Donor cell-derived acute monoblastic leukemia involving MLL gene translocation in an adult patient who received umbilical cord blood transplantation

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Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective therapy for hematological malignancies. In particular, cord blood transplantation (CBT) has been successfully performed numerous times over the past decade, and remains an attractive option since donor coordination is not necessary. In contrast, there are still serious problems associated with CBT. Donor cell leukemia (DCL) is a rare but one of the most serious complications following HSCT. Some researchers recently reported cases with donor cell-derived leukemia (DCL) following CBT,1, 2, 3 whereas its clinical features and pathogenesis remain to be fully elucidated.

A 31-year-old man who had a 3-year history of refractory Hodgkin's lymphoma underwent CBT from a two-antigen-mismatched unrelated female donor in April 2004. The number of infused CD34-positive cells was 3.0 × 107 cells/kg. Preparative regimen comprised fludarabine, busulfan and total body irradiation.4 GVHD prophylaxis was mycophenolate mofetil and cyclosporine. Neutrophil engraftment was documented on day 26. He developed grade III acute GVHD of the gut, which was successfully treated with prednisolone. His clinical courses had been uneventful except mild chronic GVHD involving the oral mucosa and the skin, for which cyclosporine and prednisolone were given.

In August 2005, blasts appeared in the peripheral blood. There were no signs suggesting recurrence of Hodgkin's lymphoma. Bone marrow examination disclosed over 50% of blasts, which were negative for myeloperoxidase and positive for fluoride-inhibitable nonspecific esterase. Immunophenotyping revealed moderate to strong expression of CD4, CD7, CD13, CD33, CD34 and HLA-DR. Cytogenetic analysis revealed karyotypic abnormalities of 45XX, add(4)(q31.1), der(6)t(6:7)(p23;q11.2), monosomy 7 and del(11)(q23) (Figure 1a). Rearrangement of MLL gene was confirmed by Southern blot hybridization (Figure 1b), while reverse transcription-PCRs using MLL-AF4, MLL-AF6, MLL-MEN and MLL-ENL were negative. Short tandem repeat sequence of leukemic cells was identical with that of the donor. Based on these findings, donor cell-derived acute monoblastic leukemia (AMoL) was diagnosed. He never achieved remission despite intensive chemotherapy. He died from sepsis 13 months after development of DCL. The Cord Blood Bank has not received any reports on leukemia development in the donor now aged 3 years.

Figure 1
figure1

Cytogenetic analysis of donor-derived leukemic cells following cord blood transplantation (CBT). (a) Karyotypic analysis using high-resolution G-banding. The leukemic cells showed complex abnormalities involving 45XX, add(4)(q31.1), der(6)t(6:7)(p23;q11.2), monosomy 7 and del(11)(q23). (b) Southern blot hybridization using an MLL cDNA probe showing rearrangement of MLL gene in a patient with donor-derived acute myeloid leukemia. A, positive control; B, sample. Restriction enzyme: BamHI for lane 1 and HindIII for lane 2.

Interestingly, the leukemic cells shared some characteristics with infant leukemia. He had AMoL with complex karyotype containing 11q23 abnormality and monosomy 7. Rearrangement of MLL gene at 11q23 region is common in infant leukemia, especially AMoL,5 and monosomy 7 is the most frequent abnormality in childhood myeloid disorders.6 Furthermore, he developed DCL 16 months after CBT, which was comparable with age at infant leukemia development, and was earlier than DCL following allogeneic marrow or blood transplantation (median, 30 months).7

Several hypotheses may explain DCL development in this patient. First, pre-leukemic cells might have existed in the graft, and were infused to this patient. Recent studies have demonstrated the prenatal origin of leukemic translocations.8 There is strong evidence that 11q23 rearrangements in infants occur in utero.9 Systematic screening of a large series of unselected cord blood samples revealed that less than 1% and less than 2% of cord blood harbored putative pre-leukemic clones with TEL-AML1 and AML1-ETO, respectively.10 The frequency of positive cells (10−3–10−4) indicates substantial clonal expansion of progenitor population. While additional postnatal events may be required for the development of overt leukemia, CBT recipients are at risk of DCL, which might be facilitated with immunosuppression, marrow microenvironment or cytokine profiles after CBT. Second, cord blood cells might have acquired leukemic abnormalities after CBT in the environment of immunosuppression or certain cytokine profiles. Immunosuppressive agents used after CBT might impair immunological reactions, allowing development of DCL. Third, possibility of chemotherapy-induced leukemia can be excluded in our patient, since he did not receive chemotherapy between second CBT and DCL development.

While the precise mechanism of DCL following CBT remains to be unknown, this case suggests a potential risk of DCL following CBT. Further studies are warranted to investigate its pathogenesis and to establish its optimal management.

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Acknowledgements

We are grateful to Dr Tomohiko Taki at Kyoto Prefectural University of Medicine and Dr Yasuhide Hayashi at Gunma Children's Medical Center for useful suggestions in the discussion of karyotype analysis.

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Correspondence to T Hamaki.

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Hamaki, T., Kajiwara, K., Kami, M. et al. Donor cell-derived acute monoblastic leukemia involving MLL gene translocation in an adult patient who received umbilical cord blood transplantation. Bone Marrow Transplant 41, 91–92 (2008) doi:10.1038/sj.bmt.1705836

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