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The efficacy of tolvaptan in treating dasatinib-induced pleural effusions in patients with chronic myelogenous leukemia
G Model
JJCC-1893; No. of Pages 5 Journal of Cardiology xxx (2019) xxx–xxx
Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Original article
The efficacy of tolvaptan in treating dasatinib-induced pleural effusions in patients with chronic myelogenous leukemia Rie Aoyama (MD PhD)*, Joji Ishikawa (MD PhD), Kazumasa Harada (MD PhD FJCC) Department of Cardiology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 17 April 2019 Received in revised form 9 June 2019 Accepted 1 July 2019 Available online xxx
Background: Cancer treatment has been developing significantly and cancer-related cardiovascular disease treatments such as various anticancer agents and molecular target drugs have been reported often in the era of oncocardiology. Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy. Dasatinib is a novel tyrosine-kinase inhibitor approved for CML with Philadelphia (Ph) chromosome and the most common adverse effects of dasatinib are peripheral edema and pleural effusion, which sometimes impose the interruption or reduction of dosage of dasatinib treatment, accompanied by diuretic and steroid use. The goal of CML treatment is maintaining hematological control in the long term by controlling these side effects. The aim of this study is to clarify the efficacy of tolvaptan in treating dasatinib-induced fluid retention. Methods: We retrospectively analyzed six CML patients who received tolvaptan for dasatinib-induced fluid retention. Results: The mean age of patients was 60.5 11.5 years old, and the mean dosage of dasatinib and tolvaptan were 58.3 20.4 mg/day and 5.0 1.9 mg/day, respectively. Tolvaptan was introduced 564.5 369.9 days after dasatinib was introduced. Ejection fraction (EF) by echocardiography and brain natriuretic peptide (BNP) levels did not change. However, the diastolic function significantly changed [E/ e0 of the septal side: from 20.3 2.3 to 16.5 4.2, of the lateral side: from 15.0 2.1 to 12.5 3.8 (p < 0.05, respectively)]. New York Heart Association functional class was improved from 3.3 0.5 to 1.5 1.2 (p < 0.01) and the grades of fluid retention were also improved. Three patients discontinued dasatinib, and two patients could restart the administration of dasatinib after controlling fluid retention. Five patients could control fluid retention and they could continue with dasatinib therapy without any complications. Conclusions: Tolvaptan may be useful in fluid control in patients with CML treated with dasatinib. © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Onco-cardiology Heart failure Chronic myeloid leukemia Tyrosine kinase inhibitors Tolvaptan
Introduction Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy. At the cellular level, CML is characterized by the presence of the Philadelphia (Ph) chromosome. This genetic abnormality results from a reciprocal translocation between chromosomes 9 and 22, leading to the formation of a pathogenic tyrosine kinase signal transduction protein, BCR-
* Corresponding author at: Department of Cardiovascular Medicine, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakaechou, Itabashi-ku, Tokyo. E-mail address: [email protected] (R. Aoyama).
ABL. The treatment of CML was revolutionized by tyrosine kinase inhibitors (TKIs) directed against BCR-ABL. If untreated, the prognosis for patients with CML is poor. Therefore, there is a strong medical need for effective treatments for this malignancy. The main goal of the treatment of CML with TKIs has been the achievement of a so-called “major molecular response” (MMR; BCR-ABL1 0.1% on the International Scale) [1]. Dasatinib is a novel TKI approved for the treatment of BCR-ABL positive CML, and the use of TKIs has significantly improved survival in patients with CML [1,2]. The most common adverse effects of dasatinib are peripheral edema and pleural effusion. Pleural effusion was reported in 14%– 30% of patients [3–5].
https://doi.org/10.1016/j.jjcc.2019.07.008 0914-5087/© 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Aoyama R, et al. The efficacy of tolvaptan in treating dasatinib-induced pleural effusions in patients with chronic myelogenous leukemia. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.07.008
G Model
JJCC-1893; No. of Pages 5 R. Aoyama et al. / Journal of Cardiology xxx (2019) xxx–xxx
2
When pleural effusion induced by dasatinib occurs, there is a need for the interruption or reduction of dasatinib, accompanied by the use of diuretics and steroids. However, these effects are limited, and consequently, patients with CML and refractory pleural effusion show a poor prognosis. Tolvaptan, an orally active vasopressin V2-receptor antagonist has powerful effects on volume control in patients with congestive heart failure. Tolvaptan has the unique ability to attain aquaresis, the excretion of electrolyte-free water without accompanying solutes by directly blocking the binding of arginine vasopressin to its renal receptors [6–8]. The aim of this study was to asses tolvaptan for the treatment of dasatinib-induced refractory pleural effusion and heart failure in six patients with CML.
