Skip to main content

Advertisement

SpringerLink
Log in

Phase II clinical trial of pazopanib in patients with acute myeloid leukemia (AML), relapsed or refractory or at initial diagnosis without an intensive treatment option (PazoAML)

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

We evaluated pazopanib (800 mg orally QD) in patients not eligible for intensive treatment with relapsed/refractory AML or at initial diagnosis. Patients receiving pazopanib for > 14 days were analyzed for safety, tolerability, and efficacy. Co-primary endpoints were cumulative response rate and reduction of bone marrow microvessel density. Twenty patients (median age 76 years, range 52–86) were treated. Fifteen had relapsed/refractory and five had newly diagnosed AML. Median ECOG performance status was 1 (range 1–3). Four patients had adverse, 15 intermediate, and 1 patient favorable cytogenetic/molecular risk (ELN 2010 criteria). The safety profile of pazopanib was as reported. The most common adverse events of any grade were gastrointestinal. Two patients achieved PR (blast reduction > 50%), 14 stable disease (SD), and 4 progressive disease. Median PFS was 65 days (95% CI 29–105). After the end of the study, 1 CRi and 1 CRp occurred on demethylating agents, and 1 CR upon alloSCT. In these patients, SD and improved general condition on pazopanib allowed therapy escalation. Median OS for the overall study population was 191 days (95% CI 87–435) and 1-year survival was 35%. There was no significant change in microvessel density. Clinical trial information: NCT01361334.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Abdel-Wahab O, Levine RL (2010) Recent advances in the treatment of acute myeloid leukemia. F1000 Med Rep 2:55. https://doi.org/10.3410/M2-55

    Article  PubMed  PubMed Central  Google Scholar 

  2. Buchner T, Berdel WE, Haferlach C, Haferlach T, Schnittger S, Muller-Tidow C, Braess J, Spiekermann K, Kienast J, Staib P, Gruneisen A, Kern W, Reichle A, Maschmeyer G, Aul C, Lengfelder E, Sauerland MC, Heinecke A, Wormann B, Hiddemann W (2009) Age-related risk profile and chemotherapy dose response in acute myeloid leukemia: a study by the German Acute Myeloid Leukemia Cooperative Group. J Clin Oncol 27(1):61–69. https://doi.org/10.1200/JCO.2007.15.4245

    Article  CAS  PubMed  Google Scholar 

  3. Metzelder S, Wang Y, Wollmer E, Wanzel M, Teichler S, Chaturvedi A, Eilers M, Enghofer E, Neubauer A, Burchert A (2009) Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood 113(26):6567–6571. https://doi.org/10.1182/blood-2009-03-208298

    Article  CAS  PubMed  Google Scholar 

  4. Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Dohner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Dohner H (2017) Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 377(5):454–464. https://doi.org/10.1056/NEJMoa1614359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ikeda H, Kanakura Y, Tamaki T, Kuriu A, Kitayama H, Ishikawa J, Kanayama Y, Yonezawa T, Tarui S, Griffin JD (1991) Expression and functional role of the proto-oncogene c-kit in acute myeloblastic leukemia cells. Blood 78(11):2962–2968

    CAS  PubMed  Google Scholar 

  6. Wang C, Curtis JE, Geissler EN, McCulloch EA, Minden MD (1989) The expression of the proto-oncogene C-kit in the blast cells of acute myeloblastic leukemia. Leukemia 3(10):699–702

    CAS  PubMed  Google Scholar 

  7. Bieker R, Padro T, Kramer J, Steins M, Kessler T, Retzlaff S, Herrera F, Kienast J, Berdel WE, Mesters RM (2003) Overexpression of basic fibroblast growth factor and autocrine stimulation in acute myeloid leukemia. Cancer Res 63(21):7241–7246

    CAS  PubMed  Google Scholar 

  8. Fiedler W, Graeven U, Ergun S, Verago S, Kilic N, Stockschlader M, Hossfeld DK (1997) Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia. Blood 89(6):1870–1875

    CAS  PubMed  Google Scholar 

  9. Hussong JW, Rodgers GM, Shami PJ (2000) Evidence of increased angiogenesis in patients with acute myeloid leukemia. Blood 95(1):309–313

    CAS  PubMed  Google Scholar 

  10. Padro T, Bieker R, Ruiz S, Steins M, Retzlaff S, Burger H, Buchner T, Kessler T, Herrera F, Kienast J, Muller-Tidow C, Serve H, Berdel WE, Mesters RM (2002) Overexpression of vascular endothelial growth factor (VEGF) and its cellular receptor KDR (VEGFR-2) in the bone marrow of patients with acute myeloid leukemia. Leukemia 16(7):1302–1310. https://doi.org/10.1038/sj.leu.2402534

    Article  CAS  PubMed  Google Scholar 

  11. Padro T, Ruiz S, Bieker R, Burger H, Steins M, Kienast J, Buchner T, Berdel WE, Mesters RM (2000) Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. Blood 95(8):2637–2644

