R01CA251801

Outcomes for CLL Patients Treated with Novel Therapy - 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. This trial tested a combination of ibrutinib and rituximab (IR) versus the prior gold standard chemoimmunotherapy (CIT): fludarabine, cyclophosphamide, and rituximab (FCR). The results of this trial showed that both progression-free survival (PFS) and overall survival (OS) are superior with IR. As a result, the FDA approved the 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 regarding how best to 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. Therefore, 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 who 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 combinations. Our initial study on patients treated on the IR arm of E1912 found a subset of patients 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 will be needed.

We also 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, including 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 the 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 these 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 the application of immunotherapy.

Mayo Clinic

TO IMPROVE SCREENING AND EARLY DETECTION STRATEGIES AND TO DEVELOP ACCURATE DIAGNOSTIC TECHNIQUES AND METHODS FOR PREDICTING THE COURSE OF DISEASE IN CANCER PATIENTS. SCREENING AND EARLY DETECTION RESEARCH INCLUDES DEVELOPMENT OF STRATEGIES TO DECREASE CANCER MORTALITY BY FINDING TUMORS EARLY WHEN THEY ARE MORE AMENABLE TO TREATMENT. DIAGNOSIS RESEARCH FOCUSES ON METHODS TO DETERMINE THE PRESENCE OF A SPECIFIC TYPE OF CANCER, TO PREDICT ITS COURSE AND RESPONSE TO THERAPY, BOTH A PARTICULAR THERAPY OR A CLASS OF AGENTS, AND TO MONITOR THE EFFECT OF THE THERAPY AND THE APPEARANCE OF DISEASE RECURRENCE. THESE METHODS INCLUDE DIAGNOSTIC IMAGING AND DIRECT ANALYSES OF SPECIMENS FROM TUMOR OR OTHER TISSUES. SUPPORT IS ALSO PROVIDED FOR ESTABLISHING AND MAINTAINING RESOURCES OF HUMAN TISSUE TO FACILITATE RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.394 - Cancer Detection and Diagnosis Research

National Cancer Institute (NCI) [HHS - NIH]

Rochester, Minnesota 559050001 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 354% from $705,542 to $3,205,518.