Materials and methods Study design and participant recruitment We analyzed six CML patients who were treated with dasatinib and had refractory pleural effusions and heart failure complications for a periodical follow-up between March 2010 and May 2016. We investigated them retrospectively. All of them received diuretics for the side effects, but that was insufficient. So, we introduced tolvaptan in addition to diuretics. This study conformed to the principles of the Declaration of Helsinki. The study protocol was approved by the ethics committee of Tokyo Metropolitan Geriatric Hospital.
Echocardiography study We performed two-dimensional (2D), M-mode, and Doppler echocardiographic studies with PHILIPS IE 33 (Philips Healthcare, Best, The Netherlands) or GE Vivid E 9 ultrasound systems (GE Healthcare, Chicago, IL, USA). We measured the LV systolic function [EF (ejection fraction)] and diastolic function [E/e0 (peak early transmitral filling velocity/peak early diastolic mitral annulus velocity on tissue Doppler imaging) of the septal side or lateral side on tissue Doppler imaging]. The ventricular volume and ejection fraction were computed using the biapical Simpson’s rule. Measurement of brain natriuretic peptide and the number of BCR/ABL gene copies Peripheral blood samples were collected to measure serum brain natriuretic peptide (BNP) level before and after the introduction of tolvaptan and the number of BCR/ABL gene copies to evaluate the achievement of the MMR. The grades of fluid retention were evaluated according to the U.S. National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) before and after treatment with dasatinib [9]. Statistical methods Data were expressed as mean standard deviation. We performed all statistical analyses with IBM SPSS statistics version 21 (IBM, Armonk, NY, USA). A paired t-test or the Wilcoxon signedrank test was used for paired data. Statistical significance was determined as a p-value of less than 0.05.
Table 1 Baseline characteristics.
Age (years) Sex Past history of heart disease EF Before administration of tolvaptan After administration of tolvaptan NYHA functional Before administration of tolvaptan class After administration of tolvaptan Fluid retention Peripheral edema Plural effusion Pericardial effusion Duration from the initiation of dasatinib to fluid retention (days) Duration from the initiation of dasatinib to tolvaptan initiation (days) eGFR(ml/min/m2) Serum albumin (g/dl) Dosage of dasatinib (mg) Dose reduction or discontinuation of dasatinib Other diuretics before the initiation of tolvaptan
Duration from the initiation of other diuretics to tolvaptan initiation (days) Other diuretics after the initiation of tolvaptan
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
67 M – 57 56 4 1 +(grade3) +(grade3) +(grade3) 318
54 M – 56 57 3 1 +(grade3) +(grade2) – 50
74 M – 58 48 4 4 +(grade3) +(grade4) +(grade4) 174
74 F – 72 72 3 1 +(grade2) +(grade2) – 93
56 M – 69 68 3 1 +(grade2) +(grade2) – 186
75 F – 62 63 3 1 +(grade2) +(grade2) – 205
621
71
244
152
246
327
54 3.4 50 – Azosemide 30 mg/day and spironolactone 25 mg/day 203
72 4.2 150 – Torasemide 4 mg/day and furosemide 60 mg/day 21
12 3.0 50 Discontinuation Furosemide 40 mg/day
68 3.3 50 Dose reduction Furosemide 20 mg/day
65 3.5 50 – Torasemide 4 mg/day
52
59
81 3.8 150 – Torasemide 4 mg/day and furosemide 20 mg/day 60
Torasemide 4 mg/day
Furosemide 40 mg/day
Discontinuation
Discontinuation
7.5 Effective – 5.8 58.9 154.2 56.3
15 Not effective + 90.5 201.6 509.8 1417.3
3.75 Effective – 57.9 112.8 242.6 98.7
Torasemide 4 mg/day and furosemide 20 mg/day 7.5 Effective – – 322.4 452.2 252.4
Azosemide 30 mg/day and spironolactone 25 mg/day 3.75 Dosage of tolvaptan (mg) Tolvaptan effect Effective Tolvaptan side effects – BNP level (pg/ml) Before administration of dasatinib 13.2 Before administration of other diuretics 29.8 Before administration of tolvaptan 132.2 After administration of tolvaptan 26.4
122
3.75 Effective – – 142.5 189.2 98.6
EF, ejection fraction; NYHA, New York Heart Association; eGFR, estimated glomerular filtration rate; BNP, brain natriuretic peptide.
