Multiparametric Cardiac MRI in Patients Under CAR T-cell Therapy

June 11, 2022 updated by: Julian Alexander Luetkens, University Hospital, Bonn

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Observational

Enrollment (Anticipated)

60

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Germany
    • NRW
      • Bonn, NRW, Germany, 53127
        • Recruiting
        • University Hospital Bonn
        • Contact:
        • Principal Investigator:
          • Annkristin Heine, MD
        • Principal Investigator:
          • Tobias Holderried, MD
        • Principal Investigator:
          • Dmitrij Kravchenko, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

N/A

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Patients with a histopathologically confirmed B-cell lymphoma or multiple myeloma who are planned for CAR T-cell therapy who fulfill the inclusion and exlcusion criteria will be recruited.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
CAR T-cell Therapy Group
Hematooncological patients undergoing CAR T-cell therapy with Tisagenlecleucel, Axicabtagen-ciloleucel, Idecabtagen-vicleucel, Brexucabtagene autoleucel, Lisocabtagene maraleucel or Ciltacabtagene Autoleucel (dosages, frequency and duration to be determined by the treating oncologist).
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Extent and pattern of acute cardiac effects of CAR T-cell therapy
Time Frame: 2 weeks
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
Long-term cardiac remodeling effects of CAR T-cell therapy
Time Frame: 6 months
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
Correlate MRI findings with clinical course
Time Frame: 6 months
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Bonn

Investigators

  • Principal Investigator: Julian Luetkens, MD, University Hospital, Bonn
  • Principal Investigator: Annkristin Heine, MD, University Hospital, Bonn
  • Principal Investigator: Tobias Holderried, MD, University Hospital, Bonn
  • Principal Investigator: Dmitrij Kravchenko, MD, University Hospital, Bonn

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

May 16, 2022

Primary Completion (ANTICIPATED)

May 1, 2024

Study Completion (ANTICIPATED)

December 1, 2025

Study Registration Dates

First Submitted

June 7, 2022

First Submitted That Met QC Criteria

June 7, 2022

First Posted (ACTUAL)

June 10, 2022

Study Record Updates

Last Update Posted (ACTUAL)

June 15, 2022

Last Update Submitted That Met QC Criteria

June 11, 2022

Last Verified

June 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 81/22

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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