Post-transplant Events

Donor cell-derived leukemia after cord blood transplantation and a review of the literature: differences between cord blood and BM as the transplant source

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Abstract

Donor cell-derived leukemia (DCL) is a rare complication of SCT. Here, we present a case of DCL following cord blood transplantation (CBT) and review the clinical features of previously reported DCL. To our knowledge, this is the first report comparing clinical characteristics of DCL from the standpoint of the transplant source, with umbilical cord blood and BM. AML and myelodysplastic syndrome (MDS) were recognized more frequently in DCL after CBT, whereas the incidence of AML and ALL was similar after BMT. The median duration between the occurrence of DCL following CBT and BMT was 14.5 and 36 months, respectively. DCL occurred in a significantly shorter period after CBT than after BMT. Abnormal karyotypes involving chromosome 7 were observed in 52.4% of CBT recipients and 17.3% of BMT recipients; this was a statistically significant difference. Particularly, the frequency of monosomy 7 was significantly higher in DCL after CBT than after BMT. The types of abnormal karyotypes in DCL following BMT were similar to those characteristically observed in adult de novo AML and MDS. DCL patients generally have a poor prognosis in both groups. SCT is the best treatment for curing DCL. DCL appears to have different clinical features according to the transplant source.

Introduction

Donor cell-derived leukemia (DCL) is a rare but severe complication of allogeneic hematopoietic SCT. The first DCL case was reported in a patient who received BMT in 1971.1 Since then, dozens of DCL cases have been reported, and Wiseman2 has reviewed 64 cases in SCT recipients recently, in which 45 cases were of DCL occurring after BMT. On the other hand, two cases of DCL occurring after cord blood transplantation (CBT) were reported simultaneously in 2005 by Matsunaga et al.3 and Fraser et al.4 Umbilical cord blood is recognized as an alternative stem cell source for transplantation and >25 000 cases of CBT have been performed worldwide in the past 25 years.5 In this paper, we present a newly diagnosed case of DCL following CBT (that is, the 24th reported case) and review the clinical features of previously reported DCL, with a focus on the differences between umbilical cord blood and BM as the sources for transplantation.

Case report

A 52-year-old man was admitted to our hospital with a high fever that had continued for 10 days. His hematological data showed pancytopenia. On the basis of BM findings, he was diagnosed with refractory anemia with excess blasts accompanied by trilineage dysplasia, which showed 11% myeloblasts. Immunophenotyping of blasts revealed a moderate-to-strong expression of CD4 (24.6%), CD13 (89.7%), CD33 (99.3%) and CD34 (89.0%). A cytogenetic study of the blasts showed chromosomal abnormalities, including 47,XY, +8 [11]/47,XY, del(2)(q21q31) and +8[5]/46,XY [2], as well as six tetraploid-range cells having +8,+8[3 cells] or two del(2) chromosomes and +8, +8(three cells). Blasts in the peripheral blood gradually increased to 22.8% during the 1.5 months after admission, and he was diagnosed with AML that had developed from refractory anemia with excess blasts. He also suffered from psoariasis vulgaris and repeated infectious episodes. As severe infection was anticipated during induction therapy and the chance of transplantation might have been lost, he received transplantation without chemotherapy, with the CBT performed 4 months after admission. The conditioning regimen consisted of fludarabine, melphalan and 4 Gy of TBI. Short-term MTX and tacrolimus were used as GVHD prophylaxis. He received CBT from one HLA-locus-mismatched unrelated female donor. The total infused nucleated cell dose was of 2.29 × 107/kg, including 0.21 × 105/kg of CD34-positive cells (3.76 × 103/kg of GM colony-forming units). Neutrophil engraftment (>500/μL) was observed on day 13 following the administration of G-CSF. Platelet engraftment was observed on day 50. BM examination on day 28 showed normocellular marrow without myelodysplasia and cytogenetic analysis revealed a normal female karyotype of 46,XX. On day 34, he exhibited a skin rash, liver dysfunction and diarrhea and was diagnosed with GVHD, grade III. The GVHD was gradually improved by treatment with prednisolone. Pneumonia, CMV infection and hemorrhage cystitis also occurred but were controlled.

