Analysis of the Hematopoietic System in Long-Term Survivors of Allogeneic Stem Cell Transplantation and Their Respective Donors

Abstract

For a variety of malignant and non-malignant hematopoietic disorders, allogeneic stem cell transplantation (HSCT) is the only curative treatment option. Over the past decades, the outcome of patients undergoing HSCT continuously improved. However, there is limited knowledge about the hematopoietic system of long-time survivors of HSCT in comparison to their respective donors. Telomere length shortening reflects the proliferation history of cells. With respect to HSCT, seminal studies have demonstrated that accelerated telomere length shortening occurs during the early post-transplant phase but the rate of telomere shortening then slows down and becomes indistinguishable between recipients and donors thereafter, leading to a parallel decline. This results in an overall pre-mature ageing of the hematopoietic system in HSCT recipients. We here analyzed blood counts and telomere length of 45 long-time survivors of HSCT and their respective donors.Blood counts were analyzed at the University Hospital Zurich. Telomere length was measured by Flow-FISH at RWTH Aachen. The study was approved by the local ethics committee. Patients and donors gave informed consent.Of the 45 donor-recipient pairs enrolled in this study, three recipients showed hematological diseases (donor-derived Thalassemia minor, MDS, relapsed Multiple Myeloma) and were thus excluded from this analysis. All remaining 42 analyzed patients were considered to be cured from their underlying hematological disease. The sex ratio was 1:1 in donors and 1:1.1 in recipients in favor of male recipients. The median age of donors and recipients at the time of HSCT was 36 and 35 years, and the age at presentation for this study was 59 and 56 years, respectively. The median time since HSCT was 16 years (range 9-33 years). When comparing donors and recipients, we did not detect any relevant differences in hemoglobin concentration (donors: 139±12g/L, recipients: 143±15g/l, p=0.54) or erythrocyte counts (donors: 4.73±0.49T/L, recipients 4.55±0.47T/L, p=0.32). Recipients showed significantly higher MCV values (donors: 91.6±4.4fL, recipients 94.1±3.8fL, p=0.03) and significantly higher MCH (donors 30.5±1.3pg, recipients 31.3±1.3pg, p<0.001), while MCHC did not differ (donors: 329±11g/L, recipients 333±9g/L, p=0.20). Recipients showed a trend to higher relative but not absolute reticulocyte counts (donor: 1.02±0.38%, 50±17G/L, recipients: 1.23±0.40%, 56±18G/L, p=0.08 and p=0.18). Also, we did not observe significant alterations in platelet counts (donors: 248±62G/L, recipients 234±70G/L, p=0.31). In the leukocyte compartment, neutrophil counts were not altered (donors: 3.8±1.5G/L, recipients 4.2±1.6G/L, p=0.87), while recipients had significantly more monocytes (donors: 0.52±0.17G/L, recipients 0.62±0.20G/L, p<0.001). Eosinophil and basophil counts did not show differences, while recipients had higher lymphocyte counts (donors: 1.7±0.6G/L, recipients 2.2±5G/L, p=0.007).In 28 of 42 pairs, telomere length analysis was logistically possible. Telomere length was measured separately in lymphocytes as well as in granulocytes. The median telomere length of granulocytes was 8.00±1.30kb in donors and 7.46±1.16kb in recipients, respectively (p=0.043). The median difference in granulocyte telomere length between donors and recipients was 0.38±0.82kb reflecting a hypothetical age difference of 14.2 years assuming a loss in telomere length of 27bp per year. In lymphocytes, the median telomere length was 7.13±1.06kb in donors and 6.43±1.02kb in recipients (p<0.001). The median difference in telomere length between donors' and recipients' lymphocytes was 0.48±0.99kb corresponding to a longer proliferation history of approximately 17.8 years in the recipients.Peripheral blood counts are stable and widely inconspicuous in long-time HSCT-survivors. Telomere length is significantly shorter in recipients' lymphocytes and granulocytes. This telomere shortening is most likely due to increased HSC proliferation (reflected by granulocyte telomere length) and inflammatory stimuli (affecting both HSCs and lymphocytes) in HSCT recipients. However, it does not have a clinically relevant effect on blood counts in this small group of long-term HSCT-survivors. In how far the increased proliferative history of donor HSCs in allo-HSCT recipients is of biologic relevance needs further investigation. DisclosuresBrümmendorf:Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.