    CAS  Google Scholar 

  12. Fiedler W, Mesters R, Tinnefeld H, Loges S, Staib P, Duhrsen U, Flasshove M, Ottmann OG, Jung W, Cavalli F, Kuse R, Thomalla J, Serve H, O’Farrell AM, Jacobs M, Brega NM, Scigalla P, Hossfeld DK, Berdel WE (2003) A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia. Blood 102(8):2763–2767. https://doi.org/10.1182/blood-2002-10-2998

    Article  CAS  PubMed  Google Scholar 

  13. Fiedler W, Serve H, Dohner H, Schwittay M, Ottmann OG, O’Farrell AM, Bello CL, Allred R, Manning WC, Cherrington JM, Louie SG, Hong W, Brega NM, Massimini G, Scigalla P, Berdel WE, Hossfeld DK (2005) A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 105(3):986–993. https://doi.org/10.1182/blood-2004-05-1846

    Article  CAS  PubMed  Google Scholar 

  14. Mesters RM, Padro T, Bieker R, Steins M, Kreuter M, Goner M, Kelsey S, Scigalla P, Fiedler W, Buchner T, Berdel WE (2001) Stable remission after administration of the receptor tyrosine kinase inhibitor SU5416 in a patient with refractory acute myeloid leukemia. Blood 98(1):241–243

    Article  CAS  PubMed  Google Scholar 

  15. O’Farrell AM, Foran JM, Fiedler W, Serve H, Paquette RL, Cooper MA, Yuen HA, Louie SG, Kim H, Nicholas S, Heinrich MC, Berdel WE, Bello C, Jacobs M, Scigalla P, Manning WC, Kelsey S, Cherrington JM (2003) An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin Cancer Res 9(15):5465–5476

    PubMed  Google Scholar 

  16. Foss B, Ulvestad E, Bruserud O (2001) Platelet-derived growth factor (PDGF) in human acute myelogenous leukemia: PDGF receptor expression, endogenous PDGF release and responsiveness to exogenous PDGF isoforms by in vitro cultured acute myelogenous leukemia blasts. Eur J Haematol 67(4):267–278

    Article  CAS  PubMed  Google Scholar 

  17. Kulimova E, Oelmann E, Bisping G, Kienast J, Mesters RM, Schwable J, Hilberg F, Roth GJ, Munzert G, Stefanic M, Steffen B, Brandts C, Muller-Tidow C, Kolkmeyer A, Buchner T, Serve H, Berdel WE (2006) Growth inhibition and induction of apoptosis in acute myeloid leukemia cells by new indolinone derivatives targeting fibroblast growth factor, platelet-derived growth factor, and vascular endothelial growth factor receptors. Mol Cancer Ther 5(12):3105–3112. https://doi.org/10.1158/1535-7163.MCT-06-0323

    Article  CAS  PubMed  Google Scholar 

  18. Kumar R, Knick VB, Rudolph SK, Johnson JH, Crosby RM, Crouthamel MC, Hopper TM, Miller CG, Harrington LE, Onori JA, Mullin RJ, Gilmer TM, Truesdale AT, Epperly AH, Boloor A, Stafford JA, Luttrell DK, Cheung M (2007) Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 6(7):2012–2021. https://doi.org/10.1158/1535-7163.MCT-07-0193

    Article  CAS  PubMed  Google Scholar 

  19. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarba JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28(6):1061–1068. https://doi.org/10.1200/JCO.2009.23.9764

    Article  CAS  Google Scholar 

  20. Schliemann C, Gerss J, Wiebe S, Mikesch JH, Knoblauch N, Sauer T, Angenendt L, Kewitz T, Urban M, Butterfass-Bahloul T, Edemir S, Vehring K, Muller-Tidow C, Berdel WE, Krug U (2016) A phase I dose escalation study of the triple angiokinase inhibitor nintedanib combined with low-dose cytarabine in elderly patients with acute myeloid leukemia. PLoS One 11(10):e0164499. https://doi.org/10.1371/journal.pone.0164499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Recher C, Sandhu I, Bernal del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Dohner H (2015) International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 126(3):291–299. https://doi.org/10.1182/blood-2015-01-621664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysak D, Minden M, Arthur C (2012) Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 30(21):2670–2677. https://doi.org/10.1200/JCO.2011.38.9429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ossenkoppele GJ, Stussi G, Maertens J, van Montfort K, Biemond BJ, Breems D, Ferrant A, Graux C, de Greef GE, Halkes CJ, Hoogendoorn M, Hollestein RM, Jongen-Lavrencic M, Levin MD, van de Loosdrecht AA, van Marwijk Kooij M, van Norden Y, Pabst T, Schouten HC, Vellenga E, Verhoef GE, de Weerdt O, Wijermans P, Passweg JR, Lowenberg B (2012) Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: a randomized phase 2 trial of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK). Blood 120(24):4706–4711. https://doi.org/10.1182/blood-2012-04-420596

