Biology of Blood and Marrow Transplantation
Volume 16, Issue 7 , Pages 1025-1031, July 2010

Donor-Derived Second Hematologic Malignancies after Cord Blood Transplantation

Department of Medicine, Massachusetts General Hospital and Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts

Received 22 October 2009; accepted 16 February 2010. published online 22 February 2010.

Article Outline

Double umbilical cord blood transplantation (UCBT) with a reduced-intensity conditioning regimen is an effective strategy for adult patients without a matched donor. The risk of second malignancies in these patients has not yet been established, however. In the present study, 98 adults with a hematologic malignancy underwent double UCBT. Seventy patients received a reduced-intensity conditioning regimen of fludarabine 30 mg/m2/day for 6 days, melphalan 100 mg/m2/day for 1 day, and rabbit antithymocyte globulin 1.5 mg/kg/day for 4 days, and 28 patients received a myeloablative total body radiation–containing conditioning regimen. Sixty-three patients received sirolimus-based graft-versus-host disease (GVHD) prophylaxis, and 35 patients received non–sirolimus-based GVHD prophylaxis. The median patient age was 48 years (range, 19-67 years). Eighteen patients developed a second malignancy at a median of 134 days after transplantation. Sixteen patients had lymphoma, and 2 patients had myelodysplasic syndrome/myeloproliferative disorder (MDS/MPD). Sixteen of these second malignancies (both cases of MDS/MPD and 14 of the lymphomas) were donor-derived; the origins of the others were not determined. GVHD prophylaxis, HLA matching, primary disease, age, total nucleated cell dose, and CD34+ cell dose were not associated with a higher rate of second malignancy. Second myelogenous malignancies of donor origin occur after double UCBT, suggesting that a search for donor origin should be performed in all patients with suspected relapse.

Key Words: Cord blood, Second cancer

 

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Introduction 

Umbilical cord blood is an alternative stem cell source for patients without a matched related or unrelated donor. A projected disease-free survival (DFS) of approximately 30%-60% has been observed in adults receiving umbilical cord blood (UCB)–derived hematopoietic stem cell transplantation (HSCT) using either a single cord blood product 1, 2, 3, 4 or 2 cord blood products 5, 6, 7. Most of these transplantations use donors mismatched at multiple HLA antigens, however. Moreover, the products include only naïve T cells, which are present in small numbers. Thus, there is an inherent risk of posttransplantation lymphoproliferative disorder (PTLD). Stimulation of limited numbers of stem and progenitor cells may increase the risk of myelodysplasia (myelodysplasic syndrome [MDS]/myeloproliferative disorder [MPD]) and acute myelogenous leukemia (AML) [8]. Finally, mutations that are associated with the later development of leukemia have been identified in postpartum UCB [9].

Second malignancies may be of recipient or, more rarely, donor origin 10, 11, 12, 13. Recent analyses of the risk of second malignancy after allogeneic HSCT suggest an incidence of 6%-12% 14, 15. The risk of solid tumors does not appear to plateau, however. A retrospective study of 18,000 patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) indicates a 1% incidence of PTLD, with 82% of cases occurring during the first year after transplantation [14]. Known risk factors for PTLD include Epstein-Barr virus (EBV) infection, HLA mismatch, use of antithymocyte globulin (ATG), T cell depletion, and chronic graft-versus-host disease (cGVHD). The incidence of PTLD after reduced-intensity (RIC) double cord blood transplantation ranges from 3% to as high as 21% when ATG is used in the conditioning regimen [16].

Second myeloid malignancies are rare after allogeneic HSCT using living donor Bone marrow (BM) or peripheral blood stem cells (PBSCs). There have been individual case reports of secondary myeloid malignancies of donor origin after allogeneic HSCT, with an estimated incidence of <0.25% 17, 18, 19, 20, 21, 22, 23.

Because relapse of the primary disease may be difficult to distinguish from donor-derived secondary leukemia unless cytogenetic or molecular techniques are used, the actual incidence of donor-derived second malignancies may be underreported. In this study, we explored the incidence and outcomes of secondary hematologic malignancies in 98 patients who underwent double UCB HSCT.

