Identification of targeted therapies for rare adult mature T‐cell leukemia using functional ex vivo screening of primary patient samples

T-cell prolymphocytic leukemia (T-PLL) is a, rare and aggressive, ab post-thymic T-cell lymphoproliferative disorder found in patients with a median age of 64 years. Introduced in 1997, Alemtuzumab (Campath-1H) improved the median overall survival in T-PLL patients to approximately 20 months from 7.5 months. However, only about 60% of patients reach a complete remission (CR) and at least half of these patients relapse within 1 year. Those who achieve a CR are encouraged to proceed with allogeneic stem cell transplantation (SCT), however nearly half of SCT patients relapse from their disease. Genetic analyses of T-PLL have revealed a number of chromosomal rearrangements and mutations. The most common abnormalities occur in chromosome 14 (75% of cases) with an inv(14)(q11q32), followed by 8q (70% of cases) with isochromosome 8q or additional genetic material. Chromosome 14 abnormalities result in the overexpression of TCL1 and AKT, thus enhancing cell proliferation. Additional abnormalities include the loss of ataxia telangiectasia mutated (ATM) due to deletions of 11q and a high mutation rate of JAK1, JAK3, and STAT5B. It is hypothesized that small molecule inhibitors either directly, or indirectly, targeting the PI3K/AKT and/or JAK-STAT pathways may disrupt overexpression of cells in patients with these mutations. However, the lack of research specific to T-PLL makes it difficult to study targeted therapy for this disease. Thus, an ex vivo functional screening platform using multiple small molecule inhibitors simultaneously is an efficient method to investigate therapies that may be effective in patients with this disease. We present the first report retrospectively analyzing primary T-PLL patient samples and assessing their sensitivity against various targeted agents using our ex vivo functional screening platform. After obtaining informed consent using an IRB sample collection protocol, bone marrow aspirate and/or peripheral blood were obtained from patients with various hematological malignancies