Dr. Elie Mouhayar received his medical degree from Beirut's Lebanese University. A clinical fellowship in cardiology at Geisinger Medical Center and a mini-fellowship in cardiovascular computed tomography at Johns Hopkins Medical Center were among his postgraduate studies. Internal medicine, cardiology, and vascular medicine are all areas in which he is board certified. In 2008, he became a faculty member in the Department of Cardiology at M. D. Anderson. In this video Dr. Mouhayar speaks on Reversible Myocardial Edema Secondary to Tagraxofusp-Induced Capillary Leak Syndrome.https://www.jacc.org/doi/10.1016/j.jaccao.2021.09.009IntroductionIn blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare and clinically aggressive hematologic malignancy, CD123, the alpha subunit of the interleukin (IL)-3 receptor, is ubiquitously overexpressed. Tagraxofusp is a CD123-targeted diphtheria toxin (DT) conjugate medicine that was approved as a first-in-class treatment for BPDCN by the United States Food and Drug Administration in 2018. Capillary leak syndrome (CLS), characterized by hypoalbuminemia, fluid shift, and hypotension, is the most significant toxicity of tagraxofusp. As a sign of CLS, we present a case of tagraxofusp-induced, reversible cardiac edema.Presentation of a CaseBPDCN affecting the inguinal and external iliac lymph nodes was found in a 37-year-old Caucasian man with no history of heart illness. An EKG revealed sinus bradycardia, while a transthoracic echocardiogram revealed normal left ventricular (LV) wall thickness and ejection fraction (EF) with trace aortic and mitral valve regurgitation. At 25 pg/mL, the N-terminal pro–B-type natriuretic peptide was normal. Tagraxofusp 12 mcg/kg intravenously for 5 days was his first-line therapy, with premedications including intravenous (IV) methylprednisolone 50 mg daily. His serum albumin was kept above 3.2 g/dL and he was kept below his dry weight with intermittent IV albumin 25 percent and furosemide, respectively, to reduce the risk of CLS. In response to a tagraxofusp-related rise in liver transaminases (peak alanine transaminase 237 U/L, peak aspartate aminotransferase 529 U/L), he received three more days of IV methylprednisolone and was discharged from the hospital on day 8 of the first cycle. He went to the ER two days later, complaining of weariness, dyspnea, and peripheral edema. He was afebrile at first, with a blood pressure of 114/76 mm Hg, a heart rate of 115 beats per minute, and an oxygen saturation of less than 90% on room air. A computed tomography pulmonary angiogram revealed no pulmonary emboli, but rather interval development of extensive mixed solid and ground glass pulmonary nodules, interstitial pulmonary edema, small bilateral dependent pleural effusions, and a small to moderate pericardial effusion when compared to a chest computed tomography 20 days earlier. He was admitted to the hospital for further investigation and therapy after receiving empiric IV antibiotics for pneumonia and furosemide 40 mg IV. The following were included in the differential diagnosis:1.CLS secondary to tagraxofusp was the most common differential diagnosis.2.Due to the lack of extended neutropenia and fever, pneumonia/sepsis is less prevalent.3.Acute cardiomyopathy/heart failure: Acute cardiomyopathy caused by stress or infection.4.Due to the lack of risk factors, myocardial ischemia has the lowest probability.Clinical TrainingHe had no viral prodrome in the preceding weeks, according to his comprehensive medical history. At the time of admission, the patient's ECG revealed new inverted T waves in the inferolateral leads as well as freshly elevated cardiac biomarkers (high-sensitivity troponin T 118 ng/L [normal 18 ng/L] and N-terminal pro–B-type natriuretic peptide 3,498 pg/mL [normal 125 pg/mL]). Despite previous preventive albumin infusions, his serum albumin level had dropped from 4.8 to 3.2 mg/dL. His CBC revealed a 33.2 K/L leukocytosis, a hematocrit of 52 percent, and thrombocytopenia (platelet count of 40,000/L). With normal renal function, hyponatremia (sodium 132 mEq/L) was seen. His transaminase values in the liver remained significantly increased (alanine transaminase 179 U/L and