Monitoring Exceptional Responses in Patients with B-cell Malignancies

Abstract

Response to cancer treatments can be highly variable; with some patients entering durable remissions, and others either failing to respond or relapsing early. Predicting which patients may derive long term responses and enter deep remissions remains a significant challenge. “Exceptional responders”, ie patients with prolonged and deep responses, where the majority fail to respond, represent a group of patients that could help us understand the mechanisms of treatment sensitivity and enable us to study the depth of minimal residual disease (MRD) required to sustain a durable response. I examined two cohorts of “exceptional responders” to two precision medicines to understand the molecular features, that could explain their durable response: a cohort of ten relapsed/refractory (R/R) patients with Mantle Cell Lymphoma (MCL) treated with Bruton’s Tyrosine Kinase (BTK) inhibitors and a small case series of two patients with Chronic Lymphocytic Leukaemia (CLL) treated with a CD52 antibody (alemtuzumab). Molecular features included mutational profiling, IGHV gene rearrangement, copy number variation and for the MCL cases t(11;14)(q13;q32) translocation. Interestingly, all but two MCL patients had truly unmutated IGHV and three patients had TP53 mutations, features otherwise associated with poor outcomes. The depth of response was assessed using patient-specific ddPCR assays or Lymphotrack. In two MCL cases, there was evidence of disease recurrence using ddPCR before clinical and radiological relapse. In a further two MCL cases, MRD remains undetectable. In one CLL patient, still in remission twenty years post-treatment, re- emergence of polyclonal B cells with absence of the original B-cell clone was observed. A MYD88 mutation from original tumour was undetectable by ddPCR. NGS and ddPCR methods may provide precision tools for monitoring exceptional responders and for early prediction of relapse. However, further validation will be required prior to implementation within the clinic.