Clinical Application of an Ex-Vivo Platform to Guide the Choice of Drug Combinations in Relapsed/Refractory Lymphoma; A Prospective Study

Introduction While combination therapy is the standard of care for relapsed/ refractory non-Hodgkin lymphoma (RR-NHL), the choice of combinations for an individual patient is empirical, and response rates remain poor. Here we explore the use of a hybrid experimental/analytic method termed Quadratic Phenotypic Optimization Platform (QPOP), for prediction of optimal drug combinations from limited clinical material. This high-throughput platform identifies optimal drug-combinations on ex-vivo biopsies using an orthogonal array composite design to maximise search space. These features are potentially useful to assess personalized efficacious combinations among a set of drugs with single agent pre-clinical or clinical activity in lymphoma. Methods We performed a prospective cohort study of QPOP analysis in RR-NHL. Participants included RR-NHL patients across two tertiary oncology centres in Singapore, with disease amenable to biopsy or blood/ marrow aspiration, recruited between 1 st November 2017 and 5 th May 2021 - with a median follow up of 24.5 months. CD20, CD3 or CD56 selection was performed to enrich for B, T or NK cells respectively, depending on the specimen type. QPOP drug combination scores were derived from lymphoma samples (approximately 1,000,000 cells/ patient) using a matrix of drugs with known pre-clinical or clinical efficacy against NHL. Results were shared with the treating physician, and off-label QPOP-guided therapy was offered in the absence of standard options. The primary outcomes were feasibility and turnaround time of QPOP analysis. The secondary outcomes were identification of recurrent 2 and 3 drug-combinations, and concordance of QPOP results with clinical responses. Results In this interim analysis period, we recruited 63 patients comprising 36 B-NHL and 27 T/NK-NHL, with a median age of 57 years and median 2 prior lines of treatment. Successful QPOP analysis (Z' score >0.5) was feasible in 56/63 cases with an average turn-around time of 6 (±2.1) days. QPOP predicted frequent sensitivities to Copanlisib- and Venetoclax-based combinations in B-NHL, and Romidepsin-based combinations in T/NK-NHL. Importantly, efficacy of specific combinations was not entirely dependent on single agent dose responses. Greater variability in ex-vivo responses was seen with combinations of targeted therapy and cytotoxic therapy compared with combinations of cytotoxic agents. Clinical responses were evaluable for 29 independent treatments in 26 patients.