Iron chelating agent could enhance chemo in AML

Lab mouse

Chemotherapy for acute myeloid leukemia (AML) might be improved by the addition of deferoxamine, according to preclinical research published in Cell Stem Cell.

Researchers found that, when certain areas of the bone marrow are overtaken by AML cells, hematopoietic stem cells (HSCs) are lost, and the delivery of chemotherapy may be compromised.

However, the team also discovered that deferoxamine, a drug already approved to treat iron overload, can protect these areas of the bone marrow, allowing HSCs to survive and improving the efficacy of chemotherapy.

“Since the drug is already approved for human use for a different condition, we already know that it is safe,” said study author Cristina Lo Celso, PhD, of Imperial College London in the UK.

“We still need to test it in the context of leukemia and chemotherapy, but, because it is already in use, we can progress to clinical trials much quicker than we could with a brand-new drug.”

For the current study, Dr Lo Celso and her colleagues used intravital microscopy to study AML cells, healthy hematopoietic cells, and the bone marrow microenvironment in mice.

The researchers found the endosteal microenvironment was hit particularly hard by AML. Specifically, AML progression led to endosteal remodeling, with AML cells degrading endosteal endothelium, stromal cells, and osteoblastic cells.

This remodeling resulted in the loss of nonleukemic HSCs, which hindered hematopoiesis. However, preserving endosteal vessels prevented the loss of HSCs.

Previous research had shown that deferoxamine could induce endosteal vessel expansion through enhancement of hypoxia-inducible factor 1a stability and activity. So the researchers administered deferoxamine to mice with AML.

The drug had a protective effect on endosteal vessels, which were able to support healthy HSCs and improve HSC homing.

The researchers also found that enhanced endosteal vessels improved the efficacy of chemotherapy (cytarabine and doxorubicin) in mice with AML.

The team compared Fbxw7^iΔEC-mutant mice, in which the administration of tamoxifen increases the number of endosteal vessels and arterioles, to control mice. Both sets of mice had AML.

After confirming the mutant mice had increased numbers of endosteal vessels, the researchers treated the mutant mice and controls with cytarabine and doxorubicin.

Both sets of mice had significant chemotherapy-induced damage to the bone marrow vasculature, including endosteal vessels.

However, after treatment, the Fbxw7^iΔEC-mutant mice had lower numbers of surviving AML cells in the bone marrow, delayed relapse, and longer survival than control mice.

The researchers therefore concluded that rescuing endosteal vessels before starting chemotherapy can improve the efficacy of treatment in AML.

“Our work suggests that therapies targeting these blood vessels may improve existing therapeutic regimens for AML and perhaps other leukemias too,” said study author Delfim Duarte, MD, of Imperial College London.

Based on this work, the researchers are hoping to start trials of deferoxamine in patients with AML.

Lab mouse

Chemotherapy for acute myeloid leukemia (AML) might be improved by the addition of deferoxamine, according to preclinical research published in Cell Stem Cell.

Researchers found that, when certain areas of the bone marrow are overtaken by AML cells, hematopoietic stem cells (HSCs) are lost, and the delivery of chemotherapy may be compromised.

However, the team also discovered that deferoxamine, a drug already approved to treat iron overload, can protect these areas of the bone marrow, allowing HSCs to survive and improving the efficacy of chemotherapy.

“Since the drug is already approved for human use for a different condition, we already know that it is safe,” said study author Cristina Lo Celso, PhD, of Imperial College London in the UK.

“We still need to test it in the context of leukemia and chemotherapy, but, because it is already in use, we can progress to clinical trials much quicker than we could with a brand-new drug.”

For the current study, Dr Lo Celso and her colleagues used intravital microscopy to study AML cells, healthy hematopoietic cells, and the bone marrow microenvironment in mice.

The researchers found the endosteal microenvironment was hit particularly hard by AML. Specifically, AML progression led to endosteal remodeling, with AML cells degrading endosteal endothelium, stromal cells, and osteoblastic cells.

This remodeling resulted in the loss of nonleukemic HSCs, which hindered hematopoiesis. However, preserving endosteal vessels prevented the loss of HSCs.

