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Immune Sequencing Diagnoses Cutaneous T Cell Lymphoma Earlier Than Standard PCR Test

NEW YORK (GenomeWeb) – Researchers from Brigham and Women's Hospital and Adaptive Biotechnologies have demonstrated that a next-generation sequencing-based assay developed by Adaptive is better at diagnosing cutaneous T cell lymphoma than the standard PCR-based test, and that it can assess patients' response to therapy and identify disease recurrence.

The study, which was published today in Science Translational Medicine, adds to a growing body of evidence demonstrating the power of immune sequencing technologies to diagnose and monitor lymphomas and leukemias.

The researchers analyzed DNA from biopsies of 46 patients with CTCL, skin lesions from 23 patients with psoriasis, 11 patients with eczematous dermatitis, 12 patients with contact dermatitis, 12 patients with pityriasis lichenoides et varioliformis acuta (PLEVA), and six healthy donors. The team ran Adaptive Biotechnologies’ ImmunoSeq assay, which sequences T-cell receptors, on all samples.

CTCLs are a heterogenous group of non-Hodgkin's lymphomas that can be tricky to diagnose. One form of CTCL, known as mycosis fungoides (MF) has a good prognosis in about 80 percent of patients. By contrast, leukemic CTCL is hard to treat and patients have a median survival of just three years, making early diagnosis important. The most commonly used clinical test is a PCR-based test followed by CE sequencing, but it has a high false-negative rate.

In the Science Translational Medicine study, the authors wanted to see whether a sequencing-based assay could be a better diagnostic and potentially distinguish between benign and malignant T cells earlier.

The authors first compared the ImmunoSeq assay with a standard PCR test in 39 patients with clinically confirmed CTCL. The ImmunoSeq assay identified T cell clones in all 39 patients, while PCR identified clonal populations in only 27, or 70 percent, of cases. Ten of the 12 patients missed by the PCR test had early-stage disease.

The sequencing assay also helped to distinguish early recurrences of CTCL from benign inflammation. Patients sometimes develop a "cutaneous eruption" following lymphoma treatment, and distinguishing whether that is a reaction to the treatment or disease recurrence can be challenging, the authors wrote.

For example, one patient had stage IB CTCL with peripheral blood involvement that was detectable by both sequencing and flow cytometry. The patient was treated and initially had rapid improvement, but after his ninth cycle developed "an inflammatory cutaneous eruption that was worrisome for a recurrence of CTCL," the authors wrote. The sequencing assay "clearly demonstrated the loss of the malignant T cell clone from both blood and skin," suggesting he was having a reaction to the drug. His treatment was discontinued and he recovered completely.

In another patient, the sequencing assay was able to track individual T cell clones in the blood and skin over months and years. The assay was run originally in 2012 and again in 2014 after the patient had been started on the drug gemcitabine. In both cases, the assay identified the same clonal T cell population, although it was reduced after starting gemcitabine.

The sequencing assay was also able to identify disease recurrence in a third patient who was treated with stem cell transplantation. The assay was first run before the treatment and identified a malignant T cell clone. The patient then had the transplantation and appeared to be disease free until 10 months later when she developed a new skin lesion. The sequencing assay was run again and identified the same malignant T cell clone. The patient was immediately treated with UVB therapy, which induced remission.

The researchers also used the sequencing assay to determine that CTCL derives from mature T cells, and they were able to show that the malignant T cell clones involved in the development of the mycosis fungoides form of CTCL arise from a different skin compartment than those from leukemic CTCL.

Overall, the authors found that sequencing "is a valuable tool in identifying malignant T cell clones and differentiating early-stage CTCL from benign inflammatory skin disease," they wrote.