Date: December 10, 2003
by Chaya Venkat
This article responds to several enquiries regarding the use of CXCR-4 blockers such as AMD3100 in improving stem cell mobilization for autologous stem cell transplant.
First, a brief recap of the autologous bone marrow transplant procedure, so that we are all on the same page. As opposed to allogeneic bone marrow transplants, where a matched donor is needed to provide fresh bone marrow stem cells, autologous bone marrow transplants use the patient's own stem cells. The logic is that in CLL the cancerous contamination is not at the stem cell stage, but downstream in the specific B-cell lineage cells. Present day allogeneic BMTs seem to have better survival statistics, a percentage of patients seem to be "cured" for all practical purposes. The advent of "mini" allo BMTs has meant that patients can do with less aggressive chemotherapy conditioning regimes, and this appears to have a big impact on the morbidity and mortality. Patients who do not have a well matched donor (usually a sibling), and who do not succeed in finding a matching but unrelated donor ("MUD") opt for autologous BMTs.
The statistics on autologous BMTs seem to be a less positive, but this may change as new technology is brought on line, like the one we are discussing here. In some ways, autologous BMTs are easier to tolerate because they do not have to worry about graft-versus-host type of complications, the grafted bone marrow cells in this case are the patient's own cells. But the other side of the same coin is that there is also no graft-versus-leukemia effects, which means every effort has to be made to fully clean out the patient of all cancer cells before a transplant is attempted. There are no "mini" versions of autologous BMTs, as far as I know. A recent review article by Montserrat et. al. does a great job of pulling together all the information. If you are likely to be a candidate for BMT of either variety, I urge you to read this article. If you are interested in reading this article, please write to us, using the Feedback option. Our article Primer on Bone Marrow Stem Cell Transplants may provide helpful background. You will also find an abstract of the Dreger & Montserrat paper in the Primer article, which might help you get an overview before you start digging through the long and very detailed Montserrat paper.
Autologous bone marrow transplant procedures vary somewhat among institutions, but the overall procedure is pretty similar. Patients are given a variety of growth factors such as G-CSF (Neupogen), GM-CSF (Leukine) for about 4 to 5 days, in order to increase the production and availability of stem cells. It is now more common to obtain the stem cells from the patient's peripheral blood, rather than sucking them out of the bone marrow. The procedure is similar to leukapheresis, where blood is removed from one arm, goes through a machine that selectively removes the stem cells from it, and the remainder is put back into the patient through a needle in the second arm. The stem cells are then purified, to try and remove every last trace cancer cell hiding among them, and stored for future use.
The patient then undergoes serious chemotherapy and / or whole body radiation, basically to make sure every last CLL cell is killed. This is total war, take no prisoners time. Obviously, in the process of doing this the chemotherapy or radiation dosage must be high enough to get the desired effect. A lot of other cells, including any remaining stem cells are also killed in the process. The idea is to start again with a clean-if-rather-nuked-out-slate. After the cleanout, the previously harvested, cleaned and stored stem cells are reintroduced into the patient's blood. It usually takes about 3 weeks for the reintroduced stem cells to find their way back to the bone marrow, settle down and get back to work.
There are obvious risks associated with autologous BMTs. If the re-introduced stem cells do not "take", or there are too few of them, or there is a long time delay in their engraftment in the bone marrow, during that period of time the patient is basically without a functioning immune system, a very critical window of vulnerability. Long hospital stays may become necessary if this happens, and opportunistic infections can quickly become a life threatening issue. There is also the chance that the collected stem cells are not completely pure, completely free of CLL cells - even the best separation techniques are not 100% effective. In that case, re-introducing this stem cell sample effectively re-introduces the CLL into the patient, and that too at a time of deep immune suppression. This is one area where improvements are happening. Rather than depending upon purely mechanical separation techniques to select only pure stem cells, the sample obtained after leukapheresis is further treated with monoclonals like Campath to kill any remaining CLL cells. Since stem cells do not express the CD52 marker targeted by Campath, the stem cells are unaffected by the drug.
It has been observed that patients who have a good solid harvest of stem cells have a much better chance of success. Typically, stem cells of the order of 5,000,000 per kg or more are required. This is not always easy, some patients go through the whole mobilization process and come up short, their harvest of stem cells is inadequate for a good BMT. This is where AMD3100 and similar CXCR4 blocker drugs may come in. Remember, we described the strong attraction between the homing molecule SDF-1 (Stromal cell Derived Factor -1) produced in the bone marrow and the CXCR4 receptor that is drawn irresistibly to it. This receptor is present on several cell lines, including B-cells, neutrophils, platelet precursors, and stem cells. Blocking the CXCR4 receptor has the affect of cutting the strong tether holding these cell lines snugly in place in the bone marrow. Once they are cut loose, these cells are free to migrate and flush out of the bone marrow and into the peripheral blood. If this is done in combination with growth factors discussed above, the boost in production of new stem cells as well as getting them flushed out into the blood where they can be harvested may be just enough to put the patient over the top.
