Acute and fatal cardiotoxicity following high-dose cyclophosphamide in a patient undergoing autologous stem cell transplantation for systemic sclerosis despite satisfactory cardiopulmonary screening

Autologous stem cell transplantation (ASCT) using high-dose cyclophosphamide (HD CYC) is currently the best therapeutic approach for early rapidly progressive systemic sclerosis (SSc) with diffuse skin and/or visceral involvement.1, 2 The importance of a careful disease specific pre-transplantation evaluation of cardiopulmonary involvement has been recently emphasized to reduce treatment-related mortality.1, 2, 3

We report a case of acute heart failure following ASCT, related to histologically proven CYC cardiotoxicity in a rapidly progressive SSc without any evidence of SSc-related cardiopathy or pulmonary arterial hypertension (PAH) prior to transplant.

A 54-year-old woman with SSc diagnosed 2 years ago, without any other past medical history, was referred for ASCT in light of rapid extensive skin fibrosis (modified Rodnan skin score 37/51) and pulmonary involvement (decreased diffusing capacity of the lung for carbon monoxide at 60% and interstitial infiltrate). Heart function was in the normal range on all pre-transplant evaluations, including troponin Ic, 24 h Holter electrocardiogram monitoring, echocardiography (with tissue Doppler and quantitative assessment of right ventricular function) and cardiac magnetic resonance imaging (MRI). This latter included native T1 and T2 mapping before gadolinium contrast IV injection, further completed by analysis of T1 mapping and late gadolinium enhancement 15 to 20 min after injection. Left and right ventricular ejection fractions were normal without myocardial areas of gadolinium enhancement. Figure 1 illustrate the absence of flat septum or D-sign. For the left ventricle, T2, native T1 and extra cellular volume were 53 ms, 920 ms and 25%, respectively, and so considered within the normal range for our expert center, which has normal reference values in 30 subjects analyzed with exactly the same MRI methodology using the same 1.5 Tesla system.

Figure 1
figure1

Pre-transplant cardiac magnetic resonance imaging. Short axis views at two basal locations (a, b) and (c, d) at end-diastole (a, c) and telesystole (b, d) illustrating the absence of flat septum (or D-sign) and the normal ejection fraction of both left and right ventricles. A full colour version of this figure is available at the Bone Marrow Transplantation journal online.

Peripheral blood hematopoietic stem cells were mobilized with IV CYC (a total of 3 g/m2 administered in equal amounts on 2 consecutive days), and filgrastim (10 μ/kg/day for 5 days), allowing collection of 8.59 × 106 CD34+ cells/kg in one cytapheresis, that were frozen in a final DMSO and albumin concentration of 10 and 4%, respectively. There was no excess toxicity, including cardiovascular complications.

After 1 month, the patient returned for conditioning regimen and ASCT. The echocardiography showed stable left ventricular ejection fraction (LVEF) at 63% with no kinetic abnormalities, normal systolic pulmonary arterial pressure (24 mmHg) and no pericardial effusion. Brain natriuretic peptide (BNP), troponin Ic, renal and hepatic functions were in the normal range. She received IV CYC with a total dose of 200 mg/kg over 4 consecutive days (3 g/day with a total dose of 12 g) with 2 liters of 0.9% IV saline/day, and IV rabbit antithymocyte globulins (2.5 mg/kg/day for 3 consecutive days).1 The day of transplant (day 0), BNP was 285 ng/L (N<100) and troponin Ic was 0.04 μg/L (N<0.04). After thawing, the stem cells were washed twice to remove the maximum of DMSO and rapidly infused.

Within 12 h after transplant, the patient developed progressive acute pulmonary edema necessitating IV diuretics. After 10 h, she complained of intermittent anterior chest pain with acute dyspnea. Examination confirmed blood pressure at 90/45 mmHg, regular tachycardia at 130 beats/min, bilateral lung crackles and oxygen saturation of 89% on room air. Electrocardiogram showed diffuse micro-voltage and chest X-ray showed acute pulmonary edema. Troponin Ic was 9.59 μg/L and BNP was 7136 ng/L. Echocardiography showed severe global hypokinesia with a LVEF<10% and no sign of acute right pulmonary heart. A CYC-induced cardiogenic shock was suspected and the patient was transferred to the intensive care unit. Cardiac arrest occurred shortly after transfer and the patient was supported with extra corporeal membrane oxygenation. Despite intensive supportive treatment, IV dobutamine and therapeutic range anticoagulation with heparin, echocardiography showed no improvement in heart function and a left heart thrombus rapidly extending into the pulmonary veins developed while simultaneous intracerebral hemorrhage contraindicated intensive anticoagulation. Supportive care limitation was then decided and patient died within 24 h (day 9 after ASCT).

