Date: May 23, 2003
by Chaya Venkat
I have just finished reading the truly excellent review paper written by Drs. Montserrat and Dreger, detailing the state of the art for autologous and allogeneic bone marrow transplants for CLL patients. Both Drs Montserrat and Dreger are well respected CLL experts in Europe. If you are seriously considering a BMT, I would recommend that you read the full paper. Here is the PubMed abstract of the paper. If you are interested in the full paper, send us an email using the Feedback form.
Link: Nature Article
Leukemia 2002 Jun;16(6):985-92 Related Articles, Links
Autologous and allogeneic stem cell transplantation for chronic lymphocytic leukemia.
Dreger P, Montserrat E.
Department of Hematology, AK St Georg, Hamburg, Germany.
Allogeneic and autologous stem cell transplantation (SCT) are increasingly considered for treatment of patients with chronic lymphocytic leukemia (CLL). In order to assess the potential therapeutic value of SCT for CLL, the present article aims at answering the following crucial questions: (1) Is SCT a curative treatment? (2) Does SCT improve the prognosis of poor-risk CLL? (3) Do risk factors exist which are useful for defining prognostic groups in terms of feasibility and post-transplant outcome? The efficacy of auto-SCT relies exclusively on the cytotoxic therapy administered. To date, there is only limited hope that autotransplantation can cure the disease. Nevertheless, the results of the published series suggest that auto-SCT is capable of improving the prognosis of CLL with poor-risk features. Well defined favorable conditions for successful autografting are the status of the disease (CR or VGPR) and the number of lines of therapy (<2) before transplantation. The crucial anti-leukemic principle of allo-SCT consists in the immune-mediated GVL effects conferred with the graft. The GVL activity explains that allografting seems to be curative for at least a subset of patients. However, as long as allo-SCT in CLL is still associated with an excessively high treatment-related mortality, only selected patients with advanced poor-risk disease should be considered for allografting. The development of conditioning regimens with reduced intensity may allow extending the indications of allogeneic SCT for CLL in the near future.
What follows is an overall review of the basics of BMTs, just to set the stage as it were. Those of you who have already done your research on this subject may want to go straight to a reading of the Dreger & Montserrat article.
There are two types of BMTs (also referred to as SCTs, for stem cell transplants) : autologous and allogeneic. In autologous BMTs, the patient is also the donor for the stem cells; basically your own stem cells are collected, cleaned of cancer cells, stored and given back to you in the course of the transplant procedure. In allogeneic BMTs, the stem cells come from a donor, usually a close blood relative such as a sibling, parent or child, whose stem cells are typed to be a good match for your own. In case of patients with no close relative who is a good match, the bone marrow bank is searched to find an Matched Unrelated Donor (MUD).
As we said above, in an autologous BMT a patient uses his or her own stem cells. But since the CLL patient’s bone marrow and peripheral blood is typically full of cancer cells, stem cell collection cannot take place until the patient is in good remission. Typically, it is preferred to collect stem cells when you are in a complete response, CR. So, there are five general steps in autologous stem cell transplants:
1. Chemotherapy to reduce CLL cells in the body as much as possible, preferably a CR, and only minimal residual disease.
2. Collection of stem cells.
3. "Purging" of the harvested stem cells so that there are no traces of cancer in the stem cells that eventually will be given back to the patient.
4. High doses chemotherapy, often accompanied by total body radiation, to make sure every trace of cancer is gone from your body. This is called "conditioning regimen".
5. Last step is transplantation of the previously harvested and "purged" stem cells back into the 'squeaky clean' patient.
You can see the need for steps three and four. You don't want to go through the significant pain and risk of going through a SCT, just to have the CLL return because either the stem cells were not adequately cleaned, and CLL cells were re-infused back into you along with the stem cells, or there were residual CLL cells left over (minimum residual disease) in your body after step 4 above, and these grow back into full fledged CLL later on.