aspartate aminotransferase 158 U/L). His blood and urine cultures were negative, as was a nasopharyngeal PCR swab for common respiratory viral infections (including SARS-CoV-2). A repeat transthoracic echocardiography was conducted, and there were no new segmental wall motion abnormalities or changes in LV systolic function as compared to his baseline examination from a few weeks prior. However, there was a three-fold increase in the thickness of the LV apical wall, as well as poorer myocardial relaxation and lower mitral annular tissue Doppler velocities. The LV had a similar appearance to apical hypertrophic cardiomyopathy in terms of morphology. The free wall thickness of the right ventricle (RV) was also enhanced. His peak LV global longitudinal strain has decreased from 21.3 percent to 15.5 percent (an unhealthy value of 18 percent). Initial cardiac magnetic resonance imaging (1.5-T) revealed normal cardiac chamber diameters, concentric LV and RV hypertrophy, normal biventricular systolic function (LVEF 63 percent, RVEF 50 percent), and no regional wall motion abnormalities. With a modest circumferential pericardial effusion, the pericardium was of normal thickness. With an elevated T2 value of 68 milliseconds (normal 55 milliseconds) and an increased LV mass index of 89.69 g/m2 (normal 75 g/m2), there was myocardial patchy late gadolinium enhancement (Figure 1A). The extracellular volume fraction (ECV) was 28 percent (normal = 25.3 percent 3.5 percent) and the native T1 value in the midseptum was 1,462 milliseconds (normal = 1,034 39 milliseconds).His presentation was suspected to be a manifestation of CLS with subsequent myocardial edema based on the cardiac biomarker damage pattern and echocardiographic/CMR findings. He was first given supplemental oxygen through a nasal cannula, a 3 mg/h furosemide infusion, 125 mg IV methylprednisolone every 6 hours, and 25 g albumin 25% every 12 hours, with a daily negative fluid balance of 1-2 L and a target trough serum albumin >3.2 g/dL. Because of the quick clinical recovery, an endomyocardial biopsy was discussed but not performed. Over the course of five days, his fatigue, dyspnea, hypoxia, and peripheral edema improved. Three days after admission, a restricted transthoracic echocardiography revealed an LVEF of 70% and continued wall thickening, mostly in the apical segments. On a tapering dose of oral prednisone and diuretic, he was discharged home 7 days following hospitalisation. Over the course of eight weeks, he was continuously monitored in the outpatient environment, with his cardiac biomarkers gradually normalizing. A repeat CMR one month following admission revealed that the prior delayed hyperenhancement had resolved, with both T2 maps (49 milliseconds) and LV mass index (74 g/m2) values normalized (Figure 1B). The ECV and native T1 values both dropped to 1,207 milliseconds and 21%, respectively. Three months after hospitalization, a repeat echocardiography revealed complete recovery of earlier biventricular thickness alterations and pericardial effusion, as well as normalization of tissue Doppler values and LV global longitudinal strain.The patient's BPDCN-directed medication was restarted a month later with a lower dose of tagraxofusp (9 g/kg 3 days) and daily diuretic and albumin infusions as a precaution. He tolerated the next five rounds well and went on to receive an allogeneic stem cell transplant, following which he has been in total remission for over 1.5 years.DiscussionThe common biological endpoint of vascular endothelial hyperpermeability caused by a number of triggering etiologies is capillary leak syndrome (CLS). The clinical triad of hypoalbuminemia, hemoconcentration, and hypotension, which can develop to distributive shock if left untreated, is caused by extravasation of plasma and proteins into the interstitial space. Clarkson illness is the eponymous idiopathic form of CLS (1). CLS can be caused by autoimmune illnesses, viral infections, or snakebites, however medications are the most prevalent secondary cause. Chemotherapy and immunomodulatory medicines, such as gemcitabine, pemetrexed, IL-2, and others, account for 80% of the offending agents (2). Acute management