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Computed tomography-measured pulmonary artery to aorta ratio and EUTOS score for detecting dasatinib-induced pulmonary arterial hypertension

  • Takumi ToyaEmail author
  • Yuji Nagatomo
  • Kazuki Kagami
  • Midori Yukino
  • Risako Yasuda
  • Takayuki Namba
  • Yasuo Ido
  • Shinichi Kobayashi
  • Nobuyuki Masaki
  • Hirotaka Yada
  • Fumihiko Kimura
  • Takeshi Adachi
Original Paper
  • 18 Downloads

Abstract

Background

Periodic echo-based screening to detect early stages of a rare complication of dasatinib, pulmonary arterial hypertension (PAH), is inefficient and weakens the potential benefit of dasatinib as a potent drug for chronic myelogenous leukemia (CML). This study aimed to identify the predisposing factors of DASA-PAH to stratify high-risk patients for dasatinib-induced PAH (DASA-PAH).

Methods

Sixty consecutive adult patients who received dasatinib were enrolled in this case-control study. We defined DASA-PAH when at least one of the following four criteria was met: (1) recent electrocardiographic changes indicating right ventricular pressure overload, (2) estimated systolic pulmonary arterial pressure > 40 mmHg measured by Doppler echocardiography; (3) computed tomography (CT)-measured pulmonary artery to aorta diameter (PaD/AoD) ratio > 1; and (4) mean pulmonary arterial pressure > 25 mmHg and pulmonary artery wedge pressure < 15 mmHg measured by right heart catheterization.

Results

We identified 13 patients with DASA-PAH among 59 patients analyzed. Baseline PaD/AoD ratios of patients who developed DASA-PAH (PH group) were significantly larger than those who did not (NPH group). A dramatic rise in PaD/AoD ratio after dasatinib treatment was observed. Interestingly, the EUTOS score and spleen size were significantly smaller in the PH than in the NPH group.

Conclusion

High baseline PaD/AoD ratio and low EUTOS score were associated with DASA-PAH development. The spleen might play a protective role against DASA-PAH.