Please cite this article in press as: Aoyama R, et al. The efficacy of tolvaptan in treating dasatinib-induced pleural effusions in patients with chronic myelogenous leukemia. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.07.008
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Results Patients were aged 60.5 11.5 years and the dosages of dasatinib and tolvaptan were 58.3 20.4 mg/day and 5.0 1.9 mg/day, respectively. Tolvaptan was introduced 564.5 369.9 days after dasatinib was introduced. Three patients out of six discontinued dasatinib and two patients restarted dasatinib administration after fluid retention control. Five patients out of six obtained a marked urine volume that reduced their pleural effusion and peripheral edema. New York Heart Association (NYHA) functional class was improved from 3.3 0.5 to 1.5 1.2 (p < 0.01). The grades of fluid retention according to CTCAE grading before and after the treatment with dasatinib were also improved from 2.5 0.5 to 1.3 0.8 (p < 0.05) in peripheral edema and from 2.5 0.8 to 1.5 1.3 (p < 0.05) in pleural effusion. These patients could continue with dasatinib therapy without any complications such as hypernatremia. Unfortunately, one patient required hemodialysis because of an advanced chronic kidney disease (CKD) in which tolvaptan could not manifest aquaresis (Table 1). The change in EF by echocardiography was from 62.3 6.7% to 60.7 8.8% (p = 0.37) and BNP level changed from 228.7 116.0 pg/ dl to 324.9 540.8 pg/dl (p = 0.68). However, the diastolic function changed significantly [E/e0 of the septal side: from 20.3 2.3 to 16.5 4.2 (p < 0.05), E/e0 of the lateral side: from 15.0 2.1 to 12.5 3.8 (p < 0.05)] (Fig. 1). We will further discuss all cases. CASE 1. A 67-year-old man who was diagnosed with CML had been treated with hydroxyurea. Two years after the diagnosis, nilotinib (800 mg/day) was administered and the number of BCR/ABL gene copies was undetectable, therefore, the so-called MMR was achieved. Although nilotinib was continuously administered, recurrence was noticed seven years after placing the diagnostic and dasatinib (50 mg/day) was introduced instead of nilotinib. Dasatinib could bring him into the MMR state, but the side effects of dasatinib such as leg edema and plural effusion were noticed, and the level of BNP elevated from 29.8 to 132.2 pg/ml. We began the
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administration of diuretics (azosemide 30 mg/day and spironolactone 25 mg/day). The side effects did not improve by diuretics, so we added tolvaptan (3.75 mg/day) to control the side effects and continued dasatinib. Tolvaptan was able to make the leg edema and plural effusion disappear, BNP level declined to 26.4 pg/ml, and MMR was achieved again and maintained (Fig. 2a). CASE 2. A 54-year-old man who was diagnosed with CML had been treated with dasatinib (140 mg/day). One month after the administration of dasatinib, side effects of dasatinib such as leg edema and body weight gain were noted, and the BNP level was elevated. We began the administration of diuretics (torasemide 4 mg/day). Those side effects did not improve by diuretics administration, so we added tolvaptan (7.5 mg/day). After tolvaptan administration, the patient lost around 5 kg of body weight and his leg edema and plural effusion disappeared. Tolvaptan made dasatinib administration and MMR possible. CASE 3. A 74-year-old man who was diagnosed with CML a year previously was treated with dasatinib (50 mg/day). He also had CKD (estimated glomerular filtration rate 12 ml/min/m2). Eight months after the administration of dasatinib, side effects occurred, and BNP level was elevated from 90.5 to 201.6 pg/ml. So, we reduced the dosage of dasatinib (20 mg/day) and increased the dosage of diuretics. We could not control the leg edema, pericardial effusion and plural effusion, and the BNP level was elevated (509.8 pg/ml). Therefore, we introduced tolvaptan (15 mg/day) and stopped dasatinib. Unfortunately, we could not control the water valance and his renal dysfunction progressed. We introduced hemodialysis but the patient died of blast crisis of CML (Fig. 2b). Discussion A variety of anticancer agents and molecular target drugs have been reported and an efficient management of related cardiovascular diseases in the oncocardiology field is needed.
Fig. 1. The change of each parameter before and after administration of tolvaptan. EF, ejection fraction; BNP, brain natriuretic peptide; E/e0 (IVS), peak early transmitral filling velocity/ peak early diastolic mitral annulus velocity on tissue Doppler imaging of the septal side; E/e0 (sep), peak early transmitral filling velocity/ peak early diastolic mitral annulus velocity on tissue Doppler imaging of the lateral side.
Please cite this article in press as: Aoyama R, et al. The efficacy of tolvaptan in treating dasatinib-induced pleural effusions in patients with chronic myelogenous leukemia. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.07.008
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Fig. 2. Representative cases of clinical course. (a) Case 1, tolvaptan was effective for treating fluid retention induced by dasatinib. (b) Case 3, this patient had a severely reduced renal function and tolvaptan was not effective for treating fluid retention induced by dasatinib. BNP, brain natriuretic peptide; CML, chronic myeloid leukemia.
