Rituximab in patients with acute ST-elevation myocardial infarction: an experimental medicine safety study

Tian X Zhao, Muhammad Aetesam-Ur-Rahman, Andrew P Sage, Saji Victor, Rincy Kurian, Sarah Fielding, Hafid Ait-Oufella, Yi-Da Chiu, Christoph J Binder, Mikel Mckie, Stephen P Hoole, Ziad Mallat, Tian X Zhao, Muhammad Aetesam-Ur-Rahman, Andrew P Sage, Saji Victor, Rincy Kurian, Sarah Fielding, Hafid Ait-Oufella, Yi-Da Chiu, Christoph J Binder, Mikel Mckie, Stephen P Hoole, Ziad Mallat

Abstract

Aims: In pre-clinical models of acute myocardial infarction (MI), mature B cells mobilize inflammatory monocytes into the heart, leading to increased infarct size and deterioration of cardiac function, whilst anti-CD20 antibody-mediated depletion of B cells limits myocardial injury and improves cardiac function. Rituximab is a monoclonal anti-CD20 antibody targeted against human B cells. However, its use in cardiovascular disease is untested and is currently contraindicated. Therefore, we assessed the safety, feasibility, and pharmacodynamic effect of rituximab given to patients with acute ST-elevation MI (STEMI).

Methods and results: Rituximab in patients with acute ST-elevation myocardial infarction (RITA-MI) was a prospective, open-label, dose-escalation, single-arm, phase 1/2a clinical trial, which tested rituximab administered as a single intravenous dose in patients with STEMI within 48 h of symptom onset. Four escalating doses (200, 500, 700, and 1000 mg) were used. The primary endpoint was safety, whilst secondary endpoints were changes in circulating immune cell subsets including B cells, and cardiac and inflammatory biomarkers. A total of 24 patients were dosed. Rituximab appeared well tolerated. Seven serious adverse events were reported, none of which were assessed as being related to the rituximab infusion. Rituximab caused a mean 96.3% (95% confidence interval 93.8-98.8%) depletion of circulating B cells within 30 min of starting the infusion. Maximal B-cell depletion was seen at Day 6, which was significantly lower than baseline for all doses (P < 0.001). B-cell repopulation at 6 months was dose-dependent, with modulation of returning B-cell subsets. Immunoglobulin (IgG, IgM, and IgA) levels were not affected during the 6 months of follow-up.

Conclusions: A single infusion of rituximab appears safe when given in the acute STEMI setting and substantially alters circulating B-cell subsets. We provide important new insight into the feasibility and pharmacodynamics of rituximab in acute STEMI, which will inform further clinical translation of this potential therapy.

Clinical trial registration: NCT03072199 at https://www.clinicaltrials.gov/.

Keywords: B lymphocytes; Immune system; Rituximab; Myocardial infarction.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Consort diagram for RITA-MI. All patients completed dosing and follow-up. aLogistically not possible = dosing would have been on weekend which was not permitted, doctor/nurse not available to dose patient, mandated follow-up would have been on weekend or doctor not available. Top three reasons for ineligibility were timing of chest pain, previous medical history, clinical instability post-MI.
Figure 2
Figure 2
CD19+ B-cell depletion. Panel (A and B) shows the effect of four different doses of rituximab (200, 500, 700, and 1000 mg) on B-cell count and percentage (of lymphocytes) respectively. Each point and line represent a single patient in each group. Panel (C and D) shows the same data on a logarithmic scale. In panel C, blue and red dashed lines represent pre-specified levels of partial and complete B-cell depletion, respectively. Parametric ANOVA was performed comparing different timepoints against baseline. Significance was corrected for multiple testing. n = 24 patients (6/dose). **P < 0.01, ***P < 0.001, ****P < 0.0001.
Figure 3
Figure 3
Parts of whole stacked bar graph of B-cell subsets. The four columns of graphs show the data from the four rituximab doses (200, 500, 700, and 1000 mg). Panel A shows the absolute counts of B-cell subsets as a ‘part of whole’ stacked bar graph. Each colour represents a B-cell subset. Plasmablasts numbers are low and therefore poorly visible. The total of all the subsets in each bar equals total B-cell count. Panel B shows the same data but normalized so each subset is represented as a percentage of the whole. N = 24 patients (6/dose).
Figure 4
Figure 4
Grouped data showing cardiac biomarkers. Each panel shows the mean and 95% CI for each of the four rituximab doses (200, 500, 700, and 1000 mg) at different timepoints. Panels A–D show troponin, NT pro-BNP, hsCRP, and interleukin-6, respectively. N = 24 patients (6/dose). BNP, NT-pro-B-type Natriuretic Peptide; hsCRP, high-sensitivity C-reactive protein.
Figure 5
Figure 5
Grouped data showing immunoglobulin counts. Each panel shows the mean and 95% CI for each of the four rituximab doses (200, 500, 700, and 1000 mg) at different timepoints. Panels A–C show IgG, IgM, and IgA, respectively. N = 24 patients (6/dose). Ig, immunoglobulins.

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