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Updated: Apr 16, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Current challenges in clinical development of "targeted therapies": the case of acute myeloid leukemia
Elihu Estey1, Ross L Levine2, Bob Löwenberg3
1Division of Hematology, University of Washington, Seattle, WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
Abstract:
A fundamental difficulty in testing "targeted therapies" in acute myeloid leukemia (AML) is the limitations of preclinical models in capturing inter- and intrapatient genomic heterogeneity. Clinical trials typically focus on single agents despite the routine emergence of resistant subclones and experience in blast-phase chronic myeloid leukemia and acute promyelocytic leukemia arguing against this strategy. Inclusion of only relapsed-refractory, or unfit newly diagnosed, patients risks falsely negative results. There is uncertainty as to whether eligibility should require demonstration of the putative target and regarding therapeutic end points. Although use of in vivo preclinical models employing primary leukemic cells is first choice, newer preclinical models including "organoids" and combinations of pharmacologic and genetic approaches may better align models with human AML. We advocate earlier inclusion of combinations ± chemotherapy and of newly diagnosed patients into clinical trials. When a drug plausibly targets a pathway uniquely related to a specific genetic aberration, eligibility should begin with this subset, including patients with other malignancies, with subsequent extension to other patients. In other cases, a more open-minded approach to initial eligibility would facilitate quicker identification of responsive subsets. Complete remission without minimal residual disease seems a particularly useful short-term end point. Genotypic and phenotypic studies should be prespecified and performed routinely to distinguish responders from nonresponders.
Insights
Testing targeted therapies for acute myeloid leukemia (AML) is challenging due to preclinical model limitations. Clinical trials should include combination therapies and newly diagnosed patients earlier for better results.
Area of Science:
- Hematology
- Oncology
- Translational Research
Background:
- Preclinical models for acute myeloid leukemia (AML) struggle to replicate genomic heterogeneity, hindering targeted therapy testing.
- Current clinical trials often use single agents, overlooking resistance mechanisms observed in other leukemias.
- Excluding newly diagnosed or including only relapsed/refractory patients may lead to inaccurate trial outcomes.
Purpose of the Study:
- To address challenges in testing targeted therapies for acute myeloid leukemia (AML).
- To propose improvements for clinical trial design in AML, focusing on preclinical models and patient selection.
- To optimize the identification of effective treatment strategies for AML patients.
Main Methods:
- Review of limitations in current preclinical models for acute myeloid leukemia (AML).
- Analysis of clinical trial designs, including patient eligibility and therapeutic endpoints.
- Consideration of novel preclinical models like organoids and combined pharmacologic/genetic approaches.
Main Results:
- Genomic heterogeneity in AML poses a significant challenge for preclinical models.
- Single-agent therapies may be insufficient due to emergent resistance.
- Current trial designs risk yielding false-negative results.
Conclusions:
- Clinical trials for AML should incorporate combination therapies (± chemotherapy) and newly diagnosed patients earlier.
- Eligibility criteria should be flexible, starting with genetically defined subsets when applicable.
- Complete remission without minimal residual disease is a valuable endpoint; routine genotypic/phenotypic studies are crucial.
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