Abstract
Non-myeloablative conditioning regimens and the progress made in conventional transplantation have broadened the age restrictions for recipients of hematopoietic stem cell transplantation (HCT). The increasing age of the patient has naturally increased the age of the donor population. As aging is a risk factor for malignancies, and there is a variable period of time in which malignancies are asymptomatic, the odds of transferring malignant or pre-malignant clones in the process of HCT might increase. We uncovered 8 cases of clonal abnormalities with immunophenotypic or molecular aberrations, characteristic of specific hematologic malignancies found in HCT recipients arising from donor hematologic cells over a decade (1990–2001). The median age for the donors in our series is 44.5 years (range: 36–70 years). In 5 out of the 8 cases, the clone with malignant characteristics was detected both in donor and recipient, and in 3 cases only in the recipient (in 2 cases the donor was not tested). In 3 of the 8 HCT recipients, leukemia of donor origin prompted therapeutic intervention (a second transplant in two cases), while the others have remained under observation, as the aberrant cell clones of donor origin have not resulted in overt hematologic malignancies. In 4 cases, the abnormal clones were B cell in lineage, and have not yet evolved into disease, neither in the patients nor in 2 of the 4 donors studied. In case number 4 the donor developed CLL two years after the HCT, and the aberrant clone was detected with IgH VDJ specific PCR from an aliquot of the donor marrow preserved from the marrow harvest. In cases 5, 6, and 7, the time from the transplant to the detection of the clonal abnormality spanned more than one year. The donor of case 5 was tested and did not present the abnormality detected in his recipient (no information was obtained from donors in cases 6 and 7). In cases 4 and 8, the second malignancies were first detected in the donor. While the recipient in our fourth case has not developed any disease signs or symptoms, the recipient in our eighth case did develop clinical disease shortly after the transplant. The selection bias in discovering these cases makes it difficult to estimate a true prevalence of donor-derived malignancies in our transplant population. However, we speculate that the broadening of age limits for transplantation, with the associated increase of the donor age, has set the stage for the increased appearance of age-related donor malignancies. Increased sensitivity techniques to detect aberrant populations, such as flow cytometry, should perhaps be considered for routine pre-transplant screening of older donors.
Donor Tumor Cases
Pt. Patient Disease Lab Abnormality / Days post-transplant Clinical disease? / Last follow up Donor age Detected in donor? /Disease in donor? Donor last follow up ND=not done, NFU=no follow up 1 MF MCL/55d No/3.5 m 56 Yes/No 2m 2 MDS CLL/28d No/24 m 70 Yes/No NFU 3 CLL MZL/294d No/55 m 57 Yes/Yes 55m 4 AML CLL/10y No/120 m 45 Yes/Yes 120m 5 Renall Cell Carcinoma AML/15m Yes/21 m 42 No/No 21m 6 CML MDS/4y No/96 m 44 ND/NFU NFU 7 CML MDS/4y Yes/114m 44 ND/NFU NFU 8 ALL ALL/130d Yes/6m 36 Yes/Yes 65m
Donor age and C1orf132/MIR29B2C determine age-related methylation signature of blood after allogeneic hematopoietic stem cell transplantation