Volume 12, Issue 5 , Pages 511-517, May 2006
Evidence of Donor-Derived Hematologic Malignancies after Hematopoietic Stem Cell Transplantation
Article Outline
Abstract
Increasing the upper age limit for recipients of hematopoietic stem cell transplantation (HCT) naturally has also increased the age of the corresponding related donor population. Because aging is a risk factor for malignancies, the risk of transferring preexisting malignant or premalignant hemopoietic clones in the process of HCT might be expected to increase as well. Anecdotal clinical cases of malignancies derived from donor cells in patients undergoing HCT have been published since 1971. In this article, we report 12 new cases that fit 2 different categories: (1) cases in which clones with characteristics of lymphohemopoietic malignancies were transferred from the donors to the recipients and (2) cases in which the malignant clone evolved from healthy donor cells once transplanted into the recipient. Donors in the first group were significantly older than donors in the second group. A more systematic examination of the prevalence and biology of donor malignancies would merit study.
Key words: Donor-derived hematologic malignancies , Hematopoietic stem cell transplantation , Disease transmission risk
Introduction
Neoplasias arising in cells of donor origin have been described both after solid-organ transplantation and after hematopoietic cell transplantation (HCT). The incidence of donor-related malignancies is extremely low after the transplantation of solid organs (0.04%) [1]. In the realm of HCT, estimates of donor malignancies have ranged from the anecdotal to as high as 5% [2]. Steady improvements in evaluating donor-host chimerism by the molecular analysis of short tandem repeats (STR) and variable number of tandem repeats (VNTR), as well as sensitive flow cytometry, now allow for sensitive analysis of the donor or recipient origin of specific hematopoietic cell populations after HCT, thus setting the stage for increased detection of donor malignancies.
In hematologic malignancies treated by HCT, myeloablative (MA) conditioning regimens are routinely offered to patients up to 50 years old without significant comorbidities. Nonmyeloablative (NMA) or reduced-intensity conditioning transplantations, which rely on the graft-versus-tumor effect to eradicate the patient’s malignancy, have extended the age limit for transplant recipients to ≥70 years of age [3, 4]. Increased patient age is frequently accompanied by increased donor age, at least with regard to sibling donors. Because the incidence of most hematopoietic malignancies increases with age, the likelihood of donor malignancies being transplanted into the HCT recipients should be increasing as well.
Materials and methods
In this article, we describe a series of cases in which hematopoietic malignancies appeared in donor cells. All cases were identified by 1 of 2 methods: (1) a malignant clone was detected on testing or (2) leukemia was diagnosed either in the donor or the recipient. Thus, although this article is not a systematic review of all patients who underwent transplantation in our centers, it is a collective effort to gather all cases discovered during routine clinical care.
Results
These cases are grouped by whether the malignancy seemed to be actively transplanted from the donor (Table 1) or seemed to have arisen from donor cells after transplantation (Table 2).
Table 1. Secondary Donor-Derived Malignancies Transplanted from the Donor at the Time of Hematopoietic Stem Cell Infusion
| Variable | Patient No. | |||||
|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | |
| Patient characteristics | ||||||
 Sex/age (y) | Male/60 | Male/62 | Male/54 | Female/6 | Female/45 | Male/52 |
| Initial diagnosis | MF | MDS (RAEB) | CLL | CML | ALL | NHL |
| HCT type | MA | MA | NMA | MA | MA | NMA |
| Stem cell source | PB | PB | PB | BM | PB | PB |
| Conditioning | BU, CY | FLU, BU | TBI | TBI, CY | TBI, CY | TBI, FLU |
| Chronic GVHD | Yes | Yes | Yes | Yes | No | Yes |
| GVHD prophylaxis/treatment | MTX, CSP/corticosteroids | MTX, CSP/corticosteroids | CSP, MMF/corticosteroids | MTX, CSP/corticosteroids, CSP | MTX, CSP | CSP, MMF/corticosteroids |
| Secondary malignancy/time from transplantation | MCL/55 d | CLL/28 days | MZL/294 d | CLL/10 y | ALL/130 d | CLL/28 d |