The key of CML treatment is maintaining hematological control by using the molecular target drug in the long term [10–12]. The management of side effects is essential to ensure that patients
continue treatment and have the best possible chance of a positive long-term outcome. Dasatinib has been demonstrated to be active and well tolerated in patients with imatinib resistance or
Please cite this article in press as: Aoyama R, et al. The efficacy of tolvaptan in treating dasatinib-induced pleural effusions in patients with chronic myelogenous leukemia. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.07.008
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intolerance across all phases of CML [12,13]. The side effects associated with dasatinib therapy are predominantly mild or moderate (grade 1 or 2 by CTCAE grading and are self-limiting or resolve following supportive care. The incidences of grade 3–4 nonhematologic side effects in response to dasatinib treatment are minimal. However, one of the more problematic nonhematologic side effects that can occur on dasatinib treatment is fluid retention. This side effect is more common in patients with an advanced disease and/or over the age of 65 years and should also be monitored closely [14]. The mechanism of fluid retention by dasatinib treatment is currently unclear, and it is probable that pleural effusions are multifactorial [5]. Pleural effusions may be related to fluid retention resulting from a nonspecific inhibition of the plateletderived growth factor receptor-b or other kinases [15] and from immune-mediated reactions as shown by exacerbated vascular permeability and/or lymphocytic blockade [5,16,17]. It has been suggested that dasatinib may inhibit the function of normal T cells [18] and bind major regulators of the immune system [19]. Tolvaptan, the arginine vasopressin type-2 antagonist, inhibits the re-absorption of water in the renal collecting duct via aquaporin-2 which is an arginine vasopressin-regulated water channel establishing aquaresis [6,8,20–24]. Tolvaptan improves fluid retention without worsening the renal function, but there is no report on the administration of tolvaptan for drug-induced fluid retention. In five patients, tolvaptan was effective for fluid retention induced by dasatinib treatment making dasatinib treatment possible. The diastolic function was elevated according with fluid retention and improved by aquaresis of tolvaptan. Tolvaptan was insufficient for the CKD case. The exacerbated vascular permeability and/or the lymphocytic blockade may be the main cause of fluid retention due to side effects of the drug, rather than fluid retention by sodium reservoir. Therefore, it was presumed that it makes sense to use a hydrodiuretic drug rather than sodium diuretic drugs in drug-induced fluid retention. Limitations The number of patients was small due to the limited capacity of patient selection. The study was retrospective and no long-term follow-up data were addressed. Conclusions In conclusion, tolvaptan may be useful to manage fluid control in patients with CML treated with dasatinib. Conflicts of interest The authors have no conflicts of interest to declare. Funding and disclosures None Acknowledgments We thank the staff that examined patients. Particularly we thank the following people, Shigesaburo Miyakoshi and Jun Tanaka who collaborated by collecting the data.
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References [1] Huet S, Cony-Makhoul P, Heiblig M, Tigaud I, Gazzo S, Belhabri A, et al. Major molecular response achievement in CML patients can be predicted by BCRABL1/ABL1 or BCR-ABL1/GUS ratio at an earlier time point of follow-up than currently recommended. PLoS One 2014;9e106250. [2] Hochhaus A, O’Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L, et al. Sixyear follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 2009;23:1054–61. [3] Inokuchi K, Kumagai T, Matsuki E, Ohashi K, Shinagawa A, Hatta Y, et al. Efficacy of molecular response at 1 or 3 months after the initiation of dasatinib treatment can predict an improved response to dasatinib in imatinib-resistant or imatinib-intolerant Japanese patients with chronic myelogenous leukemia during the chronic phase. J Clin Exp Hematop 2014;54:197–204. [4] Breccia M, Alimena G. Pleural/pericardic effusions during dasatinib treatment: incidence, management and risk factors associated to their development. Expert Opin Drug Saf 2010;9:713–21. [5] Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006;354:2531–41. [6] Masiello D, Gorospe 3rd G, Yang AS. The occurrence and management of fluid retention associated with TKI therapy in CML, with a focus on dasatinib. J Hematol Oncol 2009;2:46. [7] Izumi Y, Miura K, Iwao H. Therapeutic potential of vasopressin-receptor antagonists in heart failure. J Pharmacol Sci 2014;124:1–6. [8] Wang C, Xiong B, Cai L. Effects of tolvaptan in patients with acute heart failure: a systematic review and meta-analysis. BMC Cardiovasc Disord 2017;17:164. [9] U.S. Department of Health and Human Services NIH, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. https:// ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ CTCAE_v5_Quick_Reference_5x7.pdf. November 27, 2017. [10] Fukunami M, Matsuzaki M, Hori M, Izumi T. Efficacy and safety of tolvaptan in heart failure patients with sustained volume overload despite the use of conventional diuretics: a phase III open-label study. Cardiovasc Drugs Ther 2011;25(Suppl. 