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Methods 

Patients 

Consecutive patients with a hematologic malignancy undergoing double UCB transplantation (UCBT) were analyzed retrospectively. Patients were eligible for RIC double UCB HSCT if they had no 5/6 or 6/6 HLA-A, -B, or -DR allele-level matched related donor or no 6/6 HLA-A, -B, or -DR allele-level matched unrelated donor. Patients with acute leukemia were eligible if they were in first remission with high-risk cytogenetics or in second or subsequent remission. Patients with refractory leukemia were not eligible. Patients with chemotherapy-sensitive relapsed lymphoma were eligible, as were patients with MDS, chronic myelogenous leukemia (CML) refractory to tyrosine kinase inhibitors, or chronic lymphocytic leukemia (CLL) that progressed after at least 2 regimens.

Conditioning Regimen and GVHD Prophylaxis 

All patients in the RIC arm received a regimen of fludarabine (Flu) 30 mg/m2/day on days -8 through -3 (total dose 180 mg/m2), melphalan 100 mg/m2/day on day -2, and rabbit ATG (Genzyme, Cambridge, MA) 1.5 mg/kg/day on days −7, −5, −3, and −1 (total dose, 6.0 mg/kg). Patients under the age of 45 years with no comorbid conditions were eligible to receive a myeloablative (MA) conditioning regimen consisting of Flu 25 mg/m2/day on days −6, −5, and −4 (total dose, 75 mg/m2); cyclophosphamide 1800 mg/m2/day on days −6 and −5 (total dose, 3600 mg/m2); and total body irradiation 14 Gy in 7 fractions on days −3, −2, −1, and 0. Four patients also received ATG in addition to the foregoing regimen. Sixty-three patients received sirolimus-based GVHD prophylaxis with sirolimus (target trough serum concentration, 3-12 ng/mL) and tacrolimus (target trough serum concentration, 5-10 ng/mL) [24]. GVHD prophylaxis was tapered after day +100 if there was no evidence of acute GVHD (aGVHD). Thirty-five patients received GVHD prophylaxis with either tacrolimus as above or cyclosporine (CsA) in continuous i.v. infusion starting on day -3 and mycophenolate mofetil (MMF) 15 mg/kg twice daily starting on day 0, with tapering of MMF after day +60 and of CsA after day +100 if there was no evidence of aGVHD [6]. Eleven patients received parathyroid hormone 100 μg/day for 28 days after transplantation on a concomitant trial. The protocols were reviewed and approved by the Dana-Farber/Harvard Cancer Center's Institutional Review Board, and written informed consent was obtained from all patients.

Cord Unit Selection 

CB units were obtained from national and international registries. Each CB unit had to meet a minimum cell dose requirement of >1.5 × 107 nucleated cells (NCs)/kg prefreeze for each individual unit and 3.7 × 107 NCs/kg prefreeze for both units combined. CB units had to be at least a 4/6 HLA-A, -B, and -DR allele-level match with the patient and with one another other. HLA-C typing was performed on the CB units, but was not used in the matching strategy. CB units were washed with dextran and albumin and infused sequentially 1-6 hours apart [25].

Second Malignancies 

All patients are followed for survival, relapse, and second malignancies. When possible, the donor origin of the second malignancy was assessed by routine cytogenetics or chimerism studies. Chimerism assays of peripheral blood buffy coat isolates were performed by short tandem repeat analysis using a multiplex kit with primers for 10 different loci (Profiler Plus; Applied Biosystems, Foster City, CA), as described previously [26]. Patients were monitored for EBV by DNA analysis every other week, and rituximab therapy was administered in patients with a sustained level >1000 copies/ml.