| Detection technique | Flow cytometry | Flow cytometry | Flow cytometry | PCR clonality analysis | Pathology and flow cytometry | Flow cytometry |
| Donor origin confirmation | Chimerism studies performed by VNTR on BM CD5+/CD19+-selected population showed 100% donor origin | Chimerism studies performed by VNTR on CD5+/CD19+-selected population showed 100% donor origin | Chimerism studies performed by VNTR on the monoclonal CD20+-selected cell population showed 100% donor origin | Leukemia-specific IgH VDJ rearrangement detected in the patient by PCR | Analysis of short tandem repeats | Chimerism studies performed by VNTR on CD5+/CD19+-selected population showed 100% donor origin |
| Progression to clinical disease/patient’s LFU | No/3.5 mo | No/2 y | No/4.5 y | Yes/12 y | Yes/4 mo | No/6 mo |
| Treatment | None | None | None | None | Chemotherapy | None |
| Cytogenetics at diagnosis of secondary malignancy | NA | 46, XY | 46, XY | NA | 46, XX | 46, XY |
| Donor characteristics | ||||||
| Donor’s match, related or unrelated/age (y) | Matched related (brother)/56 | Matched related (brother)/70 | Matched related (brother)/57 | Matched unrelated (male)/45 | Matched related (sister)/36 | Mismatched (B allele, C antigen) unrelated (male)/51 |
| Cytogenetics | NA | 46, XY | NA | NA | NA | NA |
| Neoplastic clone in donor | Yes | Yes | Yes | Yes | Yes | NA |
| Disease in donor | No | No | Yes | Yes | Yes | NA |
| Treatment in donor | No | No | Yes (chemotherapy) | Yes | Yes (matched related HCT) | NA |
| Donor’s LFU | 2 mo | NA | 4.5 y | 12 y | 5.5 y | NA |
Table 2. Secondary Donor-Derived Malignancies Developing in the Host
| Variable | Patient No. | |||||
|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | |
| Patient characteristics | ||||||
| Sex/age (y) | Male/40 | Male/48 | Female/33 | Male/45 | Male/11 | Male/4 |
| Initial diagnosis | Renal cell Ca | CML | CML | CML | PNH/AA | ALL |
| HCT type | NMA | MA | MA | MA | MA | MA |
| Stem cell source | PB | BM | BM | PB | BM | BM |
| Conditioning | CY, ATG | TBI, CY | TBI, CY | VP-16, TBI | Procarbazine, ATG, CY | TBI, CY |
| Chronic GVHD | No | Yes | Yes | Yes | Yes | Yes |
| GVHD prophylaxis/treatment | CSP, MMF | MTX, CSP/corticosteroids | MTX, CSP/corticosteroids | MTX, CSP | MTX/ATG | MTX, CSP |
| Secondary malignancy/time from transplantation | AML/15 mo | MDS (monos 7)/4 y | MDS (monos 7)/4 y | Del (20q)/3 y | MDS (5q-)/26 y | MDS inv (11)/4 y |
| Detection technique | Pathology and flow cytometry | Pathology and cytogenetics | Pathology and cytogenetics | Cytogenetics | Pathology and cytogenetics | Pathology and cytogenetics |
| Donor origin confirmation | VNTR analysis on AML cells showed donor origin | Chimerism studies by VNTR showed 100% donor origin hematopoiesis | Chimerism studies by VNTR showed 100% donor origin hematopoiesis | Cytogenetics | Cytogenetics | Cytogenetics |
| Progression to clinical disease/patient’s LFU | Yes/1.75 y | Yes/8 y | Yes/9.5 y | No/4 y | Yes/26 y | Yes/6 y |
| Treatment | Autologous transplantation | Pending matched unrelated NMA HCT | Matched unrelated HCT | None | HCT | HCT |
| Cytogenetics at diagnosis of secondary malignancy | 46, XY | 45, XY, −7 | 45, XY, −7 | 46, XX, del(20q) | 46, XX, del(5q) | 46, XX, inv (11) |
| Donor characteristics | ||||||
| Donor’s match, related or unrelated/age (y) | Matched related (brother)/42 | Matched unrelated (male)/44 | Mismatched (DR, DQ) unrelated (female)/44 | Matched related (sister)/40 | Matched related (sister)/22 | Mismatched (DR) related (sister)/3 |
| Cytogenetics | NA | NA | NA | 46, XX | 46, XX | 46, XX |
| Neoplastic clone in donor | No | NA | NA | No | No | No |
| Disease in donor | No | NA | NA | No | No | No |
| Treatment in donor | No | NA | NA | No | No | No |
| Donor’s LFU | 21 mo | NA | NA | 4 y | 26 y | 6 y |
Secondary Malignancies Apparently Transplanted from the Donor
For this group of 5 males and 1 female, the median age was 53 years (range, 6-62 years; Table 1). The original diagnoses were myelofibrosis, myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and non-Hodgkin lymphoma (NHL) in 1 patient each. Four of the patients received MA and 2 received NMA HCTs. The stem cell source was peripheral blood (PB) in 5 cases and bone marrow (BM) in 1 case.