entails detecting and eliminating any triggering substance, reversing oncotic effects with albumin or other colloids, and neutralizing humoral inflammatory mediator effects. Diuresis vs. intravenous fluid resuscitation necessitates deliberation because it is dependent on the danger of pulmonary edema and compartment syndrome. This, in turn, is dependent on patient comorbidities and CLS causation; for example, in drug-induced CLS (2), pulmonary edema is considerably more prevalent than Clarkson illness (2). (1).Several cases of Clarkson disease have been documented to have myocardial edema caused by CLS, with symptoms ranging from echocardiographic ventricular wall thickening without systolic dysfunction to cardiogenic shock with severe LV failure requiring extracorporeal life support (3-7). Importantly, both live and postmortem cardiac biopsies have consistently shown generalized edematous alterations without signs of acute inflammation or myocyte necrosis, implying myositis or infarction (3,8). Reversible biventricular thickness with concomitant systolic dysfunction is a common echocardiographic characteristic, although only in the most severe cases. By analyzing T2 values and ECV, CMR allows for a quantitative assessment of myocardial edema. Patients with current idiopathic CLS have greater cardiac ECV values than age-matched control participants and patients with a history of idiopathic CLS in remission, according to a prospective CMR study (4).Recombinant human IL-3 is fused to a truncated DT in Tagraxofusp. The uptake of the diphtheria toxin by vascular endothelium, resulting in endothelial cell death and artery wall leakage, is thought to be the cause of tagraxofusp-related CLS. On a clinical trial, CLS was recorded in 55% (7%) of those treated with tagraxofusp for BPDCN, with a median duration to onset of 5 days (9). The initial examination of tagraxofusp safety data by the US Food and Drug Administration indicated that there was no attributable particular severe cardiac harm (10). Myocarditis is a well-known side effect of a diphtheria infection in the lungs. The shortened DT utilized in tagraxofusp, on the other hand, has not been linked to myocarditis.Our patient had various symptoms that were similar to the myocardial edema seen with Clarkson disease. Within days of finishing his first cycle of tagraxofusp, he developed fast weight gain, relative hypoalbuminemia, and hypoxemia with frank pulmonary edema without indications of sepsis or LV systolic dysfunction, which is consistent with drug-induced CLS. The rapid-onset, reversible ventricular thickening seen on echocardiography is suggestive with transitory myocardial edema. The accompanying changes in T2 maps, LV index, and ECV on CMR, as well as their eventual normalization, support this diagnosis. There was no discernible alternative differential in the patient's case. Although the likelihood of undiscovered acute myocarditis cannot be ruled out, CLS-mediated myocardial damage is more likely based on the clinical presentation and cardiac imaging results.This example emphasizes the need of detecting cardiac edema as an uncommon but dangerous indication of CLS, which in this case was caused by tagraxofusp. The need of early noninvasive cardiac imaging in detecting secondary myocardial edema and ruling out other ischemic, inflammatory, and infiltrative cardiomyopathies is crucial. The reversibility of CLS-related myocardial injury is highlighted by the dynamic improvement in this patient's baseline echocardiographic and CMR abnormalities.ConclusionsTagraxofusp is a CD123-targeted diphtheria toxin conjugate medication given intravenously for the treatment of uncommon hematological malignancies. In a tagraxofusp-induced capillary leak syndrome, we present an instance of cardiac involvement (CLS). The importance of using longitudinal noninvasive cardiac imaging to recognize this pattern of reversible cardiac injury, as well as the early application of measures to reverse the fluid retention and oncotic effects of CLS, and the successful rechallenge of the CD123-directed agent in subsequent cycles after the occurrence of CLS, are highlighted in this case. - Cardiology - 653_600c9efaa3c99

