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Nilotinib cardiac toxicity: Should we still be concerned?
Leukemia Research 35 (2011) 577–578
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Guest editorial
Nilotinib cardiac toxicity: Should we still be concerned?
Nilotinib cardiac toxicity has been a concern since the early phase II studies in patients with imatinib resistant/intolerant disease. In those studies, 5 sudden deaths in 876 patients occurred which may have been related to ventricular repolarization. This was followed by a preclinical study done by Freebern et al. (Bristol Myers Squibb lab), where nilotinib did decrease the viability of primary rat cardiomyocytes at pharmacologically relevant concentrations. In addition, nilotinib more than imatinib or dasatinib lead to blockade of hERG K+ channels which may explain the prolonged QT interval seen more frequently with nilotinib [1]. This potential cardiac toxicity is especially relevant now that nilotinib is approved as frontline therapy for patients with CML and more patients will be receiving lifetime nilotinib therapy. Based on those concerns, in this issue of Leukemia Research, Dr. Wolf and colleagues (Novartis lab) conducted a preclinical study in a mouse model to evaluate the cardiotoxicity of nilotinib both in vivo and in vitro. In vitro, nilotinib did not induce changes in cellular viability [2] (as evidenced by LDH and cellular ATP content), increased apoptosis (as assessed using Mitotracker and caspase 3/7 activity) and increased endoplasmic reticulum (ER) stress reaction (as evaluated using CHOP mRNA levels) at concentrations similar to the human maximal concentration. Only the ratio of XBP1 spliced/unspliced (a measure of ER stress) was affected at clinically relevant concentration of nilotinib. Given that apoptosis did not increase, the significance of increased XBP1 splicing/unsplicing is not clear. In vivo mouse studies, using oral nilotinib at 2 different doses, did show some evidence of increased left ventricular (LV) weight to total body weight (TBW) ratio, however there was no difference in LV end diastolic volume by MRI between placebo treated mice and nilotinib treated mice. Histological examination of the cardiac muscle did show single or multifocal inflammatory foci of minimal to slight severity compared to minimal severity only in the placebo group. The authors explain that this is a common finding in male mice and do not think it is clinically significant. These effects were evaluated at 3, 14 and 28 days after administration of nilotinib. Clinically, in the early phase II studies with nilotinib, 8 patients (2.5%) had >60 ms change from baseline in QTcF interval and 4 patients (1.2%) had a post-baseline QTcF interval of >500 ms [3]. While in the randomized phase III trial of nilotinib vs. imatinib in patients with newly diagnosed CML, QTcF increases >30 ms occurred in 26% and 18% of patients on nilotinib and imatinib respectively. QTcF increases >60 ms occurred in <1% of patients on nilotinib and no patient had an increase of QTcF > 500 ms [4]. Of note, patients with a significant cardiac history were excluded from 0145-2126/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2011.01.021
the study, and all patients had an EKG prior to therapy, one week after starting therapy and every 3 months thereafter. The cardiac toxicity of tyrosine kinase inhibitors (TKIs) is not a new concern. In 2006, Kerkela et al. reported that imatinib may have a cardiotoxic effect both in vitro and in vivo [5]. Those findings were not reproduced in a more recent preclinical study by Wolf et al. [6]. More importantly, several large clinical retrospective studies did not find evidence of clinical cardiotoxicity in patients receiving imatinib [7]. So despite the contradicting preclinical results, long term follow up of patients receiving imatinib was the most reassuring that imatinib does not have significant cardiac toxicity. What does all this mean? The preclinical and clinical data appears reassuring that nilotinib does not have any acute cardiotoxic effects. In the mouse model, the mice were evaluated after only 4 weeks of therapy. The clinical data is also reassuring in the short term only. With a median follow up of 18 months in the 1st and 2nd line setting studies, there were no significant cardiac toxicities. However, given the nature of TKIs, therapy is expected to last for years. These preclinical and clinical data do not clarify the long term cardiac effects of nilotinib. Only long term clinical follow up of patients receiving nilotinib will clarify the cardiac effects of nilotinib. In the meantime proper patient selection, close follow up of electrolytes and EKG, and patient education regarding the use of new medications while on nilotinib and drug administration are mandatory to prevent any complications. Conflict of interest E.A. is on the advisory board and has research support from Novartis. Acknowledgements I would like to thank Dr. Jeanne Palmer for her help with writing this article. References [1] Freebern WJ, Fang HS, Slade MD, Wells S, Canale J, Megill J, et al. In vitro cardiotoxicity potential comparative assessments of chronic myelogenous leukemia tyrosine kinase inhibitor therapies: dasatinib, imatinib and nilotinib. In: ASH Annual Meeting Abstacts, vol. 110. 2007. p. 4582. [2] Wolf A, Couttet P, Dong M, Grenet O, Heron M, Junker U, et al. Preclinical evaluation of potential nilotinib cardiotoxicity. Leuk Res 2011;35:631–7.
