Stem cell mobilization by G-CSF – discussion of the potential risk of leukemia development in healthy donors

by Alexey Bersenev on July 29, 2008 · 2 comments

in business, clinical trials and cases, under discussion

Granulocyte Colony Stimulating Factor (G-CSF) is the most frequently used pharmacological agent for hematopoietic stem cell (HSC) mobilization (stimulation of migration from bone marrow to bloodstream) in hematology clinics. Two other applications of HSC mobilization are therapeutic regeneration of “impaired organs” (examples: heart or liver or brain) and banking of your own stem cells for future potential use.

More than a decade ago the US Biotech giant Amgen corp. introduced the first human-derived therapeutic growth factor – Neupogen, which has become biotechnology’s first blockbuster. Just in 2007 Amgen’s G-CSF generated 4,277 million US dollars. Since the first introduction, this drug saved thousands of lives and successfully continues doing it.

So it seems like G-CSF is pretty safe and has no adverse effects. Everything was fine with it until first reports appeared in 2003 and 2004, indicating a possible harmful (mutagenic) effect of G-CSF on hematopoietic cells of healthy donors. Even at that time point controversy began. Since then, I counted nearly 10 published reports about possible potential risks of leukemia development in healthy donors after short course of G-CSF injections for mobilization.

This very controversial topic captured my attention again after a recent case report in Bone Marrow Transplant Leukemogenesis in a healthy hematopoietic stem cell donor exposed to a short course of G-CSF.

A 39-year-old man developed acute myelogenous leukemia 4.6 years after hematopoietic stem cells mobilization by G-CSF and subsequent donation to his HLA-identical brother. Likely this case will not be fatal but a patient developed leukemia complications resulting in neurological impairment. Authors raised a very good question:

It is known that family members patients with myeloid leukemias are themselves at increased risk of developing leukemia. Thus, it is difficult to assess the increased risk in this potentially susceptible population and any link between G-CSF exposure and the development of leukemia in this and other reported cases remains unclear.

So where are we now in understanding this problem? What have we learned for the last 5 years? The answer is “we still don’t know”. Discussion is still on.

The significance of the problem was also highlighted in a recent review – Biologic and molecular effects of granulocyte colony-stimulating factor in healthy individuals: recent findings and current challenges.

In conclusion, there is insufficient data to determine if short exposure to G-CSF poses a leukemogenic risk in healthy stem cell donors. To further quantify this potential risk, carefully designed large prospective studies are required.

So, right now, while data is insufficient, if any of my relatives will get leukemia I’d agree to mobilize and donate my HSC to save a life. But we definitely need more independent clinical studies that evaluate a potential risk of leukemogenesis – the sooner the better! Also because of huge interest in other areas of regenerative medicine and active advertisement of companies selling G-CSF generics. So it’s a billion dollar question.
Another way to avoid this risk is using other available mobilizers, which also need to be tested in terms of hematopoietic cells mutations in healthy people.

Based on the totality of information that is currently available, the administration of rhG-CSF to healthy donors for the purpose of PBPC donation continues to have a favorable risk-benefit profile.

Tonya July 29, 2008 at 3:51 am

Despite the appearance of several sporadic reports about leukemogenesis after usage of G-CSF, only in Europe there are more than 15 000 G-CSF based allogeneic transplantations performed annualy without any remarkable side effects for the donors. Actually, the mechanism of G-CSF action as the mobilizing agent is just an exacerbated natural mechanism…

Definitely, we need long-term data on safety of G-CSF usage, but in my opinion – the results will be favorable to continue using G-CSF in healthy donors (this drug is in active use for more than 20 years and any significant problems would be evident in that period of time). Although, for this cohort I’m significantly more positive about AMD3100. Let’s just wait for the results of recent Genzyme trial for AMD3100 as a single mobilizing agent in healthy donors…

Alex July 29, 2008 at 4:01 am

“will be favorable to continue using G-CSF in healthy donors” –
until mozobil (AMD3100) will take over the market
in my opinion

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