Dr. Elie N. Mouhayar, MD- Reversible Myocardial Edema Secondary to Tagraxofusp-Induced Capillary Leak Syndrome @EMouhayar @MDAndersonNews #MyocardialEdema #Cardiology #Research

Dr. Elie N. Mouhayar, MD- Reversible Myocardial Edema Secondary to Tagraxofusp-Induced Capillary Leak Syndrome @EMouhayar @MDAndersonNews #MyocardialEdema #Cardiology #Research

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Dr. Elie Mouhayar received his medical degree from Beirut's Lebanese University. A clinical fellowship in cardiology at Geisinger Medical Center and a mini-fellowship in cardiovascular computed tomography at Johns Hopkins Medical Center were among his postgraduate studies. Internal medicine, cardiology, and vascular medicine are all areas in which he is board certified. In 2008, he became a faculty member in the Department of Cardiology at M. D. Anderson. In this video Dr. Mouhayar speaks on Reversible Myocardial Edema Secondary to Tagraxofusp-Induced Capillary Leak Syndrome.

https://www.jacc.org/doi/10.1016/j.jaccao.2021.09.009

Introduction
In blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare and clinically aggressive hematologic malignancy, CD123, the alpha subunit of the interleukin (IL)-3 receptor, is ubiquitously overexpressed. Tagraxofusp is a CD123-targeted diphtheria toxin (DT) conjugate medicine that was approved as a first-in-class treatment for BPDCN by the United States Food and Drug Administration in 2018. Capillary leak syndrome (CLS), characterized by hypoalbuminemia, fluid shift, and hypotension, is the most significant toxicity of tagraxofusp. As a sign of CLS, we present a case of tagraxofusp-induced, reversible cardiac edema.


Presentation of a Case

BPDCN affecting the inguinal and external iliac lymph nodes was found in a 37-year-old Caucasian man with no history of heart illness. An EKG revealed sinus bradycardia, while a transthoracic echocardiogram revealed normal left ventricular (LV) wall thickness and ejection fraction (EF) with trace aortic and mitral valve regurgitation. At 25 pg/mL, the N-terminal pro–B-type natriuretic peptide was normal. Tagraxofusp 12 mcg/kg intravenously for 5 days was his first-line therapy, with premedications including intravenous (IV) methylprednisolone 50 mg daily. His serum albumin was kept above 3.2 g/dL and he was kept below his dry weight with intermittent IV albumin 25 percent and furosemide, respectively, to reduce the risk of CLS. In response to a tagraxofusp-related rise in liver transaminases (peak alanine transaminase 237 U/L, peak aspartate aminotransferase 529 U/L), he received three more days of IV methylprednisolone and was discharged from the hospital on day 8 of the first cycle. He went to the ER two days later, complaining of weariness, dyspnea, and peripheral edema. He was afebrile at first, with a blood pressure of 114/76 mm Hg, a heart rate of 115 beats per minute, and an oxygen saturation of less than 90% on room air. A computed tomography pulmonary angiogram revealed no pulmonary emboli, but rather interval development of extensive mixed solid and ground glass pulmonary nodules, interstitial pulmonary edema, small bilateral dependent pleural effusions, and a small to moderate pericardial effusion when compared to a chest computed tomography 20 days earlier. He was admitted to the hospital for further investigation and therapy after receiving empiric IV antibiotics for pneumonia and furosemide 40 mg IV. The following were included in the differential diagnosis:



1.CLS secondary to tagraxofusp was the most common differential diagnosis.

2.Due to the lack of extended neutropenia and fever, pneumonia/sepsis is less prevalent.

3.Acute cardiomyopathy/heart failure: Acute cardiomyopathy caused by stress or infection.

4.Due to the lack of risk factors, myocardial ischemia has the lowest probability.


