TARGETING THE LEUKEMIA MICROENVIRONMENT BY CXCR4 INHIBITION IN STEM CELL TRANSPLA
Marina Y Konopleva, Assistant Professor
University Of Texas Md Anderson Can Ctr, Unit 0176, Houston, Tx 77030-4009
Grant 5R21CA137637-02 from National Cancer Institute
Abstract: The prognosis of patients with relapsed acute myeloid leukemia (AML) is extremely poor. Allogeneic stem cell transplantation is an effective treatment for AML in first remission, with approximately 60% achieving long-term progression-free survival. However, only 10-20% of patients with relapsed leukemia achieve durable remission. Likewise, patients with advanced remissions continue to have a relatively poor prognosis with stem cell transplantation and improved treatments are required. Our studies have demonstrated that microenvironment/leukemia interactions play a major role in chemoresistance of leukemic stem cells residing in the bone marrow niches. Our preliminary data indicate a key role for SDF-11/CXCR4 interactions in microenvironment-mediated chemoresistance. Inhibition of CXCR4 with the analogue of the only clinically available CXCR4 inhibitor AMD3100 results in mobilization of leukemic cells into the circulation and sensitization to chemotherapy, in part via blockade of the pro-survival signaling pathways. AMD3100 has been extensively used, alone or in combination with G-CSF, for the mobilization of normal hematopoietic stem cells into the circulation. Analysis of apheresis material from AML patients in remission mobilized with AMD3100/G- CSF demonstrated massive egress of AML cells into the peripheral blood, suggesting preferential mobilization of AML blasts. Based on these findings, we propose to test the hypothesis that mobilization of leukemic stem cells by CXCR4 inhibition and G-CSF will result in improved anti-leukemia activity of a standard preparative regimen followed by allogeneic stem cell transplantation. CXCR4 inhibitor AMD3100, G-CSF and busulfan/fludarabine chemotherapy will be administered sequentially to patients with advanced myeloid leukemias in the setting of allogeneic stem cell transplantation. This approach will also avoid potential concerns regarding the mobilization of normal stem cells and associated prolonged life-threatening cytopenias. To test this hypothesis, we propose the following Specific Aims #1) To conduct a prospective phase I/II clinical trial to determine if addition of AMD3100 (plerixafor), a CXCR4 inhibitor, and G-CSF will improve the antileukemia effect of high dose busulfan-fludarabine conditioning regimen with allogeneic stem cell transplantation for the treatment of AML/MDS. G-CSF will be administered at a standard dose beginning on day -9 daily for 6 days; and AMD3100 will be given 8 h prior to Fludarabine and Busulfan starting on Day -7 for 4 doses. In Phase 1, a maximum of 24 patients will be treated in cohorts of three to determine the safe dose among the three doses 80, 160, 240 mcg/kg of AMD3100. Although the proposed treatment is likely to be safer in patients with low bulk disease because of a lower potential for leukostasis, we will start enrollment in Phase I with patients not in CR, to assure the safety of this approach. In Phase 2, a maximum of 32 additional patients, up to 16 per subgroup (in complete remission (CR) or not in remission (NCR)), will be treated at the AMD3100 dose chosen in Phase 1. The objective of Phase 2 is to determine if the combination of AMD3100 and G-CSF with busulfan, fludarabine will improve progression-free survival post allogeneic stem cell transplantation from an HLA-compatible donor compared to historical controls receiving busulfan-fludarabine alone. #2) to study the in vivo biological effects of disruption of the SDF-11/CXCR4 interactions by AMD3100. These correlative studies will evaluate the relative proportions of mobilized AML and/or normal progenitor cells, analyze expression of the target receptor and adhesion molecules, determine changes in cell cycle distribution of mobilized cells, and assess induction of apoptosis in AML vs normal cells. We anticipate that focus on stroma leukemia crosstalk