Keywords

CT Dasatinib EUTOS score Pulmonary arterial hypertension 

Abbreviations

AoD

Aortic diameter

CML

Chronic myelogenous leukemia

CT

Computed tomography

DASA

Dasatinib

DASA-PAH

Dasatinib-induced pulmonary arterial hypertension

ECG

Electrocardiography

LA

Left atrium

LVEF

Left ventricular ejection fraction

MPAP

Mean pulmonary arterial pressure

PaD

Pulmonary artery diameter

PAH

Pulmonary arterial hypertension

PAWP

Pulmonary artery wedge pressure

PVR

Pulmonary vascular resistance

RHC

Right heart catheterization

SPAP

Systolic pulmonary arterial pressure

TKI

Tyrosine kinase inhibitor

TTE

Transthoracic echocardiography

WU

Wood units

Notes

Acknowledgements

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

TT designed the study, analyzed data, and drafted the paper. YN and YI helped the statistical analysis and manuscript editing. KK and MY helped the data collection. RY and TN performed echo and CT measurement. NM, SK, HY, FK, and TA supported manuscript and figure editing.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL (2004) Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305(5682):399–401.  https://doi.org/10.1126/science.1099480 CrossRefGoogle Scholar
  2. 2.
    Jabbour E, Kantarjian HM, Saglio G, Steegmann JL, Shah NP, Boque C, Chuah C, Pavlovsky C, Mayer J, Cortes J, Baccarani M, Kim DW, Bradley-Garelik MB, Mohamed H, Wildgust M, Hochhaus A (2014) Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 123(4):494–500.  https://doi.org/10.1182/blood-2013-06-511592 CrossRefGoogle Scholar
  3. 3.
    Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boque C, Shah NP, Chuah C, Casanova L, Bradley-Garelik B, Manos G, Hochhaus A (2016) Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial. J Clin Oncol 34(20):2333–2340.  https://doi.org/10.1200/jco.2015.64.8899 CrossRefGoogle Scholar
  4. 4.
    Quintas-Cardama A, Kantarjian H, O’Brien S, Borthakur G, Bruzzi J, Munden R, Cortes J (2007) Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol 25(25):3908–3914.  https://doi.org/10.1200/jco.2007.12.0329 CrossRefGoogle Scholar
  5. 5.
    Moslehi JJ, Deininger M (2015) Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia. J Clin Oncol 33(35):4210–4218.  https://doi.org/10.1200/jco.2015.62.4718 CrossRefGoogle Scholar
  6. 6.
    Gambacorti-Passerini C, Antolini L, Mahon FX, Guilhot F, Deininger M, Fava C, Nagler A, Della Casa CM, Morra E, Abruzzese E, D’Emilio A, Stagno F, le Coutre P, Hurtado-Monroy R, Santini V, Martino B, Pane F, Piccin A, Giraldo P, Assouline S, Durosinmi MA, Leeksma O, Pogliani EM, Puttini M, Jang E, Reiffers J, Piazza R, Valsecchi MG, Kim DW (2011) Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst 103(7):553–561.  https://doi.org/10.1093/jnci/djr060 CrossRefGoogle Scholar
  7. 7.
    Weatherald J, Chaumais MC, Savale L, Jais X, Seferian A, Canuet M, Bouvaist H, Magro P, Bergeron A, Guignabert C, Sitbon O, Simonneau G, Humbert M, Montani D (2017) Long-term outcomes of dasatinib-induced pulmonary arterial hypertension: a population-based study. Eur Respir J 50(1).  https://doi.org/10.1183/13993003.00217-2017
  8. 8.
    Shah NP, Wallis N, Farber HW, Mauro MJ, Wolf RA, Mattei D, Guha M, Rea D, Peacock A (2015) Clinical features of pulmonary arterial hypertension in patients receiving dasatinib. Am J Hematol 90(11):1060–1064.  https://doi.org/10.1002/ajh.24174 CrossRefGoogle Scholar
  9. 9.
    Baumgart B, Guha M, Hennan J, Li J, Woicke J, Simic D, Graziano M, Wallis N, Sanderson T, Bunch RT (2017) In vitro and in vivo evaluation of dasatinib and imatinib on physiological parameters of pulmonary arterial hypertension. Cancer Chemother Pharmacol 79(4):711–723.  https://doi.org/10.1007/s00280-017-3264-2 CrossRefGoogle Scholar
  10. 10.
    Guignabert C, Phan C, Seferian A, Huertas A, Tu L, Thuillet R, Sattler C, Le Hiress M, Tamura Y, Jutant EM, Chaumais MC, Bouchet S, Maneglier B, Molimard M, Rousselot P, Sitbon O, Simonneau G, Montani D, Humbert M (2016) Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension. J Clin Investig 126(9):3207–3218.  https://doi.org/10.1172/jci86249 CrossRefGoogle Scholar
