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Immunosuppression and Stem Cell Transplantation – How Are These Treatments Chosen?

Immunosuppressive therapy and stem cell transplantation are both used in treating


Aplastic Anemia

For around 80% of aplastic anemia patients, the underlying cause of the disease is immunologic – it’s an autoimmune disease. As with other autoimmune diseases like multiple sclerosis, lupus, or even rheumatoid arthritis, the body has misdirected its immune response. In the case of aplastic anemia, the immune system targets the bone marrow stem cells, which causes bone marrow failure. So an immunologically-based therapy has the potential to alleviate this immunologic defect. 

With patients for whom stem cell transplantation is not feasible – and there are different reasons for this -- immunosuppressive therapy is used, most often anti-thymocyte globulin (ATG), cyclosporine, or tacrolimus, and sometimes high dose cyclophosphamide.  These aren’t cures, and we don’t anticipate in an autoimmune disease that that immunosuppressive therapy will be curative. But it palliates the disease, and most patients still require long-term treatment with these immunosuppressive agents as the disease can easily recur, especially with events like pregnancy.

In 20 to 40% of aplastic anemia patients, there is significant stem cell loss, and immunosuppression does not offer much in the way of potential improvement.  In this situation, we will try to use stem cell transplantation if we have the option, as it is curative. Here, the treatment is giving a higher dose of immunosuppressive therapy, and then supply stem cells from a donor. Graft rejection can occur but it is uncommon with the intensive immunosuppression provided by the transplant conditioning regimen as well as the post-transplant immunosuppression.

A relatively new option for patients who have failed immunosuppressive therapy and are not eligible for a stem cell transplant is eltrombopag (Promacta®). Thus far, it has been shown to work in about 40% of this group. This is a marrow stimulant, that at least in the small number patients who have been studied, has been useful in stimulating blood cell production. Eltrombopag is a growth factor, which was originally developed to treat immune thrombocytopenic purpura (ITP). It mimics the effects of thrombpoeitin, which is a natural hormone that stimulates platelet production. There are some concerns about its use of because some patients develop mutated blood cells. But again, there are also concerns with ongoing immunosuppressive therapy -- patients developing PNH or MDS. So because of these scenarios, we prefer to do stem cell transplantation if possible.


For MDS, we typically try and do stem cell transplantation instead of immunosuppression. This is because MDS can sometimes progress to acute myeloid leukemia (AML) or on to progressive bone marrow failure. There’s really only one subset of MDS that responds well to immunosuppressive therapy – hypoplastic MDS – where’s there’s a nearly empty marrow, but the cells that remain are dysplastic cells.  So immunosuppressive therapy in this case does ameliorate cytopenias (low blood cell counts) and is not curative, but can be useful for older patients or those for whom transplantation is not an option.


PNH is more complicated because there are several manifestations of it – hemolysis, thrombosis, and bone marrow failure. Bone marrow failure in PNH is less responsive to immunosuppression. Here we use eculizumab (Soliris®) to reduce the risk of thrombosis (blood clots) and reduce hemolysis. This treatment is not curative and is often given for an extended term. Marrow transplantation is typically used in the setting of bone marrow failure, and there are scenarios where aplastic anemia enters the picture and complicates matters.  So immunosuppressive therapy is really only used in PNH when aplastic anemia also develops.

These are complex diseases with complex therapies which can have substantial risks. Stem cell transplantation can be curative, and the other therapies are not. But stem cell transplantation can’t and should not be used in every patient even though it is a potential cure. The other approaches can provide long term control of the disease, lessened the need for transfusion or even complete transfusion independent, and lessen the risk of complications from bone marrow failure.

Transplantation Basics

Joachim Deeg, MD is a member of the Fred Hutchinson Cancer Research Center in Seattle, Washington and professor of medicine at the University of Washington. He is also a member of the AA&MDSIF Medical Advisory Board.


Is it correct to say that stem cell transplantation is a process in which stem cells are gathered from either bone marrow, umbilical cord blood, and peripheral blood of a suitable donor and are placed in an MDS patient?

That is a correct summation. Stem cells are obtained from at least three sources – bone marrow, cord blood, or peripheral blood. So stem cell transplantation is an umbrella term covering the process  regardless of the source of the stem cells. We obtain blood-forming stem cells by directly aspirating them from the donor’s bones (usually the pelvic bones) or by treating the donor with growth factors, generally G-CSF, which push the stem cells out of the marrow into the blood so they can be collected from blood. In other words, whether we speak about ‘bone marrow transplantation’ or ‘stem cell transplantation’, in both instances we refer to transplantation of stem cells that primarily reside in the marrow.