may result in the development of strategies that alleviate the acquisition of a chemoresistant phenotype and enhance the efficacy of therapies in hematological malignancies and other tumor types. Further, differential analysis of mobilized leukemic and normal cells will provide crucial information for the incorporation of this approach in the up-front therapy for patients with untreated AML or in other hematologic malignancies. The prognosis of AML patients upon relapse remains poor. AMD3100 and G-CSF are used for stem cell mobilization. In this study we will utilize AMD3100 / G-CSF combination to mobilize leukemic cells from bone marrow niches with the goal to enhance efficacy of busulfan/fludarabine conditioning regimen. This will be done in a setting of allogeneic hematopoietic stem cell transplantation in which hematologic recovery is derived from donor cells
Keywords: 1, 4-Bis(methanesulfonoxy)butane; 1, 4-Bitanediol Dimethanesulfonate Esters; 1, 4-Butanediol, dimethanesulfonate; 1, 4-Di(methanesulfonyloxy)butane; 1, 4-Di(methylsulfonyloxy)butane; 2-Fluoro-9-beta-arabinofuranosyladenine; 2-Fluorovidarabine; 2-fluoroadenine arabinoside; 9-Beta-D-arabinofuranosyl-2-fluoro-9H-purin-6-amine; 9-Beta-D-arabinofuranosyl-2-fluoroadenine; AMD-3100; AMD3100; AML - Acute Myeloid Leukemia; Address; Adhesion Molecule; Allogenic; Animal Model; Animal Models and Related Studies; Apheresis; Apoptosis; Apoptosis Pathway; Ara-C; Biological; Blast Cell; Blasts; Blood (Leukemia); Blood Circulation; Blood Component Removal; Blood Precursor Cell; Bloodstream; Bone Marrow; Bussulfam; Busulfan; Busulfanum; C-X-C Chemokine Receptor Type 4; CD184 Antigen; CSF3; CSF3 gene; CXC-R4; CXCR-4; CXCR4; CXCR4 Receptors; CXCR4 gene; Cancers; Cell Adhesion Molecules; Cell Communication and Signaling; Cell Cycle; Cell Death; Cell Death, Programmed; Cell Division Cycle; Cell Signaling; Cell Survival; Cell Viability; Cells; Chemokine (C-X-C Motif) Receptor 4; Chemokine, CXC Motif, Receptor 4; Circulation; Clinical; Clinical Trials; Clinical Trials, Unspecified; Correlative Study; Coupled; D2S201E; Data; Detectable Residual Disease; Development; Disease; Disease remission; Disorder; Dose; Drugs; Enrollment; Extracellular Matrix, Integrins; Extracellular Signal-Regulated Kinase Gene; F Ara A; FB22; Ferrata cell; Forecast of outcome; Fusin; G-CSF; GCSF; Goals; HM89; HSC transplantation; HSY3RR; Hemapheresis; Hematohistioblast; Hematologic Cancer; Hematologic Malignancies; Hematologic Neoplasms; Hematological Malignancies; Hematological Neoplasms; Hematological Tumor; Hematopoiesis; Hematopoietic; Hematopoietic Cancer; Hematopoietic Cellular Control Mechanisms; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hemocytoblast; Hemohistioblast; Homing; In complete remission; Induction of Apoptosis; Integrins; Intracellular Communication and Signaling; LAP3; LCR1; LESTR; LEUKCL; LPS-Associated Protein 3; Leukemia, Granulocytic; Leukemia, Myelocytic, Acute; Leukemias, General; Leukemic Cell; Leukocyte-Derived Seven-Transmembrane Domain Receptor; Leukostasis; Leukostasis Syndrome; Life; Ligands; Lipopolysaccharide-Associated Protein 3; MAP Kinase Gene; MAPK; MGC45931; Maintenance; Maintenances; Malignant; Malignant - descriptor; Malignant Hematologic Neoplasm; Malignant Neoplasms; Malignant Tumor; Marrow; Mediating; Medication; Methanesulfonic acid, tetramethylene ester; Minimal Residual Disease; Mitogen-Activated Protein Kinase Gene; Molecular; Mother Cells; Myeloblastic Leukemia, Acute; Myelocytic Leukemia; Myelogenous Leukemia; Myelogenous Leukemia, Acute; Myeloid Leukemia; NPY3R; NPYR; NPYRL; NPYY3R; Neoplasm, Residual; Neuropeptide Y Receptor Y3; Non-Lymphoblastic Leukemia; Non-Lymphocytic Leukemia; Normal Cell; Outcome; PI-3K/AKT; PI3K/AKT; Pathway interactions; Patients; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Phenotype; Pheresis; Play; Progenitor Cell Transplantation; Progenitor Cells; Progenitor Cells, Hematopoietic; Prognosis; Progression-Free Survivals; Protocols, Treatment; RGM; RMSN; Receptor Protein; Receptor, LESTR; Recovery; Regimen; Relapse; Relative; Relative (related person); Remission; Residual Neoplasm; Reticuloendothelial System, Bone Marrow; Role; SDF-1 Receptor; SDF1/PBSF Receptor CXCR4; SUBGP; Safety; Seven-Transmembrane-Segment Receptor, Spleen; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Staging; Stem Cell Mobilization; Stem Cell Transplantation; Stem cell transplant; Stem cells; Stromal Cell-Derived Factor 1 Receptor; Stromal Cells; Subgroup; Sulfabutin; Survivals, Progression-Free; Testing; Tetramethylene bis[methanesulfonate]; Time; Toxic effect; Toxicities; Transplant Recipients; Treatment Efficacy; Treatment Failure; Treatment Protocols; Treatment Regimen; Treatment Schedule; acute granulocytic leukemia; acute myeloid leukemia; acute nonlymphocytic leukemia; analog; base; biological signal transduction; cell adhesion protein; chemotherapy; clinical investigation; cohort; complete response; conditioning; cytopenia; design; designing; disease/disorder; drug/agent; effective therapy; enroll; fludarabine; improved; in vivo; inhibitor; inhibitor/antagonist; innovate; innovation; innovative; leukemia; malignancy; model organism; myeloid granulocytic leukemia; myelosis; necrocytosis; neoplasm/cancer; outcome forecast; pathway; peripheral blood; prospective; public health relevance; receptor; response; social role; stem; therapeutic efficacy; therapeutically effective; transplant patient; tumor
Relevance: NARRATIVE The prognosis of AML patients upon relapse remains poor. AMD3100 and G-CSF are used for stem cell mobilization. In this study we will utilize AMD3100 / G-CSF combination to mobilize leukemic cells from bone marrow niches with the goal to enhance efficacy of busulfan/fludarabine conditioning regimen. This will be done in a setting of allogeneic hematopoietic stem cell transplantation in which hematologic recovery is derived from donor cells
Project start date: 2009-03-01
Project end date: 2011-02-28
Budget start date: 1-MAR-2010
Budget end date: 28-FEB-2011
PFA/PA: PAR-08-025
5R21CA137637-02 (2010): $338800
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Marina Y Konopleva
Targeting The Leukemia Microenvironment By CXCR4 Inhibition In Stem Cell Transpla
Marina Y Konopleva
Leukemiauniversity Of Texas Md Anderson Can Ctr
Grant 1R21CA137637-01A1 from National Cancer Institute IRG: CONC
Abstract: The prognosis of patients with relapsed acute myeloid leukemia (AML) is extremely poor. Allogeneic stem cell transplantation is an effective treatment for AML in first remission, with approximately 60% achieving long-term progression-free survival. However, only 10-20% of patients with relapsed leukemia achieve durable remission. Likewise, patients with advanced remissions continue to have a relatively poor prognosis with stem cell transplantation and improved treatments are required. Our studies have demonstrated that microenvironment/leukemia interactions play a major role in chemoresistance of leukemic stem cells residing in the bone marrow niches. Our preliminary data indicate a key role for SDF-11/CXCR4 interactions in microenvironment-mediated chemoresistance. Inhibition of CXCR4 with the analogue of the only clinically available CXCR4 inhibitor AMD3100 results in mobilization of leukemic cells into the circulation and sensitization to chemotherapy, in part via blockade of the pro-survival signaling pathways. AMD3100 has been extensively used, alone or in combination with G-CSF, for the mobilization of normal hematopoietic stem cells into the circulation. Analysis of apheresis material from AML patients in remission mobilized with AMD3100/G- CSF demonstrated massive egress of AML cells into the peripheral blood, suggesting preferential mobilization of AML blasts. Based on these findings, we propose to test the hypothesis that mobilization of leukemic stem cells by CXCR4 inhibition and G-CSF will result in improved anti-leukemia activity of a standard preparative regimen followed by allogeneic stem cell transplantation. CXCR4 inhibitor AMD3100, G-CSF and busulfan/fludarabine chemotherapy will be administered sequentially to patients with advanced myeloid leukemias in the setting of