Twenty-four months after CBT, progressive thrombocytopenia appeared again. Peripheral blood analysis showed the concentration of WBC as 5800/μL (blast 0.5%, stab 1.0%, seg 44.5%, eos 5.0%, baso 0.5%, mono 5.5%, lym 43.0%), RBC as 3.9 × 106/μL, Hb as 13.1 g/dL, Ht as 38.8% and platelet as 4.3 × 104/μL. BM examination showed 13% of the myeloblasts with dysplasia of the myeloid lineage and megakaryocytes. Immunophenotyping of blasts revealed strong expression of CD4 (78.1%), CD7 (95.0%), CD13 (96.1%), CD33 (81.0%) and HLA-DR (89.8%). However, myeloblasts increased to 60% during the 5 months from the time of relapse and a diagnosis of AML with myelodysplasia-related changes was made. We initially recognized the condition as a leukemia relapse derived from the recipient. However, a cytogenetic study of the BM showed an abnormal karyotype of 46,XX, r(7)(p10p22)[26/31] and 46,XX[5/31]. FISH analysis of the myeloblasts showed that 99.8% had the XX signal. Chimerism evaluation as performed by STR analysis revealed complete donor chimerism of the BM cells (Figure 1). Thus, we concluded that this patient had developed DCL after CBT. He received induction therapy by idarubicin and cytarabine and achieved CR. However, in the course of the consolidation therapy, he died because of septic shock and respiratory failure. The survival period was 1 year after he developed DCL and 3 years after CBT. The donor remained healthy 9 months after birth.

Figure 1
figure1

Chimerism evaluation by STR analysis. Analysis of chimerism at the locus of D18S51 and FGA. The recipient-derived BM sample at the diagnosis of RAEB (a), the sample after CBT succeeded (b) and the sample in which DCL occurred (c). b and c show the same peaks, with the patterns, different from that of a.

Review of the literature

We obtained 23 reports of DCL following CBT and 52 reports of DCL following BMT between the years 1971 and 2013 while searching for articles containing the terms ‘donor cell leukemia’ or ‘donor cell-derived leukemia’ using PubMed.

The present case and the 23 reported cases of DCL after CBT are listed in Table 1.3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 Ten and 14 were men and women, respectively. The median age of the patients was 32 years (range: 1–59 years). The median duration between CBT and the occurrence of DCL was 14.5 months (range: 2.6–47 months). The subtypes of DCL after CBT were AML in 14 cases, MDS in 7 cases, ALL in 2 cases and chronic myeloproliferative disorder in 1 case.

Table 1 Clinical features and course of reported DCL patients following CBT

The results of cytogenetic analysis were described for 21 patients. An abnormal karyotype involving No 7 was detected in 11 of the 21 patients. The most frequent abnormality was monosomy 7, which was observed in eight patients. Other abnormal karyotypes, such as der(7), r(7), t(7;11), t(1;7) and t(6;7), were observed as additional changes. Rearrangement of the MLL gene at the 11q23 region was detected in patient number 7.

The outcomes were described in 21 out of 24 cases. Nine patients were alive at the time each of the reports was written, whereas 12 patients had passed away within a short period. The median duration between the occurrence of DCL and death was 6 months (range: 0.24–16 months). Nine patients (cases number 4, 5, 10, 13, 17, 18, 19, 20 and 21) were alive at the time of each report, which included five patients with MDS (cases number 4, 17, 18, 19 and 21), who were alive without treatment. The remaining 12 patients were dead. Among them, three patients (cases number 1, 7 and 11) died before starting the treatment because of rapid disease progression. Fifteen patients (six of these were alive and nine deceased) were intended to undergo treatment, but six patients (cases number 2, 8, 12, 16 and 22) died without obtaining the second CR. The remaining nine patients entered the second CR, with six of these nine patients undergoing a second SCT. Three of the six patients (cases number 5, 10 and 20) were successfully transplanted but the other three (cases number 3, 9 and 15) died from complications of SCT. A statement that the health of the donor was good was written in 14 reports.

