Nilotinib -Induced Retroperitoneal Fibrosis In a Patient with Chronic Myelogenous Leukemia.

Abstract 4495

32 year old man was diagnosed with chronic myelogenous leukemia(CML) in accelerated phase. Karyotype analysis and fluorescent in situ hybridization of the leukemic clone revealed a 9; 22 translocation, loss of Y chromosome, and an interstitial deletion of chromosome 16. Despite treatment with imatinib and hydroxyurea, he progressed to myeloid blast crisis with the bone marrow showing three leukemic clones, including a second Ph’ and trisomy 8, consistent with karyotype evolution. He underwent myeloablative stem cell transplant from a matched sibling donor, following which he was maintained on dasatinib which was discontinued 6 months later due to anasarca. At the time of discontinuation, he was in cytogenetic and molecular remission (CMR). He was then started on nilotinib 400mg twice daily. A year later he developed grade 3 hepatotoxicity with hyperbilirubinemia. Further workup revealed gallstones for which he underwent cholecystectomy. Despite surgery, his liver enzymes remained elevated and liver biopsy revealed chronic inflammation and fibrosis. Computed tomography scan of the abdomen showed a 2.6 × 5.5 cm periaortic mass in the retroperitoneum. Biopsy revealed fibrosis and chronic inflammation consistent with retroperitoneal fibrosis (RPF). Peripheral blood reverse transcriptase polymerase chain reaction for BCR-ABL showed patient to be in ongoing CMR.

Therapy with imatinib mesylate (IM) is a standard of care for most patients with Ph+ CML. Resistance to imatinib occurs annually in 3% to 4% of patients with CML. Nilotinib is rationally designed in inhibiting the growth of 32 of 33 cell lines bearing mutations causing imatinib resistance, the exception being the T315I mutant. Reported adverse effects with nilotinib include elevated lipase levels, rash, indirect hyperbilirubinemia, myelosuppression, pancreatitis, QTc prolongation and sudden death. To our knowledge, RPF has not been previously reported with nilotinib use. We faced different diagnostic possibilities mainly (1) relapse of CML, (2) new onset of another postchemotherapy nonepithelial neoplasia and (3) idiopathic RPF (Ormond disease). Idiopathic RPF is a rare subtype of chronic periaortitis characterized by the presence of a fibroinflammatory mass surrounding the abdominal aorta and iliac arteries. It occurs predominantly in men in the fifth to sixth decade of life. Therefore, we considered this disease as statistically unlikely, although not impossible in this patient. In most cases secondary to malignant disease, RPF results from an exuberant desmoplastic response to retroperitoneal metastases—e.g. carcinoma of the prostate, breast, colon—or to the retroperitoneal primary tumour—e.g. Hodgkin's and non-Hodgkin lymphomas, various types of sarcomas. There have been no reported cases of RPF with CML. Among the drugs causing RPF most common ones are derivatives of ergot alkaloids, β-blockers, hydralazine, and analgesics.The estimation of the probability that a drug caused an adverse drug reaction (ADR) is usually based on clinical judgment. Naranjo et al developed a simple probability scale to assess the causality of ADR. The ADR was assigned to a probability category from the total score as follows: definite ≥ 9, probable 5 to 8, possible 1 to 4, doubtful ≤0 based on a simple questionnaire. We got a total score of 7 which falls in the probable category for nilotinib causing RPF. Mechanism of RPF from nilotinib use is unknown. In vitro and in vivo genetic toxicology studies conducted in animals found that nilotinib exhibited fibrotic changes in dog heart. Hematological findings, common in rats and monkeys, included elevated white counts attributed to drug-effects in the lymphoid tissues such as lymphoid hyperplasia and fibrosis. Therapy for patients with CML has grown in complexity. Nilotinib is a relatively new TKI and optimal management of patients on this drug requires intimate knowledge not only of response criteria and of timing but also of potential toxicities and how they may affect response to therapy and patient outcome.