1):S47–56. [11] Kantarjian H, Pasquini R, Hamerschlak N, Rousselot P, Holowiecki J, Jootar S, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood 2007;109:5143–50. [12] Abbott BL. Dasatinib: from treatment of imatinib-resistant or -intolerant patients with chronic myeloid leukemia to treatment of patients with newly diagnosed chronic phase chronic myeloid leukemia. Clin Ther 2012;34:272–81. [13] Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring. Am J Hematol 2018;93:442–59. [14] Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031–7. [15] Shah NP, Kantarjian HM, Kim DW, Rea D, Dorlhiac-Llacer PE, Milone JH, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 2008;26:3204–12. [16] Quintas-Cardama A, Kantarjian H, O’Brien S, Borthakur G, Bruzzi J, Munden R, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol 2007;25:3908–14. [17] Bergeron A, Rea D, Levy V, Picard C, Meignin V, Tamburini J, et al. Lung abnormalities after dasatinib treatment for chronic myeloid leukemia: a case series. Am J Respir Crit Care Med 2007;176:814–8. [18] de Lavallade H, Punnialingam S, Milojkovic D, Bua M, Khorashad JS, Gabriel IH, et al. Pleural effusions in patients with chronic myeloid leukaemia treated with dasatinib may have an immune-mediated pathogenesis. Br J Haematol 2008;141:745–7. [19] Blake S, Hughes TP, Mayrhofer G, Lyons AB. The Src/ABL kinase inhibitor dasatinib (BMS-354825) inhibits function of normal human T-lymphocytes in vitro. Clin Immunol 2008;127:330–9. [20] Rix U, Hantschel O, Durnberger G, Remsing Rix LL, Planyavsky M, Fernbach NV, et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood 2007;110:4055–63. [21] Miyazaki T, Fujiki H, Yamamura Y, Nakamura S, Mori T. Tolvaptan, an orally active vasopressin V(2)-receptor antagonist - pharmacology and clinical trials. Cardiovasc Drug Rev 2007;25:1–13. [22] Wu MY, Chen TT, Chen YC, Tarng DC, Wu YC, Lin HH, et al. Effects and safety of oral tolvaptan in patients with congestive heart failure: a systematic review and network meta-analysis. PLoS One 2017;12e0184380. [23] Imamura T, Kinugawa K. Update of acute and long-term tolvaptan therapy. J Cardiol 2018;73:102–7. [24] Oguri M, Ishii H, Ohguchi S, et al. Comparison of two dosing methods for immediate administration of tolvaptan in acute decompensated heart failure. J Cardiol 2018;72:234–9.
Please cite this article in press as: Aoyama R, et al. The efficacy of tolvaptan in treating dasatinib-induced pleural effusions in patients with chronic myelogenous leukemia. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.07.008
JJCC-1893; No. of Pages 5 Journal of Cardiology xxx (2019) xxx–xxx
Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Original article
The efficacy of tolvaptan in treating dasatinib-induced pleural effusions in patients with chronic myelogenous leukemia Rie Aoyama (MD PhD)*, Joji Ishikawa (MD PhD), Kazumasa Harada (MD PhD FJCC) Department of Cardiology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 17 April 2019 Received in revised form 9 June 2019 Accepted 1 July 2019 Available online xxx
Background: Cancer treatment has been developing significantly and cancer-related cardiovascular disease treatments such as various anticancer agents and molecular target drugs have been reported often in the era of oncocardiology. Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy. Dasatinib is a novel tyrosine-kinase inhibitor approved for CML with Philadelphia (Ph) chromosome and the most common adverse effects of dasatinib are peripheral edema and pleural effusion, which sometimes impose the interruption or reduction of dosage of dasatinib treatment, accompanied by diuretic and steroid use. The goal of CML treatment is maintaining hematological control in the long term by controlling these side effects. The aim of this study is to clarify the efficacy of tolvaptan in treating dasatinib-induced fluid retention. Methods: We retrospectively analyzed six CML patients who received tolvaptan for dasatinib-induced fluid retention. Results: The mean age of patients was 60.5 11.5 years old, and the mean dosage of dasatinib and tolvaptan were 58.3 20.4 mg/day and 5.0 1.9 mg/day, respectively. Tolvaptan was introduced 564.5 369.9 days after dasatinib was introduced. Ejection fraction (EF) by echocardiography and brain natriuretic peptide (BNP) levels did not change. However, the diastolic function significantly changed [E/ e0 of the septal side: from 20.3 2.3 to 16.5 4.2, of the lateral side: from 15.0 2.1 to 12.5 3.8 (p < 0.05, respectively)]. New York Heart Association functional class was improved from 3.3 0.5 to 1.5 1.2 (p < 0.01) and the grades of fluid retention were also improved. Three patients discontinued dasatinib, and two patients could restart the administration of dasatinib after controlling fluid retention. Five patients could control fluid retention and they could continue with dasatinib therapy without any complications. Conclusions: Tolvaptan may be useful in fluid control in patients with CML treated with dasatinib. © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Onco-cardiology Heart failure Chronic myeloid leukemia Tyrosine kinase inhibitors Tolvaptan
Introduction Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy. At the cellular level, CML is characterized by the presence of the Philadelphia (Ph) chromosome. This genetic abnormality results from a reciprocal translocation between chromosomes 9 and 22, leading to the formation of a pathogenic tyrosine kinase signal transduction protein, BCR-
* Corresponding author at: Department of Cardiovascular Medicine, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakaechou, Itabashi-ku, Tokyo. E-mail address: [email protected] (R. Aoyama).
