Outcomes for CLL patients treated with novel therapy

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PROJECT SUMMARY/ABSTRACT We have recently conducted and published a game changing phase 3 clinical North American Intergroup (NAIG) trial (E1912) for chronic lymphocytic leukemia (CLL) therapy which tested a combination of Ibrutinib and Rituximab (IR) vs. the prior gold standard chemoimmunotherapy (CIT): fludarabine, cyclophosphamide, and rituximab (FCR). This trial showed that both progression free survival (PFS) and overall survival (OS) are superior with IR and subsequently was the driving factor in FDA approval for frontline use of IR in progressive previously untreated CLL in the spring of 2020. While our work revealed distinct clinical advantages to non-CIT approaches, a number of new questions have emerged with respect to how best apply this advance. The durability of the response to first-line ibrutinib-based therapy is highly variable and requires indefinite treatment exposing patients to the risk of chronic toxicity and selective pressure that may foster resistant clones. The ability to more accurately predict the durability of response could help identify patients more likely to have long term remission with ibrutinib therapy (candidates for time limited therapy) and those more likely to have a short duration of response whom may benefit from intensive combination therapy with alternative novel agents. We wish to develop a unique model(s) incorporating multiple key prognostic factors that will have a high level of confidence in predicting patient outcomes to novel therapy combination. Our initial study on patients treated on IR arm of E1912 found a subset of patients on the IR arm with evidence for emerging mutations and changes in their clonal architecture predicting relapse. The exact mechanisms for relapse need to be defined as we predict that these patients will be difficult to treat and alternative strategies needed. We found that IR therapy was uniquely able to reactivate the previously exhausted T cell killing activity directed against the leukemic CLL cells. While we have some information on the mechanism(s) for this, much remains to be learned and also the exact timing for achieving the maximal restoration of T cell function or fitness. This beneficial impact on T cell function will also be studied as it relates to generation of CAR T cells as these cells are powerful inducers of immunotherapy which is itself capable of removing residual CLL tumor burden. We hypothesize that the outcome of the studies will add significant and important information on how to best select non-chemotherapy for CLL patients and also the treatment impact on the immune system. These goals will be accomplished through the following specific aims: Aim 1: Develop an Integrated Model to Predict Clinical Outcomes for CLL Patients Treated with Novel Agents. Aim 2: Determine the Genetic, Epigenetic and Transcriptomic Changes in Ibrutinib Treated CLL. Aim 3: Characterize the Impact of Ibrutinib Treatment on T-cell Fitness to Guide Application of Immunotherapy.