Antibody-drug conjugates (ADCs), described as ‘biological missiles’, are types of targeted cancer treatments that delivery chemotherapy to cancer cells. This powerful anti-cancer therapy is used to treat many types of advanced and metastatic cancers, including breast cancer, blood cancers, and urothelial cancers.

A study published in the Open Access journal Cancers by researchers from The University of California and University of Washington Medical Centre, looked at real-world clinical data, assessing the impact of antibody-drug conjugates on neutropenia – a type of blood condition characterized by low white blood cell count, with severe cases posing serious health risks.

Neutrophils are essential to fight infection

Neutrophils, the most common type of white blood cell present in the human body (40-70%), are critical to fighting off infection. These crucial cells respond to infection as part of the body’s primary immune defence system.

Carefully regulated by cytokines, neutrophils are triggered by the presence of foreign pathogens and enter the bloodstream to reach infected cells and tissues. They detect and engulf pathogens in a highly regulated process called phagocytosis. During phagocytosis, the engulfed pathogen is destroyed by enzymes, acting as a first line of defence. Furthermore, these versatile immune cells release potent inflammatory cytokines to recruit other vital immune cells to the site of infection.

Neutropenia, a condition characterized by a low neutrophil count, can be caused by various conditions or factors that destroy white blood cells or interrupt their function, such as cancer treatments, medicines, specific blood cancers, e.g. leukaemia, or autoimmune conditions.

Producing less than 1500 neutrophils per microliter of blood is classified as severe neutropenia and significantly increases the risk of sepsis – a life-threatening medical emergency.

Antibody-drug conjugates are used for cancer treatment

ADCs consist of a monoclonal antibody equipped with a cytotoxic drug. The antibody selectively targets and binds to a specific target cell delivering the toxic agent, thus reducing the risk of off-target side effects. The potent toxin is bonded to the monoclonal antibody by an important chemical linkage, called a linker. The stability of the linker is critical and is an important component that determines the overall tolerability of the ADC, as premature degradation before it reaches its target can produce off-target side effects.

ADCs are revolutionary cancer treatments, offering a more targeted approach to minimise the systemic side effects associated with chemotherapy. However, research shows that this type of therapy can reduce white blood cell count in patients given specific ADC types, increasing their risk of sepsis and other serious medical complications.

“Our findings demonstrate that while antibody-drug conjugates offer tremendous promise for cancer patients, clinicians must remain vigilant about potentially serious hematologic toxicities. Using real-world data allows us to understand better how these therapies affect diverse patient populations outside the controlled environment of clinical trials.” – Prof. Chan, lead author of the study.

Specific antibody drug conjugate therapies are associated with neutropenia

The study analysed data from 3511 patients across four medical centres who were most commonly diagnosed with breast cancer, lymphoid, hematopoietic or urinary tract cancers, and were treated with either of the following types of ADCs:

• Fam-trastuzumab deruxtecan
• Ado-trastuzumab emtansine
• Brentuximab vedotin
• Gemtuzumab ozogamicin
• Inotuzumab ozogamicin

Analysis of the data showed significant variation in rates of neutropenia amongst the cohorts. The most commonly prescribed ADCs (fam-trastuzumab deruxtecan, Ado-trastuzumab emtansine, and brentuximab vedotin) were associated with the lowest incidences of neutropenia.

In contrast, gemtuzumab ozogamicin and inotuzumab ozogamicin were associated with the highest incident rate of 18.1% for febrile neutropenia – a critical, life-threatening, oncological emergency characterised by high fever in a patient with an exceptionally low neutrophil count.

In this context, the patient is unable to surmount an immune response and must be given prophylactic antibiotics to fight off infection in the blood. Inotuzumab ozogamicin was associated with the highest incidence rates of hospital admissions, ICU admissions and deaths.

Furthermore, patients with anaemia or immunodeficiency disorders were at higher risk of developing neutropenia or further treatment-related complications.

Off-target effects of antibody-drug conjugates

The results reveal the risk of neutropenia and other associated adverse effects. Understanding why these haematological effects occur is critical to mitigate risk, support patients undergoing treatment – especially those with other underlying health conditions – and refine further development of antibody-drug conjugates.

“As these targeted therapies become more widely used, understanding and anticipating side effects becomes increasingly important,” Chan said. “This work can help inform safer treatment strategies and improve patient outcomes.”

Potential reasons for the haematological effects seen in the study involves the properties of the antibody-drug conjugate, and its ability to reach its target, i.e., specific cancer cells.

Non-specific binding of ADC or off-target uptake, e.g. in the bone marrow or bloodstream, can cause serious systemic repercussions, including a drop in white blood cells, as toxic chemotherapy agents destroy healthy cells and tissue.

The results presented in the study highlight the prevalence of ADC-associated neutropenia, especially in patients with pre-existing conditions such as anaemia. The authors stress the importance of early monitoring, careful treatment planning and preventative strategies for patients undergoing this type of treatment.

The future of precision medicine

Within the field of precision oncology, antibody-drug conjugates remain a revolutionary tool and monumental feat of bioengineering, helping to treat millions of patients worldwide.

Supporting patients treated with ADC requires careful planning and early monitoring to improve their safety and reduce risk of adverse events, such as neutropenia. The present, real-world study helps to further the understanding of the adverse effects of ADC, encouraging future research to address these challenges.

To learn more about research like this, you can access the Section: Cancer Drug Development published in Cancers. Alternatively, you can access the full journal list.