Corresponding author at: OHSU Division of General Internal Medicine, 3181 SW

Sam Jackson Park Road L475, Portland, OR 97239-3098, USA. Tel.: +1 503 494 6551;

fax: +1 503 494 0979.

E-mail addresses: oehler@ohsu.edu, oehlerd@gmail.com (A. Oehler).

http://dx.doi.org/10.1016/j.jccase.2014.07.010

1878-5409/� 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All right

Case report

A 24-year-old obese woman with history of a prior pregnancycomplicated by preeclampsia was admitted to an outside hospitalfor easy bruising and headaches at 27 and 1/7 weeks pregnancy. Onpresentation, she was found to be pancytopenic, with an initialwhite blood cell (WBC) count of 1.0 � 109/L. Bone marrow biopsyrevealed an abnormally elevated number of myeloid blasts.Cytogenetic studies indicated t(15;17) consistent with APL. ATRAwas initiated on day 4 of admission at a dose of 45 mg/m2/day,with dexamethasone to induce fetal lung maturity. Cell countswere supported with intermittent packed red blood cell andplatelet transfusions. At day 7 she was transferred to a tertiarycenter for further management of this complicated pregnancy.

ATRA therapy was continued after transfer. Idarubicin at a doseof 12 mg/m2 and prednisone were also initiated (for four totaldoses on days 21, 23, 25, and 27). On the evening of day 26, the22nd day of ATRA therapy, she developed substernal, sharp chestpain radiating to the back, worse with deep inspiration, andpositional changes. She had been tachycardic throughout with aheart rate ranging from 120 to 140 bpm, but she was afebrile.Systolic BP had ranged from 110 to 140 mmHg over the previous24 h. Physical examination revealed tachycardia with a regularrhythm. S1 and S2 were normal. A ventricular gallop was present.There was a Grade I pericardial rub, with the patient leaningforward at end expiration. Hemogram was remarkable for WBCcount of 9.8 � 109/L with a neutrophilic predominance. Serum

s reserved.

Table 1 Timeline of laboratory abnormalities.

Day 0 8 26 33

Event Day of admission Day of transfer Onset of symptoms Resolution of symptoms

WBC (�109/L) 1.2 2.2 9.7 0.26

Hct (%) 24.2 23.2 25.3 29.8

Plt (�103/mm3) 8 26 41 11

Sodium (mmol/L) 136 139 135 133

Potassium (mmol/L) 3.8 3.8 4.1 3.7

Chloride (mmol/L) 105 109 105 101

Bicarbonate (mmol/L) 23 22 22 24

BUN (mg/dL) 6 8 8 7

Cr (mg/dL) 0.5 0.5 0.4 0.51

Troponin (ng/mL) 3.66 1.26a

NT-proBNP (pg/mL) 2877

WBC, white blood cells; Hct, hematocrit; Plt, platelets; BUN, blood urea nitrogen; Cr, creatinine; BNP, B-type natriuretic peptide.a Specimen collected on day 27 and was the last known troponin prior to resolution of symptoms.

A. Oehler, S. Shah / Journal of Cardiology Cases 10 (2014) 200–203 201

chemistry revealed normal electrolytes and baseline creatinine of0.56 mg/dL. B-type natriuretic peptide was elevated at 2877 pg/mL. Troponin was elevated at 3.66 ng/mL. See Table 1 for timelineof laboratory abnormalities. An electrocardiogram (ECG) revealedST elevations with associated PR depressions (Fig. 1). A chest X-raywas significant for hydrostatic pulmonary edema and normal heartsize. Computed tomography angiography of the chest did notreveal evidence of pulmonary embolism or consolidation. A trans-thoracic echocardiogram showed a small, circumferential pericar-dial effusion (Fig. 2) with multiple segmental wall motionabnormalities in a non-coronary distribution. The estimatedejection fraction was mildly reduced, at 45%. The constellationof findings was felt to be consistent with acute myopericarditis inthe setting of ATRA and idarubicin therapy.