Meanwhile, cases of DCL following BMT are listed in Table 2.1, 20, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 We examined 52 cases of DCL for which precise information was provided. The articles dealing with these cases comprised four reviews containing 35 cases and 17 single reports. We listed four cases from the report of Sala-Torra,46 excluding two cases in which PBSC was used and six cases of malignant disease in the donor at the time of transplantation. We excluded five cases from the report of Cooley36 because four cases overlapped with cases from the report of Hertenstein41 and because the abnormal karyotype of the recipient continued to be present in the other case. We also excluded 20 cases from Reichard et al.50 because they overlapped with those in Cooley et al.36 and in Hertenstein et al.41

Table 2 Clinical features and course of reported DCL patients following BMT

The numbers of men and women were similar (25/27), and the median age of the patients was 31.0 years (range: 3–66 years). The median duration between BMT and the occurrence of DCL was 36 months (range: 2–312 months). The types of DCL following BMT were AML in 25 cases, ALL in 15 cases, MDS in 11 cases and CML in 1 case.

In terms of the cytogenetic analysis, 22 cases showed a normal karyotype. An abnormal karyotype involving No 7 was detected in nine cases, and eight of these nine cases had monosomy 7. An abnormal karyotype of t(8; 21) was observed in three cases. Two cases each of t(9;22) and t(9;11) were also recorded, and other abnormal karyotypes, such as t(15; 17), inv(16), del(5q), −Y, del(12), +8, 6q− and iso(17q), were observed.

The outcome was described in 49 out of the 52 cases. Twenty-four cases were alive at the time each of the reports was written, whereas 25 patients had passed away within a short period. The duration between the occurrence of DCL and death was described in 17 out of 25 cases. The median duration was 5.0 months (range: 1–34 months). Of the 24 patients who were alive, 11 received only chemotherapy; 10 patients received chemotherapy followed by a second SCT; and three patients received only supportive therapy. Most of the patients initially received BMT from a related donor, whereas nine of the patients received BMT from an unrelated donor. The age of the donor was described in 15 cases and the median age was 37 years (range: 3–50 years).

Discussion

The incidence of DCL was reported to be 3/243 (1.2%) by Boyd et al.,67 14/10 489 (0.13%) by a European Group for Blood and Marrow Transplantation report41 and 4/478 (0.84%) by the Tokyo Cord Blood Bank.9 Wiseman suggested that DCL might represent up to 5% of all the post-transplant leukemia ‘relapses’.2 However, the incidence of DCL may be underestimated because of insufficient examinations for distinguishing DCL from a relapse of the original disease and publication bias. Accordingly, an accurate estimation of the incidence of DCL is difficult.

Several differences were noted when a comparison between DCL following CBT and DCL following BMT was made (Tables 1 and 2). First, concerning the type of DCL, AML and MDS were recognized more frequently after CBT, whereas AML and ALL were similarly observed after BMT. Second, the duration of time between transplantation and the occurrence of DCL differed depending on the transplanted source. The median duration estimated using the Kaplan–Meier method was 14.5 months after CBT and 36 months after BMT (P<0.0001: Log-rank test; P=0.0001: Wilcoxon test). DCL occurred within a significantly shorter period after CBT than after BMT. It is noteworthy that the period between CBT and the occurrence of DCL (14.5 months) was similar to the period in which infant leukemia occurs with the highest incidence.68 Infant leukemia usually occurs at the age of about 1 year and shows unique biological features and the incidence is 2% of childhood leukemia.

