Multiparametric Cardiac MRI in Patients Under CAR T-cell Therapy

Multiple Myeloma Clinical Trial

Official title:

Multiparametric Cardiac MRI in Oncological Patients Under Chimeric Antigen Receptor T-Cell Therapy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05414162
• Other study ID #: 81/22
• Status: Recruiting
• Start date: May 16, 2022
• Est. completion date: December 2025

Study information

• Verified date: June 2022
• Source: University Hospital, Bonn
• Contact: Julian Luetkens, MD
• Phone: +49 228 287 11831
• Email: julian.luetkens[@]ukbonn.de
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Recently chimeric antigen receptor (CAR) T-cell therapy, a new class of chemo therapy, has gained regulatory approval for the treatment of diseases such as B-cell lymphoma. Known side effects include cytokine release syndrome, which has been described to lead to myocarditis, but larger studies exploring this relationship are currently lacking. In this prospective study, the investigators aim to explore the potential effects of CAR T-cell therapy using cardiac MRI on the heart.

Description:

Genetically modified chimeric antigen receptor (CAR) T cells specifically targeting CD19 or "B cell maturation antigen" (BCMA) have shown remarkable advances in the treatment of highly refractory and relapsing hematological malignancies including diffuse large B-cell lymphoma or multiple myeloma. However, this potent therapy is hampered by serious, potentially life threatening complications, which might also involve the cardiovascular system. The potential cardiotoxic profile remains poorly defined and insufficiently understood. This proposal describes a prospective, longitudinal, intraindividual cardiac magnetic resonance imaging (MRI) study in oncological patients, which are scheduled for CAR T cell therapy for cancer treatment. This explorative study is designed to evaluate and monitor acute and late effects of CAR T cell therapy on the heart muscle. Systematic cardiac MRI monitoring correlated with the clinical course and thorough immunological assessment is the next step in helping to understand the extent, pattern, and pathophysiology of CAR T cell therapy related cardiovascular adverse events. A chimeric antigen receptor (CAR) is a recombinant fusion protein that activates T cells upon recognition of a specific antigen on the cell surface of target cells. Therapeutic success was especially noticed with CD19-specific CAR T cells in the treatment of highly refractory and relapsing hematological malignancies. CD19 is an effective target due to its expression throughout the development line of B cells and has a frequent and high-level expression on the surface of nearly all B-cell malignancies. In addition, it is not found on other normal tissue cells, including the heart, and is not shed as a soluble form. The process of manufacturing CAR T cells typically requires 3 to 4 weeks. Autologous T cells are first collected from the patient and then genetically modified ex vivo with lentiviral or retroviral vectors to reprogram the T cells to recognize tumor cells expressing a tumor associated antigen (e.g., CD19 or BCMA). The CAR T cells a multiplied in large quantities before being administered to the patient within a single infusion. Before the infusion of CAR T cells, patients undergo lymphodepleting chemotherapy, most commonly with a combination of fludarabine and cyclophosphamide. This suppresses the patient's endogenous T cell compartment and allows an in vivo expansion of the transferred CAR T cells. Although the CAR T cell therapy has clearly advanced the treatment of highly refractory or relapsing hematological malignancies, there are potentially severe drawbacks of this therapy. One especially worrisome shortcoming is the potential therapy association with the unique toxicities of a cytokine release syndrome (CRS) and neurologic toxicities. Cardiovascular complications associated with CAR T cell therapy are less well defined but can be subclassified into autoimmune toxicities resulting from antigen-specific T cell infiltration of the heart and cytokine-mediated toxicities. Cytokine-associated cardiotoxicities have been reported especially in the setting of CRS and might be the cause for most of the observed cardiovascular side effects. In a retrospective study from Alvi et al. cardiovascular events were systematically investigated in adults treated with CAR T cell therapy. The study included 137 patients and found that up to 12% of patients had clinical apparent cardiovascular events after CAR T cell therapy initiation (median time to event 21 days). Cardiovascular events included cardiovascular death, new onset heart failure, decompensated heart failure, and new onset of arrhythmia. A