Development of original donor cell leukemia after successful engraftment from a second donor

To the editor:

We read with interest the recent review in Blood on donor cell leukemia (DCL) by Flynn and Kaufman.¹  We report a case of DCL occurring in cells from a first allogeneic stem-cell donor after the patient received a successful transplant from a second donor, following loss of the first donor graft.

The patient, a 32-year-old man, presented with severe aplastic anemia in 1995. No precipitating cause of aplasia was identified. Cytogenetic analysis, Ham test, diepoxybutane breakage analysis, telomerase reverse transcriptase, and RNA component of telomer-ase mutation screening were normal. Treatment with antilympho-cyte globulin (ALG) and cyclosporin-A initially failed, but subsequent treatment with ALG and oxymethodone led to a 3-year period of transfusion independence. Following disease recurrence with life-threatening cytopenias, after informed consent and ethical approval were obtained in accordance with the Declaration of Helsinki, he received a reduced-intensity conditioning (RIC) peripheral blood stem-cell transplant in June 1999 using fludarabine and cyclophosphamide²  and in vivo T-cell depletion with alemtuzumab. The donor was his human leukocyte antigen (HLA)–matched mother (donor 1), who was a low-resolution DRB1, DQB1, allelic match. This match was possible because both parents shared A, B, Cw, DRB1, and DQB1 antigens. After a 4-year period of good engraftment with stable, mixed chimerism, donor chimerism fell to 40% in whole blood and cytopenias recurred. A second bone marrow transplantation from donor 1 was performed, using the same conditioning. Engraftment was poor and a third RIC transplantation was performed in November 2005 using the same conditioning regimen and an HLA-matched unrelated male (donor 2). Full donor 2 chimerism of 100% was achieved by day +100 and maintained until day +270. On day +298, neutropenia and thrombocytopenia, but no circulating blasts, were noted. Whole blood donor 2 chimerism was 75% (T-cell chimerism 89%, myeloid cells undetectable). Bone marrow biopsy revealed a diagnosis of refractory cytopenia with multilineage dysplasia. Cytogenetic analysis showed that 40 of 100 cells examined were karyotypically female with monosomy-7. Polymerase chain reaction of minisatellite regions confirmed origin of these cells as donor 1 and subsequently demonstrated mixed chimerism with donor 1 myeloid cells 66%, T cells 1%, and donor 2 myeloid cells 2%, T cells 84%. Bone marrow examination of donor 1 remains normal, with normal cytogenetics. The index patient has since developed acute myeloid leukemia and is undergoing treatment.

To our knowledge, this is the first report of DCL arising in cells from a first donor after successful peripheral blood stem-cell transplantation from a second donor. The causative mechanisms of DCL remain speculative, with bone marrow irradiation implicated as a possible contributory factor in the development of DCL.^1,3  This patient did not receive radiation therapy. Nevertheless, the appearance of monosomy-7 in the leukemic clone is suggestive of therapy-related myelodysplasia/leukemia. Profound immunosuppression during the course of the treatment, DNA damage, and impairment of DNA repair mechanisms by chemotherapy may have combined to create an aberrant bone marrow micro-environment in which the malignant clone was able to evolve and gain a proliferative advantage over normal cells from donor 2. The failure of donor 2 T cells to maintain a graft versus leukemia effect is probably related to the in vivo T-cell depletion.