Statistical Analysis 

The times to the outcome events were measured from day 0 of CB infusion. Overall survival (OS) was measured until the date of death or was censored at the last follow-up for patients who were still alive. DFS was measured until the earlier date of relapse or death, and was censored at the last follow-up for patients who were alive and free of relapse. OS and DFS were estimated using the Kaplan-Meier method. Treatment-related mortality (TRM) was based on the cumulative incidence estimated in the presence of relapse as a competing risk [27]. The absolute risk of second malignancy was based on the cumulative incidence estimated by considering death as a competing risk using the method of Gray [27]. Patients who had not developed a second malignancy or died were censored at their last follow-up. To adjust for confounding, the associations between patient or CB unit characteristics and incidence of second malignancy were analyzed in a multivariate model. In particular, competing-risks regression using the method of Fine and Gray [28] was used to assess the joint effects of age, primary disease, conditioning regimen, GVHD prophylaxis, HLA matching, NC dose, and CD34+ dose. The relative risk of developing a second malignancy was based on the estimated hazard ratio (HR), with the 95% confidence interval (CI) calculated by taking exponents of the 95% CI for the regression coefficient. SAS version 9.1 (SAS Institute, Cary, NC) was used to perform the general computations, and the cmprsk package in R version 2.5.1 was used in competing-risks analyses. All P values are based on 2-sided hypothesis tests. Given the modest sample size available for a multivariate model with several covariates, a P value <.20 was considered to suggest a trend within a hypothesis-generating framework.

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Results 

Patient Characteristics 

Table 1 summarizes characteristics of the 98 patients in the study group. The median patient age was 48 years (range, 19-67 years). The majority of the patients had either acute leukemia (40 patients) or relapsed non-Hodgkin lymphoma (NHL; 19 patients); 80% were Caucasian. In terms of risk, 20% of the patients with leukemia were considered standard risk, and 80% were considered high risk. The median follow-up was 29 months (range, 6-69 months), with 43 patients alive as of September, 2009. In terms of conditioning, 29% of the patients received an MA regimen, and 71% received a RIC regimen. Patients with MDS, CML, and aplastic anemia were more common in the MA group (56% vs 21%), whereas patients with lymphoma were more often treated with the RIC regimen (28% vs 3%).

Table 1. Patient Characteristics
Age, years, median (range)48 (19-67)
Male sex, %57%
Malignancy, n (%)
AML33 (34%)
NHL19 (19%)
Hodgkin lymphoma8 (8%)
Aplastic anemia7 (7%)
MDS12 (12%)
CLL/PLL6 (6%)
Acute lymphoblastic leukemia6 (6%)
CML4 (4%)
Other3(3%)
Transplantation risk, n (%)∗
Standard18 (20%)
High70 (80%)
Conditioning regimen, n (%)
Reduced-intensity70 (71%)
Myeloablative28 (29%)
GVHD prophylaxis, n (%)
Sirolimus-based63 (64%)
Non–sirolimus-based35 (36%)

AML indicates acute myelogenous leukemia; NHL, non-hodgkin lymphoma; MDS, myelodysplastic syndrome; CLL, chronic lymphocytic leukemia; PLL, prolymphocytic leukemia; CML, chronic myelogenous leukemia; GVHD, graft-versus-host disease.

∗Standard risk: AML/acute lymphoblastic leukemia in first complete response, MDS with refractory anemia/refractory anemia with ringed sideroblasts, CML in chronic phase1; high risk: all others, excluding aplastic anemia and lymphoma.

CB Unit Characteristics 

Table 2 summarizes characteristics of the CB units infused. The median NC dose infused for the combined CB units was 4.4 × 107 NCs/kg (range, 1.3-8.5 × 107 NCs/kg), and the median CD34+ dose infused for the combined CB units was 2.4 × 105 CD34+ cells/kg (range, 0.3-11.5). Seventy-six percent of the patients received two 4/6 HLA-A, -B, and -DR allele-level matched CB units; 14% received one 4/6 and one 5/6 matched cord blood unit; and the remaining 8% received two 5/6 matched cord blood units. No patient received a 6/6 matched cord blood unit.

Table 2. Cord Blood Characteristics
Infused cell dose, combined cord blood units, median (range)
NCs/kg4.4 × 107 (1.3-8.8)
CD 34+ cells/kg2.4 × 105 (0.3-11.5)
HLA match (-A, -B, -DRB1), n (%)
4/6, 4/676 (78%)
4/6, 5/614 (14%)
5/6, 5/68 (8%)
5/6, 6/60
6/6, 6/60

Second Malignancies 

Eighteen patients (18%) developed a second malignancy, corresponding to an actuarial rate of 19% at 26 months after transplantation. The median time to development of a second malignancy was 134 days (range, 39 days to 26 months). Thirteen of these patients died, all from the second malignancy. Table 3 presents characteristics of the patients with a second malignancy. Eleven patients received parathyroid hormone after transplantation; one of these patients developed a second malignancy. No solid tumors were observed in this population, with a median follow-up after transplantation of 29 months.