decrease in left ventricular function was observed in 28% of patients while 54% of patients had an elevated troponin. Interestingly, all cardiovascular events occurred in patients with grade ≥ 2 CRS and 95% of events occurred after troponin elevation. Another retrospective study from Lefebvre et al. investigated the occurrence of major adverse cardiovascular events (MACE) in 145 adult patients treated with CAR T cell therapy. MACE included cardiovascular death, symptomatic heart failure, acute coronary syndrome, ischemic stroke, and new onset arrhythmias. In total, 31 out of 145 (21%) patients had MACE at a median time of 11 days after CAR T cell infusion. MACE was independently associated with CRS grade 3 or 4 and baseline creatinine. Overall survival after one year was 71%. Another retrospective study analyzing 116 patients with serial echocardiograms after CAR T cell therapy found that 10% of patients developed a new cardiomyopathy with a decrease of left ventricular ejection fraction (average decrease from 58% to 37%), mostly observed in patients with grade ≥ 2 CRS. Another study with a patient pool of 126, found that 10% of patients developed severe cardiac disorders after CAR T cell therapy including new onset heart failure, acute coronary syndrome, and myocardial infarction. Cardiac MRI for assessment of acute and chronic cardiac effects in CAR T cell therapy As the impact and the pathophysiology of cardiotoxicity of CAR T cell therapies to the heart is poorly understood, it is still unclear, whether cardiotoxicity is simply an early phenomenon associated with the cytokine storm within the scope of the CRS or whether there are more direct cardiotoxic effects from the CAR T cells themselves. It has also been proposed that the observed systolic dysfunction in this setting is a sequalae of a stress induced Takotsubo syndrome. In this context, the physiological stress from the CRS could trigger the occurrence of Takotsubo syndrome. To explore the extent of cardiac injury and inflammation and the pattern of myocardial involvement related to CAR T cell therapy, cardiac MRI must be considered as the imaging modality of choice, particularly due to its inherent capabilities of advanced tissue characterization. Cardiac MRI can characterize myocardial tissue alterations, analyze involvement patterns, and give important insights into the remodeling processes. To date, no cardiac MRI studies in patients with CAR T cell therapy exist. However, in this context, multiparametric cardiac MRI can be used to detect and quantify acute diffuse myocardial tissue alterations, such as myocardial edema and fibrosis. Furthermore, alterations in myocardial function can be detected with high sensitivity by using myocardial strain analysis. Late gadolinium enhancement imaging has a very high specificity for the detection of necrotic inflammatory lesions, especially in the context of inflammatory cardiomyopathies, and could directly show inflammatory lesions associated with CAR T cell therapy. Also, cardiac MRI could reliably identify different patterns of wall motion abnormalities which are associated with Takotsubo syndrome (i.e., apical, midventricular, basal or focal types). A recent study from our group in patients under immune checkpoint inhibitors (ICI) for cancer treatment suggests that cardiac MRI is able to show subtle therapy related treatment effects and can support evidence of a specific imaging pattern of ICI-related myocarditis. Also, cardiac MRI is the imaging modality of choice to show longterm, cardiotoxic effects of chemotherapy. It is considered the reference standard for measurement of ventricular volumes and function making it ideally suited to assess adverse cardiac remodeling after termination of cancer treatment.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: December 2025
• Est. primary completion date: May 2024
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients undergoing CAR T-cell therapy
• Consent to participate in study

Exclusion Criteria:

• Inability to undergo MRI examinations due to large metallic implants, cardiac pacemakers/neurostimulators, or claustrophobia
• Known cardiac conditions such as status post heart attack or myocarditis, complex congenital heard disease, or cardiomyopathies.
• Birth control using an IUD.
• Pregnancy or breastfeeding.
• Renal insufficiency with a GFR below 30 ml/min/1.73m2

Related Conditions & MeSH terms

• ALL
• Cytokine Release Syndrome
• DLBCL
• Follicular Lymphoma
• MCL
• Multiple Myeloma
• Myocarditis

Intervention

Diagnostic Test:
• Cardiac MRI
Hematooncology patients under CAR T-cell therapy will receive 3 MRI examinations: at baseline, within 2 weeks of start of CAR T-cell therapy, and at 6 months follow-up.