ABL. The treatment of CML was revolutionized by tyrosine kinase inhibitors (TKIs) directed against BCR-ABL. If untreated, the prognosis for patients with CML is poor. Therefore, there is a strong medical need for effective treatments for this malignancy. The main goal of the treatment of CML with TKIs has been the achievement of a so-called “major molecular response” (MMR; BCR-ABL1 0.1% on the International Scale) [1]. Dasatinib is a novel TKI approved for the treatment of BCR-ABL positive CML, and the use of TKIs has significantly improved survival in patients with CML [1,2]. The most common adverse effects of dasatinib are peripheral edema and pleural effusion. Pleural effusion was reported in 14%– 30% of patients [3–5].
https://doi.org/10.1016/j.jjcc.2019.07.008 0914-5087/© 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Aoyama R, et al. The efficacy of tolvaptan in treating dasatinib-induced pleural effusions in patients with chronic myelogenous leukemia. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.07.008
G Model
JJCC-1893; No. of Pages 5 R. Aoyama et al. / Journal of Cardiology xxx (2019) xxx–xxx
2
When pleural effusion induced by dasatinib occurs, there is a need for the interruption or reduction of dasatinib, accompanied by the use of diuretics and steroids. However, these effects are limited, and consequently, patients with CML and refractory pleural effusion show a poor prognosis. Tolvaptan, an orally active vasopressin V2-receptor antagonist has powerful effects on volume control in patients with congestive heart failure. Tolvaptan has the unique ability to attain aquaresis, the excretion of electrolyte-free water without accompanying solutes by directly blocking the binding of arginine vasopressin to its renal receptors [6–8]. The aim of this study was to asses tolvaptan for the treatment of dasatinib-induced refractory pleural effusion and heart failure in six patients with CML.
Materials and methods Study design and participant recruitment We analyzed six CML patients who were treated with dasatinib and had refractory pleural effusions and heart failure complications for a periodical follow-up between March 2010 and May 2016. We investigated them retrospectively. All of them received diuretics for the side effects, but that was insufficient. So, we introduced tolvaptan in addition to diuretics. This study conformed to the principles of the Declaration of Helsinki. The study protocol was approved by the ethics committee of Tokyo Metropolitan Geriatric Hospital.
Echocardiography study We performed two-dimensional (2D), M-mode, and Doppler echocardiographic studies with PHILIPS IE 33 (Philips Healthcare, Best, The Netherlands) or GE Vivid E 9 ultrasound systems (GE Healthcare, Chicago, IL, USA). We measured the LV systolic function [EF (ejection fraction)] and diastolic function [E/e0 (peak early transmitral filling velocity/peak early diastolic mitral annulus velocity on tissue Doppler imaging) of the septal side or lateral side on tissue Doppler imaging]. The ventricular volume and ejection fraction were computed using the biapical Simpson’s rule. Measurement of brain natriuretic peptide and the number of BCR/ABL gene copies Peripheral blood samples were collected to measure serum brain natriuretic peptide (BNP) level before and after the introduction of tolvaptan and the number of BCR/ABL gene copies to evaluate the achievement of the MMR. The grades of fluid retention were evaluated according to the U.S. National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) before and after treatment with dasatinib [9]. Statistical methods Data were expressed as mean standard deviation. We performed all statistical analyses with IBM SPSS statistics version 21 (IBM, Armonk, NY, USA). A paired t-test or the Wilcoxon signedrank test was used for paired data. Statistical significance was determined as a p-value of less than 0.05.
Table 1 Baseline characteristics.