Earlier on stem cell collection was done in the operating room under general anesthesia, and about 2 pints of bone marrow is removed, usually from the pelvic area. More recently, an alternative to this bone marrow harvest has been developed, namely peripheral blood stem cell collection. The main advantage of this approach is that it avoids the need for a general anesthetic and is easier on the patient than a formal bone marrow harvest.
Generally speaking, prior to the process of stem cell collection the patient is given drugs such as G-CSF (Neupogen), or GM-CSF (Leukine) which help push the stem cells out of the bone marrow and into the bloodstream, making collection easier. Aphaeresis is performed and the blood is sent to a machine that separates the stem cells from the plasma and blood. The gathered stem cells are further treated ("purged") to remove last traces of cancerous CLL cells, and then stored till they are needed for transplantation. The plasma and other blood cells are returned back to the patient. The whole process of aphaeresis may take about three to four hours.
The combination of drugs and/or total body radiation before transplant is called the conditioning regimen. In an autologous bone marrow transplant, patients can be given five to ten times the standard dose because the stem cells needed for the transplant have been collected already, and it does not matter if the 'nuke' the rest. Toxicity to other organs such as heart, liver and lungs is what limits radiation dosage. Therefore, autologous SCTs allows larger doses of anticancer therapy, be it chemotherapy or radiation, but the amount is supposedly limited to what is safe for the patient. I will have more to say about this aspect of auto-SCTs in later articles in this series.
Once the patient has been through the conditioning regimen, transplantation of the previously collected and purged stem cells can take place. The stem cells are injected relatively quickly, over about five to ten minutes for each syringe full of the stuff. The stem cells gradually find their way back to the bone marrow, where they attach themselves to the supporting cells there and start to grow, and begin their crucial job of making the various blood cell lines. This process is called "engraftment".
Neutrophils are usually the first cells to return, especially if the patient is supported with growth factor like G-CSF ("Neupogen", "Neulasta"). Platelets are next to return. Sometimes, it may take as much as a 100 days for the red blood cells to return in full strength. During the period when your immune system is working with not quite a full deck, so to speak, patients will need to be supported by blood transfusions. They are also more likely to be at risk for opportunistic infections during this period because of deficits in the immune system cells and may need to be on prophylactic medications.
The most obvious advantage for an autologous SCT versus an allogeneic SCT is that you don't have to find a well matched donor. Since you are your own donor, you are bound to match, better than any other person can hope to. There is therefore little risk of your body rejecting the transplant as foreign material and therefore dangerous. I will go into the details of the statistics of morbidity (death) attributable to the transplant process itself when I review the Montserrat paper, for now it is enough to know that treatment related death due to auto SCT is significantly lower than that for allogeneic SCT. Auto SCT is much easier on patients.
Since the "donor" in an auto SCT is a cancer patient to begin with, collection of sufficient quantity and purity of stem cells is sometimes tricky. Heavily pretreated patients may not be able to muster sufficient numbers of stem cells in their peripheral blood. And as we discussed above, it is important to collect the stem cells at a time when the patient is in as deep a remission as possible, so that the collected stem cells are only slightly contaminated with cancerous cells, hopefully this low level of contamination can be "purged" later on when the stem cells are treated prior to storage. For this reason, some patients in early stage disease may elect to have their stem cells harvested right after their first therapy, and have the harvested stem cells stored for a rainy day in the future when they may need/wish to go through an auto SCT. This is not quite as simple as it sounds, perhaps some of our members who I know have been through this "insurance policy" approach will provide details.
No doubt about it, the conditioning regimen that has to endured by the auto SCT patient is a bitch. The high severity of the chemo and radiation is necessary to try and get the patient squeaky clean prior to receiving the purged stem cells. But there is a price tag, anytime your body absorbs this much toxic chemotherapy and radiation: secondary cancers occur at a significantly higher rate in auto SCT recipients as compared to allogeneic SCT patients.
