Clinically approved immunotoxins targeting hematological cancers: “the best of both worlds”

Hematological malignancies contribute significantly to the overall cancer burden. Certain subtypes, such as hairy cell leukemia (HCL), are chronic and characterized by residual disease after first-line therapy, while others, such as blastic plasmacytoid dendritic cell neoplasm (BPDCN), are aggressive and associated with poor prognosis. Although cornerstone interventions such as radiation and chemotherapy are efficiently used to treat some malignant blood neoplasms, these treatments are often limited by resistance, relapse, lack of enduring disease-free survival/complete remission, and systemic toxicity. Immunotoxins were developed to improve tumor targeting and have evolved into recombinant immunotoxins (RITs). These novel bioengineered chimeras genetically combine potent cytotoxins with targeted binding domains. In this review, we analyze three FDA-approved RITs, namely, moxetumomab pasudotox, tagraxofusp, and denileukin diftitox, that utilize bacterial toxins from <i>Pseudomonas</i> and <i>Corynebacterium diphtheriae</i> to treat refractory/relapsed (R/R) HCL, BPDCN, and adult R/R cutaneous T-cell lymphoma (CTCL), respectively. We reviewed their comprehensive safety profiles, describe complications associated with these fusion proteins, and, finally, discuss potential risk management strategies that may enhance their clinical outcomes. Overall, RITs have demonstrated efficacy, and researchers continue to extend these findings to other indications.