Unexpected Hematologic Effects of Biotherapeutics in Nonclinical Species and in Humans

Abstract

Biotherapeutics are expanding the arsenal of therapeutics available for treating and preventing disease. Although initially thought to have limited side effects due to the specificity of their binding, these drugs have now been shown to have potential for adverse drug reactions including effects on peripheral blood cell counts or function. Hematotoxicity caused by a biotherapeutic can be directly related to the activity of the biotherapeutic or can be indirect and due to autoimmunity, biological cascades, antidrug antibodies, or other immune system responses. Biotherapeutics can cause hematotoxicity primarily as a result of cellular activation, cytotoxicity, drug-dependent and independent immune responses, and sequelae from initiating cytokine and complement cascades. The underlying pathogenesis of biotherapeutic-induced hematotoxicity often is poorly understood. Nonclinical studies have generally predicted clinical hematotoxicity for recombinant cytokines and growth factors. However, most hematologic liabilities of biotherapeutics are not based on drug class but are species specific, immune-mediated, and of low incidence. Despite the potential for unexpected hematologic toxicity, the risk-benefit profile of most biotherapeutics is favorable; hematologic effects are readily monitorable and managed by dose modification, drug withdrawal, and/or therapeutic intervention. This article reviews examples of biotherapeutics that have unexpected hematotoxicity in nonclinical or clinical studies.

Cetuximab or nimotuzumab plus intensity-modulated radiotherapy versus cisplatin plus intensity-modulated radiotherapy for stage II-IVb nasopharyngeal carcinoma

“…9 Biotherapeutics have been shown to have the potential for causing adverse drug reactions, including effects on peripheral blood cell counts, as a result of cellular activation, cytotoxicity, drug-dependent and independent immune responses. 21 Accordingly, increased risks of G3 leucopenia and/or neutropenia and anemia events have been reported in patients treated with CTX plus standard chemotherapeutic agents. 22 Notably, the occurrences of skin reactions and mucositis were the most frequent complaints by patients treated with CTX, with a higher frequency of G3 of 39.6%, G3-G4 of 48.3%, respectively.…”

Biological Characterization of a Stable Effector Functionless (SEFL) Monoclonal Antibody Scaffold in Vitro

“…Several mAbs have now shown off-target effects (8), although the mechanisms involved are not well understood. Our results further support that some of these off-target effects require Fc-Fc␥R binding (10), and that the elimination of the effector function of a mAb may eliminate off-target reactions as well (as shown for mAbX and mAbY (9, 10)).…”

“…In addition, IgG2 can also bind to Fc␥ receptors to induce non-cytotoxic effector functions. For example, IgG2 isotypes can mediate phagocytosis via monocytes/macrophages and neutrophils through interaction with the Fc␥RIIa on platelets (8), and binding to the Fc␥RIIa along with a cell surface antigen has been implicated in off-target effects of mAbs on platelets (9,10).…”

Severe thrombocytopenia in a patient with hepatitis C treated with eltrombopag from off-label drug use to on-label drug use: a case report

“…HCV infection can directly suppress megakaryocyte production. Interferon treatment also has a direct myelosuppressive effect that could lead to thrombocytopenia [7]. Patients are considered eligible for HCV infection treatment if their platelet count is above 90×10 9 /L [8].…”