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 Unpublished data of the recently completed 03-01 study of the BMT/CDN, the results were quite remarkable.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
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
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.
Transplantation success rates
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.
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.