Transplantation Update | Aplastic Anemia and MDS International Foundation

Transplantation Update

AA&MDSIF recently spoke with Dr. Joachim Deeg of Fred Hutchinson Cancer Center, about updates and changes in stem cell transplantation over the two years since his last interview with AA&MDSIF.

Pre-transplant Conditioning

In my view, the major progress has been in reducing unacceptable toxicity from the regimens used to prepare patients for stem cell transplants regardless of who the donor is or the source of stem cells used.  There has been a focus on the low or reduced intensity conditioning regimens. They are beneficial, but are also linked to higher relapse rates for MDS.

With aplastic anemia patients, the effort always has been to have low-intensity regimens.  Unpublished data of the recently completed 03-01 study of the BMT/CDN, the results were quite remarkable. Using 97 aplastic anemia patients who received transplants from unrelated donors after having failed immunosuppressive therapy, this study was to answer the question is it possible to reduce or even completely avoid cyclophosphamide (Cytoxan®) by instead using fludarabine, combining with ATG and low dose body radiation as the conditioning regimen, thereby reducing toxicity.

The results showed that this can work, but we can’t completely omit cyclophosphamide because there was failure of engraftment when this drug was not used.  However, smaller doses (50 or 100 mg per kg) of cyclophosphamide were shown to be useful when used with fludarabine, anti-thymocyte globulin (ATG), and low dose total body irradiation (TBI) resulting in a survival rate in excess of 90 percent. So clearly there’s progress in this area.

As far as stem cell transplantation in MDS, the best results are with a regimen using treosulfan rather than busulfan in combination with fludarabine and with or without low dose TBI. We recently published data suggesting this regimen may be beneficial even for patients who have what we consider complex,  high-risk cytogenetics (monosomy 7 and others) which was the major cause of failure due to relapse in earlier studies.

The most recent data suggested that with treosulfan, higher-risk patients have an increased survival (in remission) probability of 65-70%, which if sustained, would be tremendous. We’re currently doing some genetic studies in that context.

In patients with aplastic anemia, there are studies underway on a 3-Y randomization, now pruned down to 2, including using serolimus, tacrolimus, and MMF as GVHD prophylaxis, although there are no results yet to show it reduces GVHD in related or unrelated donors.

PNH with prominent hemolysis is treated effectively, in most patients, with eculizumab (Soliris®), and additional therapies are under investigation. However, for unresponsive patients, and patients who develop marrow failure or experience leukemic transformation, hematopoietic cell transplantation may offer curative therapy. Results are superior in patients transplanted for marrow failure, with survival rates  similar to those observed in patients with aplastic anemia. Results are inferior in patients with severe hemolysis or thrombotic complications. Outcome tends to be better with HLA-matched related donors than with unrelated donors.

Sources of Stem Cells

Our view is that patients with non-malignant disease such as aplastic anemia, should receive stem cells from bone marrow rather than mobilized stem cells that are harvested from peripheral blood, because the incidence of GVHD is higher with peripheral blood.

In patients with clonal malignant disease like MDS, we typically use mobilized stem cells from peripheral blood with good success. I should emphasize that a randomized study using bone marrow vs. mobilized stem cells from unrelated donors really showed a 10 to 15% higher incidence of GVHD and no difference in survival. Since chronic GVHD is really an issue, the transplant community is trying to reassess who exactly should get stem cells from bone marrow and who should get them from peripheral blood. 

At Hutchinson, we’re looking at cord blood cells from HLA haploidentical donors only if we can’t find an HLA matched related or unrelated donor. There are now studies on the relative benefit of HLA haploid identical versus cord blood and there are retrospective analyses that have already been presented comparing cord blood to matched unrelated donors and there may nor not be significant differences. It has not been compared yet in a prospective fashion.

Age Ceiling for Stem Cell Transplantation

The maximum age for stem cell transplantation has been raised higher, but there’s a note of caution here.  As we treat older individuals, we are often dealing with other medical comorbid conditions that can interfere with the success of transplantation. Some published data suggest that age is not a factor, but this data on older patients in their late 60s or 70s is based on a selected population of patients – selected on the absence of comorbid conditions. So this can’t be presumed to be the case with the general population in that age group.

I will add that even patients who are 70 may be doing well with an allogeneic transplant but if they develop problems, like GVHD and they are then treated with steroids, the post-transplant scenario may become more difficult. This is because older patients do not tolerate steroids with all its side effects as well as younger patients would. More study on assessing who in the older patient group is truly suited for stem cell transplantation is needed.

Graft-Versus-Host Disease

GVHD is still an issue, but can be less severe with lower intensity regimens. A new study is under design that uses thymoglobulin early in the pre-transplant conditioning, as early as nine days, and suggests that this may further enhance results. This is even when cord blood is the stem cell source or when HLA haploid (half matched) donor cells are used. Most of us agree that GVHD is still a major issue for those who have nonmalignant diseases where we do not expect any potential benefit from the graft versus host reaction, particularly in its chronic form.  Whether additional, or early use of thymoglobulin is beneficial—we’ll have to wait and see.

Transplantation success rates

It’s not new data, but it’s important -- we can see that results with unrelated donors are approaching or even equal to those with matched siblings for many of these indications.

Long term survival depends more on which disease is being treated. With aplastic anemia, most recent studies show long term success rates of 90%. In some indications, especially the reduced intensity regimen, from AML resulted with match donors are somewhat higher/better than matched related presumably because the graft vs. leukemia link a CIBMTR study showed there was no significant advantage.

H. Joachim Deeg, MD

Lead Photo
Position / Title: 
Professor of Medicine
University of Washington and Fred Hutchinson Cancer Research Center

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.