Treatment and outcomes for patients with severe aplastic anemia (SAA) have improved markedly over past 40 years due to advances in hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST). Nonetheless, these treatments have limitations such as failure to engraft or graft versus host disease for HSCT and lack of response or clonal evolution to myelodysplastic syndrome (MDS) with IST. Refinements are needed in our treatment algorithms to determine who is best suited to each treatment to minimize these complications.
We hope to improve on outcomes further in SAA through use of additional information that predicts which patients are more likely to have a normalization of their blood counts versus relapse or progress to MDS. Throughout the medical literature, multiple markers have been studied as potential predictors, including the presence of a paroxysmal nocturnal hemoglobinuria (PNH) clone and reticulocyte count.
Telomere length measurements are another example of a potentially useful clinical marker to predict outcome in patients with SAA. Telomeres are regions of repetitive nucleotides (special molecules for building DNA) at the ends of chromosomes that are there to protect the chromosomes from damage and breakdown. As we age over time, telomeres shorten progressively. Once telomeres are critically short, the result is cell death. Given that telomeres are intended to protect the chromosome, when the telomeres are shorter, the cells’ chromosomes are at greater risk for damage and thus disease. Telomeres have been implicated in many illnesses in this way including cancers, lung diseases and especially cases of bone marrow failure like AA.
Reports suggest that telomeres are short in up to one-third of patients with acquired SAA. To study the relationship of telomeres to outcome in SAA, telomere length (TL) was measured in the white blood cells of 183 patients treated at the NIH with IST (antithymocyte globulin and cyclosporine) for their SAA. The TL was not found to predict who would have improved blood counts at 6 months after IST. What TL was found to be associated with were the longer term outcomes of relapse and MDS. Patients with shorter TL compared to those with longer TL were found to be more likely to relapse as well as more likely to have clonal evolution with higher risk karyotypes in their MDS. Other studies also from the NIH population showed similar findings in patients with shorter TL having higher risk MDS. It is unlikely the TL alone is a simple marker for these late events after treatment in SAA. The telomere’s role may be more associated with instability in the genes and causal for the MDS. There are observations from multiple lab studies showing that short and dysfunctional telomeres limit the normal blood-making cells and lead to the selection of these bad clones. Additional studies are ongoing to be show how to measure TL and use this information for patients. It also stands to reason that it would be helpful to patients to attempt to lessen telomere shortening in order to prevent these unfavorable outcomes. Androgens may be one possible way to do this based on some preliminary laboratory results. A clinical study is ongoing.
In summary, it is an active area of research to utilize TL measurements in the decision making for patients with SAA. There is continued interested in improving the outcomes in this disease through markers that predict response and we are hopeful that telomeres will play an active role in these ways.