ATRA and idarubicin were immediately discontinued due toconcern for acute cardiotoxic effects. Prednisone 60 mg daily wasinitiated to treat the myopericarditis. Chest pain improved onlyafter an increase in prednisone dosage to 80 mg daily. Metoprololwas added for arrhythmia prophylaxis and treatment of cardio-myopathy. Hydralazine and isosorbide dinitrate were used for

Fig. 1.12-lead electrocardiogram from day 26 with chest pain. Notice ST segment el

indicative of both ventricular and atrial epicardial inflammation.

afterload reduction. Low-dose furosemide was given for diuresis asneeded. The patient developed a brief, symptomatic episode ofatrial fibrillation with rapid ventricular response on hospital day31 with spontaneous conversion to sinus rhythm. The metoprololdose was subsequently increased. No further atrial or ventriculararrhythmias occurred.

Chest pain resolved completely 7 days after initiation ofprednisone. Troponin down trended. A repeat transthoracicechocardiogram at admission day 40 showed normalization ofleft ventricular function and segmental wall motion abnormalities.The pericardial effusion was no longer present. There was noevidence of pericardial constriction.

The patient’s course was further complicated by Gram-negativebacteremia and hyperglycemia secondary to steroid administra-tion. Labor was induced, and she delivered vaginally at 34 weekswith an estimated blood loss of 200 mL. The baby was healthy withonly a brief hospital stay for hyperbilirubinemia. The patient wasdischarged shortly after delivery with plans for outpatientconsolidation chemotherapy. A slow prednisone taper of 10 mgper week was recommended. Metoprolol was continued. Therapy

evations in leads I, II, aVL, and V3–V6 with PR depressions in the associated leads

Fig. 2. Parasternal long-axis view demonstrating a posterior pericardial effusion (see arrow).

A. Oehler, S. Shah / Journal of Cardiology Cases 10 (2014) 200–203202

with an angiotensin-converting enzyme inhibitor was initiated,and isosorbide dinitrate and hydralazine were discontinued.

Discussion

This patient developed myopericarditis in the setting of thirdtrimester pregnancy, APL, and administration of ATRA andidarubicin. The acute cardiotoxic effects were resolved with thediscontinuation of ATRA and idarubicin, initiation of high-doseprednisone, and standard heart failure therapy. The differentialdiagnosis for her syndrome included: takotsubo cardiomyopathy,anthracycline-induced cardiomyopathy, ATRA-induced myoper-icarditis, viral myocarditis, and peripartum cardiomyopathy.

Acute myopericarditis is a known, rare complication of ATRAtherapy in the setting of APL with a total of 6 reported cases [5–9],but it has never been reported in pregnancy. One case reportedhistological findings on autopsy of APL cells infiltrating themyocardium in this setting, suggesting pathophysiologic correla-tion with differentiation syndrome [7]. Differentiation syndrome(DS) is a complication of APL therapy with ATRA due to rapidtherapeutic differentiation of undifferentiated peripheral promye-locytes leading to tissue infiltration of cells. Myopericarditistraditionally lies outside the recognized pattern of DS, typicallypresenting clinically as unexplained fever, weight gain, peripheraledema, dyspnea with interstitial infiltrates, pleuropericardialeffusion, hypotension, and acute kidney injury [10]. Differentiationsyndrome occurs in 2–31% of patients receiving induction therapydepending on adjunctive agents administered with ATRA (anthra-cyclines diminish this risk) and the presence of other risk factors,including elevated WBC count at start of therapy, peak WBC countduring therapy, elevated body mass index (BMI), and creatininelevel [10–12]. Our patient did have a significantly elevated BMI,although WBC count at onset of therapy was unremarkable. Thesyndrome carries a mortality rate in non-pregnant populationsfrom 2% to 10% [13]. Management typically includes stoppage ofATRA and initiation of steroid immunosuppression.

The patient also recently received idarubicin, so the questionarises about the contribution of anthracycline toxicity. There arethree known time frames of toxicity: early, chronic, and late onset.Early onset toxicity can occur anytime in the acute phase followinginitiation of idarubicin therapy, is dose-dependent, and characteris-tically involves high rates of atrial and ventricular arrhythmias[14,15]. Our patient received a relatively low total dose of idarubicin,48 mg/m2, well under the prescribed toxic point of 350 mg/m2 [16].In addition, she had only one self-limited episode of an atrialarrhythmia. In the setting of receiving ATRA therapy, acuteanthracycline-induced cardiotoxicity was felt to be less likely.