Locations

Country	Name	City	State
Germany	University Hospital Bonn	Bonn	NRW

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Bonn

Country where clinical trial is conducted

Germany, 

References & Publications (23)

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Kravchenko D, Isaak A, Zimmer S, Mesropyan N, Reinert M, Faron A, Pieper CC, Heine A, Velten M, Nattermann J, Kuetting D, Duerr GD, Attenberger UI, Luetkens JA. Cardiac MRI in Patients with Prolonged Cardiorespiratory Symptoms after Mild to Moderate COVID-19. Radiology. 2021 Dec;301(3):E419-E425. doi: 10.1148/radiol.2021211162. Epub 2021 Aug 10. — View Citation

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Luetkens JA, Doerner J, Schwarze-Zander C, Wasmuth JC, Boesecke C, Sprinkart AM, Schmeel FC, Homsi R, Gieseke J, Schild HH, Rockstroh JK, Naehle CP. Cardiac Magnetic Resonance Reveals Signs of Subclinical Myocardial Inflammation in Asymptomatic HIV-Infected Patients. Circ Cardiovasc Imaging. 2016 Mar;9(3):e004091. doi: 10.1161/CIRCIMAGING.115.004091. — View Citation

Luetkens JA, Doerner J, Thomas DK, Dabir D, Gieseke J, Sprinkart AM, Fimmers R, Stehning C, Homsi R, Schwab JO, Schild H, Naehle CP. Acute myocarditis: multiparametric cardiac MR imaging. Radiology. 2014 Nov;273(2):383-92. doi: 10.1148/radiol.14132540. Epub 2014 Jun 6. — View Citation

Luetkens JA, Faron A, Isaak A, Dabir D, Kuetting D, Feisst A, Schmeel FC, Sprinkart AM, Thomas D. Comparison of Original and 2018 Lake Louise Criteria for Diagnosis of Acute Myocarditis: Results of a Validation Cohort. Radiol Cardiothorac Imaging. 2019 Jul 25;1(3):e190010. doi: 10.1148/ryct.2019190010. eCollection 2019 Aug. — View Citation

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Luetkens JA, von Landenberg C, Isaak A, Faron A, Kuetting D, Gliem C, Dabir D, Kornblum C, Thomas D. Comprehensive Cardiac Magnetic Resonance for Assessment of Cardiac Involvement in Myotonic Muscular Dystrophy Type 1 and 2 Without Known Cardiovascular Disease. Circ Cardiovasc Imaging. 2019 Jun;12(6):e009100. doi: 10.1161/CIRCIMAGING.119.009100. Epub 2019 May 29. — View Citation

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Sprinkart AM, Luetkens JA, Träber F, Doerner J, Gieseke J, Schnackenburg B, Schmitz G, Thomas D, Homsi R, Block W, Schild H, Naehle CP. Gradient Spin Echo (GraSE) imaging for fast myocardial T2 mapping. J Cardiovasc Magn Reson. 2015 Feb 12;17:12. doi: 10.1186/s12968-015-0127-z. — View Citation

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* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Extent and pattern of acute cardiac effects of CAR T-cell therapy	To investigate to what extent and with which patterns CAR T cell therapy leads to acute cardiac effects in terms of inflammation, fibrosis, and myocardial dysfunction that can be detected with cardiac MRI.	2 weeks
Primary	Long-term cardiac remodeling effects of CAR T-cell therapy	To explore whether CAR T cell therapy leads to long-term cardiac remodeling effects in terms of inflammation, fibrosis, and myocardial dysfunction that can be detected with cardiac MRI.	6 months
Primary	Correlate MRI findings with clinical course	To assess whether changes in cardiac MRI parameters obtained from objectives 1 and 2 correlate with the clinical course (e.g., CRS development), cytokines and immunological markers and might predict major adverse cardiac events (MACE).	6 months