Plerixafor Treatment Improves Mobilization Of Cells In Donors During Bone Marrow Stem Cell Collection Procedures

Main Category: Stem Cell Research
Also Included In: Cancer / Oncology;  Lymphoma / Leukemia
Article Date: 19 Aug 2008 - 0:00 PDT

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In a study of 25 bone marrow donors, treatment with plerixafor, an antagonist able to disrupt a critical pathway associated with stem cell mobilization, was shown to mobilize cells faster than treatment with granular colony-stimulating factor (G-CSF), the current standard method used to collect bone marrow stem cells from healthy donors. According to the study results, two-thirds of donors treated with plerixafor were shown to mobilize a sufficient number of cells for transplantation after only one day. Donors treated with G-CSF require four to five days of treatment before collection is initiated. Results of the study are reported today in the peer-review publication Blood.

Each year, thousands of healthy donors undergo treatment to mobilize stem cells for collection and transplantation into patients with leukemia, other hematological malignancies, and a number of rare genetic errors. The interaction between the chemokine stromal-derived factor 1 (SDF-1/CXL 12) and its receptor (CXCR4) is a key regulator of mobilization in hematopoietic stem and progenitor cells (HSPC) from the bone marrow into the bloodstream where they can be collected for transplantation. Plerixafor is a direct antagonist of this interaction.

Treatment with G-CSF, which is thought to indirectly affect the interaction of CXCR-4 and SDF-1, requires donors to be treated for several days, which may result in absence from work or other inconvenience during the mobilization process. Treatment with G-CSF has also been associated with moderate morbidity including bone pain and some reported cases of acute toxicities such as chest pain.

"The current standard of care in allograft stem cell mobilization involving G-CSF requires donors to undergo treatment over a period of several days. It is also associated with established risks such as bone pain, and there have always been theoretical concerns that it could stimulate bone marrow abnormalities. Clearly a treatment that can reduce time to collection and also reduce risks associated with the use of G-CSF would represent a major advance for both donors and the patients who need blood stem cell transplants in the years ahead," said Steven M. Devine, MD director of Ohio State University's Comprehensive Cancer Hospital and principal investigator and lead author of the study.

In the study plerixafor induced the mobilization of sufficient numbers of HSPC for transplant within four hours for two-thirds of donors. Plerixafor appears to be at least as safe as G-CSF, with no donors experiencing more than a grade one toxicity. In the study, a set target for the amount of HSPCs needed for transplant was established in advance. If the target was met on the first day of treatment, no further collections were performed. If the minimum cell dose was not achieved following the first day of collection, the donor was asked to return in two days to repeat the process. Using that method, the use of plerixafor was considered a success if the combined total of HSPC was at or above the minimum required for transplantation after two days.

Data also indicate that plerixafor has a safety and efficacy profile similar to treatment with G-CSF. The cells collected using plerixafor were functionally similar to G-CSF collected cells when transplanted into cancer patients after receiving high dose chemotherapy. Based on historical controls, results in terms of engraftment and the incidence of graft versus host disease (GVHD) were also similar.

"These results indicate that HSPC mobilization with plerixafor, a direct antagonist of the SDF-1/CXCR interaction, can safely and effectively mobilize functional HSPC for the reconstitution of hematopoiesis without the requirement of G-CSF," Dr. Devine added.

About Plerixafor

Approximately 55,000 autologous and allogeneic stem cell transplants are performed worldwide each year for multiple myeloma, lymphoma, leukemia and other conditions. Plerixafor, a novel small molecule CXCR4 chemokine antagonist, has been shown in multiple earlier studies to rapidly and effectively increase the number of stem cells in circulation in the blood. Plerixafor is in development at Genzyme Corporation and has completed two phase III trials as potential therapy for autologous stem cell mobilization in patients with multiple myeloma and lymphoma. Results of these trials were reported in December 2007. Genzyme filed for regulatory approval for plerixafor for these indications with the FDA and EMEA in June 2008.

http://www.genzyme.com

"Rapid mobilization of functional donor hematopoietic cells without G-CSF using AMD3100, an antagonist of the CXCR4/SDF-1 interaction"
Steven M. Devine, Ravi Vij, Michael Rettig, Laura Todt, Kiley McGlauchlen, Nicholas Fisher, Hollie Devine, Daniel C. Link, Gary Calandra, Gary Bridger, Peter Westervelt, and John F. DiPersio
Blood, 15 August 2008, Vol. 112, No. 4, pp. 990-998
Click here to view abstract online

Journal Blood