Table 3. Second Malignancies
Primary DiseaseType of Second MalignancyDerivationOutcome
AMLMDS/MPDDonorFatal
Hodgkin lymphomaPTLDDonorFatal
NHLMDS/MPDDonorFatal
Hodgkin lymphomaPTLDUnknownFatal
CLLPTLDDonorFatal
MDSPTLDDonorFatal
AMLPTLDDonorFatal
MDSPTLDDonorAlive, in CR
NHLPTLDDonorFatal
Hodgkin lymphomaPTLDDonorFatal
AMLPTLDDonorFatal
AMLPTLDDonorAlive, in CR
NHLPTLDDonorFatal
NHLPTLDDonorFatal
MDSPTLDDonorFatal
Aplastic anemiaPTLDDonorAlive, in CR
Aplastic anemiaPTLDDonorAlive, in CR
CMLPTLDUnknownAlive, in CR

CR indicates complete response; AML, acute myelogenous leukemia; NHL, non-hodgkin lymphoma; CLL, chronic lymphocytic leukemia; MDS, myelodysplastic syndrome; CML, chronic myelogenous leukemia.

EBV PTLD 

Sixteen patients had EBV PTLD, 14 with donor-derived disease as measured by chimerism assay and 2 with disease of undetermined origin. In 1 patient, the BM demonstrated chimerism from one CB unit, and the lung tissue with PTLD exhibited chimerism from the other cord blood unit. Posttransplantation lymphoma developed a median of 117 days after transplantation (range, 39-368 days). The primary diseases were Hodgkin lymphoma (n = 3), NHL (n = 3), CLL (n= 1), CML (n = 1), aplastic anemia (n = 2), MDS/MPS (n = 3), and AML (n = 3). The median maximum EBV viral load was 9500 copies/mL (range, 240-5.4 million copies/mL). Thirteen patients had widespread organ involvement at the time of diagnosis, and 2 patients were treated for an elevated EBV viral load. Twelve patients were treated with rituximab; 3 patients received rituximab and CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone). Eight patients died with fulminant disease within 2 weeks of diagnosis. Three patients also received EBV-specific cytotoxic T lymphocytes after failure of rituximab; 1 of these patients is alive in sustained remission. EBV PTLD was fatal in 11 patients.

Overall, 5 patients were alive and in remission a median of 12 months after the diagnosis of PTLD. These surviving patients developed PTLD at a median of 5 months posttransplantation (range, 4-12 months), similar to the general cohort of PTLD patients. The median EBV viral load in these 5 patients was 7000 copies/mL (range, 603-340,000 copies/mL). All 5 patients received rituximab; 1 patient also received R-CHOP, and 1 patient also received EBV-specific cytotoxic T lymphocytes.

Patients were monitored for the development of EBV viremia every other week up to day +180 and as clinically indicated after day +180. An additional 12 patients developed EBV viremia, but did not progress to a PTLD; these patients had a median EBV viral load of 500 copies/mL (range, 200-3300 copies/mL). EBV viremia occurred at a median of 89 days after transplantation (range, 22-1460 days). Two of these patients received rituximab as part of treatment for relapsed disease.

Second Malignancy with MDS/MPD 

Two patients developed MDS/MPD and died. The actuarial rate of donor-derived myelogenous disease was 3%. Both of these patients had received RIC with Flu, melphalan, and rabbit ATG. One of these patients was a male who underwent HSCT for NHL 21 months after undergoing double CBT. He had been slow to engraft and was receiving filgrastim. He developed myelodysplasia, with BM showing 11% myeloblasts, consistent with refractory anemia with excess blasts, and 100% XX cytogenetics. He was treated with 5 azacytidine without improvement. The other patient, a female, experienced confirmed donor-derived secondary myelodysplasia at 26 months after HSCT for AML. She had hypercellular BM with left-shifted myelogenous cells, erythroid dysplasia, and 100% XY cytogenetics, and was treated with steroids and splenectomy without improvement.

These cases of donor-derived second myelogenous malignancies were reported to the CB banks that provided the CB units. In the first case, follow-up determined that both CB donors were healthy. No information was available for the second cases.

