Patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia (CML-AP) have very limited therapeutic options. Nilotinib is a highly selective BCR-ABL tyrosine kinase inhibitor. This phase 2 trial was designed to characterize the efficacy and safety of nilotinib (400 mg twice daily) in this patient population with hematologic response (HR) as primary efficacy endpoint. A total of 119 patients were enrolled and had a median duration of treatment of 202 days (range, 2–611 days). An HR was observed in 56 patients (47%; 95% confidence interval [CI], 38%-56%). Major cytogenetic response (MCyR) was observed in 35 patients (29%; 95% CI, 21%-39%). The median duration of HR has not been reached. Overall survival rate among the 119 patients after 12 months of follow-up was 79% (95% CI, 70%-87%). Nonhematologic adverse events were mostly mild to moderate. Severe peripheral edema and pleural effusions were not observed. The most common grade 3 or higher hematologic adverse events were thrombocytopenia (35%) and neutropenia (21%). Grade 3 or higher bilirubin and lipase elevations occurred in 9% and 18% of patients, respectively, resulting in treatment discontinuation in one patient. In conclusion, nilotinib is an effective and well-tolerated treatment in imatinib-resistant and -intolerant CML-AP. This trial is registered at www.clinicaltrials.gov as NCT00384228.

In BCR-ABL-positive chronic myeloid leukemia (CML), the tyrosine kinase inhibitor (TKI) imatinib acts as an antileukemic agent and reconstitutes normal hematopoiesis ( 1 ). Because imatinib-treated patients may develop drug resistance or intolerance, the second generation TKI nilotinib (Tasigna; Novartis Pharmaceuticals, East Hanover, NJ) was designed and has been approved for treatment of CML ( 2 ). In newly diagnosed CML, nilotinib (300 or 400 mg twice daily) was superior to standard therapy with imatinib, with major molecular response rates of 44% (300 mg) and 43% (400 mg) vs 22% for imatinib at 1 year. Adverse events with nilotinib at either dose included reversible constitutional symptoms and elevations in lipase (24%–29% of patients), bilirubin (53%–62%), fasting glucose (36%–41%), and cholesterol (22%) ( 3 , 4 ).

Hepatitis E virus (HEV) is the major cause of several outbreaks of waterborne hepatitis in tropical and subtropical countries and of sporadic cases of viral hepatitis in endemic and industrialised countries. Generally, HEV causes an acute self-limiting hepatitis. The clinical course is characterised by transient viraemia and transaminasaemia followed by a full hepatic recovery. Recent studies describe prolonged and chronic HEV infections in some immunosuppressed patients after solid organ transplantation. Here, an indigenous acute limited hepatitis E in a patient with Philadelphia chromosome-positive acute lymphoblastic leukaemia prior to allogeneic stem cell transplantation is reported. Fourteen weeks after stem cell transplantation, reappearance of HEV viraemia was observed, with increasing viral load and modestly elevated serum transaminases. Sequence analysis of the viral RNAs revealed a reactivation of endogenous HEV genotype 3, indicating viral persistence after recovery from acute hepatitis E.

Background Nilotinib is a second-generation tyrosine kinase inhibitor with significant efficacy as first- or second-line treatment in patients with chronic myeloid leukemia. Despite preclinical evidence indicating a risk of prolongation of the QT interval, which was confirmed in clinical trials, detailed information on nilotinib’s cardiac safety profile is lacking. Design and Methods Here, we retrospectively assessed cardiovascular risk factors in 81 patients who were being or had previously been treated with nilotinib therapy and evaluated cardiovascular parameters by longitudinal monitoring of the QT interval and left ventricular ejection fraction. Detailed information on the occurrence and management of defined cardiac adverse events was extracted. Results The median duration of nilotinib therapy was 26 months (range, 1–72). The median QT interval at baseline was 413 msec (range, 368–499 msec). During follow-up, the median QT was not significantly different from the baseline value at any time-point. Sixteen of 81 patients (20%) had new electrocardiographic changes. Cardiac function, as assessed by measurement of left ventricular ejection fraction, did not change significantly from baseline at any time-point. During a median follow-up of 44 months (range, 2–73), seven patients (9%), all of whom had received prior imatinib therapy, developed 11 clinical cardiac adverse events requiring treatment. The median time from the start of nilotinib therapy to an event was 14.5 months (range, 2–68). Five of seven patients were able to continue nilotinib therapy with only one brief interruption. Conclusions Whereas new electrocardiographic abnormalities were recorded in 20% of all patients and some of them developed severe or even life-threatening coronary artery disease, QT prolongation, changes in left ventricular ejection fraction, and clinical cardiac adverse events were uncommon in patients treated with nilotinib.

Nilotinib (Tasigna(®)) is a more potent BCR-ABL inhibitor than imatinib and was designed to overcome imatinib's deficiencies. Nilotinib has significant efficacy in patients with chronic myeloid leukemia (CML) in chronic phase, accelerated phase and blastic phase, following imatinib failure. Based on the results of the Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study, the US FDA has granted accelerated approval of nilotinib for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase. Imatinib has changed our perceptions of the therapeutic power of targeted inhibition of a pathologically active kinase. Nilotinib, a designer agent built on the imatinib scaffold, has proven superior to its template agent by every significant surrogate marker we use in monitoring CML. Nilotinib's clinical superiority over imatinib, as demonstrated by the ENESTnd study, has established it as an agent that we believe is a significant further step towards the cure of CML.