Successful Treatment of Chronic Myeloid Leukemia With Dasatinib After Kidney Transplantation: A Case Report

Successful Treatment of Chronic Myeloid Leukemia With Dasatinib After Kidney Transplantation: A Case Report Hiroaki Yamanea, Kentaro Idea,*, Asuka Tanakaa, Shinji Hashimotoa, Hisao Nagoshib, Hiroyuki Taharaa, Masahiro Ohiraa, Akhmet Seidakhmetova, Doskali Marlena, Yuka Tanakaa, and Hideki Ohdana a

Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University; and bDepartment of Hematology and Oncology, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University

ABSTRACT Objective. Chronic myeloid leukemia (CML) is a rare malignancy in kidney transplant (KT) recipients. Although dasatinib is the first-line treatment for CML, it has inhibitory activity against CYP3A4; this might increase the blood concentration of tacrolimus (administered to KT patients for immune suppression). Furthermore, tacrolimus can also increase blood concentrations of dasatinib through P-glycoprotein inhibition. Methods. Here, we report a case of sustained molecular remission of CML with prolonged first-line dasatinib therapy in a KT recipient being treated with tacrolimus. A 61-year-old woman developed CML-chronic phase (CML-CP) 38 months post KT. Her maintenance immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil, and methylprednisolone. Considering the potential drug interaction with tacrolimus, dasatinib was administered at a low dose of 50 mg/day. Her immune status was evaluated regularly by assessing the mixed lymphocyte reaction (MLR) using an intracellular carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeling technique; immunosuppressive therapy was adjusted accordingly. Results. The patient achieved complete hematologic remission (CHR) after 1 month of dasatinib treatment. Six months after dasatinib treatment, she achieved a major molecular response. During the observation period, neither antibody-mediated nor acute cellular rejection were encountered in the patient. She remained in CHR with a major molecular response 12 months after the diagnosis of CML-CP. Conclusion. Data obtained from immune monitoring assays using CFSE-MLR helped us to successfully manage a KT recipient with CML-CP being treated with dasatinib. Drugdrug interactions are a key consideration while designing treatment regimens; such strategies would ensure that drug-drug interactions do not negatively affect the treatment outcomes.

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IDNEY transplantation (KT) has been established as the optimal treatment for patients with end-stage renal disease as it offers a significant survival benefit and improved quality of life compared to dialysis [1e3]. However, this improved survival results in the development of comorbidities, including an increased risk of cancer [4]. KT recipients have a 2- to 3-fold higher incidence of malignancy than the general population [4]. Common malignancies encountered in KT recipients are skin carcinomas, lymphoproliferative disorders, Kaposi sarcoma, and renal cell ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169

Transplantation Proceedings, XX, 1e4 (2019)

carcinoma [5]. While post-transplant lymphoproliferative disorders comprise a major component among hematolymphoid neoplasms, other hematolymphoid neoplasms, *Address correspondence to Kentaro Ide, MD, Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima 734-8551, Japan. Tel: þ81-82257-5222; Fax: þ81-82-257-5224. E-mail: ideken@hiroshima-u. ac.jp 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.06.006

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YAMANE, IDE, TANAKA ET AL

such as myeloid neoplasms occurring after solid organ transplantation, are relatively infrequent, and their association with transplantation is poorly characterized [6]. Chronic myeloid leukemia (CML) is a rare malignant disorder after KT [7]. The BCR-ABL1 fusion gene, caused by a typical t (9;22) (q34;q11) chromosomal translocation, is the pathogenic driver of the disease and is used as a target to monitor minimal residual disease by the quantitative reverse-transcription polymerase chain reaction [8]. Imatinib, a selective BCR-ABL1 protein tyrosine kinase inhibitor (TKI), is effective and currently approved for first-line treatment of CML [9]. Although a complete cytogenetic response of CML with imatinib has been reported in KT recipients [10,11], the efficiency and tolerance of imatinib in these patients remains to be confirmed. Recently, dasatinib, a second-generation TKI for CML, has shown advantages in newly diagnosed CML compared to imatinib [12,13]. The metabolism of dasatinib is mainly hepatic via CYP3A4; less than 4% of dasatinib and its metabolites are excreted via the kidney [14]. Although dasatinib is generally well-tolerated, it has inhibitory activity against CYP3A4; this might increase the blood concentrations of immunosuppressive agents such as tacrolimus and cyclosporine, which are usually provided to KT patients. Furthermore, tacrolimus has inhibitory activity against P-glycoprotein that might increase the blood concentration of dasatinib [15]. To the best of our knowledge, we report the first case of sustained molecular remission of CML with first-line prolonged dasatinib therapy using an intracellular carboxyfluorescein diacetate succinimidyl ester labeling technique for detecting a mixed lymphocyte reaction (CFSE-MLR) in a KT recipient being treated with tacrolimus.