  11. 11.
    Zamorano JL, Lancellotti P, Rodriguez Munoz D, Aboyans V, Asteggiano R, Galderisi M, Habib G, Lenihan DJ, Lip GYH, Lyon AR, Lopez Fernandez T, Mohty D, Piepoli MF, Tamargo J, Torbicki A, Suter TM (2016) 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 37(36):2768–2801.  https://doi.org/10.1093/eurheartj/ehw211 CrossRefGoogle Scholar
  12. 12.
    McGoon M, Gutterman D, Steen V, Barst R, McCrory DC, Fortin TA, Loyd JE (2004) Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 126(1 Suppl):14s–34s.  https://doi.org/10.1378/chest.126.1_suppl.14S CrossRefGoogle Scholar
  13. 13.
    Al-Naamani K, Hijal T, Nguyen V, Andrew S, Nguyen T, Huynh T (2008) Predictive values of the electrocardiogram in diagnosing pulmonary hypertension. Int J Cardiol 127(2):214–218.  https://doi.org/10.1016/j.ijcard.2007.06.005 CrossRefGoogle Scholar
  14. 14.
    Nikus K, Perez-Riera AR, Konttila K, Barbosa-Barros R (2018) Electrocardiographic recognition of right ventricular hypertrophy. J Electrocardiol 51(1):46–49.  https://doi.org/10.1016/j.jelectrocard.2017.09.004 CrossRefGoogle Scholar
  15. 15.
    Porter TR, Shillcutt SK, Adams MS, Desjardins G, Glas KE, Olson JJ, Troughton RW (2015) Guidelines for the use of echocardiography as a monitor for therapeutic intervention in adults: a report from the American Society of Echocardiography. J Am Soc Echocardiogr 28(1):40–56.  https://doi.org/10.1016/j.echo.2014.09.009 CrossRefGoogle Scholar
  16. 16.
    McQuillan BM, Picard MH, Leavitt M, Weyman AE (2001) Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects. Circulation 104(23):2797–2802CrossRefGoogle Scholar
  17. 17.
    Iyer AS, Wells JM, Vishin S, Bhatt SP, Wille KM, Dransfield MT (2014) CT scan-measured pulmonary artery to aorta ratio and echocardiography for detecting pulmonary hypertension in severe COPD. Chest 145(4):824–832.  https://doi.org/10.1378/chest.13-1422 CrossRefGoogle Scholar
  18. 18.
    Ng CS, Wells AU, Padley SP (1999) A CT sign of chronic pulmonary arterial hypertension: the ratio of main pulmonary artery to aortic diameter. J Thorac Imaging 14(4):270–278CrossRefGoogle Scholar
  19. 19.
    Corson N, Armato SG 3rd, Labby ZE, Straus C, Starkey A, Gomberg-Maitland M (2014) CT-based pulmonary artery measurements for the assessment of pulmonary hypertension. Acad Radiol 21(4):523–530.  https://doi.org/10.1016/j.acra.2013.12.015 CrossRefGoogle Scholar
  20. 20.
    Rajaram S, Swift AJ, Condliffe R, Johns C, Elliot CA, Hill C, Davies C, Hurdman J, Sabroe I, Wild JM, Kiely DG (2015) CT features of pulmonary arterial hypertension and its major subtypes: a systematic CT evaluation of 292 patients from the ASPIRE Registry. Thorax 70(4):382–387.  https://doi.org/10.1136/thoraxjnl-2014-206088 CrossRefGoogle Scholar
  21. 21.
    Montani D, Bergot E, Gunther S, Savale L, Bergeron A, Bourdin A, Bouvaist H, Canuet M, Pison C, Macro M, Poubeau P, Girerd B, Natali D, Guignabert C, Perros F, O’Callaghan DS, Jais X, Tubert-Bitter P, Zalcman G, Sitbon O, Simonneau G, Humbert M (2012) Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 125(17):2128–2137.  https://doi.org/10.1161/circulationaha.111.079921 CrossRefGoogle Scholar
  22. 22.
    Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M (2016) 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 37(1):67–119.  https://doi.org/10.1093/eurheartj/ehv317 CrossRefGoogle Scholar
  23. 23.
    Seegobin K, Babbar A, Ferreira J, Lyons B, Cury J, Seeram V (2017) A case of worsening pulmonary arterial hypertension and pleural effusions by bosutinib after prior treatment with dasatinib. Pulm Circ 7(4):808–812.  https://doi.org/10.1177/2045893217733444 CrossRefGoogle Scholar
  24. 24.
    Quilot FM, Georges M, Favrolt N, Beltramo G, Foignot C, Grandvuillemin A, Montani D, Bonniaud P, Camus P (2016) Pulmonary hypertension associated with ponatinib therapy. Eur Respir J 47(2):676–679.  https://doi.org/10.1183/13993003.01110-2015 CrossRefGoogle Scholar
  25. 25.
    Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galie N, Gomez-Sanchez MA, Grimminger F, Grunig E, Hassoun PM, Morrell NW, Peacock AJ, Satoh T, Simonneau G, Tapson VF, Torres F, Lawrence D, Quinn DA, Ghofrani HA (2013) Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation 127(10):1128–1138.  https://doi.org/10.1161/circulationaha.112.000765 CrossRefGoogle Scholar
  26. 26.
    Uitdehaag JC, de Roos JA, van Doornmalen AM, Prinsen MB, de Man J, Tanizawa Y, Kawase Y, Yoshino K, Buijsman RC, Zaman GJ (2014) Comparison of the cancer gene targeting and biochemical selectivities of all targeted kinase inhibitors approved for clinical use. PLoS ONE 9(3):e92146.  https://doi.org/10.1371/journal.pone.0092146 CrossRefGoogle Scholar
  27. 27.
    Jardim C, Rochitte CE, Humbert M, Rubenfeld G, Jasinowodolinski D, Carvalho CR, Souza R (2007) Pulmonary artery distensibility in pulmonary arterial hypertension: an MRI pilot study. Eur Respir J 29(3):476–481.  https://doi.org/10.1183/09031936.00016806 CrossRefGoogle Scholar
  28. 28.
    Estepar RS, Kinney GL, Black-Shinn JL, Bowler RP, Kindlmann GL, Ross JC, Kikinis R, Han MK, Come CE, Diaz AA, Cho MH, Hersh CP, Schroeder JD, Reilly JJ, Lynch DA, Crapo JD, Wells JM, Dransfield MT, Hokanson JE, Washko GR (2013) Computed tomographic measures of pulmonary vascular morphology in smokers and their clinical implications. Am J Respir Crit Care Med 188(2):231–239.  https://doi.org/10.1164/rccm.201301-0162OC CrossRefGoogle Scholar
  29. 29.
    Naeije R, Barbera JA (2001) Pulmonary hypertension associated with COPD. Crit Care 5(6):286–289CrossRefGoogle Scholar
  30. 30.
    Crary SE, Buchanan GR (2009) Vascular complications after splenectomy for hematologic disorders. Blood 114(14):2861–2868.  https://doi.org/10.1182/blood-2009-04-210112 CrossRefGoogle Scholar
  31. 31.
    Singer ST, Kuypers FA, Styles L, Vichinsky EP, Foote D, Rosenfeld H (2006) Pulmonary hypertension in thalassemia: association with platelet activation and hypercoagulable state. Am J Hematol 81(9):670–675.  https://doi.org/10.1002/ajh.20640 CrossRefGoogle Scholar
  32. 32.
    Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, Brown B, Coles WA, Nichols JS, Ernst I, Hunter LA, Blackwelder WC, Schechter AN, Rodgers GP, Castro O, Ognibene FP (2004) Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 350(9):886–895.  https://doi.org/10.1056/NEJMoa035477 CrossRefGoogle Scholar
  33. 33.
    Cederleuf H, Bjerregard Pedersen M, Jerkeman M, Relander T, d’Amore F, Ellin F (2017) The addition of etoposide to CHOP is associated with improved outcome in ALK+ adult anaplastic large cell lymphoma: a Nordic Lymphoma Group study. Br J Haematol 178(5):739–746.  https://doi.org/10.1111/bjh.14740 CrossRefGoogle Scholar
  34. 34.
    Habib A, Kunzelmann C, Shamseddeen W, Zobairi F, Freyssinet JM, Taher A (2008) Elevated levels of circulating procoagulant microparticles in patients with beta-thalassemia intermedia. Haematologica 93(6):941–942.  https://doi.org/10.3324/haematol.12460 CrossRefGoogle Scholar
  35. 35.
    Jais X, Ioos V, Jardim C, Sitbon O, Parent F, Hamid A, Fadel E, Dartevelle P, Simonneau G, Humbert M (2005) Splenectomy and chronic thromboembolic pulmonary hypertension. Thorax 60(12):1031–1034.  https://doi.org/10.1136/thx.2004.038083 CrossRefGoogle Scholar
  36. 36.
    Hoeper MM, Niedermeyer J, Hoffmeyer F, Flemming P, Fabel H (1999) Pulmonary hypertension after splenectomy? Ann Intern Med 130(6):506–509CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Takumi Toya
    • 1
    Email author
  • Yuji Nagatomo
    • 1
  • Kazuki Kagami
    • 1
  • Midori Yukino
    • 1
  • Risako Yasuda
    • 1
  • Takayuki Namba
    • 1
  • Yasuo Ido
    • 1
  • Shinichi Kobayashi
    • 2
  • Nobuyuki Masaki
    • 1
  • Hirotaka Yada
    • 1
  • Fumihiko Kimura
    • 2
  • Takeshi Adachi
    • 1
  1. 1.Division of CardiologyNational Defense Medical CollegeTokorozawaJapan
  2. 2.Division of HematologyNational Defense Medical CollegeTokorozawaJapan

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