allogeneic stem cell transplantation. This approach will also avoid potential concerns regarding the mobilization of normal stem cells and associated prolonged life-threatening cytopenias. To test this hypothesis, we propose the following Specific Aims #1) To conduct a prospective phase I/II clinical trial to determine if addition of AMD3100 (plerixafor), a CXCR4 inhibitor, and G-CSF will improve the antileukemia effect of high dose busulfan-fludarabine conditioning regimen with allogeneic stem cell transplantation for the treatment of AML/MDS. G-CSF will be administered at a standard dose beginning on day -9 daily for 6 days; and AMD3100 will be given 8 h prior to Fludarabine and Busulfan starting on Day -7 for 4 doses. In Phase 1, a maximum of 24 patients will be treated in cohorts of three to determine the safe dose among the three doses 80, 160, 240 mcg/kg of AMD3100. Although the proposed treatment is likely to be safer in patients with low bulk disease because of a lower potential for leukostasis, we will start enrollment in Phase I with patients not in CR, to assure the safety of this approach. In Phase 2, a maximum of 32 additional patients, up to 16 per subgroup (in complete remission (CR) or not in remission (NCR)), will be treated at the AMD3100 dose chosen in Phase 1. The objective of Phase 2 is to determine if the combination of AMD3100 and G-CSF with busulfan, fludarabine will improve progression-free survival post allogeneic stem cell transplantation from an HLA-compatible donor compared to historical controls receiving busulfan-fludarabine alone. #2) to study the in vivo biological effects of disruption of the SDF-11/CXCR4 interactions by AMD3100. These correlative studies will evaluate the relative proportions of mobilized AML and/or normal progenitor cells, analyze expression of the target receptor and adhesion molecules, determine changes in cell cycle distribution of mobilized cells, and assess induction of apoptosis in AML vs normal cells. We anticipate that focus on stroma leukemia crosstalk may result in the development of strategies that alleviate the acquisition of a chemoresistant phenotype and enhance the efficacy of therapies in hematological malignancies and other tumor types. Further, differential analysis of mobilized leukemic and normal cells will provide crucial information for the incorporation of this approach in the up-front therapy for patients with untreated AML or in other hematologic malignancies. The prognosis of AML patients upon relapse remains poor. AMD3100 and G-CSF are used for stem cell mobilization. In this study we will utilize AMD3100 / G-CSF combination to mobilize leukemic cells from bone marrow niches with the goal to enhance efficacy of busulfan/fludarabine conditioning regimen. This will be done in a setting of allogeneic hematopoietic stem cell transplantation in which hematologic recovery is derived from donor cells
Project start date: 2009-03-01
Project end date: 2011-02-28
TARGETING HYPOXIC BONE MARROW MICROENVIRONMENT IN ACUTE MYELOID LEUKEMIA (AML)
Marina Y Konopleva, Assistant Professor
University Of Texas Md Anderson Can Ctr, Unit 0176, Houston, Tx 77030-4009
Grant 1R21CA153019-01 from National Cancer Institute
Abstract: The main challenge in the treatment of acute myeloid leukemia (AML) is overcoming resistance to chemotherapy. We have shown that bone marrow (BM) in leukemia patients is highly hypoxic, and that BM hypoxia promotes resistance to drugs commonly used to treat AML. These data provide a rationale for use of hypoxia-activated prodrugs to eliminate AML cells within hypoxic niches. In our preclinical models, utilization of the novel hypoxia-activated prodrug PR104 has significantly decreased leukemia burden and cured mice transplanted with human leukemia. In the ongoing clinical trials in solid tumors, the principal toxicity of PR104 is bone marrow suppression; such toxicity indicates PR104 may be active in AML. Based on these findings, we will conduct Phase I/II clinical trial in patients with relapsed or refractory AML to investigate the safety and anti-leukemia efficacy of