Dr Querfeld on Sequencing Strategies for Mogamulizumab

The clinical features — and even if you do biopsies, the pathology features — can sometimes be very difficult and not provide a definitive answer. This molecular analysis clearly identifies that. You can combine it with T-cell receptor sequencing, so you see this is a reaction.

Mogamulizumab helps many patients with mycosis fungoides and Sézary syndrome, but the benefit is uneven and clinical features alone can’t predict who will respond nor whether a relapse is genuine. Christiane Querfeld, MD, PhD, director of the Cutaneous Lymphoma Program at City of Hope, is using targeted sequencing of patient biopsies to find the molecular signatures that clinical assessment misses.

Speaking at the 6th World Congress of Cutaneous Lymphoma (WCCL), Querfeld discussed targeted sequencing from the MOGA-2MG-Q4W trial, an analysis aimed at explaining why responses differ between disease subtypes and whether molecular tools can guide mogamulizumab use. She expanded on what those responses mean for patients in a second part of this discussion.

The sequencing was built to answer two questions, Querfeld explained. The first is why Sézary syndrome has consistently responded to mogamulizumab somewhat better than mycosis fungoides. The second is what separates responders from non-responders within the treated population — a difference that the data suggest tracks with disease subtype biology.

The molecular patterns pointed in a consistent direction. Responders, primarily Sézary syndrome patients, carried mutations in immune-signaling and T-cell-activation genes such as CD28 and CREBBP. These alterations may heighten the malignant cell’s vulnerability to CCR4-directed depletion and to the antibody-dependent killing through which mogamulizumab works.

Non-responders, more often patients with mycosis fungoides, were enriched for mutations in chromatin-remodeling and cell-cycle genes linked to immune evasion. This profile may help explain why responses are harder to achieve in that group.

Querfeld noted that this kind of mapping could eventually nominate targets, or rational combinations, to convert non-responders into responders.

She also addressed one of the most practical problems clinicians face with the drug: mogamulizumab-associated rash (MAR). Long described as a drug reaction, it is better understood as an immune flare that can accompany response, Querfeld said — which raises the question of whether a molecular signature could identify it, and whether it may even be linked to durable disease control.

The same ambiguity applies to reactive changes that can masquerade as progression, where clinical and even pathological features sometimes cannot give a definitive answer. Here, she argued, molecular analysis combined with T-cell receptor sequencing can distinguish a treatment-related immune reaction from true lymphoma progression. This may allow clinicians to tune the immune response rather than risk a treatment that exacerbates the disease.