Telomere Length in Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia

Abstract

Severe aplastic anemia is a heterogeneous bone marrow failure syndrome, characterized by peripheral blood pancytopenia and bone marrow aplasia. The disease affects both children and young adults. The incidence is estimated at 2per 1millionannally.1-3Early treatmentmaydeterminepatientoutcomes, thusdevelopingbetter treatments for this condition could have an important clinical implications. Immunosuppressionanduseof somenewerdrugshavebeen shown tobeeffective.4-6However, allogeneichematopoietic stemcell transplant (HSCT) canbecurative for severeaplastic anemia.7-9 Although the survival results of HLA-matched related donor andHLA-matchedunrelateddonorHSCT in leukemiaare comparable, this is not the case in severe aplastic anemia.10 The results of matched unrelated donor HSCT for severe aplastic anemiahavebeensuboptimal.Comparedwith80%to90%expected long-term survival withmatched related donorHSCT, that ofmatchedunrelateddonorHSCThasbeen39%to64%.10 Thus, further improvement of the survival results inmatched unrelateddonorHSCT insevereaplastic anemia is critically important; thus, risk factors associatedwith improved outcome need to be identified. The article by Gadalla et al11 in this issue of JAMA evaluated the association between leukocyte telomere length and outcomes inmatchedunrelateddonorHSCT for severe aplastic anemia. A telomere is a noncoding region of repetitive nucleotide at each end of the chromatid that becomes progressively shorterwith serial cellularmitosis, thus protecting telomeric (terminally located) genes during mitosis. Telomeres become shorter with cellular aging (genomic senescence).12 Based on donor telomere length distribution, the authors classified recipient and donor leukocyte telomere length as long (third tertile) and short (first and second tertiles combined) and examined the associationwith overall survival, neutrophil recovery, and acute and chronic graft-vshostdiseaseduring follow-up toMarch2013.Longerdonor leukocyte telomere lengthwasassociatedwithhigheroverall survivalaftermatchedunrelateddonorHSCT;amongpatientswho received HCT from donors with longer telomeres (third tertile,n = 113)vs shorter telomeres (first andsecond tertiles combined, n = 217), the survival probabilities were 60%vs 50% at 1 year, 58% vs 44% at 3 years, and 56% vs 40% at 5 years. Although the outcomeofmatchedunrelateddonorHSCT has been shown to be betterwith younger donors,13 the study by Gadalla et al showed that shorter donor leukocyte telomere length is an independent risk factor fromdonor age. Importantly, the authors found that recipient leukocyte telomere length was not associated with outcome after matched unrelated donor HSCT, although recipient leukocyte telomere lengthhas been shown tobe associatedwith survival after immunosuppressive therapy alone.14 Although the findings reported by Gadalla et al may help in choosing optimal donors for HSCT, many questions remainunanswered.For instance,whywassurvivalbetteramong patients who received grafts from donors with longer leukocyte telomere length?Asnotedby the authors, leukocyte telomere length is a marker of cellular replicative capacity, cellular senescence, and aging. If leukocyte telomere length were associatedwithengraftmentstatus, itwouldprovideastraightforward explanation. However, leukocyte telomere length is not associated with any engraftment characteristics such as neutrophil andplatelet engraftment or graft failure rate nor is leukocyte telomere length associated with acute or chronic graft-vs-host disease. The authors cited a report showingpossible effect of leukocyte telomere lengthonengraftment in the pediatric population.15However, in the studybyGadalla et al, the engraftment patterns seemed to overlap in the longer and shorter leukocyte telomere length cohorts and did not show any difference. In addition, if engraftment is not the reason for the survival difference,whichmechanisms account for the apparent association between leukocyte telomere length and survival? It thenstands toreasonthat thedifferencemustbeduetotransplant-relatedmortality, although the authors didnot find any relationshipbetweendonor leukocyte telomere lengthandspecific causes of death in this study. Were there less infections or less regimen-related toxicities? If there were fewer infections, is longer leukocyte telomere lengthassociatedwithmore rapid immunereconstitution?Furtherdataareneededtoclarify these issues. This observational report by Gadalla et al11 provides potentially important data and may mark the beginning of other new findings to come. Another question iswhether leukocyte telomere length is an independent risk factor for transplant outcome, particularly in any other transplant populations. The authors analyzed the outcome of matched unrelated donor HSCT for severeaplastic anemiaamongrelativelyyoungpatientsprimarily using bone marrow graft. Would similar findings occur with different type of grafts, such as peripheral blood stem cells or Related article page 594 Opinion