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A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy

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Abstract

Patients with chronic lymphocytic leukemia (CLL) who receive chemoimmunotherapy and do not achieve complete remission experience significantly shortened progression-free interval (PFS). Additionally, the majority of patients treated for relapsed disease demonstrate evidence of measurable disease. Eradication of minimal residual disease (MRD) results in improved PFS and overall survival. Maintenance therapy might result in eradication of MRD and improve response duration but might be associated with an increase in incidence of infectious complications. Flavopiridol is a broad cyclin-dependent kinase (CDK) inhibitor with established safety and efficacy in patients with relapsed CLL, particularly patients with high-risk cytogenetic features. A pharmacologically derived schedule was utilized as consolidation therapy in this phase I study to assess the safety and feasibility of outpatient therapy with flavopiridol in patients with low tumor burden. Flavopiridol was administered as a 30-min loading dose of 30 mg/m2 followed by a 4-h infusion of 30 mg/m2 once weekly for 3 weeks every 5 weeks (1 cycle) for planned 2 cycles in ten patients. Therapy was extremely well tolerated and no patient developed acute tumor lysis syndrome. The most common toxicities were gastrointestinal. Of the patients, 22 % improved their response from a PR to CR. Eighty-eight percent experienced a reduction in tumor burden as measured by extent of bone marrow involvement including patients with del17p and complex karyotype. The study establishes the safety and efficacy of flavopiridol as consolidation therapy after chemoimmunotherapy for patients with CLL. Further evaluation is required in larger trials for the utility of CDK inhibitors as consolidation or maintenance strategies.

Registration number at ClinicalTrials.gov: NCT00377104.

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References

  1. Hallek M, Fischer K, Fingerle-Rowson G et al (2010) Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 376:1164–74

    Article  CAS  PubMed  Google Scholar 

  2. Awan FT, Hillmen P, Hellmann A et al (2014) A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia. Br J Haematol 167:466–77

    Article  CAS  PubMed  Google Scholar 

  3. Robak T, Dmoszynska A, Solal-Celigny P et al (2010) Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 28:1756–65

    Article  CAS  PubMed  Google Scholar 

  4. Awan FT, Byrd JC (2014) New strategies in chronic lymphocytic leukemia: shifting treatment paradigms. Clin Cancer Res 20:5869–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Schweighofer CD, Ritgen M, Eichhorst BF et al (2009) Consolidation with alemtuzumab improves progression-free survival in patients with chronic lymphocytic leukaemia (CLL) in first remission: long-term follow-up of a randomized phase III trial of the German CLL Study Group (GCLLSG). Br J Haematol 144:95–8

    Article  CAS  PubMed  Google Scholar 

  6. Shanafelt TD, Ramsay AG, Zent CS et al (2013) Long-term repair of T-cell synapse activity in a phase II trial of chemoimmunotherapy followed by lenalidomide consolidation in previously untreated chronic lymphocytic leukemia (CLL). Blood 121:4137–41

    Article  CAS  PubMed  Google Scholar 

  7. Del Poeta G, Del Principe MI, Buccisano F et al (2008) Consolidation and maintenance immunotherapy with rituximab improve clinical outcome in patients with B-cell chronic lymphocytic leukemia. Cancer 112:119–28

    Article  PubMed  Google Scholar 

  8. van Oers MH, Kuliczkowski K, Smolej L et al (2015) Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol 16(13):1370–9

    Article  PubMed  Google Scholar 

  9. Blum KA, Ruppert AS, Woyach JA et al (2011) Risk factors for tumor lysis syndrome in patients with chronic lymphocytic leukemia treated with the cyclin-dependent kinase inhibitor, flavopiridol. Leukemia 25:1444–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Byrd JC, Lin TS, Dalton JT et al (2007) Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 109:399–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Byrd JC, Peterson BL, Gabrilove J et al (2005) Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous infusion or 1-hour bolus infusion of flavopiridol: results from Cancer and Leukemia Group B study 19805. Clin Cancer Res 11:4176–81