Age (years) Sex Past history of heart disease EF Before administration of tolvaptan After administration of tolvaptan NYHA functional Before administration of tolvaptan class After administration of tolvaptan Fluid retention Peripheral edema Plural effusion Pericardial effusion Duration from the initiation of dasatinib to fluid retention (days) Duration from the initiation of dasatinib to tolvaptan initiation (days) eGFR(ml/min/m2) Serum albumin (g/dl) Dosage of dasatinib (mg) Dose reduction or discontinuation of dasatinib Other diuretics before the initiation of tolvaptan
Duration from the initiation of other diuretics to tolvaptan initiation (days) Other diuretics after the initiation of tolvaptan
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
67 M – 57 56 4 1 +(grade3) +(grade3) +(grade3) 318
54 M – 56 57 3 1 +(grade3) +(grade2) – 50
74 M – 58 48 4 4 +(grade3) +(grade4) +(grade4) 174
74 F – 72 72 3 1 +(grade2) +(grade2) – 93
56 M – 69 68 3 1 +(grade2) +(grade2) – 186
75 F – 62 63 3 1 +(grade2) +(grade2) – 205
621
71
244
152
246
327
54 3.4 50 – Azosemide 30 mg/day and spironolactone 25 mg/day 203
72 4.2 150 – Torasemide 4 mg/day and furosemide 60 mg/day 21
12 3.0 50 Discontinuation Furosemide 40 mg/day
68 3.3 50 Dose reduction Furosemide 20 mg/day
65 3.5 50 – Torasemide 4 mg/day
52
59
81 3.8 150 – Torasemide 4 mg/day and furosemide 20 mg/day 60
Torasemide 4 mg/day
Furosemide 40 mg/day
Discontinuation
Discontinuation
7.5 Effective – 5.8 58.9 154.2 56.3
15 Not effective + 90.5 201.6 509.8 1417.3
3.75 Effective – 57.9 112.8 242.6 98.7
Torasemide 4 mg/day and furosemide 20 mg/day 7.5 Effective – – 322.4 452.2 252.4
Azosemide 30 mg/day and spironolactone 25 mg/day 3.75 Dosage of tolvaptan (mg) Tolvaptan effect Effective Tolvaptan side effects – BNP level (pg/ml) Before administration of dasatinib 13.2 Before administration of other diuretics 29.8 Before administration of tolvaptan 132.2 After administration of tolvaptan 26.4
122
3.75 Effective – – 142.5 189.2 98.6
EF, ejection fraction; NYHA, New York Heart Association; eGFR, estimated glomerular filtration rate; BNP, brain natriuretic peptide.
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Results Patients were aged 60.5 11.5 years and the dosages of dasatinib and tolvaptan were 58.3 20.4 mg/day and 5.0 1.9 mg/day, respectively. Tolvaptan was introduced 564.5 369.9 days after dasatinib was introduced. Three patients out of six discontinued dasatinib and two patients restarted dasatinib administration after fluid retention control. Five patients out of six obtained a marked urine volume that reduced their pleural effusion and peripheral edema. New York Heart Association (NYHA) functional class was improved from 3.3 0.5 to 1.5 1.2 (p < 0.01). The grades of fluid retention according to CTCAE grading before and after the treatment with dasatinib were also improved from 2.5 0.5 to 1.3 0.8 (p < 0.05) in peripheral edema and from 2.5 0.8 to 1.5 1.3 (p < 0.05) in pleural effusion. These patients could continue with dasatinib therapy without any complications such as hypernatremia. Unfortunately, one patient required hemodialysis because of an advanced chronic kidney disease (CKD) in which tolvaptan could not manifest aquaresis (Table 1). The change in EF by echocardiography was from 62.3 6.7% to 60.7 8.8% (p = 0.37) and BNP level changed from 228.7 116.0 pg/ dl to 324.9 540.8 pg/dl (p = 0.68). However, the diastolic function changed significantly [E/e0 of the septal side: from 20.3 2.3 to 16.5 4.2 (p < 0.05), E/e0 of the lateral side: from 15.0 2.1 to 12.5 3.8 (p < 0.05)] (Fig. 1). We will further discuss all cases. CASE 1. A 67-year-old man who was diagnosed with CML had been treated with hydroxyurea. Two years after the diagnosis, nilotinib (800 mg/day) was administered and the number of BCR/ABL gene copies was undetectable, therefore, the so-called MMR was achieved. Although nilotinib was continuously administered, recurrence was noticed seven years after placing the diagnostic and dasatinib (50 mg/day) was introduced instead of nilotinib. Dasatinib could bring him into the MMR state, but the side effects of dasatinib such as leg edema and plural effusion were noticed, and the level of BNP elevated from 29.8 to 132.2 pg/ml. We began the
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administration of diuretics (azosemide 30 mg/day and spironolactone 25 mg/day). The side effects did not improve by diuretics, so we added tolvaptan (3.75 mg/day) to control the side effects and continued dasatinib. Tolvaptan was able to make the leg edema and plural effusion disappear, BNP level declined to 26.4 pg/ml, and MMR was achieved again and maintained (Fig. 2a). CASE 2. A 54-year-old man who was diagnosed with CML had been treated with dasatinib (140 mg/day). One month after the administration of dasatinib, side effects of dasatinib such as leg edema and body weight gain were noted, and the BNP level was elevated. We began the administration of diuretics (torasemide 4 mg/day). Those side effects did not improve by diuretics administration, so we added tolvaptan (7.5 mg/day). After tolvaptan administration, the patient lost around 5 kg of body weight and his leg edema and plural effusion disappeared. Tolvaptan made dasatinib administration and MMR possible. CASE 3. A 74-year-old man who was diagnosed with CML a year previously was treated with dasatinib (50 mg/day). He also had CKD (estimated glomerular filtration rate 12 ml/min/m2). Eight months after the administration of dasatinib, side effects occurred, and BNP level was elevated from 90.5 to 201.6 pg/ml. So, we reduced the dosage of dasatinib (20 mg/day) and increased the dosage of diuretics. We could not control the leg edema, pericardial effusion and plural effusion, and the BNP level was elevated (509.8 pg/ml). Therefore, we introduced tolvaptan (15 mg/day) and stopped dasatinib. Unfortunately, we could not control the water valance and his renal dysfunction progressed. We introduced hemodialysis but the patient died of blast crisis of CML (Fig. 2b). Discussion A variety of anticancer agents and molecular target drugs have been reported and an efficient management of related cardiovascular diseases in the oncocardiology field is needed.