Clinical Training

He had no viral prodrome in the preceding weeks, according to his comprehensive medical history. At the time of admission, the patient's ECG revealed new inverted T waves in the inferolateral leads as well as freshly elevated cardiac biomarkers (high-sensitivity troponin T 118 ng/L [normal 18 ng/L] and N-terminal pro–B-type natriuretic peptide 3,498 pg/mL [normal 125 pg/mL]). Despite previous preventive albumin infusions, his serum albumin level had dropped from 4.8 to 3.2 mg/dL. His CBC revealed a 33.2 K/L leukocytosis, a hematocrit of 52 percent, and thrombocytopenia (platelet count of 40,000/L). With normal renal function, hyponatremia (sodium 132 mEq/L) was seen. His transaminase values in the liver remained significantly increased (alanine transaminase 179 U/L and aspartate aminotransferase 158 U/L). His blood and urine cultures were negative, as was a nasopharyngeal PCR swab for common respiratory viral infections (including SARS-CoV-2). A repeat transthoracic echocardiography was conducted, and there were no new segmental wall motion abnormalities or changes in LV systolic function as compared to his baseline examination from a few weeks prior. However, there was a three-fold increase in the thickness of the LV apical wall, as well as poorer myocardial relaxation and lower mitral annular tissue Doppler velocities. The LV had a similar appearance to apical hypertrophic cardiomyopathy in terms of morphology. The free wall thickness of the right ventricle (RV) was also enhanced. His peak LV global longitudinal strain has decreased from 21.3 percent to 15.5 percent (an unhealthy value of 18 percent). Initial cardiac magnetic resonance imaging (1.5-T) revealed normal cardiac chamber diameters, concentric LV and RV hypertrophy, normal biventricular systolic function (LVEF 63 percent, RVEF 50 percent), and no regional wall motion abnormalities. With a modest circumferential pericardial effusion, the pericardium was of normal thickness. With an elevated T2 value of 68 milliseconds (normal 55 milliseconds) and an increased LV mass index of 89.69 g/m2 (normal 75 g/m2), there was myocardial patchy late gadolinium enhancement (Figure 1A). The extracellular volume fraction (ECV) was 28 percent (normal = 25.3 percent 3.5 percent) and the native T1 value in the midseptum was 1,462 milliseconds (normal = 1,034 39 milliseconds).

His presentation was suspected to be a manifestation of CLS with subsequent myocardial edema based on the cardiac biomarker damage pattern and echocardiographic/CMR findings. He was first given supplemental oxygen through a nasal cannula, a 3 mg/h furosemide infusion, 125 mg IV methylprednisolone every 6 hours, and 25 g albumin 25% every 12 hours, with a daily negative fluid balance of 1-2 L and a target trough serum albumin >3.2 g/dL. Because of the quick clinical recovery, an endomyocardial biopsy was discussed but not performed. Over the course of five days, his fatigue, dyspnea, hypoxia, and peripheral edema improved. Three days after admission, a restricted transthoracic echocardiography revealed an LVEF of 70% and continued wall thickening, mostly in the apical segments. On a tapering dose of oral prednisone and diuretic, he was discharged home 7 days following hospitalisation. Over the course of eight weeks, he was continuously monitored in the outpatient environment, with his cardiac biomarkers gradually normalizing. A repeat CMR one month following admission revealed that the prior delayed hyperenhancement had resolved, with both T2 maps (49 milliseconds) and LV mass index (74 g/m2) values normalized (Figure 1B). The ECV and native T1 values both dropped to 1,207 milliseconds and 21%, respectively. Three months after hospitalization, a repeat echocardiography revealed complete recovery of earlier biventricular thickness alterations and pericardial effusion, as well as normalization of tissue Doppler values and LV global longitudinal strain.



The patient's BPDCN-directed medication was restarted a month later with a lower dose of tagraxofusp (9 g/kg 3 days) and daily diuretic and albumin infusions as a precaution. He tolerated the next five rounds well and went on to receive an allogeneic stem cell transplant, following which he has been in total remission for over 1.5 years.

