Aplastic anemia is a hematopoietic disorder characterized by pancytopenia (general loss of all blood cell lineages). Although several pathophysiologic mechanisms may be involved, a profound defect in the stem cell compartment, specifically a decrease in progenitor cells expressing the membrane protein CD34, is a unifying feature in most patients with aplastic anemia, leading to anemia, thrombocytopenia and leukopenia. Because of the extensive impairment of the hematopoietic system, lack of treatment results in a fatal outcome. Improvements in diagnosis and treatment have reduced morbidity and mortality caused by aplastic anemia, but stem cell transplantation remains the only cure.
Transplant procedures can result in rejection of the donor tissue when cells are recognized as non-self by the recipient immune system. The opposite scenario can also occur, known as graft versus host disease (GVHD), where the donor cells react against host HLA antigens, as well as to other minor antigens of the recipient. A preconditioning treatment of alternating cyclophosphamide and antithymocyte globulin for bone marrow transplantation from HLA-identical siblings has been introduced to reduce the high incidence of transplant rejection. Acute and chronic GVHD are still observed respectively in 24 and 26% of transplant recipients. Investigators at Fred Hutch previously showed that reducing the number of transplanted cells from 3.4x108 cells/kg to 2.3x108 cells/kg significantly reduced the incidence of chronic GVHD, showing a link between the number of transplanted cells and the incidence of GVHD.
A prospective study conducted on 21 patients receiving marrow grafts from HLA-identical sibling evaluated the effect of transplanting less than 2.5x108 cells/kg with a median follow-up of 4 years. The results of the study were published in Bone Marrow Transplantation by Dr. Susanna Gallo, a visiting fellow in the laboratory of Dr. Rainer Storb (Clinical Research Division). Importantly, the study validated the safety of the procedure. In fact, no graft rejections were observed and all patients had reconstituted neutrophil and platelet numbers at day 26 and 19, respectively. Acute GVHD was seen in 46% of transplanted patients and resolved by first line therapy. Chronic GVHD was observed in 24% of patients, comparably with previous studies. Interestingly, if three patients who received more than 2.5x108 cells were removed from the analyses, a drop in chronic GVHD to 16% was observed. No correlations were identified between the numbers of transplanted CD34+, CD14+, CD3+, CD4+ or CD8+ cells, likely due to the study size. "Patients with Aplastic Anemia treated with bone marrow transplant have seen, in the last 20 years, an incredible improvement in prognosis, but chronic GVHD and immunosuppressive treatments are still responsible for long-term morbidity with consequent impact on overall survival. The results of this study are encouraging. In fact, after reducing the dose of transplanted marrow, we didn't see problems with engraftment, all our patients are alive after more than 4 years from transplant, and all but one has been able to discontinue completely the immunosuppressive therapy. This approach could be, in this particular population of young patients, an additional step for limiting the incidence and the gravity of cGVHD and for improving their quality of life", commented Dr. Gallo.
Even though a clear conclusion on the effects of reducing the numbers of transplanted cells on GVHD cannot be drawn from this study, a trend toward a decrease and the safety of the procedure open the possibility of new trials.
"Ideally I would like to continue the study and carry out careful studies of the transplanted marrow product to see what cell types are involved in chronic GVHD. Given that aplastic anemia is a rare disease, this might have to be a multi-center study but I don't know whether I can pull this off", said Dr. Storb. Given the possible clinical implications for patients with aplastic anemia, we wish Dr. Storb and his group best of luck!
The study was supported by National Institutes of Health.
Gallo S, Woolfrey AE, Burroughs LM, Storer BE, Flowers ME, Hari P, Pulsipher MA, Heimfeld S, Kiem HP, Sandmaier BM, Storb R. 2016. Marrow grafts from HLA-identical siblings for severe aplastic anemia does limiting the number of transplanted marrow cells reduce the risk of chronic GvHD?. Bone Marrow Transplant. Epub ahead of print.