Efficacy, safety and resistance mechanisms of FDA-approved antibody–drug conjugates for hematologic malignancies

Hematologic malignancies such as multiple myeloma, acute myeloid leukemia, classic Hodgkin’s lymphoma, diffuse large B-cell lymphoma and acute lymphoblastic leukemia are high-risk cancers with poor prognosis and resistance to chemotherapy and immunomodulatory agents. CAR-T-cell therapies, while efficacious, pose logistical challenges in terms of administration and manufacturing. Thus, there is a need to assess the current landscape of antibody–drug conjugates (ADCs) as optimal precision medicine therapeutic agents for hematologic malignancies. Literature searches were conducted in PubMed/MEDLINE and Google Scholar in April 2026, covering articles published between 2011 and April 2026. The search strategy combined three concept blocks: “Antibody-Drug Conjugates” OR ADC OR ADCs) AND (“hematologic malignancies” OR lymphoma OR “acute myeloid leukemia” OR “acute lymphoblastic leukemia” OR “multiple myeloma”) AND (“FDA approval” OR “mechanism of action” OR target * OR “clinical trial * ” OR efficacy OR safety OR toxicity AND “resistance mechanism * ”. Eligible records were narrative reviews and primary research articles addressing FDA-approved ADCs in hematologic malignancies, with emphasis on mechanism of action, molecular targets, efficacy and safety/toxicity profiles, comparative trial data, and resistance mechanisms. Systematic reviews were excluded for lack of relevant data. Studies confined to solid tumors or other non-hematologic malignancies were excluded, as were investigational ADCs lacking FDA approval. Immune checkpoint inhibitors, bispecific antibodies, CAR T cell therapies, chemotherapy, monoclonal antibodies, and related immunomodulatory agents were excluded as standalone subjects but retained where evaluated in combination with an FDA-approved ADC. ADCs for hematologic malignancies, namely, belantamab mafodotin (BM), a BCMA-targeted ADC approved for multiple myeloma (MM); gemtuzumab ozogamicin (GO), a CD33-targeted ADC approved for acute myeloid leukemia (AML); inotuzumab ozogamicin (InO), a CD22-targeted ADC approved for ALL; brentuximab vedotin (BV), a CD30-targeted ADC approved for classic Hodgkin’s lymphoma; polatuzumab vedotin (PV), a CD79b-targeted ADC approved for DLBCL; and loncastuximab tesirine (LT, Lonca), a CD19-targeted ADC approved for DLBCL, are described. ADCs have emerged as major precision oncology therapeutics in hematologic malignancies, demonstrating significant efficacy both as monotherapies and in combination regimens. However, resistance mechanisms including antigen modulation, payload resistance, and microenvironment-mediated escape remain major clinical challenges that may guide the development of next-generation ADCs and biomarker-driven therapeutic strategies.