The biggest downside of auto SCTs is that there is little hope of a permanent cure. Even with extensive and careful purging of the collected stem cells, and heavy duty chemo plus radiation conditioning of the patient prior to transplant, it seems there will inevitably be some CLL cells lurking around somewhere. All auto SCT recipients will eventually relapse, some sooner rather than others. Again, we will discuss the detailed statistics later on. The million dollar question is this: does an auto SCT provide sufficiently long and sufficiently high quality remission to make it worth while, compared to other salvage therapies that may be available to the patient at this usually late stage of his/her cancer? The Montserrat review article is important in that it provides some good data on which to base our assessment to this all important question.
In an allogeneic stem cell transplant a healthy, "matched" donor supplies the stem cells for transplantation.
We are all familiar with the concept of blood types, and why you can only be transfused whole blood that is matched to your blood type. Well, it is sort of the same thing with stem cells. The donor's and patient's "tissue type" must closely match in order for the transplant to be successful. There are genetic markers on the surface of white blood cells called HLA-antigens (HLA stands for Human Leukocyte Antigen), and these define a person's tissue type. Since each of us inherits these genetic markers from our parents, brothers and sisters are much more likely to have similar HLA-antigens than unrelated persons. There is roughly 30% chance that your brother or sister is a good HLA match. Here is where you get down on your knees and thank your parents for raising a lot of kids; the more siblings you have, the better chance you have of finding a close to perfect match.
If you do not have a close blood relative that is a good match, you will have to look for a donor in the general population, specifically the various bone marrow donor banks. Here the chances of finding a good match can range from pretty good to pretty slim, depending upon your ethnic type. Most of the available tissue in the bone marrow banks is likely to reflect the ethnic mix of the population, but some ethnic cultures are more or less generous in their donation practices, due to cultural differences. The odds of finding a good match can be as high as 1 in 1,000 to as poor as less than 1 in a million. The other frustrating aspect of finding a suitable donor in the general population is the amount of time it takes to search the available donor banks. It could take anywhere from 3-10 months, and if this is the route you have to take, it really helps to get started as soon as possible. Most of us looking at SCTs as therapy option do not have an unlimited time horizon to wait for an answer.
Last but not least, another source of stem cells is cord blood. For those of you who may be unfamiliar with this term, cord blood is the blood present in the umbilical cord that is cut when a baby is born. This cord blood is rich in stem cells, and very adaptable and malleable stem cells at that. The problem thus far has been the very limited availability of cord blood. There are some interesting developments along this front, which might make this a viable option for patients who do not have HLA matched relatives. I will discuss this encouraging development in my 4th article in this series.
We are all pretty unique, each of us, there are literally millions of combinations of subtly different HLA "fingerprint" patterns and combinations. But to simplify matters, scientists have identified six HLA markers to judge the quality of a match. A six out of six (6/6) match between the donor and the patient is considered a "perfect" match. Obviously, a match on five out of the 6 HLA markers is not quite as perfect, but sometimes there maybe no better solution than to go for a 5/6 HLA match.
Our immune systems are very well programmed to attack and kill "foreign" cells as dangerous enemy infiltrators. T-cells are particularly good at this, they look at the set of HLA displayed on cell surfaces in order to decide whether or not the cell is "self" or "non-self". Non-self cells are quickly attacked and killed. When stem cells are transplanted from a donor, the T-cells will examine the newly arrived stem cells and decide to attack or not. The more closely matched the HLA of the patient (host) and the donor (graft), the less likely are the T-cells to attack and kill the precious transplanted stem cells. If the HLA match is not good, and the T-cells (with the help of other immune system cells) are able to kill off the transplanted stem cells, the transplant does not "take". This is called a graft rejection, your body has rejected the graft.
