The outcome of adults with acute lymphoblastic leukemia (ALL) remains poor. While 90% of adult patients will achieve an initial remission with chemotherapy, the majority will relapse and only 30-40% will achieve long-term disease free survival. Evidence suggests that similar to normal hematopoietic stem/progenitor cells, leukemic cells receive key growth and survival signals from the bone marrow microenvironment. Moreover, direct physical interaction of leukemic cells with stromal cells in the bone marrow may limit their sensitivity to chemotherapy. Thus, targeting leukemia-stromal interactions is an emerging and promising strategy to sensitize leukemic cells to cytotoxic chemotherapy. Preclinical studies performed by our group suggest that treatment with granulocyte-stimulating factor (G- CSF) provides a potent and well-tolerated method to disrupt the leukemia niche in the bone marrow. Indeed, treatment with G-CSF prior to initiating chemotherapy augments clearance of ALL cells in mice. We initiated a pilot clinical trial of upfront G-CSF treatment prior to salvage chemotherapy in patients with relapsed ALL. Preliminary data show that G-CSF induces mobilization of ALL cells into the blood, while inducing apoptosis of ALL cells resident in the bone marrow. There is strong evidence that CXCL12 provides a key survival signal for normal and malignant lymphocytes. Preliminary data show that treatment with POL5551, a novel and potent CXCR4 antagonist, mobilizes ALL cells into the blood in mice and renders them more sensitive to chemotherapy. Since G-CSF results in only partial suppression of CXCL12 in the bone marrow, we hypothesize that treatment with G-CSF and a CXCR4 antagonist will cooperate to disrupt leukemia-stromal cell signals, rendering ALL cells more sensitive to chemotherapy. The following specific aims are proposed.
Aim 1. To optimize strategies to disrupt the leukemic niche in the bone marrow and sensitize human ALL cells to chemotherapy.
Aim 2. To test the feasibility of priming with G-CSF and POL6326 with chemotherapy in adults with relapsed or refractory ALL.
This proposed research is relevant to public health because it seeks to translate fundamental observations on the effects of G-CSF and CXCR signalling in to an early phase clinical trial with an overall goal of improving the clinical outcomes of patients with acute lymphoblastic leukemia.
|Ghobadi, Armin; Choi, Jaebok; Fiala, Mark A et al. (2016) Phase I study of azacitidine following donor lymphocyte infusion for relapsed acute myeloid leukemia post allogeneic stem cell transplantation. Leuk Res 49:1-6|
|Al-Hussaini, Muneera; Rettig, Michael P; Ritchey, Julie K et al. (2016) Targeting CD123 in acute myeloid leukemia using a T-cell-directed dual-affinity retargeting platform. Blood 127:122-31|
|Welch, John S; Petti, Allegra A; Miller, Christopher A et al. (2016) TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med 375:2023-2036|
|Rashidi, Armin; Ebadi, Maryam; Colditz, Graham A et al. (2016) Outcomes of Allogeneic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-analysis. Biol Blood Marrow Transplant 22:651-7|
|Fehniger, Todd A; Cooper, Megan A (2016) Harnessing NK Cell Memory for Cancer Immunotherapy. Trends Immunol 37:877-888|
|Wong, Terrence N; Miller, Christopher A; Klco, Jeffery M et al. (2016) Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML. Blood 127:893-7|
|Rashidi, Armin; Walter, Roland B; Tallman, Martin S et al. (2016) Maintenance therapy in acute myeloid leukemia: an evidence-based review of randomized trials. Blood 128:763-73|
|Shirai, Cara Lunn; Ley, James N; White, Brian S et al. (2015) Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo. Cancer Cell 27:631-43|
|Wong, Terrence N; Ramsingh, Giridharan; Young, Andrew L et al. (2015) Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature 518:552-5|
|Uy, Geoffrey L; Hsu, Yen-Michael S; Schmidt, Amy P et al. (2015) Targeting bone marrow lymphoid niches in acute lymphoblastic leukemia. Leuk Res 39:1437-42|
Showing the most recent 10 out of 32 publications