Acute leukaemia following renal transplantation

Subar, Milayna; Gucalp, Rasim; Benstein, Judith A.; Williams, Gail; Wiernik, Peter H.

doi:10.1007/bf02988836

Cited by 13 publications

(5 citation statements)

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“…There are sporadic case reports of AML/MDS in recipients of organ transplants (see, for example, Ferry et al 37 and Subar et al 38 ), and Huebner et al 39 have described 5 within a single institution. Our analysis of more than 170 000 patients provides unequivocal evidence that organ transplantation and long-term immunosuppression are associated with an increased risk for this disease.…”

Section: Discussionmentioning

confidence: 99%

Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation

Offman

Opelz²,

Doehler³

et al. 2004

Blood

146

116

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Immunosuppression after organ transplantation is an acknowledged risk factor for skin cancer and lymphoma. We examined whether there was also an excess of leukemia in patients after transplantation and whether this might be related to a particular immunosuppressive treatment. Data from more than 170 000 patients indicated that organ transplantation is associated with a significantly increased risk for acute myeloid leukemia (AML). AML was more frequent after heart transplantation and lung transplantation than after kidney transplantation and was associated with immunosuppression by azathioprine, a thiopurine prodrug. Cellular resistance to thiopurines is associated with DNA mismatch repair (MMR) deficiency. We demonstrate that thiopurine treatment of human cells in vitro selects variants with defective MMR. Consistent with a similar selection in patient bone marrow, in 7 of 7 patients, transplantrelated AML/myelodysplastic syndrome (MDS) exhibited the microsatellite instability (MSI) that is diagnostic for defective MMR. Because MSI occurs infrequently in de novo AML, we conclude that the selec- IntroductionThe immunosuppression required to prevent the rejection of a transplanted organ is associated with an increased risk for cancer. Skin carcinoma, non-Hodgkin lymphoma, and other cancers are more frequent among transplant recipients. 1-3 Part of the increased cancer risk reflects immunosuppression and is paralleled by a high incidence of malignancies in HIV-immunocompromised patients (for reviews see Penn 1 and Mueller 4 ). Long-term treatment with drugs may also be a risk factor for cancer. The ability of therapeutic drugs to inflict DNA damage may contribute to the increasing incidence of therapy-related malignancy, particularly therapyrelated acute myeloid leukemia/myelodysplastic syndrome (tAML/ MDS) (for a review, see Leone et al 5 ).Azathioprine is a thiopurine prodrug that is related to 6-mercaptopurine and 6-thioguanine (6-TG). 6 Azathioprine is widely used as an immunosuppressant in recipients of organ transplant, often in conjunction with cyclosporin A and steroids. Although the mechanism of action of the thiopurines is not completely understood despite more than 3 decades of clinical use, the cell's DNA mismatch repair (MMR) system is known to be an important cofactor. It is widely accepted that the formation of thiopurine nucleotides and the eventual incorporation of 6-TG into DNA underlie the cytotoxicity and therapeutic effect of thiopurines (for a review, see McLeod et al 7 ). Although substituting DNA with 6-TG is not, in itself, particularly detrimental, nonenzymatic methylation of DNA 6-TG generates DNA lesions. 8 The rare DNA 6-thiomethylguanine (6-meTG) bases are then processed by MMR. 9 MMR-dependent processing is linked to apoptosis, and inactivation of repair provides an escape from thiopurine-induced cell death. Thus, MMR-deficient cells can tolerate 6-meTG in their DNA, and their resistance to killing by 6-TG is well documented. MMR performs similar lethal processing on the structurall...

