D Parasternal long-axis view that shows posterior wall thickening with a speckled appearance. A moderate pericardial effusion is noted with inversion of RV free wall consistent with increased intrapericardial pressures. Frequent contraction bands were seen. The adjacent myocardium showed reactive changes with myocyte swelling, interstitial edema and hemorrhage, and a mixed inflammatory cell infiltrate of macrophages, neutrophils, and lymphocytes. The coronary arteries were free from atherosclerosis and vasculitis, but microvascular thrombosis was evident Figure 1B.
The morphologic findings were compatible with cyclophosphamide-induced toxic myocarditis. The precise mechanism of cyclophosphamide-induced cardiac toxicity has not been established. Cyclophosphamide metabolites are believed to cause oxidative stress and direct endothelial capillary damage with resultant extravasation of proteins, erythrocytes, and toxic metabolites Figure 2.
Breakdown of endothelial cells in the presence of toxic metabolites causes direct damage to the myocardium and capillary blood vessels resulting in edema, interstitial hemorrhage, and formation of microthrombi. These insults manifest clinically as acute heart failure and arrhythmias.
In , Appelbaum et al established the histopathological correlate in 3 out of 4 patients who developed fatal cyclophosphamide-induced cardiotoxicity. Although many of these findings were nonspecific for myocardial damage, capillary microthrombosis and fibrin deposition in myocardial interstitium were unique to cyclophosphamide-induced cardiac injury. Features in keeping with myocardial necrosis on electron microscopy included hypercontraction bands, myofibrillar damage, lysis, intramitochondrial electron dense inclusions, and fibrin deposition in myocyte cytoplasm.
Several subsequent gross pathological examinations have confirmed myocardial edema, thickening of the left ventricular wall and interventricular septum, myocardial necrosis, serosanguinous pericardial effusions, and fibrinous pericarditis.
Pathophysiology and clinical manifestations of cyclophosphamide-induced cardiac toxicity. A Carboxyphosphamide is an inactive metabolite. B Acrolein is associated with hemorrhagic cystitis. C Phosphamide mustard is the active cytotoxic metabolite. The spectrum of clinical manifestations from cyclophosphamide-induced cardiac toxicity is variable in presentation and in severity Figure 2. Common manifestations include tachyarrhythmias, hypotension, heart failure, myocarditis, and pericardial disease.
Hemorrhagic myocarditis is a rare complication that is uniformly and rapidly fatal. Once established, it invariably progresses from acute heart failure, to pericardial effusion with tamponade, cardiogenic shock, and eventually to death. It is difficult to establish the true incidence of cyclophosphamide cardiac toxicity as the literature relies on case reports in which the dose of cyclophosphamide administered is variable, and the drug is often administered in the presence of other cardiotoxins.
The lack of clearly defined predictive variables for cyclophosphamide cardiac toxicity makes it difficult to determine which patients will be at the greatest risk. There have been several case reports and series of young, otherwise healthy patients developing fatal cardiac toxicity.
The total dose of an individual course of cyclophosphamide therapy is a well-recognized risk factor for cardiac toxicity, but there is no consensus regarding a threshold dose. Drug—drug interactions at the hepatic microsomal cytochrome p level also influence the metabolism of cyclophosphamide to its active and toxic metabolites.
In , Brockstein et al found that advanced age and the type of malignancy were independent predictors of cyclophosphamide cardiac toxicity. They postulated that lymphoma might permit immune-mediated enhancement of cyclophosphamide-induced organ toxicity. Patients with preexisting risk factors for ischemic heart disease, prior or concomitant use of other cardiotoxins such as anthracyclines, and a history of radiation therapy to the mediastinum or left chest wall may have elevated baseline risk for cyclophosphamide cardiac toxicity.
Although little is known about the incidence of cardiac toxicity in patients with severe baseline left ventricular dysfunction, symptomatic heart failure is a reliable risk factor for predicting cardiac toxicity. Considering the potential for rapidly progressive lethal cardiac toxicity, early detection of cyclophosphamide-related cardiac insult is of paramount interest.
The most commonly employed noninvasive method of monitoring cardiac toxicity from chemotherapeutic agents is echocardiography. However, both depend on preload and afterload, which can be variable in these patients.
Cyclophosphamide-induced hemorrhagic myocarditis is associated with hypertrophy, increased myocardial echogenicity, a decrease in left ventricular ejection fraction, and a normal chamber size. Prolonged corrected QT QTc and increased QTc dispersion, the difference between maximum and minimum QTc interval on a lead ECG, are among the earliest changes in acute heart failure from high-dose cyclophosphamide-containing chemotherapy.