On autopsy, the heart showed moderate hemorrhagic pericarditis, intra-cavity thrombus extended to the pulmonary veins and inferior vena cava (Figure 2a). Standard frozen sections revealed spotting under the epicardium and within the myocardium, diffuse myocardial necrosis and hemorrhages without inflammatory or malignant cells (Figures 2b and c). There was no interstitial fibrosis or myocyte hypertrophy and no sign of viral myocarditis. The coronary arteries were normal. These results were consistent with an acute CYC-induced cardiotoxicity.

Figure 2
figure2

Post-mortem light microscopy of heart section (hematoxylin–eosin staining). (a) Adherent thrombus (left side) to the endocardium with diffuse interstitial edema (black arrows) (× 4 magnification). (b) Interstitial hemorrhage (white arrow), diffuse interstitial edema (black arrow) and no evidence of fibrosis neither inflammatory infiltrate (× 20 magnification). (c) Evidence for diffuse ischemic myocardial necrosis: nuclear extravasation or pycnosis (white arrows), hyper-eosin staining of the cytoplasm. Intracellular edema (black arrows) and diffuse interstitial edema are also observed (× 40 magnification).

We report the first histologically proven case of fulminant fatal CYC-related cardiotoxicity in a patient treated by ASCT for an autoimmune disease, a situation that appears very rare and unpredictable.

Acute CYC-related cardiotoxicity has been previously reported in cancer patients who received simultaneous cardiotoxic drugs such as anthracyclines.4, 5 Post-mortem examinations, the only means of confirming direct CYC causality, are rare. CYC-related cardiotoxicity usually occurs in the first 3 weeks after drug administration.6 Clinical presentation is an acute and severe congestive heart failure. A micro-voltage with sinus tachycardia is commonly observed as well as increased serum levels of troponin Ic.4, 5, 7 Echocardiography constantly reveals severe biventricular failure and global hypokinesia. Pericardial effusion can be observed.4, 5, 6 In one reported case of a patient treated for non-Hodgkin lymphoma, post-mortem examination showed normal arteries, myocardial hemorrhage and necrosis, without inflammatory cells or fibrosis, a picture similar to our findings.5

Pathogenesis of acute CYC toxicity is thought to be related to toxic endothelial damage leading to extravasation of active CYC metabolites and increased free oxygen radicals, with consequent cardiomyocyte apoptosis, interstitial hemorrhage and edema.6 Elderly patients, history of mediastinal irradiation and prior anthracycline exposure may confer a higher risk of acute CYC cardiotoxicity.8 Acute severe toxicity is so rare that susceptibility factors have been suggested, but no correlation was shown between hepatic cytochromes genotype and CYC clearance in vivo.9 Moreover, a pre-emptive strategy using anti-oxidant agents seems inefficient.10

In this case report, the causal relationship is certain. First, our patient had no cardiac risk factors and received a standard conditioning CYC regiment dose.1 Based on the strict normality of both echocardiography and MRI including T1 mapping before and after gadolinium injection at the time of pre-transplant evaluation, right heart catheterization with fluid challenge was not performed.1 Pre-ASCT screening was normal excluding SSc-related myocardial fibrosis, PAH as well as a cardiomyopathy of other cause. Second, the clinical presentation was typical. Finally, and above all, post-mortem histological examination confirmed an acute CYC-related cardiotoxicity with no evidence of fibrosis, infarction or inflammatory cells. Moreover, while DMSO has been reported to possibly induce cardiotoxicity—especially by in vitro studies11—its contribution seems unlikely here. In our patient, the stem cells were washed twice to remove the maximum of DMSO before infusion, with a final concentration thus much lower than the 10% before freezing (the residual DMSO concentration is not evaluated in our standard practice), and the symptoms and cardiac necropsy were typical of an acute CYC-related cardiotoxicity.