The donor clones with a malignant immunophenotype included CLL in 3 cases and marginal zone lymphoma, mantle cell lymphoma, and ALL in 1 case each. The methods used to confirm that the aberrant clones were of donor origin were VNTR analysis in 4 cases, analysis of STR in 1 case (performed in the selected population with the malignant immunophenotype), and detection of the same clonal immunoglobulin heavy chain variable (v), diverse (D), and joining (J) gene segments (immunoglobulin [Ig]H VDJ) rearrangement in the last case. The time interval from transplantation to the detection of the malignant clone was relatively short (28-294 days) in 5 of these 6 cases. In the remaining case, the patient was tested for the first time 10 years after the transplantation. The secondary malignant clones evolved to overt malignancies in 2 of the 6 cases (follow-up, 3.5 months to 12 years). The 2 cases of leukemia included ALL at 3 months after HCT and CLL 12 years after transplantation.
The median age of the donors in this group was 53.5 years (range, 36-70 years). Evidence of the malignant clone was detected in 5 of the 6 donors. In 4 cases, the clones detected had the same immunophenotype by flow cytometry that was found in their respective recipients, and in the last case, the donor and recipient presented with identical clonal IgH VDJ rearrangements. For the sixth case, the donor was not available for testing. In 3 of the 5 available donors, the clone evolved to clinical disease (1 ALL, 1 CLL, and 1 NHL).
The malignant clone was detected first in the donor, rather than the patient, in 2 cases. In 1 case, the donor had a diagnosis of ALL, and in the second case the donor had a diagnosis of CLL (2 months and 2 years after donating stem cells, respectively). The donor of the first of these 2 cases developed ALL 2 months after collection of stem cells. When the recipient presented with a recurrence of her ALL, 130 days after the transplantation, the question arose whether this represented a true relapse or whether the new leukemia arose in the donor cells. To determine the origin of this second leukemic episode in the recipient, STR analysis was performed on DNA obtained from BM of the recipient at the time of relapse, blood samples from both sisters in remission, and buccal swabs of the recipient, representing the pretransplantation STR phenotype. The studies showed identical profiles for 5 of the 5 informative loci tested for the donor blood sample and the recipient BM at the time of relapse. However, a different profile was obtained from the DNA extracted from the buccal swab of the recipient, thus indicating the donor origin of the recipient’s second leukemia.
In the second of these 2 cases, the donor was diagnosed with CLL 2 years after the stem cell collection. Polymerase chain reaction analysis on an aliquot of the donor’s BM stored at the time of the transplantation and on a PB sample of the patient obtained 10 years after the transplantation revealed evidence of the same clonal IgH VDJ rearrangement present in the donor CLL. The patient in this case developed clinical CLL 12 years after the transplantation.
Secondary Malignancies in Donor Cells Developing in the Host
The patients in this group included 5 males and 1 female (Table 2). The median age was 36.5 years (range, 4-48 years), and the original diagnoses included CML in 3 and ALL, paroxysmal nocturnal hemoglobinuria/aplastic anemia, and renal cell carcinoma in 1 patient each. Five of the patients received a full ablative transplant, and 1 patient received an NMA transplant. The stem cell source was PB in 2 cases and BM in 4 cases.
The secondary malignant clones were indicative of MDS in 5 cases [monosomy 7 in 2 cases and del(5q), del(20q), and inv(11) in 1 case each] and acute myeloid leukemia in 1 case. The methods used to confirm that the secondary malignant clone was of donor origin included karyotype analysis performed on the malignant flow-sorted cell populations in 3 of the cases in which patient and donor were of different sexes and VNTR analysis in the other 3 cases. In all 6 cases, the time from the transplantation to the detection of the new malignant clone was >1 year (median, 4 years; range, 1.25-26 years).
