Chronic myeloid leukemia following kidney transplantation

Leukemia Research 29 (2005) 353–355

Case report

Chronic myeloid leukemia following kidney transplantation Lu´ıs Arthur Flores Pellosoa , Mireille Guimar˜aes Vaz de Camposa , Mar´ılia Nascimentoa , Maria Regina R´egis Silvab , Jos´e Osmar Medina Pestanac , Maria de Lourdes L.F. Chauffaillea,∗ a

Disciplina de Hematologia e Hemoterapia, UNIFESP-EPM, Rua Botucatu 740, 04023-900 S˜ao Paulo, SP Brazil b Disciplina de Patologia Aplicada, UNIFESP-EPM, Rua Botucatu 740, 04023-900 S˜ ao Paulo, SP Brazil c Disciplina de Nefrologia, UNIFESP-EPM, Rua Botucatu 740, 04023-900 S˜ ao Paulo, SP Brazil Received 1 April 2004; accepted 13 July 2004 Available online 18 November 2004

Abstract Immunosuppressed renal recipients are at an increased risk of developing cancer. Leukemias are less frequent than other hematopoietic tumours and development of CML after immunosuppression is rare. We describe a 37-year-old male who presented with left-shifted leukocytosis, hypercellular bone marrow 32 months after the kidney transplant. G-banding karyotype revealed 46,XY,t(9;22)(q34;q11) and the diagnosis of chronic myeloid leukemia was made. This is the 13th case of CML after kidney transplant reported. Whether this CML appeared as a random phenomenon or chemically induced is a matter of debate. Some individuals might have an increased susceptibility to the effects of azathioprine. © 2004 Elsevier Ltd. All rights reserved. Keywords: Chronic myeloid leukemia; Chemically induced leukemia; Kidney transplantation; Immunossupressive drugs; Immunossupression; Azathioprine

1. Introduction Immunosuppressed renal transplant recipients are at an increased risk of developing cancer. Three types of malignancies are considered in this setting: malignancies transferred with renal grafts; recurrence of malignancies treated before transplantation and malignancies manifested de novo longer after transplantation. The latent period between transplantation and the development of the neoplasia is shorter than in other situations of oncogenic influence due to immunosuppressive therapy [1]. The majority of malignancies diagnosed following immunosuppression are non-Hodgkin’s lymphoma, squamous cell carcinoma and Kaposi sarcoma (>65% cases) [1]. Leukemias are less frequent than other hematopoietic tumours. Development of chronic myeloid leukemia (CML) after immunosupression following a systemic disease has not been well understood and recently more than 10 cases of ∗

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CML were reported in this context [2]. We describe a male patient who developed CML, 2.5 years after kidney transplantation and immunosuppression with cyclosporine, azathioprine and prednisone.

2. Case report In 1990, a 37-year-old male presented at end-stage renal disease without specific etiology. He denied diabetes, systemic hypertension, or chronic glomerulonephritis. His past medical history included contact with pesticides for 8 h a day, 3 days a month, for 6 months, 12 years before. He did not wear gloves but wore mask during the manipulation of the pesticides. He was submitted to a chronic hemodialysis regimen for 8 years till 1998 when he received an HLA class II kidney transplantation. He had acute graft rejection (acute tubular necrosis by kidney biopsy) treated with hemodialysis and methylprednisolone followed by a regimen based on azathioprine, prednisone and cyclosporine. His creatinine level was 1.6 mg/dl. Thirty-two months after the

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L.A.F. Pelloso et al. / Leukemia Research 29 (2005) 353–355

Table 1 CML patients after genotoxic exposure Reference, year

No.