    Article  CAS  PubMed  Google Scholar 

  24. Zahiragic L, Schliemann C, Bieker R, Thoennissen NH, Burow K, Kramer C, Zuhlsdorf M, Berdel WE, Mesters RM (2007) Bevacizumab reduces VEGF expression in patients with relapsed and refractory acute myeloid leukemia without clinical antileukemic activity. Leukemia 21(6):1310–1312. https://doi.org/10.1038/sj.leu.2404632

    Article  CAS  PubMed  Google Scholar 

  25. DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, Frankfurt O, Konopleva M, Wei AH, Kantarjian HM, Xu T, Hong WJ, Chyla B, Potluri J, Pollyea DA, Letai A (2019) Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 133(1):7–17. https://doi.org/10.1182/blood-2018-08-868752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank our study nurses and study administrators for their kind support.

Funding

This study was supported by a grant from GSK and Novartis Germany. The laboratories of G.L. and W.E.B. are supported by Deutsche Forschungsgemeinschaft, Cluster of Excellence: Cells in Motion (EXC 1003).

Author information

Author notes

  1. Carsten Müller-Tidow and Wolfgang E. Berdel shared senior authorship

Authors and Affiliations

  1. Department of Medicine A, University Hospital Muenster, Muenster, Germany

    Torsten Kessler, Christoph Schliemann, Jan-Henrik Mikesch, Matthias Stelljes, Michele Pohlen, Georg Lenz, Anna Kirsch, Kerstin Vehring, Carsten Müller-Tidow & Wolfgang E. Berdel

  2. Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany

    Steffen Koschmieder, Martina Crysandt & Tim H. Brümmendorf

  3. Institute for Pathology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany

    Saskia von Stillfried

  4. Gerhard-Domagk-Institute for Pathology, University Hospital Muenster, Muenster, Germany

    Eva Wardelmann & Wolfgang Hartmann

  5. Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany

    Eike Bormann & Joachim Gerss

  6. Department of Medicine V, University of Heidelberg, Heidelberg, Germany

    Carsten Müller-Tidow

Authors
  1. Torsten Kessler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steffen Koschmieder
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christoph Schliemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martina Crysandt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jan-Henrik Mikesch
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Saskia von Stillfried
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Matthias Stelljes
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michele Pohlen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Georg Lenz
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Anna Kirsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kerstin Vehring
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Eva Wardelmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Wolfgang Hartmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Eike Bormann
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Joachim Gerss
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Tim H. Brümmendorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Carsten Müller-Tidow
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Wolfgang E. Berdel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.K., S.K., C.S., and W.E.B. designed the study. T.K. and S.K. were principal investigators. E.W. and W.H. were involved in the MVD analysis. E.B., J.G., T.K., and S.K. were involved in the statistical analysis. T.K., S.K., C.S., M.C., J.-H. M., S.v.S., M.S., M.P., G.L., A.K., K.V., T.B., C.M.-T., and W.E.B. provided and treated patients. T.K., S.K., and W.E.B. wrote the manuscript. All authors revised and agreed to the manuscript.

Corresponding authors

Correspondence to Torsten Kessler, Steffen Koschmieder or Wolfgang E. Berdel.

Ethics declarations

Institutional review board or independent ethics committee approval and written informed consent from all patients for being included in the study were obtained. The study was performed in accordance with the ethical principles of the Declaration of Helsinki and in compliance with national laws.

Conflict of interest

Dr. Koschmieder declares Consultancy, Honoraria, and Research Funding by Novartis. Dr. Stelljes declares Pfizer Consultancy, Honoraria and Research Funding; MSD Consultancy; JAZZ Honoraria; Amgen Honoraria; Novartis Honoraria. Dr. Lenz reports the following: Celgene Corp. Consultancy, Honoraria, Travel, Accommodations, Expenses, Research Funding and Speakers Bureau; Janssen Consultancy, Honoraria, Travel, Accommodations, Expenses, Research Funding and Speakers Bureau; Roche Consultancy, Honoraria, Travel, Accomodations, Expenses, and Research Funding; Bayer Consultancy, Honoraria, Research Funding and Speakers Bureau; Novartis Research Funding; Gilead Consultancy and Honoraria. Dr. Brümmendorf reports Pfizer Consultancy and Research Funding, Novartis Consultancy and Research Funding, Takeda Consultancy, Janssen Consultancy, and Merck Consultancy. Dr. Müller-Tidow reports Pfizer Research Funding. Dr. Berdel reports research grants by GSK and Novartis. The other authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Torsten Kessler and Steffen Koschmieder shared first authorship

Electronic supplementary material

ESM 1

(PDF 838 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kessler, T., Koschmieder, S., Schliemann, C. et al. Phase II clinical trial of pazopanib in patients with acute myeloid leukemia (AML), relapsed or refractory or at initial diagnosis without an intensive treatment option (PazoAML). Ann Hematol 98, 1393–1401 (2019). https://doi.org/10.1007/s00277-019-03651-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-019-03651-9

Keywords

Search

Navigation