Previous research had shown that deferoxamine could induce endosteal vessel expansion through enhancement of hypoxia-inducible factor 1a stability and activity. So the researchers administered deferoxamine to mice with AML.

The drug had a protective effect on endosteal vessels, which were able to support healthy HSCs and improve HSC homing.

The researchers also found that enhanced endosteal vessels improved the efficacy of chemotherapy (cytarabine and doxorubicin) in mice with AML.

The team compared Fbxw7^iΔEC-mutant mice, in which the administration of tamoxifen increases the number of endosteal vessels and arterioles, to control mice. Both sets of mice had AML.

After confirming the mutant mice had increased numbers of endosteal vessels, the researchers treated the mutant mice and controls with cytarabine and doxorubicin.

Both sets of mice had significant chemotherapy-induced damage to the bone marrow vasculature, including endosteal vessels.

However, after treatment, the Fbxw7^iΔEC-mutant mice had lower numbers of surviving AML cells in the bone marrow, delayed relapse, and longer survival than control mice.

The researchers therefore concluded that rescuing endosteal vessels before starting chemotherapy can improve the efficacy of treatment in AML.

“Our work suggests that therapies targeting these blood vessels may improve existing therapeutic regimens for AML and perhaps other leukemias too,” said study author Delfim Duarte, MD, of Imperial College London.

Based on this work, the researchers are hoping to start trials of deferoxamine in patients with AML.

Lab mouse

Chemotherapy for acute myeloid leukemia (AML) might be improved by the addition of deferoxamine, according to preclinical research published in Cell Stem Cell.

Researchers found that, when certain areas of the bone marrow are overtaken by AML cells, hematopoietic stem cells (HSCs) are lost, and the delivery of chemotherapy may be compromised.

However, the team also discovered that deferoxamine, a drug already approved to treat iron overload, can protect these areas of the bone marrow, allowing HSCs to survive and improving the efficacy of chemotherapy.

“Since the drug is already approved for human use for a different condition, we already know that it is safe,” said study author Cristina Lo Celso, PhD, of Imperial College London in the UK.

“We still need to test it in the context of leukemia and chemotherapy, but, because it is already in use, we can progress to clinical trials much quicker than we could with a brand-new drug.”

For the current study, Dr Lo Celso and her colleagues used intravital microscopy to study AML cells, healthy hematopoietic cells, and the bone marrow microenvironment in mice.

The researchers found the endosteal microenvironment was hit particularly hard by AML. Specifically, AML progression led to endosteal remodeling, with AML cells degrading endosteal endothelium, stromal cells, and osteoblastic cells.

This remodeling resulted in the loss of nonleukemic HSCs, which hindered hematopoiesis. However, preserving endosteal vessels prevented the loss of HSCs.

Previous research had shown that deferoxamine could induce endosteal vessel expansion through enhancement of hypoxia-inducible factor 1a stability and activity. So the researchers administered deferoxamine to mice with AML.

The drug had a protective effect on endosteal vessels, which were able to support healthy HSCs and improve HSC homing.

The researchers also found that enhanced endosteal vessels improved the efficacy of chemotherapy (cytarabine and doxorubicin) in mice with AML.

The team compared Fbxw7^iΔEC-mutant mice, in which the administration of tamoxifen increases the number of endosteal vessels and arterioles, to control mice. Both sets of mice had AML.

After confirming the mutant mice had increased numbers of endosteal vessels, the researchers treated the mutant mice and controls with cytarabine and doxorubicin.

Both sets of mice had significant chemotherapy-induced damage to the bone marrow vasculature, including endosteal vessels.

However, after treatment, the Fbxw7^iΔEC-mutant mice had lower numbers of surviving AML cells in the bone marrow, delayed relapse, and longer survival than control mice.

The researchers therefore concluded that rescuing endosteal vessels before starting chemotherapy can improve the efficacy of treatment in AML.

“Our work suggests that therapies targeting these blood vessels may improve existing therapeutic regimens for AML and perhaps other leukemias too,” said study author Delfim Duarte, MD, of Imperial College London.

Based on this work, the researchers are hoping to start trials of deferoxamine in patients with AML.