On the other side of the coin, the T-cells present in the donated bone marrow can go out on a rampage, decide the host's own cells are "non-self", and start attacking perfectly healthy cells in the patient. This is a case of Graft Versus Host Disease (GVHD). Except in severe cases of GVHD, this undesired response of the transplant procedure is not life threatening. But it sure can make your life miserable for a while, with a multitude of unpleasant side effects. GVHD is a very well researched field of study, as is graft rejection. There are mountains of science behind these concepts, I am doing no more than explain what the acronyms stand for. Later in this series, if there is real interest in this subject, we can get into more detail.
Obviously, you are lucky if you happen to have an identical twin. There is virtually no chance of a graft rejection or GVHD in transplants using donated bone marrow between identical twins. With a sibling donor, and a 6/6 match, it is not quite as perfect as with an identical twin, and the risk of severe GVHD goes up to about 20%, but the more important graft rejection stays at less than 1%. For related donors with less than perfect match, say a 5 out of 6 HLA antigen match, the risk of GVHD goes up to 30%, and the risk of graft rejection also increases to about 10%. The good news is that even though the risk of severe GVHD is higher, as long as the transplant 'takes' and the graft rejection is avoided, the long term survival rate in such cases is about the same as a 6/6 matched transplant.
New techniques are being developed to purify the stem cells, by removing the T-cells from the donor's marrow (the cells believed responsible for causing GVHD), and this has the potential to make allogeneic SCTs a lot more palatable to patients. I will address this and other new developments in the fourth of this series of articles. Just so you keep reading these less-than-spell-binding articles, I started out with very negative opinion of SCTs in general, and allo SCTs in particular. I must say I am getting more optimistic as I read about all the work that is going on, work that might make these valuable and viable options for many CLL patients. Don't get me wrong, no one in their right mind would want to go through a bone marrow transplant if they did not need one. The question to ask is always the same one: is the risk worth the reward? It seems the balance point of this equation may be tilting towards higher rewards and lower risk. Time only will tell if my optimism is justified.
In recent years, collecting stem cells from the donor's peripheral blood is becoming more common than getting it out of his/her bone marrow. Thank the lord for that, it is heck of a lot easier to get people to volunteer stem cell donations if they do not have to go through general anesthesia involved in bone marrow donation. The donor typically receives injections of Filgrastim (G-CSF, or Neupogen) for four or five consecutive days ahead of the donation day. Filgrastim is a cytokine that increases the number of stem cells released from the marrow into peripheral blood stream, thereby improving the stem cell harvest efficiency. As in the case of autologous stem cell collection, the collection procedure involves aphaeresis. Blood is removed through a sterile needle placed in a vein in one arm and passed through an aphaeresis machine that separates out the stem cells. The remaining blood, minus the stem cells, is returned to the donor through a sterile needle in the other arm. The efficiency of the first harvest and the number of stem cells required by the recipient will determine if the procedure needs to be repeated the following day. Donors commonly experience bone and muscle pain, headache and fatigue prior to the donation, side effects of Filgrastim injections. But these effects die down in a couple of days after the last dose of Filgrastim. In addition to the stem cell donation described above, the donor may also be required to donate lymphocytes (white blood cells). More on this later.
As conditioning regimen for "standard" allo-SCT, the patient is given very high doses of chemotherapy and/or radiation therapy. This conditioning therapy is given so as to destroys the patient's marrow and immune system, and thereby prevent the patient's immune system from attacking the stem cells transplanted from the donor. In other words, one of the reasons for the conditioning regimen is to avoid rejection of the graft. The other reason for high dose preparatory chemotherapy is to kill all of the cancer cells. This level of therapy severity is only possible when it is part of a transplant procedure, because the transplanted stem cells will then replace and take over the functions of the immune system.
It may be necessary to "purge" and clean the donated blood stem cells before the transplant. Typically, any red blood cells in the collected stem cell sample are separated out and discarded, especially if the blood groups of the donor and patient do not match. Some hospitals also reduce the number of T cells in the stem cells, as a way to reduce GVHD. We discussed this concept above.