The median donor age in this group was 41 years (range, 3-44 years). None of the 3 donors tested had evidence of a hematopoietic malignant clone. We do not have information on the other 3 donors. All but 1 of the recipients developed overt disease and received aggressive treatment with chemotherapy or a second transplantation.
In summary, secondary malignancies in our first group tended to occur in the setting of older donors, were detected far sooner after transplantation, and were all of lymphoid lineage. In contrast, cases in the second group were associated with younger donors, had a longer time from transplantation to detection, and were exclusively myeloid. The donors in this first group of cases were significantly older than the donors in the second group (P < .05; Student t test).
Discussion
Between 1974 and 2004, more than 10 000 transplantations have been performed at our institutions. Here we report 12 new cases with clonal abnormalities characteristic of hematologic malignancies derived from donor cells after an HCT. These cases add to the literature of at least 49 cases of hematologic malignancies in donor cells after HCT published since 1971 [5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34]. Four previous articles have presented cases of acute myeloid leukemia, MDS, T-cell lymphoma, and CML [8, 10, 31, 32] that were transplanted from the donor into the patient. Here we present 6 additional cases that fit in this category: 3 CLLs, 1 marginal zone lymphoma, 1 mantle cell lymphoma, and 1 ALL.
We divided this series of “secondary” hematologic malignancies into 2 categories on the basis of the hypothesis that they represent 2 different pathogenic mechanisms. The first category includes patients in whom the malignant clone was probably transferred at the time of transplantation, concurrent with the infusion of normal hemopoietic stem cells. The donor malignancy in all cases was lymphoid. The second category includes patients in whom the donor cells seemed to have transformed into a malignancy after transfer into the recipient. Curiously, the donor malignancy in these cases was always myeloid. The median donor age in the first group (53.5 years) was significantly older than the median donor age in the second group (41 years); this offers a suggestive association of donor age and the development and transfer of lymphoid disease. Studies have shown that B lymphocytes with abnormal CD5+CD23+ clonal immunophenotypes may be present in healthy individuals [35], and their incidence may increase with age [36]. In addition, the bcl2-IgH translocation found in most follicular NHL cases has been found frequently in healthy individuals, with an increasing incidence with progressive age [37, 38]. Although it is not clear that these age-related changes are premalignant, they nonetheless underscore that with age come genetic changes in the “normal” lymphohematopoietic system.
It is difficult to estimate a true prevalence of donor-derived malignancies in our transplant population or to tell whether the incidence has increased over the years. The advent of sensitive techniques (eg, flow cytometry) to detect malignant clones confounds a historical comparison. However, we speculate that extending the age limits for transplantation, with the associated increase in donor age, has set the stage for the increased appearance of age-related donor-derived malignancies in transplant recipients. Given the relative rarity of these cases, however, it is difficult to advocate wholesale screening of all donors for a “silent” hematologic malignancy. A cost-effective approach might include more complete testing (ie, flow cytometry) of older donors with a family history of hematologic malignancies or suspicious hematologic test results in routine workup tests [39].
The detection of a donor malignancy in a patient raises the question as to workup and consoling of the donor. The small total number of cases reported thus far in the literature makes concrete advice difficult. From our report and other recent publications [34], it is clear that not all donors are destined to develop disease themselves, particularly when the recipient develops a myeloid malignancy. Nonetheless, a careful physical and laboratory examination would seem in order for these donors.
Several mechanisms with respect to the transformation of donor-derived cells have been hypothesized: viral or oncogene transfection from the host into the donor cells, which is favored by the immunosuppressed status that follows transplantation; chronic antigenic stimulation of donor cells once in the host; or premature aging of the donor’s cells as a consequence of the replicative effort to repopulate the donor’s marrow [40]. Here we present evidence that the infusion of malignant cells into HCT recipients may also account for some of the cases of malignancies in donor cells. A systematic research study of the prevalence of occult secondary hematologic malignancies in older donors would be useful to determine whether the hypothesized increased risk of donor malignancies is real.
Acknowledgments
This work was supported by grant nos. BEFI 01/9534 (Instituto de Salud Carlos III), NCI CA18029, NCI 30206, NCI 33572, and CA 102542.
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PII: S1083-8791(06)00068-1
doi:10.1016/j.bbmt.2006.01.006
© 2006 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 12, Issue 5 , Pages 511-517, May 2006