Takotsubo and peripartum cardiomyopathy (CM) were alsoentertained in the differential; however her echocardiographicwall motion pattern was not consistent with takotsubo (i.e. basalsegment hypokinesis with apical ballooning). Peripartum CM canpresent in the last trimester of pregnancy, but typically does notinvolve the pericardium [17]. A viral myopericarditis was felt to beunlikely given a more proximal culprit, the ATRA therapy, and thepatient’s lack of a viral prodrome [18].

Classic findings of myopericarditis on transthoracic echocar-diogram often include a pericardial effusion, with segmental leftventricular wall motion abnormalities and depressed left ventric-ular ejection fraction. Cardiac biomarkers are also typicallyelevated. Prognosis varies by etiology, but reported mortalityrates for biopsy-verified myocarditis are upwards of 20% and 56%at 1 and 4 years [19]. Treatment of myopericarditis is largelysupportive, namely with the initiation of standard heart failuretherapy [20]. Few rigorous comparisons have been drawn betweentherapies for various etiologies of the syndrome. Therapy forisolated pericarditis focuses specifically on symptom control withanti-inflammatory medications including aspirin, non-steroidalanti-inflammatory drugs (NSAIDs), colchicine, and prednisone.Non-aspirin NSAIDs have not traditionally been used in treatmentof pericarditis when myocardium is involved due to the risk of poorscar formation and wound healing [21]. Therapeutic modalitiesavailable in the pregnant patient with myocarditis, pericarditis, ormyopericarditis are limited (Table 2) by fetal concerns [22].

Table 2 Treatment modalities for acute pericarditis in the gravid female.

Medication FDA Pregnancy Risk

Classificationa

All NSAIDs Class D

Aspirin <100 mg/day Class B

Prednisone Class B

Colchicine Class C

FDA, Food and Drug Administration; NSAIDs, non-steroidal anti-inflam-

matory drugs.a Class A: Adequate studies fail to demonstrate risk to fetus in first

trimester. Class B: No adequate studies, but animal studies do not

demonstrate risk. Class C: No adequate studies, but animal studies have

shown an adverse effect in the fetus. Class D: Positive evidence of human

fetal risk based on adverse reaction data, but benefit may outweigh risk.

Class X: Positive evidence of human fetal risk based on adverse reaction

data, and risk clearly outweighs benefit.

A. Oehler, S. Shah / Journal of Cardiology Cases 10 (2014) 200–203 203

ATRA-associated myopericarditis in the pregnant patient hasnever been reported. In this setting, it can be difficult to identify thetrue inciting agent amongst a plethora of potential toxic agents.ATRA is the most likely culprit for reasons described above, althoughthe mechanism of insult, whether by direct toxicity or leukemicinfiltration, remains unclear. A management strategy similar to thenon-pregnant patient was used. Future studies will be limited by thelow prevalence of this treatment complication, but may focus onduration of therapy, as the side effects of prednisone in the pregnantpopulation are accentuated by fetal concerns.

Contributors

We would like to thank the Knight Cancer Institute and OHSUObstetrics & Gynecology for their aid in caring for this patient. Wewould also like to thank Drs Alan Hunter and Joseph Chiovaro fortheir aid in the project.

Funding

None.

Conflict of interest

Andrew Oehler and Shimoli Shah have no conflicts of interest toreport.

References

[1] Yang D, Hladnik L. Treatment of acute promyelocytic leukemia during preg-nancy. Pharmacotherapy 2009;29:709–24.

[2] Brenner B, Avivi I, Lishner M. Haematological cancers in pregnancy. Lancet2012;379:580–7.

[3] Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, Naoe T,Lengfelder E, Buchner T, Dohner H, Burnett AK, Lo-Coco F. Management ofacute promyelocytic leukemia: recommendations from an expert panel onbehalf of the European LeukemiaNet. Blood 2009;113:1875–91.

[4] Ganzitti L, Fachechi G, Driul L, Marchesoni D. Acute promyelocytic leukemiaduring pregnancy. Fertil Steril 2010;94:2330.e5–0.e.

[5] Fabbiano F, Magrin S, Cangialosi C, Felice R, Mirto S, Pitrolo F. All-trans retinoicacid induced cardiac and skeletal myositis in induction therapy of acutepromyelocytic leukaemia. Br J Haematol 2005;129:444–5.