Predictors of Second Malignancies 

Age, primary disease, conditioning regimen, GVHD prophylaxis, HLA matching, NC dose, and CD34+ cell dose were studied in a multivariate analysis to identify independent predictors of a second malignancy (Table 4). RIC was associated with a trend toward an increased incidence of second malignancy compared with MA conditioning (24% vs 7%), but this effect was confounded with the effect of ATG. ATG was administered to all patients receiving a RIC regimen, as opposed to only 4 patients (14%) receiving a MA regimen. A RIC regimen with ATG was associated with a trend toward an increased risk of developing a second malignancy, but the effect was not significant (P = .23). Patients with primary Hodgkin lymphoma had a 38% incidence of second malignancy, higher than the 18% associated with other diseases, but this effect was not significant (P = .06). Older age, GVHD prophylaxis, HLA matching, total NC dose, and CD34+ cell dose were not associated with an increased incidence of second malignancy. Both of the patients with donor-derived MDS/MPD had received ATG, but risk factors for MDS/MPD could not be determined because of the small number of patients.

Table 4. Predictors for Second Malignancies
Patient or Cord Unit CharacteristicRisk GroupCumulative IncidenceHR (95% CI)P value
Age>50 years26%1.8 (0.8-4.8).270
≤50 years14%
Primary diseaseHodgkin lymphoma38%2.8 (0.6-4.8).064
Other malignancies18%
Conditioning regimenReduced-intensity24%2.5 (0.6-10.6).230
Myeloablative7%
GVHD prophylaxisSirolimus-based20%1.1 (0.5-2.9).800
Other agents18%
HLA matching4/6, 5/6 or 5/6, 5/6, 4/6, 4/630%0.9 (0.3-2.6).350
16%
NC dose infused>4.4 × 107/kg21%1.5 (0.6-3.9).350
≤4.4 × 107/kg17%
CD34+ cell dose infused≤2.4 × 105/kg21%1.5 (0.6-3.6).380
>2.4 × 105/kg15%

GVHD indicates graft-versus-host disease.

Survival 

As reported previously, the RIC CsA/MMF group had 1-year overall and disease-free survivals of 71% and 62%, respectively [6]. Two-year overall and disease-free survival was 57% and 57%. The reduced-intensity group with either CsA/MMF or sirolimus/tacrolimus GVHD prophylaxis had overall and disease-free survivals of 63% and 51% respectively at 1 year and 48% and 33% at 2 years. In the MA group, OS and DFS were 35% and 35% at 1 and 2 years, respectively. For the entire cohort, 100-day TRM was 26%, with infection the leading cause of death. The majority of deaths from second malignancy occurred after 100 days, and thus these patients were not included in the 100-day TRM. With a median follow-up of 29 months for the 43 patients still alive, the OS and DFS for the entire cohort were 55% and 47% at 1 year and 44% and 32% at 2 years (Figure 1, Figure 2), respectively. Twenty-four patients experienced disease relapse; in 10 of these patients, cytogenics determined the relapse to be of recipient origin.

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Discussion 

Approximately 10,000 UCB HSCTs have been performed worldwide, the majority for hematologic malignancies 1, 2, 3, 4. Recently, double UCB HSCT has been used in adult patients to shorten engraftment times and reduce the risk of infection 5, 6, 7, 29. Although second malignancies have been reported after double CB HSCT, the magnitude of the risk is uncertain. We report a high incidence (19%) of second malignancies, including a surprising 3% incidence of donor-derived myeloid malignancies.