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Guest editorial / Leukemia Research 35 (2011) 577–578
[3] Kantarjian HM, Giles FJ, Bhalla KN, Pinilla-Ibarz JA, Larson RA, Gattermann N, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase following imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011 Jan 27;117(4):1141-5. Epub 2010 Nov 22. [4] Larson RA, Hochhaus A, Saglio G, Rosti G, Lopez JL, Stenke L, et al. Cardiac safety profile of imatinib and nilotinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): results from ENESTnd. ASH Annual Meeting Abstracts 2010;116:2291. [5] Kerkela R, Grazette L, Yacobi R, Iliescu C, Patten R, Beahm C, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006;12:908–16. [6] Wolf A, Couttet P, Dong M, Grenet O, Heron M, Junker U, et al. Imatinib does not induce cardiotoxicity at clinically relevant concentrations in preclinical studies. Leuk Res 2010;34(9):1180–8. [7] Atallah E, Durand JB, Kantarjian H, Cortes J. Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood 2007;110:1233–7.
Ehab Atallah ∗ Division of Hematology and Oncology, Medical College of Wisconsin, 9200 W. Wisconsin Ave, Milwaukee, WI 53226, USA ∗ Tel.:
+1 414 805 4600; fax: +1 414 805 4600. E-mail address: [email protected] 19 January 2011 Available online 17 February 2011
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Guest editorial
Nilotinib cardiac toxicity: Should we still be concerned?
Nilotinib cardiac toxicity has been a concern since the early phase II studies in patients with imatinib resistant/intolerant disease. In those studies, 5 sudden deaths in 876 patients occurred which may have been related to ventricular repolarization. This was followed by a preclinical study done by Freebern et al. (Bristol Myers Squibb lab), where nilotinib did decrease the viability of primary rat cardiomyocytes at pharmacologically relevant concentrations. In addition, nilotinib more than imatinib or dasatinib lead to blockade of hERG K+ channels which may explain the prolonged QT interval seen more frequently with nilotinib [1]. This potential cardiac toxicity is especially relevant now that nilotinib is approved as frontline therapy for patients with CML and more patients will be receiving lifetime nilotinib therapy. Based on those concerns, in this issue of Leukemia Research, Dr. Wolf and colleagues (Novartis lab) conducted a preclinical study in a mouse model to evaluate the cardiotoxicity of nilotinib both in vivo and in vitro. In vitro, nilotinib did not induce changes in cellular viability [2] (as evidenced by LDH and cellular ATP content), increased apoptosis (as assessed using Mitotracker and caspase 3/7 activity) and increased endoplasmic reticulum (ER) stress reaction (as evaluated using CHOP mRNA levels) at concentrations similar to the human maximal concentration. Only the ratio of XBP1 spliced/unspliced (a measure of ER stress) was affected at clinically relevant concentration of nilotinib. Given that apoptosis did not increase, the significance of increased XBP1 splicing/unsplicing is not clear. In vivo mouse studies, using oral nilotinib at 2 different doses, did show some evidence of increased left ventricular (LV) weight to total body weight (TBW) ratio, however there was no difference in LV end diastolic volume by MRI between placebo treated mice and nilotinib treated mice. Histological examination of the cardiac muscle did show single or multifocal inflammatory foci of minimal to slight severity compared to minimal severity only in the placebo group. The authors explain that this is a common finding in male mice and do not think it is clinically significant. These effects were evaluated at 3, 14 and 28 days after administration of nilotinib. Clinically, in the early phase II studies with nilotinib, 8 patients (2.5%) had >60 ms change from baseline in QTcF interval and 4 patients (1.2%) had a post-baseline QTcF interval of >500 ms [3]. While in the randomized phase III trial of nilotinib vs. imatinib in patients with newly diagnosed CML, QTcF increases >30 ms occurred in 26% and 18% of patients on nilotinib and imatinib respectively. QTcF increases >60 ms occurred in <1% of patients on nilotinib and no patient had an increase of QTcF > 500 ms [4]. Of note, patients with a significant cardiac history were excluded from 0145-2126/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2011.01.021
