Acute Myeloid Leukemia

The OSUCCC – James has an international reputation for clinical research in acute myeloid leukemia at the chromosomal, gene and molecular levels. Its world-renowned experts have contributed to World Health Organization diagnostic and treatment guidelines.

Research Strengths

  • Predicting treatment outcome for cytogenetically normal AML
  • Gene mutations that drive AML
  • microRNA and gene expression changes in AML
  • Epigenetic changes that might influence treatment
  • Molecular markers for patient stratification to predict treatment outcomes

Affiliated/Supporting/Collaborating Programs

  • Alliance for Clinical Trials in Oncology
  • Blood and Marrow Transplant Clinical Trials Network
  • The Ohio State University Center for Clinical and Translational Science
  • European LeukemiaNet (ELN)

Clinical Trials

OSU-12062: Safety Study of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients with Advanced Hematological Cancer
PI: Ramiro Garzon, MD
NCT ID: NCT01607892
Objectives:

  • Number of participants with adverse events
  • Area under the plasma-concentration versus time curve of KPT-330

OSU-13182: Phase I Study of Decitabine (Dacogen) and Selinexor (KPT-330) in Acute Myeloid Leukemia
PI: Ramiro Garzon, MD
NCT ID: NCT02093403
Objectives:

  • Evaluate the safety and tolerability of Selinexor (KPT‐330) in combination with decitabine in AML patients
  • Define the specific toxicities, maximum tolerated dose and dose-limiting toxicity of this combination
  • Determine the overall response rate and the rate and duration of complete remission
  • Conduct pharmacodynamic studies by measuring the effect of this regimen on the kinome, micronome and epigenome

Research Grants

Developing CRM1 Inhibitor Treatment for AML (1R01CA188269)
PI: Ramiro Garzon, MD
Objectives:

CRM1 is a nuclear export protein that is overexpressed in AML. It inactivates tumor-suppressor proteins such as P53 by moving them out of the nucleus, thereby promoting AML development. A phase I study at the OSUCCC – James of the oral CRM1 inhibitor KPT-330 is assessing the agent’s safety, tolerability and preliminary efficacy in refractory, relapsed and newly diagnosed elderly AML patients.

Additional studies of KPT-330 in AML supported by the grant:

  • Correlative studies using specimens from the phase I trial for pharmacokinetic and pharmacodynamic endpoints of the agent, and to identify pretreatment biomarkers associated with clinical response and drug activity
  • Pharmacokinetic and pharmacodynamic correlative studies using specimens from the phase I trial, and studies to identify pretreatment biomarkers associated with clinical response and drug activity
  • A phase I trial of decitabine followed by KPT-330 in newly diagnosed unfit elderly (over age 60) or refractory and relapsed AML patients to determine safety and preliminary efficacy and to establish the recommended Phase II dose
  • Evaluate a treatment to overcome chemotherapy resistance in refractory and relapsed AML blasts. The studies will examine whether the anti-leukemic effects of cytarabine or topoisomerase II inhibitors are enhanced by concomitant or sequential treatment with KPT-330

Functional Characterization of MLL Gene Fusions (5R01CA089341)
PI: Michael A. Caligiuri, MD
Objectives:

This work is designed to identify the best treatment for AML patients with partial tandem duplication (PTD) of the mixed lineage leukemia (MLL PTD) gene. The overall goal is to elucidate the molecular mechanisms that underlie this subset of AML, which could lead to increased cure rates for this disease using molecular-based risk stratification and targeted therapeutics.

The central hypothesis of this work is that the MLL PTD is responsible, at least in part, for leukemic transformation, and that it will be a valuable target for therapeutic intervention in this AML subgroup, which has a poor prognosis. This research will build on previous work—which includes generating generated a Mll ptd/Flt3 itd double-mutant mouse model, 100 percent of which develop aggressive acute leukemia—with the following aims:

  • Further characterize the Mll ptd to best understand how this mutation impacts the genesis and propagation of AML;
  • Elucidate cooperating events that together with the Mll ptd give rise to AML.

Collectively, this work is expected to provide critical insights into how to best treat MLL PTD AML patients.

Role of 11Q23 Chromosome Abnormalities in the Causation of Acute Leukemia (5P01CA129242)
PI: Carlo M. Croce, MD
Objectives:

ALL1-associated leukemias account for most infant and therapy-related leukemias, and have a poor prognosis.

ALL1 is the human homologue of Drosophila TRITHORAX (TRX), which is critical for establishing body pattern during embryonic development. Earlier work by this team of investigators focused on TRX and yielded unexpected and important insights that also applied to ALL1.

This new research is a wide-angle investigation of ALL1/TRX and ALL1 leukemogenesis. The goal is to achieve a deeper understanding of the fundamentals of gene fusion-mediated leukemogenesis and gene regulation and of ALL1 leukemia pathogenesis.

It aims to identify molecules critical for ALL1 leukemia pathogenesis, and to further understand how ALL1 fusion proteins trigger leukemia. These critical leukemogenic molecules can then be targeted by innovative new therapies.

Translational Research Accomplishments

A Gene Within a Gene Contributes to the Aggressiveness of AML. Over-expression of a gene called BAALC is associated with poor survival of acute myeloid leukemia (AML) patients. BAALC has a second smaller gene embedded within it that is also active in AML. This study showed that the smaller of the two genes is the major driver of AML development. The study also identified a drug that might inhibit the smaller gene’s activity. Published in the journal Science Signaling.

A seven-gene score that combines genetic and epigenetic changes might help guide therapy. The seven-gene scoring system for AML cells is based on gene mutations and on epigenetic change, DNA methylation. The study, led by OSUCCC – James researchers, suggests that patients with low-scoring AML cells—none or only one of the seven genes is overexpressed—had the best outcomes. Patients with high-scoring AML cells—in which six or seven of the genes are overexpressed—had the poorest outcomes. The findings suggest that epigenetic changes in prognostically important mutated genes can identify novel patient subgroups, which might better guide therapy, and that this scoring system might help determine treatment for AML patients. Published in the Journal of Clinical Oncology.

A reduced intensity regimen prior to bone marrow transplantation improves outcomes for older leukemia patients. Blood or bone marrow transplants can be a viable option for younger patients, but conventional preparative regimens leading up to the procedure are often too toxic for patients over age 60. This study, led by OSUCCC – James researchers, showed that using a reduced-intensity conditioning regimen to prepare older AML patients for bone marrow transplants can be associated with higher rates of disease-free survival compared with the treatments usually given these patients. The study was presented at the 2012 American Society of Hematology (ASH) Annual Meeting in Atlanta, GA.

Inhibitors of shuttle molecule show promise in acute leukemia. A novel family of experimental agents called KPT-SINEs (selective inhibitors of nuclear export) might offer a new treatment for AML patients, according to a study by OSUCCC – James researchers. The agent targets a nuclear transport protein called CRM1, which shuttles proteins out of the cell nucleus. Using AML cells and an animal model, OSUCCC – James researchers showed that the agents inhibited leukemia-cell proliferation, arrested cell division and induced cell death and differentiation. KPT-SINEs were particularly effective when the AML cells had mutations in the NPM1 tumor-suppressor gene. These mutations are present in about one-third of all adult AML patients. In the AML animal model, KPT-SINEs extended survival by 46 percent compared with controls. Published in the journal Blood.


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