Longitudinal assessment of hematopoietic abnormalities after autologous hematopoietic cell transplantation for lymphoma.
OBJECTIVE
Autologous hematopoietic cell transplantation (HCT) is being increasingly used as an effective treatment strategy for patients with relapsed or refractory Hodgkin's lymphoma (HL) or non-Hodgkin's lymphoma (NHL) but is associated with therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) as a major cause of nonrelapse mortality. The phenomenon of hematopoietic reconstitution after autologous HCT and the role of proliferative stress in the pathogenesis of t-MDS/AML are poorly understood.


METHODS
Using a prospective longitudinal study design, we evaluated the nature and timing of alterations in hematopoietic progenitors and telomere length after HCT in patients undergoing autologous HCT at City of Hope Cancer Center (Duarte, CA).


RESULTS
A significant reduction in primitive and committed progenitors was observed before HCT compared with healthy controls. Further profound and persistent reduction in primitive progenitors but only transient reduction in committed progenitors were seen after HCT. Primitive progenitor frequency in pre-HCT marrow and peripheral-blood stem cells predicted for primitive progenitor recovery after HCT. Shortening of telomere length was observed in marrow cells early after HCT, with subsequent restoration to pre-HCT levels. Patients within this cohort who developed t-MDS/AML had reduced recovery of committed progenitors and poorer telomere recovery, possibly indicating a functional defect in primitive hematopoietic cells.


CONCLUSIONS
Our studies suggest that hematopoietic regeneration after HCT is associated with increased proliferation and differentiation of primitive progenitors. Increased proliferative stress on stem cells bearing genotoxic damage could contribute to the pathogenesis of t-MDS/AML. Extended follow-up of a larger number of patients is required to confirm whether alterations in progenitor and telomere recovery predict for increased risk of t-MDS/AML.
Bhatia
Ravi
R
Division of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA 91010, USA. rbhatia@coh.org
Van Heijzen
Khristine
K
Palmer
Ann
A
Komiya
Asako
A
Slovak
Marilyn L
ML
Chang
Karen L
KL
Fung
Henry
H
Krishnan
Amrita
A
Molina
Arturo
A
Nademanee
Auayporn
A
O'Donnell
Margaret
M
Popplewell
Leslie
L
Rodriguez
Roberto
R
Forman
Stephen J
SJ
Bhatia
Smita
S
D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects* / Q000379:methods; D006413:Hematopoietic System / Q000473:pathology*; D006689:Hodgkin Disease / Q000175:diagnosis / Q000401:mortality / Q000628:therapy*; D006801:Humans; D008137:Longitudinal Studies; D008228:Lymphoma, Non-Hodgkin / Q000175:diagnosis / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011336:Probability; D011446:Prospective Studies; D018570:Risk Assessment; D018709:Statistics, Nonparametric; D013234:Stem Cells / Q000502:physiology*; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000379:methods; D014182:Transplantation, Autologous; D016896:Treatment Outcome