PR104. This trial will utilize novel statistical design to determine "individualized" doses based on each patient´s AML history such as previous remission duration and age. We have designed optional laboratory studies to measure BM hypoxia and hypoxic responses in leukemic cells to study whether these markers can add to clinical characteristics in selecting patient-specific doses of PR104. If successful, this approach of targeting hypoxic microenvironment, alone or in combination with other chemotherapeutic or targeted agents, may significantly impact AML therapy and ultimately improve outcomes of patients. The prognosis of acute myeloid leukemia (AML) patients upon relapse remains poor. PR104 is a novel hypoxia-activated agent, which is metabolized into cytotoxic derivatives in hypoxic leukemic bone marrow microenvironment. In this study, we will investigate the safety and anti-leukemia efficacy of PR104 in patients with relapsed or refractory AML
Keywords: 2-((nitroimidazol-1-yl)methyl)-1-piperdineethanol; 2-nitro-alpha-(piperidinomethyl)-1-imidazole ethanol; 2-nitroimidazole; 2-pimonidazole; ABC20; ABCB1; ABCB1 gene; AML - Acute Myeloid Leukemia; ATP-Binding Cassette, Sub-Family B (MDR/TAP), Member 1 Gene; Age; Biologic Marker; Biological Markers; Blast Cell; Blasts; Blood (Leukemia); Bone Marrow; Bone Marrow Suppression; Bone marrow biopsy; CD31; CXC-R4; CXCR-4; CXCR4; CXCR4 gene; Cancer Center; Cell Survival; Cell Viability; Cell/Tissue, Immunohistochemistry; Cells; Characteristics; Clinical; Clinical Trials; Clinical Trials, Unspecified; Complex; D2S201E; Data; Disease remission; Doctor of Medicine; Dose; Drug Precursors; Drug resistance; Drug-sensitive; Enrollment; FB22; Ferrata cell; Forecast of outcome; Fred Hutchinson Cancer Research Center; GP170; HM89; HSY3RR; Hematohistioblast; Hematopoiesis; Hematopoietic; Hematopoietic Cellular Control Mechanisms; Hemocytoblast; Hemohistioblast; History; Hour; Human; Human, General; Hypoxia; Hypoxia Inducible Factor; Hypoxic; IHC; Image; Immunohistochemistry; Immunohistochemistry Staining Method; Injection of therapeutic agent; Injections; Intermediary Metabolism; LAP3; LCR1; LESTR; LEUKCL; Laboratory Study; Leukemia, Myelocytic, Acute; Leukemias, General; Leukemic Cell; M.D.; MDR-1; MDR1; MDR1 Gene; METBL; Mammals, Mice; Man (Taxonomy); Man, Modern; Marrow; Measures; Metabolic Marker; Metabolic Processes; Metabolism; Methods; Mice; Molecular Marker; Mother Cells; Murine; Mus; Myeloblastic Leukemia, Acute; Myelogenous Leukemia, Acute; Myelosuppression; NPY3R; NPYR; NPYRL; NPYY3R; Outcome; Oxygen Deficiency; P-GP; P-Glycoprotein 1 Gene; PECAM1; PECAM1 gene; PGY1; Patients; Phase; Pimonidazole; Pre-Clinical Model; Preclinical Models; Pro-Drugs; Prodrugs; Progenitor Cells; Prognosis; RMSN; Recording of previous events; Refractory; Relapse; Remission; Resistance; Resistance Gene-1, Multidrug; Resistance Gene-1s, Multidrug; Reticuloendothelial System, Bone Marrow; Role; Safety; Sample Size; Sampling; Signature Molecule; Solid Neoplasm; Solid Tumor; Staging; Staining method; Stainings; Stains; Stem cells; Testing; Toxic effect; Toxicities; Transplantation; acute granulocytic leukemia; acute myeloid leukemia; acute nonlymphocytic leukemia; adduct; angiogenesis; azomycin; base; biomarker; chemotherapy; clinical investigation; cytotoxic; design; designing; drug resistant; enroll; imaging; improved; in vitro Assay; in vivo; leukemia; novel; outcome forecast; prospective; public health relevance; resistance to Drug; resistant; resistant to Drug; response; social role; transcription factor; transplant
Relevance: The prognosis of acute myeloid leukemia (AML) patients upon relapse remains poor. PR104 is a novel hypoxia-activated agent, which is metabolized into cytotoxic derivatives in hypoxic leukemic bone marrow microenvironment. In this study, we will investigate the safety and anti-leukemia efficacy of PR104 in patients with relapsed or refractory AML
Project start date: 2010-08-01
Project end date: 2012-07-31
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2011
PFA/PA: PAR-08-025
1R21CA153019-01 (2010): $319990