Circulatory cardiac markers may also be valuable in predicting chemotherapy-induced early cardiac toxicity. B-type natriuretic peptide BNP is perhaps the most promising in the setting of high-dose cyclophosphamide, since it is elevated within the first 24 hours of therapy and remains persistently elevated for up to 1 week after the clinical presentation of acute heart failure.
BNP is subsequently released as a response to increased cardiac filling pressures. Monitoring of highly sensitive plasma cardiac troponin I or troponin T, specific markers of myocardial damage, may also have some value in the monitoring of cyclophosphamide-induced cardiotoxicity. Troponin level tends to peak anywhere between 8 and 15 days after the administration of high-dose cyclophosphamide and is generally indicative of direct myocardial damage.
A general schematic approach to the baseline evaluation and subsequent sttif in the management of patients initiated on cyclophosphamide is provided in Figure 3. Cyclophosphamide therapy should be stopped with any potential clinical or laboratory signs of cardiac toxicity. Algorithm for cyclophosphamide initiation and monitoring for cyclophosphamide cardiac toxicity.
Once diagnosed, the treatment of cyclophosphamide-induced heart failure and arrhythmias should be no different from the general approach. Mild to moderate heart failure and small pericardial effusions generally resolve within a few days to weeks after discontinuation of cyclophosphamide.
In the presence of suspected cardiac tamponade, hemorrhagic myocarditis, and cardiogenic shock, early recognition and involvement of the intensive care unit or coronary care unit are imperative Figure 3. Based on our experience, these patients require aggressive monitoring and circulatory support for hemodynamics. Early diagnosis and interventions such as the consideration of extracorporeal membrane oxygenation and mechanical circulatory support to prevent hypoperfusion-related injury and death are required.
Due to its almost uniform fatality, the natural history of cyclophosphamide-induced severe cardiomyopathy in the presence of mechanical circulatory support is not known.
In the absence of alternative effective therapies, mechanical circulatory support may be a valuable tool for bridge to decision, recovery, or possibly cardiac transplantation.
Although we have outlined an algorithm detailing sttif that should be considered when planning cyclophosphamide therapy, the efficacy of this approach has not been validated in the clinical setting Figure 3. Cyclophosphamide has been used for several decades, but the pathophysiology of cyclophosphamide-induced cardiac toxicity remains poorly understood.
Moreover, differences in genetic susceptibilities to this potentially lethal medication have not been evaluated and may explain some of the variability seen in cardiotoxicity based on conventional dosing.
The greater off-label use of cyclophosphamide and other chemotherapeutic agents may increase the incidence of chemotherapy-induced cardiotoxicity, and clinicians need to be very aware of the diagnosis and management of this condition. Although the effect of early mechanical circulatory support implementation on overall outcome remains uncertain, it has the potential to support patients with an otherwise rapidly deteriorating course, allowing time for more rational and aggressive interventions, such as cardiac transplantation, which may be the only viable option for this end-stage cardiac toxicity.
The authors would like to acknowledge the physicians, surgeons, nurses, and other health care team members that provided such prodigious care of this patient.
We also thank Dr Todd Chaba from the Department of Anatomical Pathology at the University of Alberta for his interpretation of the pathology images for this case. National Center for Biotechnology Information , U. Published online Jan 1. Michael P. Gavin Y. Daniel H. Author information Copyright and License information Disclaimer. Corresponding author. Email: ac. This article is distributed under the terms of the Creative Commons Attribution 3. This article has been cited by other articles in PMC.
Abstract Cyclophosphamide is increasingly used to treat various types of cancers and autoimmune conditions. Keywords: cyclophosphamide, cardiotoxicity, cardiomyopathy, myocarditis, heart failure, mechanical circulatory support. Introduction Chemotherapy-induced cardiac dysfunction has become an important cause of morbidity and mortality in patients. Case Presentation A year-old female was initiated on high-dose cyclophosphamide for treatment of refractory neuromyelitis optica spectrum disorder—a group of demyelinating disorders affecting the optic nerve and spinal cord.