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Section: Discussionmentioning

confidence: 99%

Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation

Offman

Opelz²,

Doehler³

et al. 2004

Blood

146

116

View full text Add to dashboard Cite

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“…Acute leukemias and MDS occurring in recipients of solid organ transplants were either considered rare or thought to occur at rates similar to the general population [10][11][12][13][14][15]. However, recent studies have reported an increased risk of AML in patients who have undergone solid organ transplantation, which has largely been attributed to azathioprine toxicity [10,11,16,17]. The incidence and etiology of MDS post-solid organ transplantation are not well understood, although aza-thioprine induced DNA damage has also been implicated in the pathogenesis of these disorders [12,16,17].…”

Section: Introductionmentioning

confidence: 99%

“…However, recent studies have reported an increased risk of AML in patients who have undergone solid organ transplantation, which has largely been attributed to azathioprine toxicity [10,11,16,17]. The incidence and etiology of MDS post-solid organ transplantation are not well understood, although aza-thioprine induced DNA damage has also been implicated in the pathogenesis of these disorders [12,16,17]. Moreover, since chromosome 7 abnormalities are frequently observed in AML/MDS following treatment with azathioprine, mechanisms similar to alkylating therapy-associated MDS are thought to underlie MDS post-solid organ transplantation [18,19].…”

Section: Introductionmentioning

confidence: 99%

The spectrum of myelodysplastic syndromes post-solid organ transplantation: A single institutional experience

et al. 2007

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An increased incidence of acute myeloid leukemia (AML) has recently been documented in patients post-solid organ transplantation but the incidence and types of myelodysplastic syndromes (MDS) occurring in this patient population are not known. We identified 5 patients (3M, 2F, age 48-64 years) who developed MDS ranging from 1.8 to 25 years (median 4.2 years) post-solid organ transplantation, only 2 patients had received azathioprine. The cumulative incidence of MDS in heart and lung transplant recipients at 15 years was 0.5% and 1.8%, respectively, which is markedly higher compared to the general population. Low-risk types of MDS predominated, 3 of 5 patients are alive (median 3.9 years) since diagnosis. Deletions of chromosome 20q, which have not been previously reported in post-transplant MDS/AML, were identified in 3 cases. Our findings expand the morphologic and cytogenetic spectrum of MDS occurring post-solid organ transplantation and suggest that mechanisms beside azathioprine toxicity might be important in disease pathogenesis.

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“…7,8 Several cases with AML post-renal transplantation have been published. 7,[9][10][11][12][13][14][15][16][17][18][19] One patient with AML out of a series of 124 cardiac allograft recipients has been reported. 20 AML as a complication of lung or liver transplantation has not been described yet.…”

Section: Introductionmentioning

confidence: 99%

Post-transplant acute myeloid leukemia (PT-AML)

et al. 1999

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Acute myeloid leukemia following organ transplantation (PT-AML) is a rare event with only a few published cases in the literature. We present three patients who developed AML (FAB M1, M5, M4) after renal, double lung or liver transplantation. Molecular analysis detected a t(9;11) in one patient and documented the recipient origin of AML in a second patient. All patients were treated with chemotherapy. Immunosuppression was reduced to cyclosporin A (CsA) and prednisone in two patients and to prednisone alone in one patient. Two patients achieved a complete remission (CR), with a remission duration of 4.6 months in one patient, the other patient died from septicemia after 15.2 months in CR. One patient was refractory to chemotherapy and died from septicemia. This report together with the documented cases in the literature suggests that PT-AML (1) develops after a median interval of 5 years after transplantation with variable latency (range, Ͻ1-17 years); (2) is heterogeneous with respect to FAB classification; (3) shows chromosomal and molecular changes typical of therapy-related AML (t-AML: −7, +8, 11q23, inv16, t(15;17)); (4) standard chemotherapy is feasible after reduction of immunosuppression and produces a CR rate of 56% with a median remission duration of 4.6 months and an overall survival of 2.6 months; (5) the major complications are early death (25%), Gram-negative septicemia, progressive disease or relapse. This review provides diagnostic and therapeutic experiences and guidelines for the management of this increasing group of post-transplant patients.

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Acute leukaemia following renal transplantation

Cited by 13 publications

References 14 publications

Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation

Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation

The spectrum of myelodysplastic syndromes post-solid organ transplantation: A single institutional experience

Post-transplant acute myeloid leukemia (PT-AML)

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