Third, the characteristics of the karyotypes of DCL occurring in DCL after BMT were different from those occurring in DCL after CBT. In DCL after CBT, the frequency of the normal karyotype was slightly lower than that after BMT (7/21, 33.3% vs 22/52, 42.3%). The types of abnormal karyotypes in DCL following BMT were similar to those observed in adult de novo AML or MDS, such as t(8; 21), t(9;22), t(9;11), t(15;17), inv(16), del(5q), +8, and those involving No 7. Abnormal karyotypes involving chromosome 7 were observed in 11/21 (52.4%) CBT recipients and 9/52 (17.3%) BMT recipients. Significant differences in the frequency of cases involving chromosome 7 were observed between CBT and BMT (χ2-test, P<0.003). Particularly, the frequency of monosomy 7 in DCL after CBT was significantly higher than that in DCL after BMT (8/21, 38.1% vs 8/52, 15.4%, P<0.034). Monosomy 7 is frequently reported in infant leukemia as well.68 Several studies12, 14, 20, 65 previously reported that monosomy 7 was frequently observed in DCL, but the populations were too small to consolidate the broader validity of this finding, and no comparisons were made on the donor sources.

As for the prognosis, DCL patients generally had a poor prognosis in both groups. The median survival in DCL following CBT and DCL following BMT was 6.0 months and 5.0 months, respectively. DCL following CBT tended to be resistant to chemotherapy, and surviving with chemotherapy alone is difficult. Only patients who received a second SCT were alive for a long duration. SCT seems to be the best treatment for curing DCL following CBT. However, chemotherapy seems to be more effective in DCL patients after BMT, compared with after CBT, because 11 of 24 patients were alive with chemotherapy alone. Chemotherapy and SCT seem to offer similar results for curing DCL following BMT.

Several mechanisms for the development of DCL after CBT have been proposed. One possibility is that the donor cord blood itself may contain leukemic clones at the time of transplantation. Mori et al.69 reported the presence of the TEL–AML1 fusion gene in 6 of 567 cases of unselected umbilical cord blood cells and the AML1–ETO fusion gene in 1 of 496 cases. The presence of the AML1–ETO fusion gene sequence was also reported in the neonatal blood spots of children who developed AML later.70 A transferred leukemic clone would be ‘the first hit’ of leukemogenesis after CBT, and then additional hits could lead to leukemia. From the data showing a shorter period for the occurrence of DCL following CBT and the high frequency of monosomy 7 in DCL, it is natural enough to consider that an umbilical leukemia clone could have been transplanted into the recipient, which could cause DCL. Another possibility that may explain the development of DCL after CBT is that even if the transplanted cord blood cells are intact, the environment of the recipients may permit the occurrence of leukemia. This mechanism might be also applicable to DCL following BMT. The microenvironments in recipients, including stem cell niches or stromal cells, have been reported to be changed by irradiation or chemical agents,71 which may lead to impaired immune surveillance or dysregulation of cytokines or homeostasis for hematopoiesis. Indeed, deficiencies in antigen-specific cellular immunity within the first 100 days after CBT have been demonstrated.72 Further, a high proliferation of cord blood cells may be sufficient for inducing replication errors or mutations in the DNA.73

To identify pre-existing leukemic clones in cord blood, the retrospective examination of stored cord blood cells is required in patients who developed DCL. Further, in the future, an examination of every sample before transplantation to determine whether the cord blood cells contain abnormal clones would be ideal. To accomplish this goal, obtaining informed consent before the donation of the cord blood will be important, even if potentially challenging. In addition, long-term surveillance of SCT recipients and donors is also required.

In conclusion, this study revealed that the characteristics of DCL differ depending on sources. In DCL following CBT, a tendency for a shorter interval between CBT and the occurrence of DCL and for a higher proportion of abnormal karyotypes involving chromosome 7 (particularly monosomy 7) was observed. These differences may be caused by the properties of the transplanted cells. Further, long-term follow-up of SCT recipients will be necessary, as CBT has a shorter history than BMT.

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Correspondence to K Yoshinaga.

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Shiozaki, H., Yoshinaga, K., Kondo, T. et al. Donor cell-derived leukemia after cord blood transplantation and a review of the literature: differences between cord blood and BM as the transplant source. Bone Marrow Transplant 49, 102–109 (2014) doi:10.1038/bmt.2013.127

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Keywords

  • donor cell leukemia
  • cord blood cell transplantation
  • acute myeloid leukemia

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