Can you explain how the source of stem cells is chosen?

There has been a trend to use ‘G-CSF mobilized’ stem cells – the ones harvested from blood - and there are some advantages to this. These cells tend to engraft faster, making the elapsed time that the patient has low blood cell counts shorter than when we transplant cells harvested directly from bone marrow, at least by a few days. In addition, they may have a stronger eff ect (the graft versus leukemia or graft versus tumor effect) against the patient’s disease.

There is a potential drawback, however. Typically, the incidence of chronic graft-versus-host-disease (GVHD) is higher with those mobilized stem cells than with marrow. This was illustrated in a recently published paper describing results in patients who were randomized to receive stem cells (from unrelated donors) harvested either from bone marrow or from blood, showing a 15% higher incidence of chronic GVHD in patients who received the mobilized stem cells. As a result, there is some re-assessment going on as to which type of stem cells should be used for which patient. We may well see a shift back to a more frequent use of bone marrow, particularly for patients who do not have a high probability of relapse after transplantation.

Can you explain why, even though stem cell transplantation is the only potential cure for MDS, not all MDS patients are being transplanted?

Well, some patients may not need treatment. But you are correct, the non-transplant treatments we have available, while buying time for the patient, and possibly even inducing remission, none of them eliminate the cells that cause MDS and therefore cannot cure the disease. On the other hand, a transplant, which replaces the patient’s abnormal cells with healthy cells, offers the potential of cure.

So, why are not all patients who need treatment being transplanted? Despite all progress with transplantation, especially in regards to preventing toxicity and reducing the risk of dying from complications, the success rate is not where we would like it to be. Even with optimal candidates for transplant, that is patients who do not have abnormal chromosomes that carry a high risk of relapse, or high blast counts, the long-term success is somewhere around 75, maybe 80%.

The decision on transplantation comes down to weighing the risks associated with transplant against the quality of life and life expectancy of a non-transplant strategy. This requires individual patient input. As the stage of MDS advances in a given patient, or in patients who present with high-risk MDS from the start, the decision to proceed to transplantation is made more readily. The outlook without transplantation is poor, while transplantation offers the chance of long-term survival. Patients with lowrisk MDS often forego transplantation in favor of observation and non-transplant treatment. With close follow-up, signs of progression of MDS can be recognized promptly, and the option of transplantation can be discussed at that time.

Why is age a factor in evaluating a patient’s suitability for transplantation?

Transplants are tolerated better by younger patients. As we grow older, our body’s ability to repair damage decreases. It is really the development of age-associated medical conditions (other than MDS) that affect the outcome after transplantation. A healthy 70 year old with no other significant medical problems might do as well as or better than a 50 year old with a number of co-morbidities, such as heart disease, diabetes, and other factors.

Does the IPSS score also play a part in deciding on stem cell transplantation?

We have been discussing so far mostly patient characteristics. The IPSS is about disease  characteristics. IPSS factors include myeloblast count in bone marrow, types of chromosomal abnormalities, and peripheral blood cytopenias (low blood cell counts, in particular anemia). The revised IPSS (IPSS-R), just recently introduced, still includes those factors, but is more specific with regard to the chromosomal abnormalities as well as the degree of cytopenias in blood.

Is there a difference between the terms ‘blood transfusion’ and ‘blood transplantation’?

The term transfusion refers to the method of replacing mature blood cells to treat anemia (from low red blood cell counts) or to increase the platelet count. “Blood transplantation” is not a good term, but it refers to transplanting stem cells that have been harvested after from blood after mobilizing them out of the bone marrow.

What is the meaning and relationship of the terms ‘matched donor’, ‘unrelated matched donor’, and ‘partially matched donor’?

This is all about genes that we inherit, which determine our tissue (HLA) type. We inherit half our genes from our mother and half from the father. Due to the way that genes are passed on from parents to children, there is a 25% chance that one of our siblings has inherited the same combination of HLA genes as we did.  This is an ‘HLA-matched’ sibling -- the most frequently used matched related donor and the best matched donor a patient can have. Because of the one in four chance of a  matched sibling donor, transplant physicians started looking for alternative donors among unrelated individuals.