Fig. 1. The change of each parameter before and after administration of tolvaptan. EF, ejection fraction; BNP, brain natriuretic peptide; E/e0 (IVS), peak early transmitral filling velocity/ peak early diastolic mitral annulus velocity on tissue Doppler imaging of the septal side; E/e0 (sep), peak early transmitral filling velocity/ peak early diastolic mitral annulus velocity on tissue Doppler imaging of the lateral side.
Please cite this article in press as: Aoyama R, et al. The efficacy of tolvaptan in treating dasatinib-induced pleural effusions in patients with chronic myelogenous leukemia. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.07.008
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Fig. 2. Representative cases of clinical course. (a) Case 1, tolvaptan was effective for treating fluid retention induced by dasatinib. (b) Case 3, this patient had a severely reduced renal function and tolvaptan was not effective for treating fluid retention induced by dasatinib. BNP, brain natriuretic peptide; CML, chronic myeloid leukemia.
The key of CML treatment is maintaining hematological control by using the molecular target drug in the long term [10–12]. The management of side effects is essential to ensure that patients
continue treatment and have the best possible chance of a positive long-term outcome. Dasatinib has been demonstrated to be active and well tolerated in patients with imatinib resistance or
Please cite this article in press as: Aoyama R, et al. The efficacy of tolvaptan in treating dasatinib-induced pleural effusions in patients with chronic myelogenous leukemia. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.07.008
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intolerance across all phases of CML [12,13]. The side effects associated with dasatinib therapy are predominantly mild or moderate (grade 1 or 2 by CTCAE grading and are self-limiting or resolve following supportive care. The incidences of grade 3–4 nonhematologic side effects in response to dasatinib treatment are minimal. However, one of the more problematic nonhematologic side effects that can occur on dasatinib treatment is fluid retention. This side effect is more common in patients with an advanced disease and/or over the age of 65 years and should also be monitored closely [14]. The mechanism of fluid retention by dasatinib treatment is currently unclear, and it is probable that pleural effusions are multifactorial [5]. Pleural effusions may be related to fluid retention resulting from a nonspecific inhibition of the plateletderived growth factor receptor-b or other kinases [15] and from immune-mediated reactions as shown by exacerbated vascular permeability and/or lymphocytic blockade [5,16,17]. It has been suggested that dasatinib may inhibit the function of normal T cells [18] and bind major regulators of the immune system [19]. Tolvaptan, the arginine vasopressin type-2 antagonist, inhibits the re-absorption of water in the renal collecting duct via aquaporin-2 which is an arginine vasopressin-regulated water channel establishing aquaresis [6,8,20–24]. Tolvaptan improves fluid retention without worsening the renal function, but there is no report on the administration of tolvaptan for drug-induced fluid retention. In five patients, tolvaptan was effective for fluid retention induced by dasatinib treatment making dasatinib treatment possible. The diastolic function was elevated according with fluid retention and improved by aquaresis of tolvaptan. Tolvaptan was insufficient for the CKD case. The exacerbated vascular permeability and/or the lymphocytic blockade may be the main cause of fluid retention due to side effects of the drug, rather than fluid retention by sodium reservoir. Therefore, it was presumed that it makes sense to use a hydrodiuretic drug rather than sodium diuretic drugs in drug-induced fluid retention. Limitations The number of patients was small due to the limited capacity of patient selection. The study was retrospective and no long-term follow-up data were addressed. Conclusions In conclusion, tolvaptan may be useful to manage fluid control in patients with CML treated with dasatinib. Conflicts of interest The authors have no conflicts of interest to declare. Funding and disclosures None Acknowledgments We thank the staff that examined patients. Particularly we thank the following people, Shigesaburo Miyakoshi and Jun Tanaka who collaborated by collecting the data.
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Please cite this article in press as: Aoyama R, et al. The efficacy of tolvaptan in treating dasatinib-induced pleural effusions in patients with chronic myelogenous leukemia. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.07.008