Age (years)

Sex

Initial diagnosis

Type of therapy

Interval

Survival

Battin et al. (1976) [8] Adler et al. (1978) [9] Lubynski et al. (1978) [10] Mooy et al. (1978) [11] Hilario et al. (1980) [12] Kirchner et al. (1983) [13] Frist et al. (1994) [6]

1 1 1 1 1 1 1

15 18 20 40 26 31 31

M M M M F F M

IR Renal Tx Renal tx Renal Tx Renal Tx 3 × Renal Tx 2 × Heart Tx

AZA A+P+I A+P A + P + Ac A+P A + P + RT P + Okt3 + RT + Cya + A

Dead (18) 10+ 19+ Dead (3) 31+ Dead (30) 9+ 59+

Sanz et al. (1996) [3] Stein et al. (1978) [14] Mignozzi and Picca (2001) [2] Pescovitz et al. (1996) [15]

1 1 1 1

59 19 18 52

M M M M

Renal Tx Renal Tx Renal Tx Leukocytosis + Renal Tx

Penn (1998) [16] Present case, 2004

1 1

Child 37

? M

Renal TX Renal TX

A A+P A + P + C + Okt3 A+P+C+ anti-lymphoblast globulin A + Okt3 A+P+C

48 32 35 48 60 42 841st TX 602nd TX 70 18 288 0 ? 30

?

15 28+ Dead (72)

19+

Legend: (?) refers to unpublished data; F, female; M, male; AZA, azathioprine; P, prednisone; I, irradiation; C, cyclophosphamide; Cya, cyclosporine A; Tx, transplant.

transplant left-shifted leukocytosis was observed and CBC showed hemoglobin of 14.9 g/dl, hematocrit of 45%, platelets 274 × 109 /l, WBC count 92 × 109 /l, with 19% myelocytes, 12% metamyelocytes, 29% band forms, 30% neutrophils, 1% eosinophils, 2% basophils and 7% lymphocytes. The spleen tip was palpable. Bone marrow aspiration was hypercellular due to granulocytic series hyperplasia. There was also fibrosis grade II by Gomori staining. G-banding karyotype revealed 46,XY,t(9;22)(q34;q11) [20] and the diagnosis of chronic myeloid leukemia in chronic phase was made.

3. Discussion This is the 13th case of CML after kidney transplant reported in literature (Table 1). Whether this CML appeared as a random phenomenon or chemically induced is a matter of debate. Some individuals might have an increased susceptibility to the effects of azathioprine. Two aspects can be ellicted from these statements: use of immunosuppressive drugs and immune surveillance impairment. Immunosuppressive agents have a pivotal role in the development of cancer. All the seven patients described by Sanz et al. [3] used azathioprine prior to development of CML. Azathioprine was the main stay immunosuppressive drug in the 1980s till the use of cyclosporine A. It is well known that azathioprine induce structural chromosomal aberrations characterized by chromatid and chromosome breaks with acentric fragmentation [4]. CML has also been recognized after the sole use of cyclosporine and after lymphoid irradiation for heart transplant in another case [5,6]. Addition of other toxic drugs as prednisone and cyclosporine enhance the compromising immune surveillance [4]. Patients receiving triple therapy (azathioprine– prednisone–cysclosporine A) in short term are at slightly in-

creased risk of developing de novo cancer as compared to those scheduled to dual therapy [7]. Chromosome abnormalities additional to Philadelphia are not seen in CML that is treatment related. Treatment related CML could not be cytogenetically distinguished from de novo CML due to few cases reported. Specific therapy for CML after kidney transplantation has some obstacles. First, the curative regimen of allogeneic hematopoietic stem-cell transplantation depends on the normal organ functions, specifically kidney and liver. The use of interferon (IFN) in patients with poor renal function could be potentially toxic [17]. Adverse effects of IFN therapy on the kidney are proteinuria, rarely nephrotic syndrome, renal failure or chronic progressive renal failure, and thrombotic microangiopathy potentially progressing to end-stage renal failure [18]. Rare reports showed that the use of imatinib mesylate may contribute to the development of renal failure especially in patients with prior renal failure or exposure to nephrotoxins [19,20], while others stated that no adverse effect was seen in patients with impaired kidney function due to transplantation [21]. The patient here reported was scheduled to imatinib mesylate, and is doing well, in hematological and cytogenetics remission for 8 months now. This entity might be increasingly recognized due to a higher number of patients treated with intensive therapy regimens [4]. To our knowledge this is 13th case with CML after kidney transplantation and we would like to reinforce the importance of recognizing this entity in the clinical setting.

References [1] Ondrus D, Pribylincova V, Breza J, et al. The incidence of tumours in renal transplant recipients with long-term immunosuppressive therapy. Int Urol Nephrol 1999;31(4):417–22.

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