AnorMED, INC. (http://www.anormed.com/) received federal "orphan drug" status for their candidate AMD3100 in June of this year. The drug is administered as a single injection, and seems to be well tolerated and effective in increasing stem cell mobilization and harvest. The effect of the drug is transient, and things return back to where they were in a couple of days. Phase II Multiple Myeloma and NHL clinical trials are ongoing. They are also working on the same approach with healthy bone marrow donors in allogeneic BMTs. It is too soon to tell for sure, but the early indications are that there is no difference in the quality of the stem cells harvested with the help of AMD3100, compared to those harvested by earlier techniques. This new development may be of significant importance to CLL patients. Not all candidates for BMTs are fortunate enough to have an exactly matched donor, and autologous BMT may be the only option. In that case, having a good harvest of stem cells is an essential first step in getting good results. You can read more about AMD3100 and stem cell harvesting at http://www.anormed.com/documents/amd3100ab_Srour.pdf.
Given below is the abstract of a paper that describes the safety studies done with healthy volunteers. You can also read the full paper for free, click on the URL link provided. Remember, the origins of this drug was as a possible AIDs drug. The hope was that blocking the CXCR4 receptor would block the entryway of the AIDs virus into T-cells. As it turns out, the virus has access to its victim cells through one or even more back doors, and except in a few strains of the virus, it is not limited to CXCR4 alone. So, while this drug has been a bit of a disappointment in the AIDs community, its mode of action may be of value in other areas, such as in improving bone marrow harvests for BMTs.
AnorMED is exploring other interesting uses for AMD3100, among them the use of this drug in heart attack patients. They suggest that getting progenitor cells to the site of the damaged heart tissue makes it easier for it to heal. If you are interested, you can read a short report on it at http://www.anormed.com/documents/amd3100_amheart03.pdf.
Antimicrob Agents Chemother. 2000 Jun;44(6):1667-73.
Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers.
Hendrix CW, Flexner C, MacFarland RT, Giandomenico C, Fuchs EJ, Redpath E, Bridger G, Henson GW.
Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287
AMD-3100, a bicyclam, is a novel agent that uniquely inhibits the entry of human immunodeficiency virus type 1 (HIV-1) into CD4(+) T cells via selective blockade of the chemokine CXCR-4 receptor. Twelve healthy volunteers were given AMD-3100 as a single 15-min intravenous infusion at 10, 20, 40, or 80 microg/kg. Five subjects also received a single subcutaneous injection of AMD-3100 (40 or 80 microg/kg). Three subjects received two escalating oral doses each (80 and 160 microg/kg). All subjects tolerated their dose(s) well without any grade 2 toxicity or dose adjustment. Six subjects experienced mild, transient symptoms, primarily gastrointestinal in nature and not dose related. All subjects experienced a dose-related elevation of the white blood cell count, from 1.5 to 3.1 times the baseline, which returned to the baseline 24 h after dosing. AMD-3100 demonstrated dose proportionality for the maximum drug concentration in serum (C(max)) and the area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)) over the entire dose range. At the highest intravenous dose (80 microg/kg), the median C(max) was 515 (range, 470 to 521) ng/ml and the AUC(0-infinity) was 1,044 (range, 980 to 1,403) ng-h/ml. The median systemic absorption after subcutaneous dosing was 87% (range, 67 to 106%). No drug was detectable in the blood following oral dosing. Using a two-compartment model, the median pharmacokinetic parameter estimates (ranges) were as follows: volume of distribution, 0.34 (0. 27 to 0.36) liter/kg; clearance, 1.30 (0.97 to 1.34) liters/h; elimination half-life, 3.6 (3.5 to 4.9) h. After a single, well-tolerated intravenous dose of AMD-3100, concentrations were sustained for 12 h above the in vitro antiretroviral 90% inhibitory concentrations and for 8 h above antiviral concentrations identified in the SCID-hu Thy/Liv mouse model of HIV infection.
Disclaimer: The content of this website is intended for information only and is NOT meant to be medical advice. Please be sure to consult and follow the advice of your doctors on all medical matters.
Copyright © 2002-2007 CLL Topics, Inc. All Rights Reserved.
All materials contained on this site are protected by United States copyright law and may not be reproduced, distributed, transmitted, displayed, published or broadcast without the prior written permission of CLL Topics, Inc. You may not alter or remove any trademark, copyright or other notice from copies of the content.
However, you may download and print material from CLLTopics.org exclusively for your personal, noncommercial use.