For North American caucasians, the chances of finding an HLA-matched unrelated donor may be as high as 50%. The probability is considerably lower for patients with minority ethnic backgrounds. For those patients, the use of HLA haplo-identical -- meaning half-matched – donors (e.g. a parent or a child) or the use of umbilical cord blood will be of interest. Much work has gone into this clinical research, and there is a growing number of patients who have been transplanted successfully from HLA haplo-identical donors (often referred to as ‘partially matched donors”). The number of patients transplanted with cord blood cells is also increasing rapidly. Whether HLA haplo-identical or cord blood transplants lead to superior results remains to be determined.

What are the current degrees of transplant success in these three categories?

With matched unrelated donors (if we select the unrelated donor on the basis of identity by high-resolution typing, i.e. DNA sequencing) the results are comparable to those with matched related donors, although there is a slightly higher incidence of GVHD. Results with haplo-identical donors are not at the same level, but are improving; however, there appears to be a higher relapse rate for MDS than observed with certain other diseases. The frequency and severity of GVHD is remarkably low.

Are chemotherapy and radiation treatment prior to stem cell transplant always required?

In general, some degree of patient treatment is needed (conditioning) to suppress the immune system so that the donor stem cells can become established and not run in to a ‘brick wall’ and be rejected by the immune system. Also, the intent is to kill off as many of the bad (MDS) cells as possible to lower the probability of relapse after transplantation. The chance of the transplant being eff ective increases as the amount of bad cells is reduced. Conditioning does not necessarily involve radiation -- some regimens use just chemotherapy, but others use combinations of both. Antibodies, such as anti-CD3 monoclonal or polyclonal antibodies including anti-thymocyte globulin (ATG) have some benefit in facilitating engraftment of donor cells and in reducing the incidence of GVHD. However, by themselves, they have generally not been sufficient to secure engraftment of donor cells.

Even for a good candidate for stem cell transplantation, there are risks. Can you explain what the risks are and if there is any way to know in advance which ones may be more likely to occur?

Any drug we use will have side effects, as does radiation. Conditioning will affects healthy cells as well as the bad (MDS) cells. Mucositis and diarrhea are frequent, but just about any part of the body can be aff ected, either early or late after transplantation. We also know that patients can develop new malignancies, years after transplantation. The two most frequent complications remain GVHD and relapse (recurrence of MDS).

We have identified some risk factors, but we are currently not able to predict for individual patients whether they will develop GVHD or relapse.

What are mini-transplants, and have these had an effect on stem cell transplantation for MDS?

I prefer to call these ‘reduced or low intensity-conditioning transplants’, where the intensity of the regimen we give to prepare the patient for transplantation is lower than in regimens that have been used historically. Here at FHCRC, a high dose regimen might consist of busulfan combined with cyclophosphamide (Cytoxan®), while a low intensity regimen might consist of a combination of 3 Gy of total body irradiation in combination with fl udarabine. The subsequent infusion of the donor cells, and the regimens we use to prevent GVHD are very similar. Importantly, however, the up-front likelihood of severe toxicity from conditioning is very low. In many studies, reduced intensity conditioning has been associated with a higher risk of relapse in MDS patients. Nevertheless, transplants using reduced intensity conditioning have had a major impact -- without this strategy, we could not transplant many older patients.

Have success rates in stem cell transplants changed in recent years?

Yes, they have improved. Several studies are confirming this. There has been a progressive improvement in overall long-term survival as the years have passed.

Is the Fred Hutchinson Cancer Research Center working on anything to improve patient eligibility for transplants and transplant success rates?

We are integrating non-transplant strategies with transplantation to identify patients early and develop an overall treatment strategy. Should the treatment be with hypomethylating agents or other drugs? Should this be used in preparation for transplantation? Will that approach improve transplant  outcome? We have developed some novel regimens using a drug called treosulfan. We have had some promising results, showing 65 or 70% survival, even among patients with high-risk MDS.

Also, there is a lot of work going on using immunotherapy. One approach is the removal of naïve T-cells from among the donor cells, which seems to have reduced the frequency of GVHD without increasing the risk of relapse. Other studies use T-cells that have been genetically modified to attack patient cells (cellular immunotherapy), among other strategies. It will also be important to continue to monitor non-transplant therapies and incorporate those into the overall treatment plan for the patient.

Education Topics: 


AAMDSIF hosts Patient & Family Conferences around the United States each year. Conferences are free to attend and include presentations by the leading medical experts in rare blood cancers and bone marrow failure diseases. It is also an incredible and important opportunity for patients to connect with one another and share support, answers and hope.

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