Blinatumomab provoked fatal heart failure

Mentioned in Blinatumomab (Blincyto®) clinical safety report, a 5 year old boy with acute lymphoblastic leukemia (ALL) receiving Blincyto® with the concentration of 30μg/m²/day on the fourth day of therapy developed both Cytokine Release Syndrome (CRS) and Tumor Lysis Syndrome (TLS). Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and Bilirubin peaks were 18, 7 and 8 folds more than upper normal limit (UNL) respectively. However, albumin was reduced to approximately half of the lower Normal limit (LNL). Although Blincyto® administration was immediately withdrawn, he expired in the day 10 due to a fatal cardiac failure. Based on evidence, FDA concluded that CRS was the main cause of death in this patient. Evoking evidence now propose that aberrant pro-inflammatory cytokines secretion, the hallmark of CRS, and subsequent elevation in nitric oxide (NO) can result in both inotropic and chronotropic alterations in myocardial excitation-contraction coupling, myocardial contractility suppression, desensitization of β-adrenergic receptors stimulation, development of acute cardiac failure and death. The probably neglecting point here is that TLS itself can also develop life threatening conditions including sudden cardiac failure through induction of hypocalcemia, hyperkalemia and hyperuricemia, making CRS monitoring and proper required supportive interventions more complex. Here, first we enumerate probable mechanisms through which CRS results in development of fatal cardiac failure and then explain the possible neglected role of TLS in development of the fatal cardiac failure.