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First Stable, Serially Transplantable M5 AML PDX Model Published

It is traditionally difficult to develop stable blood cancer patient-derived xenograft (PDX) models. Historically, commercially available models have been transient and non-transferable through passages. This only allows one-shot studies providing a gross measure of response, not suitable for efficacy studies.

A recent publication has now detailed the first stable serially transplantable PDX of M5 acute myeloid leukemia in mice, and looked at the differing responses to anti-leukemia drug activity, including chemotherapy and a newer targeted agent.

M5 AML Patient, with Confirmed Diagnosis and Common AML Features

The foundation of the paper is the development of the PDX model, from a patient with M5 subtype AML. The patient’s bone marrow cells were positive for typical myeloid surface markers CD45, CD33, CD123, and CD13, and negative for nonmyeloid markers, for example, CD19 and CD3. Sequencing/mutation analysis also confirmed many features often seen in AML including heterozygous FLT3-ITD, along with IDH2-R140Q, DNMT3A-R882H, and NPM1.

Mononuclear cells isolated from the sample were engrafted into five irradiated NOD/SCID mice, and monitored weekly for the peripheral appearance of leukemic cells (CD45+), which appeared after a 5 month latency period with typical AML symptoms. The engraftment had a high take rate, and particularly high levels of engraftment.

Stable, Transplantable PDX Model Developed, Recapitulating Patient Disease

Leukemic cells from this P0 model were then serially passaged with a 100% take rate, with re-engraftments showing robust growth and 100% mortality, creating a robust and stable AML model.

Flow cytometry analysis of the PDX model revealed markers identical to the patient (CD45+, CD33+, CD13+, CD123+, CD38+, and CD19-, CD34-, HLA-DR-) and genotyping of the model confirmed the heterozygous IDH2 R140Q mutation, FLT3-ITD, DNMT3A R882H, and NPM1, as seen for the patient.

These results confirmed the presence of stable AML in the mice without phenotypic and genotypic shift, and provided the first AML model with both FLT3-ITD and IDH2 mutations.

Model Robust Growth Likely Supported by a GM-CSF and IL-3 Autocrine Mechanism

GM-CSF and IL-3 are the two key cytokines required for myeloid lineage cell growth and differentiation, and they are also important for the growth of some AML cells. Murine GM-CSF and IL-3 don’t recognize their human counterpart receptors, so can’t promote human PDX growth.

High levels of human GM-CSF and IL-3 were found in the blood of the mice implanted with the PDX, produced by leukemic cells, suggesting that an autocrine mechanism involving these factors could be responsible for the robust growth of the model (which has been published on previously).

Chemotherapy vs Targeted Therapy Efficacy Studies

The stable PDX provides the perfect model for efficacy studies, and the paper went on to compare current standard of care (SoC) treatment with a possible future targeted AML therapy, aiming to provide useful information for the clinical application of these drugs:

Treatment options for AML remained static for many years, with new progress only being seen this year with agents approved which target FLT3 mutation as well as IDH2 mutation. Further targeted agents such as AC220 are needed to help treat this complex disease.

Current SoC Induces Temporary Remission in Peripheral Blood

Treatment with AraC initially went well – treatment of the model almost completely suppressed leukemia in the peripheral blood, and to a lesser extent other organs. Disease symptoms were reduced, and lifetime extended.

However, treatment withdrawal caused a rapid relapse in peripheral blood within days, with clinical symptoms returning and eventual mortality. Continuous dosing was also trialed, which did delay disease onset but could still not prevent eventual death.

FLT3 Targeted Agent Suggested a “Possible Cure”

In comparison, treatment with AC220 produced stellar results. The drug caused complete remission – suppressing leukemia in peripheral blood, as well as in bone and spleen, as far as 130 days post-inoculation. This translated into a reduction in symptoms and an extension of life.

There was also no relapse of symptoms after high dose treatment withdrawal, and no clinical signs of disease until the end of the study. Leukemia was not detected in a range of organs and gross pathology examination during autopsy, suggesting the possibility of a “cure”.

AC220 and AML PDX Model Validated in AML Treatment Research

This study seemed to reveal an important limitation of standard induction chemotherapy – with only a temporary/incomplete suppression of AML in an M5 FLT3-ITD PDX. This disease relapse is somewhat reflective of the clinical situation, and demonstrates why new treatment options are needed.

The study also confirms that FLT3-ITD plays a critical role in at least maintaining AML in this model – acting as an oncogenic driver, and that AC220 could play an important role in the future treating patients with this mutation.

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