Discussion

The common biological endpoint of vascular endothelial hyperpermeability caused by a number of triggering etiologies is capillary leak syndrome (CLS). The clinical triad of hypoalbuminemia, hemoconcentration, and hypotension, which can develop to distributive shock if left untreated, is caused by extravasation of plasma and proteins into the interstitial space. Clarkson illness is the eponymous idiopathic form of CLS (1). CLS can be caused by autoimmune illnesses, viral infections, or snakebites, however medications are the most prevalent secondary cause. Chemotherapy and immunomodulatory medicines, such as gemcitabine, pemetrexed, IL-2, and others, account for 80% of the offending agents (2). Acute management entails detecting and eliminating any triggering substance, reversing oncotic effects with albumin or other colloids, and neutralizing humoral inflammatory mediator effects. Diuresis vs. intravenous fluid resuscitation necessitates deliberation because it is dependent on the danger of pulmonary edema and compartment syndrome. This, in turn, is dependent on patient comorbidities and CLS causation; for example, in drug-induced CLS (2), pulmonary edema is considerably more prevalent than Clarkson illness (2). (1).



Several cases of Clarkson disease have been documented to have myocardial edema caused by CLS, with symptoms ranging from echocardiographic ventricular wall thickening without systolic dysfunction to cardiogenic shock with severe LV failure requiring extracorporeal life support (3-7). Importantly, both live and postmortem cardiac biopsies have consistently shown generalized edematous alterations without signs of acute inflammation or myocyte necrosis, implying myositis or infarction (3,8). Reversible biventricular thickness with concomitant systolic dysfunction is a common echocardiographic characteristic, although only in the most severe cases. By analyzing T2 values and ECV, CMR allows for a quantitative assessment of myocardial edema. Patients with current idiopathic CLS have greater cardiac ECV values than age-matched control participants and patients with a history of idiopathic CLS in remission, according to a prospective CMR study (4).

Recombinant human IL-3 is fused to a truncated DT in Tagraxofusp. The uptake of the diphtheria toxin by vascular endothelium, resulting in endothelial cell death and artery wall leakage, is thought to be the cause of tagraxofusp-related CLS. On a clinical trial, CLS was recorded in 55% (7%) of those treated with tagraxofusp for BPDCN, with a median duration to onset of 5 days (9). The initial examination of tagraxofusp safety data by the US Food and Drug Administration indicated that there was no attributable particular severe cardiac harm (10). Myocarditis is a well-known side effect of a diphtheria infection in the lungs. The shortened DT utilized in tagraxofusp, on the other hand, has not been linked to myocarditis.



Our patient had various symptoms that were similar to the myocardial edema seen with Clarkson disease. Within days of finishing his first cycle of tagraxofusp, he developed fast weight gain, relative hypoalbuminemia, and hypoxemia with frank pulmonary edema without indications of sepsis or LV systolic dysfunction, which is consistent with drug-induced CLS. The rapid-onset, reversible ventricular thickening seen on echocardiography is suggestive with transitory myocardial edema. The accompanying changes in T2 maps, LV index, and ECV on CMR, as well as their eventual normalization, support this diagnosis. There was no discernible alternative differential in the patient's case. Although the likelihood of undiscovered acute myocarditis cannot be ruled out, CLS-mediated myocardial damage is more likely based on the clinical presentation and cardiac imaging results.



This example emphasizes the need of detecting cardiac edema as an uncommon but dangerous indication of CLS, which in this case was caused by tagraxofusp. The need of early noninvasive cardiac imaging in detecting secondary myocardial edema and ruling out other ischemic, inflammatory, and infiltrative cardiomyopathies is crucial. The reversibility of CLS-related myocardial injury is highlighted by the dynamic improvement in this patient's baseline echocardiographic and CMR abnormalities.

Conclusions
Tagraxofusp is a CD123-targeted diphtheria toxin conjugate medication given intravenously for the treatment of uncommon hematological malignancies. In a tagraxofusp-induced capillary leak syndrome, we present an instance of cardiac involvement (CLS). The importance of using longitudinal noninvasive cardiac imaging to recognize this pattern of reversible cardiac injury, as well as the early application of measures to reverse the fluid retention and oncotic effects of CLS, and the successful rechallenge of the CD123-directed agent in subsequent cycles after the occurrence of CLS, are highlighted in this case.

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