The stem cells are infused through an intravenous line, just like a blood transfusion. The process can take any where from one to five hours. Then the waiting period begins as the stem cells migrate to the patient's bone marrow, and start to do what stem cells do best, grow and produce the various types of blood cells required for proper functioning of the blood. In some cases, patients are given drugs such as prednisone or cyclosporine, which help to suppress any remnants of the patient's original immune system that may want to put up a fight, and thereby rejecting the precious graft. The first month after transplant is critical. The patient is supported by intravenous nutrition, antibacterial and antifungal antibiotics, red blood cell transfusions, platelet transfusions, etc. Patients are sometimes also given growth factors such as Neupogen and Leukine, that may help the brand new stem cells engraft more quickly. About 2-3 weeks after the transplant, if everything is going well, the first effects of the transplanted stem cells is seen, as they start producing white blood cells. Next comes platelet production, followed several weeks later by red blood cell production. During the initial phase patients are vulnerable to infections, and therefore kept in protective isolation until their white blood cell count is above 0.5K. When their white blood cell count approaches 1K, patients can be sprung from the hospital. Some level of regular monitoring for six months to a year is necessary after successful transplantation.
There is a lot of excitement and interest in this new approach to allogeneic SCTs. The methodology was originally developed for other blood cancers, and is now being applied to CLL. The therapy related mortality rate with the mini-transplant approach is roughly half that of conventional, full strength, high-dose chemotherapy approaches. This "kinder and gentler" approach to conditioning patients ahead of transplant makes it possible to treat patients up to age 70 with matched related donors, and to age 60 with matched unrelated donors (MUD transplants).
The need for high-dose and high severity conditioning regimens has been challenged since the development of the mini-transplants. At the heart of the rationale for mini-transplants is the hypothesis of "graft-vs.-leukemia" effect. The idea is to allow donated stem cells to co-exist with the patient's own stem cells, by using of less intensive but sufficiently immunosuppressive conditioning regimens that establishes stable, mixed donor-patient hematopoietic chimerism. ("Chimersim" is just a fancy word for a mix of cells from two different people). Obviously, since the conditioning chemotherapy is not as heavy duty as in the older "standard" allo-SCT protocols, it is reasonable to expect that not all of the CLL cells would have been eradicated, some would be lurking around. This is where the graft-versus-leukemia effect comes in. The grafted stem cells are from a healthy donor. Unlike the original immune system of the CLL patient, which had been defeated and beaten into the ground by the cancer, the new and feisty immune system cells of the transplant are more than capable of hunting down and killing any remaining traces of CLL cells. In some case, additional lymphocyte transfusions from the donor are also given as a way of helping along the process of graft-versus-leukemia.
To summarize, in mini-transplants the goal of the conditioning regimen (chemotherapy, radiation therapy or combination) ahead of the actual transplant is not to eradicate the CLL cells completely, but to provide sufficient immunosuppression to prevent graft rejection, and allow tolerance between the immune systems of the donor and patient, so that a mixed "chimeric" population can be established. The purpose of donor T lymphocytes infusion (DLI) is to finish the job and eradicate malignant clone. It some cases the additional infusion of donor lymphocytes may not be necessary, just the mixed chimerism is sufficient to correct the situation.
Different cancer centers seem to have slightly different definitions of "nonmyeloablative" regimens (same thing as mini-transplant approach discussed above, just another term for it). There seems to be no standard established yet, for the drugs used, their dosages, and durations. This makes it a little harder to compare the statistics. Available data suggest that toxicity with mini-allo-transplants might be lower than that observed with standard allo-SCT, so much so that that some clinical trials used mini-allo-SCT as an outpatient treatment, since the patients experienced only minimal toxicity. It has also been reported that only about a quarter of patients undergoing mini-allo-SCT received platelet transfusions compared with 100% of patients undergoing conventional high severity allo-SCT. Similarly, a third of patients treated with mini-allo-SCT did not need red blood cell transfusions, compared with almost no patients given conventional grafts that could manage without red blood cell transfusions.
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.