MPNforum Magazine

Drug scores bulls-eye in treating anemia of inflammation.

by Zhenya Senyak

The weakness and fatigue experienced by most MPN patients is often a result of depleted iron stores, anemia.  So it’s little wonder the story  in Blood would grab any MPN patient’s attention. “Drug Represents First Potential Treatment for Common Anemia.”

The anemia/inflammation connection

According to the American Society of Hematology, “Anemia is a condition that occurs when red blood cells are in short supply or do not function properly. When an individual has anemia, the body does not get enough oxygen, since there are fewer red blood cells to carry the iron-rich protein hemoglobin that helps distribute oxygen throughout the body. This can result in symptoms such as weakness and fatigue.”

Increasingly investigators are focusing on inflammation as both the driving force of that anemia as well as an underlying factor in progression of the myeloproliferative neoplasm disease state and opportunistic cancers. Here’s why:

The most common form of anemia in the hospital setting is anemia of inflammation, which occurs when the body’s immune response is activated during illness or infection.  When the body fights a disease, it deploys an inflammatory response that triggers increased secretion of a hormone called hepcidin that reduces the amount of iron available in the bloodstream. As iron is needed for the production of red blood cells in the bone marrow, many patients develop anemia.

Inflammation — a burning issue

Dr. Hans Hasselbalch, in the current issue of MPN Quarterly Journal  and in earlier issues of Blood discusses chronic inflammation as the driving force of clonal evolution in MPNs.

“In the perspective, that chronic inflammation may be an important contributing factor in MPN pathogenesis, it seems rational to interrupt clonal evolution at the earliest disease stage – ET – thereby aiming at reducing or eliminating all potential factors which might contribute to morbidity and mortality. In the ET-population these factors include elevated leukocyte and platelet counts but – in addition – circulating leukocyte-platelet aggregates elicited by in vivo leukocyte and platelet activation and being sustained and perpetuated by inflammatory products released from the malignant clone

“Furthermore, in the context of chronic inflammation as a potential promoter of cancer development and progression and given that ET and PV patients indeed have an increased risk of second cancer – both hematological and non-hematological — it is also for these reasons important to alleviate the chronic inflammatory drive. Chronic inflammation and a deregulated immune system with impaired tumor immune surveillance may be important factors in the pathogenesis and progression of MPNs . Accordingly, a rational therapeutic approach may include immune-enhancing treatment with IFN at the time of diagnosis when the tumor burden is the least and consequently the outcome of IFN likely the very best.`”

Do-it-yourself inflammation lab

Inflammation is an integral part of the body’s immune system.  A scratch, puncture, trauma, onset of infection or illness triggers inflammation.  It’s a response that is at least 500 million years old and predates vertebrate life on Earth.   Birds do it, bees do it, educated fleas and even fruit flies do it.

Vasodilation, opening of the surrounding blood vessels, is one means through which inflammation originates, And it’s something we can easily demonstrate by scratching an arm firmly several times. Almost immediately you’ll see evidence of the four classic ” -0rs “of inflammation appear on the skin’s :  rubor (redness). Tumor (swelling). Calor (heat) and Dolor (pain). The red coloration and heat are alike due to the increased blood flow to the area, swelling derives from perfusion of white blood cells into the area. Pain is not always a concomitant of inflammation depending upon the nerve-rich landscape of the area affected.

Inflammation is an ancient, complex, and crude mechanism to deal with infection  and trauma. The good part is inflammation results in an immediate flood of cytokines summoning a variety of white blood cells to a damaged sites, spraying and jabbing the intruder, summoning Killer Cells and macrophages to destroy and eat the invader.  (Scabbing and reconstruction follow. ) The bad part is inflammation, like a rabid dog, can also turn against the host or even join forces with a cancerous tumor or runaway blood production and contribute to metastases and proliferation.

This inflammatory mechanism so effective in protecting the organism when human life was brief and violent can turn against us when life has been extended. Lingering inflammation is a major factor in chronic diseases like arthritis, Crohn’s, heart disease, myeloproliferative neoplasm and other cancers.

Hepcidin — the iron control hormone

We can see inflammation but what we can’t see is hepcidin, the hormone triggered by the onset of inflammation, likely signaled by the cytokine IL-6.  Hepcidin, produced by the liver in response to the inflammatory cytokines is responsible for reducing the iron rich hemoglobin bearing capacity of red blood cells  in two way. Hepcidin denies life-sustaining iron to invading organisms by locking up iron-bearing molecules on cell surfaces. The hormone also  directly limits bone marrow erythropoiesis.   By increasing or up-regulating disease fighting white blood cells — produced from the same stem cell creating red blood cells — hepcidin further contributes to the organism’s anemia by reducing the numbers of oxygen bearing red blood cells.

The clinical trial:  Lexaptepid as hepcidin inhibitor

In clinical trial NCT01522794 Lucas T. van Eijk and  a Dutch team from Radboud University in the Netherlands clinically tested the ability of NOX-H94 lexaptepid to block hepicidin from driving down iron levels as a consequence of the body’s inflammatory response.

24 healthy 18-34 year old male subjects were randomized into two groups. Investigators induced a temporary inflammatory response resulting in flu-like symptoms and the release of pro-inflammatory cytokines IL-65, TNF-alfa causing the induction of the hormone hepcidin. One half hour after inducing inflammation, the investigators injected subject either with lexaptepid or placebo.

The results were dramatic.  Nine hours later, in response to high hepcidin levels the placebo subjects saw their serum iron plummet by 8.3 to 9.0 micromoles while the lexaptepid subjects saw an increase in serum iron over baseline of 15.9 to 9.8 microlmoles.  The investigators conclude:”This study delivers proof of concept that lexaptepid achieves clinically relevant hepicidin inhibition….”
Take me back to the Contents

© MPNforum.com, 2014. Unauthorized use and/or duplication of this material without express and written permission is prohibited. Excerpts and links may be used, provided that full and clear credit is given to MPNforum.com with appropriate and specific direction to the original content.