Effects of Jak2 type 1 inhibitors NVP-BSK805 and NVP-BVB808 on Jak2 mutation-positive and Bcr-Abl-positive cell lines.

Janus kinases are critical components of signaling pathways that regulate hematopoiesis. Mutations of the non-receptor tyrosine kinase JAK2 are found in many BCR-ABL-negative myeloproliferative neoplasms. Preclinical results support that JAK2 inhibitors could show efficacy in treating chronic myeloproliferative neoplasms. JAK2 has also been postulated to play a role in BCR-ABL signal transduction. Therefore, inhibitors of JAK2 kinases are turning into therapeutic strategies for treatment of chronic myelogenous leukemia (CML). In this study, the effects of two novel JAK2 inhibitors, NVP-BSK805 and NVP-BVB808, have been investigated in cell lines expressing either BCR-ABL or mutant JAK2. Possible synergies between NVP-BSK805/NVP-BVB808 and the kinase inhibitors imatinib and nilotinib were assessed. Proliferation and apoptosis tests with both substances showed response in the following cell lines: CHRF-288-11, SET-2 and UKE-1. All BCR-ABL-positive cell lines showed some reduction in proliferation, but with half-maximal growth-inhibitory values >1 µM. Combination of the JAK2 inhibitors with imatinib and nilotinib showed no significant additive or synergistic effects, although all BCR-ABL-positive cell lines responded well to both CML therapeutic agents. Interestingly, it seemed that the combination of imatinib with NVP-BSK805 had a protective effect on the cells. Combination treatment with nilotinib did not show this effect.

Clinical cardiac safety profile of nilotinib.

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.

Thyroid dysfunction caused by second-generation tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia.

BACKGROUND: Thyroid dysfunction is a well-known adverse effect of first-generation tyrosine kinase inhibitors (TKIs), like sunitinib. The aim of this study was to investigate the effect of second-generation TKIs on thyroid function. METHODS: We retrospectively assessed the effect of the first-generation TKI imatinib and the second-generation TKI nilotinib and dasatinib on thyroid function tests in 73 Philadelphia chromosome-positive (Ph-positive) chronic myeloid leukemia patients. RESULTS: Overall, 33 of 73 (45%) had one or more thyroid function test abnormalities during follow-up. Hypothyroidism or hyperthyroidism were found in 18 of 73 (25%) and 21 of 73 (29%) cases after a median of 6 and 22 weeks, respectively. In most patients (29 of 39, 74%) thyroid dysfunction was transient without clinical symptoms. Therapy of hypo-/hyperthyroidism was required in three patients. Thyroid dysfunction never resulted in the discontinuation of TKI therapy. Under treatment with imatinib, nilotinib, and dasatinib, thyroid abnormalities were detected in 25%, 55%, and 70%, respectively. Four of 55 patients (7%) treated with nilotinib had evidence for an autoimmune thyroiditis (antibody positive in 3 of 4 patients) with an episode of hyperthyroidism preceding hypothyroidism. CONCLUSIONS: Thyroid dysfunction is a common adverse event with second-generation TKI therapy in patients with Ph-positive chronic myeloid leukemia. Although the mechanism is still unclear, the high frequency of thyroid abnormalities, including autoimmune thyroiditis, warrants regular and long-term monitoring of thyroid function in these patients.