[6] Klein S, Biemond B, Van Oers M. Two cases of isolated symptomatic myocar-ditis induced by all-trans retinoic acid (ATRA). Ann Hematol 2007;86:917–8.

[7] Van Rijssel R, Wegman J, Oud M, Pals S, Van Oers M. A case of ATRA-inducedisolated myocarditis in the absence of circulating malignant cells: demonstra-tion of the t(15;17) translocation in the inflammatory infiltrate by in situhybridization. Leuk Res 2010;34:e142–4.

[8] Is ık P, Cetin I, Tavil B, Azik F, Kara A, Yarali N, Tunc B. All-transretinoic acid(ATRA) treatment-related pancarditis and severe pulmonary edema in a childwith acute promyelocytic leukemia. J Pediatr Hematol Oncol 2010;32:e346–8.

[9] De Santis G, Madeira M, De Oliveira L, Falcao R, Rego E. Cardiac stunning as amanifestation of ATRA differentiation syndrome in acute promyelocytic leu-kemia. Med Oncol 2012;29:248–50.

[10] Montesinos P, Bergua JM, Vellenga E, Rayon C, Parody R, de la Serna J, Leon A,Esteve J, Milone G, Deben G, Rivas C, Gonzalez M, Tormo M, Dıaz-Mediavilla J,Gonzalez JD, et al. Differentiation syndrome in patients with acute promye-locytic leukemia treated with all-trans retinoic acid and anthracycline che-motherapy: characteristics, outcome, and prognostic factors. Blood 2009;113:775–83.

[11] Breccia M, Mazzarella L, Bagnardi V, Disalvatore D, Loglisci G, Cimino G, TestiAM, Avvisati G, Petti MC, Minotti C, Latagliata R, Foa R, Pelicci PG, Lo-Coco F.Increased BMI correlates with higher risk of disease relapse and differentiationsyndrome in patients with acute promyelocytic leukemia treated with theAIDA protocols. Blood 2012;119:49–54.

[12] Leblebjian H, DeAngelo DJ, Skirvin JA, Stone RM, Wadleigh M, Werner L,Neuberg DS, Bartel S, McDonnell AM. Predictive factors for all-trans retinoicacid-related differentiation syndrome in patients with acute promyelocyticleukemia. Leuk Res 2013;37:747–51.

[13] Rogers J, Yang D. Differentiation syndrome in patients with acute promyelo-cytic leukemia. J Oncol Pharm Pract 2012;18:109–14.

[14] Bristow M, Thompson P, Martin R, Mason J, Billingham M, Harrison D. Earlyanthracycline cardiotoxicity. Am J Med 1978;65:823–32.

[15] Woods T, Vidarsson B, Mosher D, Stein J. Transient effusive-constrictivepericarditis due to chemotherapy. Clin Cardiol 1999;22:316–8.

[16] Volkova M, Russell R. Antracycline cardiotoxicity: prevalence, pathogenesisand treatment. Curr Cardiol Rev 2011;7:214–20.

[17] Blauwet L, Cooper L. Diagnosis and management of peripartum cardiomyop-athy. Heart 2011;97:1970–81.

[18] Mahfoud F, Gartner B, Kindermann M, Ukena C, Gadomski K, Klingel K, KandolfR, Bohm M, Kindermann I. Virus serology in patients with suspected myocar-ditis: utility or futility? Eur Heart J 2010;32:789–903.

[19] Mahfoud F, Gartner B, Kindermann M, Ukena C, Gadomski K, Klingel K, KandolfR, Bohm M, Kindermann I. A clinical trial of immunosuppressive therapy formyocarditis. N Engl J Med 1995;333:269–75.

[20] Magnani J, Dec G, Myocarditis:. Current trends in diagnosis and treatment.Circulation 2006;113:876–90.

[21] Mahfoud F, Gartner B, Kindermann M, Ukena C, Gadomski K, Klingel K, KandolfR, Bohm M, Kindermann I. Pericardial disease: diagnosis and management.Mayo Clin Proc 2010;85:572–93.

[22] Imazio M, Brucato A, Rampello S, Armellino F, Trinchero R, Spodick DH, Adler Y.Management of pericardial diseases during pregnancy. J Cardiovasc Med2010;11:557–62.