CASE REPORT A 58-year-old woman with end-stage renal disease due to rapidly progressive glomerulonephritis received a KT from an unrelated, ABO-incompatible living donor after being on hemodialysis for 11 months. She received a preconditioning regimen consisting of a single dose of rituximab (375 mg/m2) before KT. Her maintenance immunosuppression therapy consisted of tacrolimus, mycophenolate mofetil, and methylprednisolone. Thirty-eight months after transplantation, her white blood cell and platelet counts increased to 23,130/mL (normal range, 3040e8540/mL) and 692,000/mL (normal range, 150,000e360,000/mL), respectively. Physical examination revealed mild splenomegaly and bone marrow hypercellularity in the presence of the 46, XY, t (9;22) (q34; q11.2) translocation, which confirmed the diagnosis of CML in chronic phase (CML-CP) (Fig 1). Genetic testing by the polymerase chain reaction revealed the patient was BCR-ABL1-positive; quantitation of the BCR-ABL1 transcript was 96.1%. Dasatinib was started at a reduced dose of 50 mg/day considering the potential drug interaction with tacrolimus. Although the dose of tacrolimus was also reduced from 3 to 1 mg/day at the initiation of dasatinib therapy, a 5 mg/day dose was eventually required to reach the target trough level of tacrolimus. The patient achieved complete hematologic remission (CHR) after 1 month of dasatinib treatment. Three months post dasatinib treatment, the BCR-ABL1 transcript decreased to 0.42%. Six months after dasatinib treatment, her

Fig 1. Bone marrow aspirate results prior to treatment. The bone marrow examination shows hypercellularity with marked myeloid hyperplasia. The myeloid/erythroid (M/E) ratio is 19.3. A and B are WrighteGiemsa-stained. (A) original magnification 200; (B) original magnification 1000.

BCR-ABL1 transcript level was less than 0.1%, consistent with a major molecular response. Her immune status was evaluated regularly by the CFSE-MLR assay, and immunosuppressive therapy was adjusted accordingly. At 12 months after dasatinib treatment, limited proliferation of CD4þ and CD8þ T-cells was observed in the antidonor response (Fig 2), and a kidney allograft biopsy specimen revealed no signs of rejection. She remained CHR and with a major molecular response 12 months after the diagnosis of CML.

DISCUSSION

Post-transplantation CML is a relatively rare malignancy. The incidence is about 5 cases/100,000 person each year. The risk does not vary by time since transplantation, and risks do not differ significantly by organ type [7]. The risk was calculated to be more than 20-fold higher than in the normal population [16]. The pathogenesis, risk factors, treatment, and prognosis for CML after KT are unclear. Therefore, further analyses with additional cases are of

CHRONIC MYELOID LEUKEMIA

Fig 2. Kinetics of the stimulation indexes (SIs) for CD4þ and CD8þ T-cells. To evaluate the patient’s immune status, the carboxyfluorescein diacetate succinimidyl ester-mixed lymphocyte reaction assay was performed regularly, and immunosuppressive therapy was adjusted accordingly. Twelve months after dasatinib treatment, limited proliferation of CD4þ and CD8þ T cells is observed in the antidonor response.

great importance to prevent and treat this rare complication after KT. Treatment of CML is based on immunomodulation and inhibiting expression of the BCR-ABL oncogene and function of its protein, as well as inhibiting other genes important to the pathogenesis of this disease [17]. Imatinib is a first-generation BCR-ABL TKI administered as a firstline medication to treat CML-CP [18]. However, some patients develop resistance to imatinib therapy because of BCR-ABL gene amplification [19], low imatinib absorption or, more frequently, point mutations into the oncoprotein sequence [20]. Dasatinib, a second-generation BCR-ABL TKI, is an effective first-line treatment option for patients with CMLCP that can produce an early, deep response [12]. Although dasatinib is a potent, efficacious, and generally welltolerated drug for CML, patients are subject to various hematologic and nonhematologic adverse events. The most common drug-related nonhematologic adverse event in dasatinib clinical trials was fluid retention (including pleural effusion) [21]. However, little is known about the effects of

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dasatinib on renal function, either because dasatinib and its metabolites are minimally excreted via the kidney or patients with decreased renal function were excluded from clinical studies. A recent report revealed that patients with pre-existing renal dysfunction who were treated with dasatinib had an increased risk of acute kidney injury [22]. Possible mechanisms were related either to tubular dysfunction caused by the drug itself, where predisposing factors or pre-existing renal failure seemed to play a role, or to factors associated with an advanced hematological state, predisposing for the tumor lysis syndrome [23]. Thus, patients with renal dysfunction require close monitoring of renal function to allow for dose adjustments or transient cessation of therapy. T-cells have a fundamental role in the immunologic control of CML [24]. Thus, immunosuppressive therapy, which impairs critical immunosurveillance functions, might result in a substantially increased risk of CML after transplantation. To monitor a patient’s immune status, the CFSE-MLR assay is a reliable method to measure allogeneic antidonor responsiveness [25,26]. We routinely monitor alloimmune responses in recipients by the CFSE-MLR assay instead of surveillance biopsies [27,28]. A lack of CD4þ and CD8þ T-cell proliferation in the CFSE-MLR assay indicates suppression of antidonor responses, whereas a remarkable proliferation of these T cells reflects a strong antidonor response. Alloreactive T cells play key roles in the development of acute cellular rejection and the de novo production of donor-specific antibodies, which is the leading cause of late allograft failure after transplantation. Therefore, the CFSE-MLR assay could be a reliable technique to measure antidonor responsiveness and to optimize immunosuppressive therapy. In conclusion, data obtained from the immune monitoring assays helped us to successfully manage a KT recipient with CML-CP treated by dasatinib. Such strategies for monitoring patient immune responses would help prevent the adverse effects associated with drug-drug interactions in the background of KT. ACKNOWLEDGMENTS This work was carried out at the Natural Science Center for Basic Research and Development of Hiroshima University, and was supported by a Grant-in-Aid for Sciences Research from the Japan Society for the Promotion of Science and a Grant-in-Aid from the Japanese Ministry of Health, Welfare, and Labor.

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