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  • We describe a novel case wherein a

    2019-05-23

    We describe a novel case, wherein a patient with AML with inv (16) underwent allogeneic bone marrow transplantation from a related sibling donor which contained a small subpopulation of premalignant stem WST Cell Proliferation Colorimetric Assay Kit plus with trisomy 11. Fourteen years following transplantation, this patient presented with a de novo AML derived from this inadvertently transmitted premalignant clone. Significantly, over time, this premalignant clone has remained quiescent but persisted in the donor.
    Methods
    Results A 42-year-old man was diagnosed with Stage IIIA immunoblastic lymphoma and treated with cyclophosphamide, doxorubicin, etoposide, bleomycin, vincristine, methotrexate and prednisone. He achieved a complete remission but 17 months later developed acute myeloid leukemia (AML) with an inv(16)(p13q22) clonal cytogenetic abnormality, known to be associated with AML-M4 sub-type, as the sole abnormality detected by karyotype analysis. Standard induction therapy with cytarabine and idarubicin was administered and the patient achieved a complete remission. He subsequently underwent allogeneic stem cell transplantation from his 54 year old HLA-identical brother after conditioning with total-body irradiation, thiotepa and cyclophosphamide. The patient achieved a sustained complete remission. However, 14 years following transplantation, the patient developed fatigue and easy bruising. The laboratory findings included WBC count of 29,300/uL, 31% blasts, Hb 12.3gm/uL and platelets 29,000/uL. Bone marrow morphologic and flow cytometric profile was consistent with AML. The clonal abnormality detected by karyotype included a 47,XY,+11 (Fig. 1A), which was confirmed by FISH analysis (Fig. 1B). DNA chimerism assays of both peripheral blood and bone marrow from the patient at the time of relapse showed full donor chimerism, demonstrating that the leukemic clone was of donor origin (Fig. 1C). At the time of this second AML diagnosis, the donor was well and without evidence of any hematologic disorder and normal male karyotype. However, FISH analysis revealed trisomy 11 in 2% of the cells analyzed (upper limit of normal <0.2%); frozen peripheral blood from the donor stored at the time of the initial bone marrow transplantation 14 years earlier also showed trisomy 11 in 0.4% cells (Fig. 1D).
    Discussion Immunodeficiency may facilitate the neoplastic transformation of a premalignant clone. Primary immunodeficiency is well documented in patients with ataxia-telangiectasia (AT) and Bloom׳s Syndrome (BS) and such immune deficient states are known to permit clonal expansion of cells with underlying mutations in the lymphoid and myeloid systems respectively [2]. The primary immunodeficiency as a contributory factor in the development of donor leukemia in the patient is unlikely. Secondary immunodeficiency due to chemotherapy and radiation administered is likely a possibility in leukemia arising following autologous stem cell transplantation with short latency period, but highly unlikely in this case given the long latency period of fourteen years in this case. We suggest, alternatively, that premature senescence and or programmed cell death of the normal transplanted donor stem cells due to telomere erosion may have played a role (Fig. 2). The difference in telomere dynamics between normal donor cells and donor cells with trisomy 11 may contribute significantly to the selective proliferation and neoplastic transformation of the latter. In fact, Notaro et al. (1997)[3] previously found that telomere length of engrafted donor cells was significantly reduced when compared to donor cells, suggesting that telomere shortening may reduce the proliferative potential of the engrafted donor cells. In addition, it is also well recognized that telomere erosion also results in a significant genomic instability, the hall mark of malignant transformation [4]. It is furthermore known that following allogeneic stem cell transplantation, the reduction in telomere length of donor hematopoietic cells is equivalent to approximately 15 years, and in some instances 40–60 years, of aging [5,6]. Several studies suggest that the reduction in telomere length, which occurs predominantly during the first year following transplantation, is unlikely to significantly compromise bone marrow function. However, it is important to recognize that such data is largely derived from a younger donor and recipient population (age<40) [7]. It is therefore conceivable that in the present case, with an older donor (54 at the time of stem collection), this well recognized reduction in telomere length may have compounded the overall effect of this phenomenon. Therefore, normal stem cells from an older donor are placed under replicative stress, which in turn may reduce the proliferative capacity of these cells [3]. The resulting senescence of normal donor hematopoietic cells over the 14 years following transplantation in our patient may have set the stage for the expansion of cells with trisomy 11. The amplification of MLL protein in these, now dividing cells may have triggered a cascade of events leading to frank leukemia [8]. Several studies reviewed elsewhere have suggested that amplification of MLL gene may activate HOX genes which are known to play important role in leukemogenesis [8].