the study, and all patients had an EKG prior to therapy, one week after starting therapy and every 3 months thereafter. The cardiac toxicity of tyrosine kinase inhibitors (TKIs) is not a new concern. In 2006, Kerkela et al. reported that imatinib may have a cardiotoxic effect both in vitro and in vivo [5]. Those findings were not reproduced in a more recent preclinical study by Wolf et al. [6]. More importantly, several large clinical retrospective studies did not find evidence of clinical cardiotoxicity in patients receiving imatinib [7]. So despite the contradicting preclinical results, long term follow up of patients receiving imatinib was the most reassuring that imatinib does not have significant cardiac toxicity. What does all this mean? The preclinical and clinical data appears reassuring that nilotinib does not have any acute cardiotoxic effects. In the mouse model, the mice were evaluated after only 4 weeks of therapy. The clinical data is also reassuring in the short term only. With a median follow up of 18 months in the 1st and 2nd line setting studies, there were no significant cardiac toxicities. However, given the nature of TKIs, therapy is expected to last for years. These preclinical and clinical data do not clarify the long term cardiac effects of nilotinib. Only long term clinical follow up of patients receiving nilotinib will clarify the cardiac effects of nilotinib. In the meantime proper patient selection, close follow up of electrolytes and EKG, and patient education regarding the use of new medications while on nilotinib and drug administration are mandatory to prevent any complications. Conflict of interest E.A. is on the advisory board and has research support from Novartis. Acknowledgements I would like to thank Dr. Jeanne Palmer for her help with writing this article. References [1] Freebern WJ, Fang HS, Slade MD, Wells S, Canale J, Megill J, et al. In vitro cardiotoxicity potential comparative assessments of chronic myelogenous leukemia tyrosine kinase inhibitor therapies: dasatinib, imatinib and nilotinib. In: ASH Annual Meeting Abstacts, vol. 110. 2007. p. 4582. [2] Wolf A, Couttet P, Dong M, Grenet O, Heron M, Junker U, et al. Preclinical evaluation of potential nilotinib cardiotoxicity. Leuk Res 2011;35:631–7.
578
Guest editorial / Leukemia Research 35 (2011) 577–578
[3] Kantarjian HM, Giles FJ, Bhalla KN, Pinilla-Ibarz JA, Larson RA, Gattermann N, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase following imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011 Jan 27;117(4):1141-5. Epub 2010 Nov 22. [4] Larson RA, Hochhaus A, Saglio G, Rosti G, Lopez JL, Stenke L, et al. Cardiac safety profile of imatinib and nilotinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): results from ENESTnd. ASH Annual Meeting Abstracts 2010;116:2291. [5] Kerkela R, Grazette L, Yacobi R, Iliescu C, Patten R, Beahm C, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006;12:908–16. [6] Wolf A, Couttet P, Dong M, Grenet O, Heron M, Junker U, et al. Imatinib does not induce cardiotoxicity at clinically relevant concentrations in preclinical studies. Leuk Res 2010;34(9):1180–8. [7] Atallah E, Durand JB, Kantarjian H, Cortes J. Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood 2007;110:1233–7.
Ehab Atallah ∗ Division of Hematology and Oncology, Medical College of Wisconsin, 9200 W. Wisconsin Ave, Milwaukee, WI 53226, USA ∗ Tel.:
+1 414 805 4600; fax: +1 414 805 4600. E-mail address: [email protected] 19 January 2011 Available online 17 February 2011