Acute CYC-cardiotoxicity can be fatal but its incidence seems very low. To date, based on the European Group for Blood and Marrow Transplantation registry, among the 400 treated SSc patients, four died within 10 days after HD CYC for ASCT from acute cardiac failure. In the ASTIS trial, only one patient in the transplant group died from progressive heart failure 11 days after transplant but it was attributed to underlying SSc involvement.1 Other data have clearly shown that early death from cardiovascular events are mainly due to underevaluation of pre-existing cardiovascular involvement (including PAH, primary cardiac involvement and pericardial disease).12 SSc has complex cardiac manifestations and a robust pre-transplant disease specific screening is needed to limit underlying misdiagnosed SSc-related cardiopathy. Such screening however does not prevent from severe acute CYC-cardiotoxicity.

In conclusion, we report here the first histologically proven case of acute HD CYC-related cardiotoxicity following ASCT for SSc. Fortunately, this transplant complication is exceptional, but further research is warranted given its unpredictable nature, and that current management is reactive with supportive care. In the meantime, we alert clinicians to the need for careful monitoring during administration of intermediate to high doses of CYC (and accompanying fluids) as conditioning for ASCT. When possible, consideration of lower and fractioned schedule doses of CYC is a reasonable recommendation.

References

  1. 1

    van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA 2014; 311: 2490.

    CAS  Article  Google Scholar 

  2. 2

    Burt RK, Shah SJ, Dill K, Grant T, Gheorghiade M, Schroeder J et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet 2011; 378: 498–506.

    CAS  Article  Google Scholar 

  3. 3

    Snowden JA, Saccardi R, Allez M, Ardizzone S, Arnold R, Cervera R et al. Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2012; 47: 770–790.

    CAS  Article  Google Scholar 

  4. 4

    Katayama M, Imai Y, Hashimoto H, Kurata M, Nagai K, Tamita K et al. Fulminant fatal cardiotoxicity following cyclophosphamide therapy. J Cardiol 2009; 54: 330–334.

    Article  Google Scholar 

  5. 5

    Atalay F, Gulmez O, Ozsancak Ugurlu A . Cardiotoxicity following cyclophosphamidetherapy: a case report. J Med Case Reports 2014; 8: 252.

    Article  Google Scholar 

  6. 6

    Morandi P, Ruffini PA, Benvenuto GM, Raimondi R, Fosser V . Cardiac toxicity of high-dose chemotherapy. Bone Marrow Transplant 2005; 35: 323–334.

    CAS  Article  Google Scholar 

  7. 7

    Dadfarmay S, Berkowitz R, Kim B . Irreversible end-stage cardiomyopathy following a single dose of cyclophosphamide. Congest Heart Fail 2012; 18: 234–237.

    Article  Google Scholar 

  8. 8

    Senkus E, Jassem J . Cardiovascular effects of systemic cancer treatment. Cancer Treat Rev 2011; 37: 300–311.

    CAS  Article  Google Scholar 

  9. 9

    Raccor BS, Claessens AJ, Dinh JC, Park JR, Hawkins DS, Thomas SS et al. Potential contribution of cytochrome P450 2B6 to hepatic 4-hydroxycyclophosphamide formation in vitro and in vivo. Drug Metab 2012; 40: 54–63.

    CAS  Article  Google Scholar 

  10. 10

    Nishikawa T, Miyahara E, Kurauchi K, Watanabe E, Ikawa K, Asaba K et al. Mechanisms of fatal cardiotoxicity following high-dose cyclophosphamide therapy and a method for its prevention. PLoS ONE 2015; 10: e0131394.

    Article  Google Scholar 

  11. 11

    Himmel HM . Drug-induced functional cardiotoxicity screening in stem cell-derived human and mouse cardiomyocytes: effects of reference compounds. J Pharmacol Toxicol Methods 2013; 68: 97–111.

    CAS  Article  Google Scholar 

  12. 12

    Burt RK, Oliveira MC, Shah SJ, Moraes DA, Simoes B, Gheorghiade M et al. Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: a retrospective analysis. Lancet 2013; 381: 1116–1124.

    Article  Google Scholar 

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Martin, M., Fornecker, Lm., Marcellin, L. et al. Acute and fatal cardiotoxicity following high-dose cyclophosphamide in a patient undergoing autologous stem cell transplantation for systemic sclerosis despite satisfactory cardiopulmonary screening. Bone Marrow Transplant 52, 1674–1677 (2017). https://doi.org/10.1038/bmt.2017.188

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