    Article  CAS  PubMed  Google Scholar 

  12. Phelps MA, Rozewski DM, Johnston JS et al (2008) Development and validation of a sensitive liquid chromatography/mass spectrometry method for quantitation of flavopiridol in plasma enables accurate estimation of pharmacokinetic parameters with a clinically active dosing schedule. J Chromatogr B Analyt Technol Biomed Life Sci 868:110–5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jones JA, Rupert AS, Poi M et al (2014) Flavopiridol can be safely administered using a pharmacologically derived schedule and demonstrates activity in relapsed and refractory non-Hodgkin’s lymphoma. Am J Hematol 89:19–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hofmeister CC, Poi M, Bowers MA et al (2014) A phase I trial of flavopiridol in relapsed multiple myeloma. Cancer Chemother Pharmacol 73:249–57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ramaswamy B, Phelps MA, Baiocchi R et al (2012) A dose-finding, pharmacokinetic and pharmacodynamic study of a novel schedule of flavopiridol in patients with advanced solid tumors. Invest New Drugs 30:629–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fischer K, Cramer P, Busch R et al (2011) Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 29:3559–66

    Article  CAS  PubMed  Google Scholar 

  17. Wierda W, O’Brien S, Wen S et al (2005) Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol 23:4070–8

    Article  CAS  PubMed  Google Scholar 

  18. Lin TS, Ruppert AS, Johnson AJ et al (2009) Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J Clin Oncol 27:6012–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Stephens DM, Ruppert AS, Blum K et al (2012) Flavopiridol treatment of patients aged 70 or older with refractory or relapsed chronic lymphocytic leukemia is a feasible and active therapeutic approach. Haematologica 97:423–7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Abrisqueta P, Villamor N, Terol MJ et al (2013) Rituximab maintenance after first-line therapy with rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) for chronic lymphocytic leukemia. Blood 122:3951–9

    Article  CAS  PubMed  Google Scholar 

  21. Byrd JC, Furman RR, Coutre SE et al (2013) Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 369:32–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Brown JR, Byrd JC, Coutre SE et al (2014) Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood 123:3390–7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Roberts AW, Davids MS, Pagel JM et al (2016) Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 374:311–22

    Article  PubMed  Google Scholar 

  24. Byrd JC, Harrington B, O’Brien S et al (2016) Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med 374:323–32

    Article  PubMed  Google Scholar 

  25. Furman RR, Sharman JP, Coutre SE et al (2014) Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370:997–1007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors thank all of the patients and their families who participated in this trial as well as the dedicated nurses, nurse practitioners, and physicians who cared for them at the James Cancer Hospital inpatient/outpatient Leukemia Units and the Clinical Treatment Unit. This work was supported by the Leukemia and Lymphoma Society, Lymphoma Research Foundation, and the D Warren Brown Foundation.

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Authors and Affiliations

  1. Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, 320 W. 10th Avenue, Columbus, Ohio, 43210, USA

    Farrukh T. Awan, Jeffrey A. Jones, Kami Maddocks, Ming Poi, Michael R. Grever, Amy Johnson, John C. Byrd & Leslie A. Andritsos

  2. Starling Loving Hall, 320 W. 10th Avenue, Columbus, Ohio, 43210, USA

    Leslie A. Andritsos

Authors
  1. Farrukh T. Awan
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  2. Jeffrey A. Jones
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  3. Kami Maddocks
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  4. Ming Poi
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  5. Michael R. Grever
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  6. Amy Johnson
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  7. John C. Byrd
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  8. Leslie A. Andritsos
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Corresponding authors

Correspondence to Farrukh T. Awan or Leslie A. Andritsos.

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Conflict of interest

The authors declare no relevant conflicts of interest except for research funding from Lymphoma Research Foundation, Leukemia and Lymphoma Society, and D Warren Brown Foundation.

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Awan, F.T., Jones, J.A., Maddocks, K. et al. A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy. Ann Hematol 95, 1137–1143 (2016). https://doi.org/10.1007/s00277-016-2683-1

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  • DOI: https://doi.org/10.1007/s00277-016-2683-1

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