Similar to the Minnesota group [16], we found a high incidence of PTLD in our patients who underwent double CB HSCT. Our incidence of PTLD is higher than that reported in some double CBT series, but is comparable to the incidence reported by the Minnesota group in patients undergoing reduced-intensity HSCT with ATG [16]. Brunstein et al. reported a 3% incidence of PTLD in patients who received an MA conditioning regimen containing ATG (3% with ATG vs 0 with no ATG); however, the incidence of PTLD was significantly higher in patients who received a RI regimen with ATG (21%, compared with 2% with no ATG). The increased incidence of PTLD after cord blood HSCT may be related to the absence of EBV-specific memory T cells in CB grafts [30]. The reason for the increase with reduced-intensity conditioning is not completely understood but may be related to the number of residual recipient B cells remaining after conditioning [31]. Although weekly or biweekly EBV monitoring may help identify early viral reactivation, the PTLD occurring after CB HSCT appears to be more aggressive than that occurring after solid organ transplantation, with rapid progression to multiorgan involvement and lack of responsiveness to rituximab 31, 32. However, the risk of death in our patients who developed PTLD (69%) was similar to that reported in other stem cell transplantation series; for example, a German group reported 82% mortality in their HSCT patients who developed PTLD 33, 34. PTLD after HSCT of all sources has a poorer prognosis than PTLD after solid organ transplantation.

Previous analyses of conventional HSCT identified T cell depletion, HLA disparity, GVHD, and the use of ATG as risk factors for PTLD 14, 33, 34. After the first year, however, the major risk factor was cGVHD [14]. In our cord blood cohort, no variables were found to be statistically significant, although reduced-intensity conditioning with the use of ATG was associated with a trend toward increased risk of a second malignancy. Intensive monitoring, decreased ATG doses, prompt administration of EBV-specific cytotoxic T cells, and the addition of rituximab to the conditioning might decrease the incidence of PTLD 35, 36, 37. For example, an Italian group administered a single dose of rituximab on day +5 after CB HSCT [38].

We found no second solid tumors; however, our follow-up was short, a median of 30 months after HSCT. An increased incidence of squamous cell cancer has been reported in older patients with cGVHD, some of which are of donor origin 39, 40, 41.

The incidence of donor-derived MDS/MPD in this study (3%) is higher than that reported in the literature after adult HSCT with donor bone marrow or PBSCs (<0.25%) 17, 18, 19, 20, 21, 22, 23. Our incidence is also higher than that reported in other CBT series; however, donor-derived myeloid malignancy may be underreported, because donor-derived AML is difficult to distinguish from relapsed leukemia in the absence of cytogenetic or chimerism data 4, 5, 7. Because donor derivation by chimerism or cytogenetics is not done routinely after HSCT, the true incidence after CB or standard transplantation is unknown. The biology underlying the development of a second malignancy is unclear. Both of our patients with donor-derived MDS/MPD had received an RIC regimen containing ATG, but the small number of patients precludes identification of specific risk factors.

The possibility exists that compared with adult blood, cord blood may be more likely to contain preleukemic cells and contribute to a first “hit” in the “two-hit” development of a second malignancy. In one study, a TEL-AML 1 translocation was detected in 6 of 567 CB samples [9]. Investigators estimate that up to 5% of CB units may contain preleukemic clones [42]. The use of growth factors to drive a low number of viable hematopoietic stem cells also might foster preleukemic mutations, as has been postulated in patients with aplastic anemia 8, 43, 44.

Comparing the incidence of a second myelogenous malignancy after CB and adult-donor BM or stem cell transplantation is difficult. In our institution, donor origin is not routinely tested at the time of suspected relapse. We believe that the findings of the present study (which have altered our own practices) should encourage other investigators to monitor donor origin for second malignancies after all allogeneic, unrelated, or CB HSCTs.

Donor-derived second myelogenous malignancies present unique ethical issues, especially when the donor is an infant. A consistent system of testing for donor origin in all patients with suspected relapse would help distinguish relapsed disease from a donor-derived second malignancy. Should the donor and his or her parents be notified whenever a donor-derived second malignancy is diagnosed? Should these donors have any special follow-up or monitoring? These issues will need to be addressed as we perform more CBT with modern technology that allows determination of donor origin.

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Acknowledgments 

This work was supported in part by National Heart, Lung and Blood Institute Grant U54HL081030 and PO1 CA142106. Yi-Bin Chen is a Special Fellow in Clinical Research of the Leukemia Lymphoma Society.

Financial disclosure: Thomas R. Spitzer has received consulting fees from Genzyme.

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 Financial disclosure: See Acknowledgments, page 1030.

PII: S1083-8791(10)00085-6

doi:10.1016/j.bbmt.2010.02.014

Biology of Blood and Marrow Transplantation
Volume 16, Issue 7 , Pages 1025-1031, July 2010

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