Long-term lymphoma survivors following high-dose chemotherapy and autograft: evidence of permanent telomere shortening in myeloid cells, associated with marked reduction of bone marrow hematopoietic stem cell reservoir.
OBJECTIVE
To investigate telomere length (TL) and hematopoietic progenitors in long-term survivors after high-dose chemotherapy and peripheral blood stem cell (PBSC) autograft.


METHODS
Peripheral blood (PB) and bone marrow (BM) samples were obtained from 31 subjects in continuous complete remission from a high-risk lymphoma, at a median of 5.8 years (range: 1-11 years) since autograft. Most of them were grafted with large PBSC quantities (median CD34(+ve) cells/kg: 7 x 10(6)). TL was determined by Southern blot analysis, BM progenitors by in vitro long-term culture-initiating cells (LTC-IC) and colony assays.


RESULTS
TL of PB granulocytes was significantly shortened in autografted subjects compared with age-matched healthy subjects; a similar finding was observed in BM. The median TL reduction in granulocytes from autografted subjects compared with age-matched controls (Delta(TelShortening)) was then assessed according to time interval since autograft. Three subject subgroups were identified-at 1 to <3 years, 3 to <6 years, and 6 to 11 years since autograft-and their telomere loss was the same, with Delta(TelShortening) of 1132, 1379, and 1214 bp in the three subgroups, respectively. The longitudinal assessment of TL in five representative patients followed for up to 40 months since autograft confirmed that telomere shortening occurring during exposure to chemotherapy as well as postautograft is persistent at long term. BM LTC-IC and multipotent and committed progenitors were assessed in subjects at >3 years after autograft and found to be markedly reduced compared with normal controls.


CONCLUSIONS
High-dose chemotherapy and PBSC autograft may result in myelopoietic cell abnormalities that appear to be irreversible.
Rocci
Alberto
A
Divisione di Ematologia, Dipartimento di Medicina ed Oncologia Sperimentale-Universitá di Torino, Italy.
Ricca
Irene
I
Dellacasa
Chiara
C
Longoni
Paolo
P
Compagno
Mara
M
Francese
Roberto
R
Lobetti Bodoni
Chiara
C
Manzini
Paola
P
Caracciolo
Daniele
D
Boccadoro
Mario
M
Ferrero
Dario
D
Ladetto
Marco
M
Carlo-Stella
Carmelo
C
Tarella
Corrado
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000601:surgery / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D017741:Survivors; D016615:Telomere
D000970:Antineoplastic Agents