Phase I/II study of dasatinib and exploratory genomic analysis in relapsed or refractory non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) is one of the most prevalent cancers in the Western world with an increasing incidence in US (Zelenetz, et al 2010) This group of lymphomas encompasses a heterogeneous group of diseases with a wide range of histology, pathogenesis and clinical course ranging from indolent to aggressive diseases. The most common indolent subtype of B-cell lineage is follicular lymphoma (FL), and that of the T-cell lineage is cutaneous T-cell lymphoma (CTCL), whereas aggressive subtypes include diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL), representing approximately 80% of all NHL diagnoses in adults (Swerdlow et al 2016). There is often patient-to-patient variability in clinical course, with a significant proportion of patients relapsing or refractory to first line therapies. While many treatment difficulties exist in NHL, relapsed/refractory disease represents a major challenge and is currently under intense investigation, especially in the rituximab era for B-cell lineage lymphomas. The use of the monoclonal antibody rituximab, as a single agent or in combination with cytotoxic chemotherapy, is currently the standard of care in the first line setting for B-cell NHLs and has significantly improved the prognosis of affected patients. However, rituximab resistance has been reported in multiple NHL subtypes, including relapsed FL or low-grade NHL, and is associated with poor prognosis (Davis, et al 2000, Hagberg and Gisselbrecht 2006, Martin, et al 2008). Patients with PTCL generally have a poor prognosis with current standard-of-care therapy, and no progress in their outcome has been achieved in the past two decades (Xu and Liu 2014). The prognosis of relapsed PTCL is very poor and novel effective treatments are urgently needed. Autologous haematopoietic stem cell transplantation has been associated with extended survival in relapsed/refractory NHL, however the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) demonstrated that, in the post-rituximab era, patients with DLBCL, the most common type of NHL in the US, derive less benefit from autologous transplant, with a dismal progression-free survival (PFS) of 20% at 3 years (Gisselbrecht, et al 2010). As patients relapse after autologous transplant, progress through multiple lines of treatment, the subsequent responses achieved are incrementally shorter, with eventual exhaustion of meaningful options. This clearly highlights the need for additional safe, effective and targeted agents for this high-risk population. Several novel classes of drugs, such as next generation monoclonal antibodies, antibody–drug or radioactive isotope conjugates and specific small-molecule inhibitors of oncogenic pathways, are emerging as therapeutic options in NHL. However, despite the recent array of drug approvals, long-term remission remains elusive for a significant proportion of NHL patients, particularly those with relapsed/refractory disease (Crump, et al 2017). In this context, we studied the safety and efficacy of single agent dasatinib in patients with relapsed/refractory NHL. Dasatinib, originally developed as a pan-Src kinase inhibitor, is a potent and broad-spectrum multi-kinase inhibitor with proven safety and efficacy in chronic myeloid leukaemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) (Cortes, et al 2016, Lilly, et al 2010). Dasatinib has selective 100-fold higher affinity for ABL1 than imatinib mesylate (Shah, et al 2004), and targets several tyrosine kinase families that are implicated in cell survival in NHLs (Brave, et al 2008, Sprangers, et al 2006). The half-life of the drug is approximately 5 h, shown to be well tolerated in CML patients (Talpaz et al. 2004), and achieves sustained inhibition of Lyn kinase, which is critical for B-cell survival. Given that Lyn could be inhibited by dasatinib at tolerable doses, we initiated this phase 1/2 trial in patients with relapsed NHLs.