IL6 blockade helped promote the differentiation of red blood cell precursors, leading to reduced anemia and prolonged survival in a xenograft mouse model of AML. If validated in patients, the therapeutic strategy could reduce the need for blood transfusions, but it would not target the root cause of the disease.
A drug approved to treat a rare lymph node disease that is currently being tested against COVID-19 might also provide a remedy for bone marrow failure in patients with acute myeloid leukemia (AML).
That's according to a new study, which found that siltuximab (Sylvant; EUSA Pharma)—an IL6-neutralizing antibody used to treat people with multicentric Castleman disease—helped promote differentiation of red blood cell precursors, leading to reduced anemia and prolonged survival in a xenograft mouse model of AML.
Describing the results as “striking,” James DeGregori, PhD, of the University of Colorado Cancer Center in Aurora, who was not involved in the study, says the authors “clearly show how AML cells impair the production of normal hematopoietic cells,” while simultaneously offering “a potential solution” to the problem through IL6 inhibition.
AML has traditionally been thought of as a disease in which immature blood cells, known as blasts, crowd out healthy cells in the bone marrow, leading to defects in blood cell formation. Yet, a growing number of studies have begun to challenge this view, showing instead that declines in normal bone marrow function arise as a direct consequence of intrinsic properties of AML blasts.
A team led by Ravi Majeti, MD, PhD, and lead author Tian Zhang, MD, PhD, of Stanford University in California, validated this emerging view by analyzing data from nearly 300 patients with AML. They found no correlation between the percentage of blasts in the bone marrow, a standard estimate of disease burden, and the degree of cytopenia at the time of diagnosis, substantiating the idea that AML cells do not disturb the normal hematopoietic system through overcrowding, as originally thought.
The researchers next turned to mice to better understand the origins of the disease. Standard xenograft models compensate for AML-induced bone marrow failure by ramping up hematopoiesis in the spleen, they found. So, they surgically removed the lymphatic organ and showed that the mice developed blood abnormalities as the bone marrow progressively lost blood-forming stem cells—all in a manner mirroring the course of human disease.
Using these splenectomized mice, the researchers then determined that the AML cells were blocking the maturation of early erythroid precursors and that blast-secreted IL6 was to blame. They gave the mice siltuximab to squelch IL6 signaling and observed increases in hemoglobin concentration as well as elevated numbers of red blood cell precursors.
Notably, siltuximab had no effect on blast counts in the bone marrow, yet the drug significantly extended survival in the mice—highlighting the value of a therapy that helps manage AML-induced anemia even if it does not address the root cause of the disease.
Siltuximab is not the only approved IL6-signaling blocker that could offer this benefit. According to Majeti, his team has unpublished data showing that, in cell culture at least, antibody drugs such as tocilizumab (Actemra; Roche) that are directed against the IL6 receptor can augment erythroid differentiation as well. –Elie Dolgin