Open in a separate window. Figure 1. Pathophysiology of Cyclophosphamide-Induced Cardiomyopathy The precise mechanism of cyclophosphamide-induced cardiac toxicity has not been established. Figure 2. Abbreviation: LV, left ventricular. Clinical Presentation of Cyclophosphamide-Induced Cardiomyopathy The spectrum of clinical manifestations from cyclophosphamide-induced cardiac toxicity is variable in presentation and in severity Figure 2. Risk Factors for Cyclophosphamide-Induced Cardiomyopathy The lack of clearly defined predictive variables for cyclophosphamide cardiac toxicity makes it difficult to determine which patients will be at the greatest risk.
Screening and Management of Cyclophosphamide-Induced Cardiomyopathy Considering the potential for rapidly progressive lethal cardiac toxicity, early detection of cyclophosphamide-related cardiac insult is of paramount interest. Figure 3. Concluding Remarks Although we have outlined an algorithm detailing sttif that should be considered when planning cyclophosphamide therapy, the efficacy of this approach has not been validated in the clinical setting Figure 3.
Acknowledgments The authors would like to acknowledge the physicians, surgeons, nurses, and other health care team members that provided such prodigious care of this patient. References 1. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management.
Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol. Force T, Kolaja KL. Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes. Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer.
In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Since the rise of the COVID pandemic, clinicians aim to understand the implications of this new infectious disease, enabling them to make evidence based clinical decisions for their specific patient populations. Despite increasing knowledge on the antibody response of SARS-CoV-2 vaccinations in hematological patients and more specifically in patients treated by means of an allogeneic stem cell transplantation, limited data are available on the impact of treatment with cyclophosphamide post transplantation PTCy.
We hypothesize that this might preserve the ability to mount a robust antibody response against SARS-CoV-2, even in case of vaccination early after allogeneic stem cell transplantation. In this single-center, retrospective analysis, we describe a cohort of 70 consecutive patients transplanted for acute myeloid leukemia AML between February and July , who all received PTCy containing conditioning.
All patients were vaccinated with at least one dose of any type of SARS-CoV-2 vaccine, with the majority of patients receiving their first vaccination in April or May The antibody status of patients prior to vaccination was unknown. Previous exposure to endemic seasonal coronaviruses was also not documented [ 3 ].
Characteristics of the analyzed patient cohort are depicted in Table 1. Three patients, who had been diagnosed with a symptomatic COVID infection prior to initiation of the vaccination program, received only one vaccination all BNTb2.
Median time between transplantation and administration of the first vaccination was Of the 7 non-responders, 4 were treated with immune suppression for chronic graft versus host disease cGVHD 1 patient with tacrolimus and ibrutinib, 1 with tacrolimus and low dose prednisone and 2 with ruxolitinib monotherapy at the time of vaccination.
Two of the non-responders had stopped immunosuppressive medication 20 and 60 days before vaccination. Within our cohort, 10 patients were vaccinated soon after transplantation between 18 and days, with 4 patients still using tacrolimus. Only 1 of these 10 patients, who received ChAdOx1 nCoV vaccination, appeared to be a non-responder. Although the patient numbers are small, our data show that vaccination shortly after allogeneic stem cell transplantation with concurrent GVHD prophylaxis with tacrolimus, results in sufficient antibody responses see Fig.
This is in line with the general vaccination recommendations by the ECIL 7 guidelines, which recommend to start the revaccination program 3 months after transplantation, since sufficient immune reconstitution is to be expected to induce an adequate response to vaccination [ 4 ]. Type of conditioning or ongoing use of immune suppression was not reported [ 5 ].
Details concerning transplant regimens, the use of PTCy specifically and treatment with immune suppression were again not available.
It remains unclear whether these adequate vaccination responses after transplantation are a result of a specific pattern of immune reconstitution related to the use of PTCy, allowing a relative early cessation of immune suppression or that these responses can also be achieved in patients transplanted with different conditioning strategies ATG or alemtuzumab-based T-cell depletion or no T-cell depletion with prolonged use of multiple immunosuppressive agents.
This retrospective analysis of a consecutive patient cohort shows that AML patients, after allogeneic stem cell transplantation using PTCy conditioning, show a robust immune response to a SARS-CoV-2 mRNA-vaccination, even when administered relatively early after transplantation while still using tacrolimus. Fuchs EJ. HLA-haploidentical blood or marrow transplantation with high-dose, post-transplantation cyclophosphamide.
Bone Marrow Transpl. Lancet Oncol. J Clin Invest. Lancet Infect Dis. Article Google Scholar. Lancet Haematol. Vaccines Basel. Download references. Morsink, J. Choi, C. Hazenberg, A.
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