Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia

Clinical Pharmacokinetics

Volumn 56, Issue 5, 2017, Pages 515-523

  Freise, Kevin J ^a   Jones, Aksana K ^a   Eckert, Doerthe ^a   Mensing, Sven ^a   Wong, Shekman L ^a   Humerickhouse, Rod A ^a   Awni, Walid M ^a   Salem, Ahmed Hamed ^a  

^a ABBVIE INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

RITUXIMAB; VENETOCLAX; ANTINEOPLASTIC AGENT; FUSED HETEROCYCLIC RINGS; SULFONAMIDE;

ADULT; AGED; ARTICLE; CANCER COMBINATION CHEMOTHERAPY; CANCER PATIENT; CANCER SIZE; CHRONIC LYMPHATIC LEUKEMIA; CONCENTRATION AT STEADY-STATE; DRUG BLOOD LEVEL; DRUG DISPOSITION; DRUG DOSE ESCALATION; DRUG DOSE INCREASE; DRUG EFFICACY; DRUG EXPOSURE; DRUG SAFETY; FEMALE; HUMAN; INFECTION; LEUKEMIA RELAPSE; LEUKEMIA REMISSION; LYMPHOCYTE; LYMPHOCYTE COUNT; LYMPHOCYTIC LYMPHOMA; MAJOR CLINICAL STUDY; MALE; MONOTHERAPY; NEUTROPENIA; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; PLASMA CONCENTRATION-TIME CURVE; PRIORITY JOURNAL; REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA; SOMATIC MUTATION; TREATMENT RESPONSE; CHEMICALLY INDUCED; CLINICAL TRIAL; DRUG ADMINISTRATION; MIDDLE AGED; ORAL DRUG ADMINISTRATION; RECURRENT DISEASE; TREATMENT OUTCOME; VERY ELDERLY;

ADMINISTRATION, ORAL; ADULT; AGED; AGED, 80 AND OVER; ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; BRIDGED BICYCLO COMPOUNDS, HETEROCYCLIC; DRUG ADMINISTRATION SCHEDULE; FEMALE; HUMANS; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; MALE; MIDDLE AGED; NEUTROPENIA; RECURRENCE; SULFONAMIDES; TREATMENT OUTCOME;

EID: 84988442696     PISSN: 03125963     EISSN: 11791926     Source Type: Journal    
DOI: 10.1007/s40262-016-0453-9     Document Type: Article

References (41)

1. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202–8.
2. AbbVie. Venclexta (venetoclax) tablets full prescribing information. North Chicago: AbbVie; 2016.
3. Willis S, Day CL, Hinds MG, Huang DC. The Bcl-2-regulated apoptotic pathway. J Cell Sci. 2003;116(Pt 20):4053–6.
4. Bouillet P, Purton JF, Godfrey DI, Zhang LC, Coultas L, Puthalakath H, et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature. 2002;415(6874):922–6.
5. Borner C. The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions. Mol Immunol. 2003;39(11):615–47.
6. Cory S, Huang DC, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003;22(53):8590–607.
7. Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311–22.
8. Gerecitano JF, Roberts AW, Seymour JF, Wierda WG, Kahl BS, Pagel JM, et al. A phase 1 study of venetoclax (ABT-199 / GDC-0199) monotherapy in patients with relapsed/refractory non-Hodgkin lymphoma. Blood. 2015;126(23):254.
9. Moreau P, Chanan-Khan A, Roberts AW, Agarwal AB, Facon T, Kumar S, et al. Safety and efficacy of venetoclax (ABT-199/GDC-0199) in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma: phase 1b results. Blood. 2015;126(23):3038.
10. DiNardo C, Pollyea D, Pratz K, Thirman MJ, Letai A, Frattini M, et al. A phase 1b study of venetoclax (ABT-199/GDC-0199) in combination with decitabine or azacitidine in treatment-naive patients with acute myelogenous leukemia who are ≥ to 65 years and not eligible for standard induction therapy. Blood. 2015;126(23):327.
11. Ma S, Brander DM, Seymour JF, Kipps TJ, Barrientos JC, Davids MS, et al. Deep and durable responses following venetoclax (ABT-199 / GDC-0199) combined with rituximab in patients with relapsed/refractory chronic lymphocytic leukemia: results from a phase 1b study. Blood. 2015;126(23):494.
12. Stilgenbauer S, Eichhorst Barbara, Schetelig J, Coutre S, Seymour JF, Munir T, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768–78.
13. Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. doi:10.1158/2159-8290.cd-16-0313. (Epub 12 Aug 2016).
14. Leverson JD, Phillips DC, Mitten MJ, Boghaert ER, Diaz D, Tahir SK, et al. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci Transl Med. 2015;7(279):279ra40.
15. Ackler S, Oleksijew A, Chen J, Chyla BJ, Clarin J, Foster K, et al. Clearance of systemic hematologic tumors by venetoclax (Abt-199) and navitoclax. Pharmacol Res Perspect. 2015;3(5):e00178.
16. Jaglowski S, Jones JA. Choosing first-line therapy for chronic lymphocytic leukemia. Expert Rev Anticancer Ther. 2011;11(9):1379–90.
17. Francis S, Karanth M, Pratt G, Starczynski J, Hooper L, Fegan C, et al. The effect of immunoglobulin VH gene mutation status and other prognostic factors on the incidence of major infections in patients with chronic lymphocytic leukemia. Cancer. 2006;107(5):1023–33.
18. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343(26):1910–6.
19. Geisler CH, Philip P, Christensen BE, Hou-Jensen K, Pedersen NT, Jensen OM, et al. In B-cell chronic lymphocytic leukaemia chromosome 17 abnormalities and not trisomy 12 are the single most important cytogenetic abnormalities for the prognosis: a cytogenetic and immunophenotypic study of 480 unselected newly diagnosed patients. Leuk Res. 1997;21(11–12):1011–23.
20. Stilgenbauer S, Zenz T. Understanding and managing ultra high-risk chronic lymphocytic leukemia. Hematol Am Soc Hematol Educ Program. 2010;2010:481–8.
21. Byrd JC, Gribben JG, Peterson BL, Grever MR, Lozanski G, Lucas DM, et al. Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy. J Clin Oncol. 2006;24(3):437–43.
22. Jones AK, Freise KJ, Agarwal S, Humerickhouse RA, Wong SL, Salem AH. Clinical predictors of venetoclax pharmacokinetics, a selective BCL-2 inhibitor, in chronic lymphocytic leukemia and non-Hodgkin’s lymphoma patients: a pooled population pharmacokinetic analysis. AAPS J. 2016;18(5):1192–202.
23. Jones AK, Freise KJ, Agarwal S, Verdugo M, Humerickhouse RA, Wong SL, Salem AH. Venetoclax pharmacokinetics in hematological malignancies subjects with renal and hepatic impairment. American College of Clinical Pharmacology Annual Meeting. 2016. September 25–27, North Bethesda, MD.
24. Agarwal SK, Hu B, Chien D, Wong SL, Salem AH. Evaluation of rifampin’s transporter inhibitory and CYP3A inductive effects on the pharmacokinetics of venetoclax, a Bcl-2 Inhibitor: results of a single- and multiple-dose study. J Clin Pharmacol. doi:10.1002/jcph.730. (Epub 7 Mar 2016).
25. Salem AH, Agarwal S, Dunbar M, Nuthalapati S, Chien D, Freise KJ, et al. Effect of low and high fat meals on the pharmacokinetics of venetoclax, a selective first-in-class Bcl-2 inhibitor. J Clin Pharmacol. doi:10.1002/jcph.741. (Epub 31 Mar 2016).
26. Salem AH, Agarwal SK, Dunbar M, Enschede SLH, Humerickhouse RA, Wong SL. Pharmacokinetics of venetoclax, a novel BCL-2 inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or non-Hodgkin’s lymphoma. J Clin Pharmacol. doi:10.1002/jcph.821. (Epub 25 Aug 2016).
27. Jones J, Mato AR, Coutre S, Wierda W, Choi MY, Davids MS, et al. Preliminary results of a phase 2, open-label study of venetoclax (ABT-199/GDC-0199) monotherapy in patients with chronic lymphocytic leukemia relapsed after or refractory to ibrutinib or idelalisib therapy. Blood. 2015;126(23):715.
28. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446–56.
29. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579–86.
30. Wahlby U, Jonsson EN, Karlsson MO. Comparison of stepwise covariate model building strategies in population pharmacokinetic-pharmacodynamic analysis. AAPS PharmSci. 2002;4(4):E27.
31. van Gent R, Kater AP, Otto SA, Jaspers A, Borghans JA, Vrisekoop N, et al. In vivo dynamics of stable chronic lymphocytic leukemia inversely correlate with somatic hypermutation levels and suggest no major leukemic turnover in bone marrow. Cancer Res. 2008;68(24):10137–44.
32. Committee for Medicinal Products for Human Use (CHMP). Guideline on evaluation of anticancer medicinal products in man. London: European Medicines Agency (EMA); 2016.
33. Thijssen R, Slinger E, Weller K, Geest CR, Beaumont T, van Oers MH, et al. Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors. Haematologica. 2015;100(8):e302–6.
34. Davids MS, Letai A, Brown JR. Overcoming stroma-mediated treatment resistance in chronic lymphocytic leukemia through BCL-2 inhibition. Leuk Lymphoma. 2013;54(8):1823–5.
35. Bojarczuk K, Sasi BK, Gobessi S, Innocenti I, Pozzato G, Laurenti L, et al. BCR signaling inhibitors differ in their ability to overcome Mcl-1-mediated resistance of CLL B cells to ABT-199. Blood. 2016;127(25):3192–201.
36. Chiron D, Dousset C, Brosseau C, Touzeau C, Maiga S, Moreau P, et al. Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma. Oncotarget. 2015;6(11):8750–9.
37. Wodarz D, Garg N, Komarova NL, Benjamini O, Keating MJ, Wierda WG, et al. Kinetics of CLL cells in tissues and blood during therapy with the BTK inhibitor ibrutinib. Blood. 2014;123(26):4132–5.
38. Byrd JC, Jones JJ, Woyach JA, Johnson AJ, Flynn JM. Entering the era of targeted therapy for chronic lymphocytic leukemia: impact on the practicing clinician. J Clin Oncol. 2014;32(27):3039–47.
39. Hallek M. Chronic lymphocytic leukemia: 2015 update on diagnosis, risk stratification, and treatment. Am J Hematol. 2015;90(5):446–60.
40. Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M, et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125(16):2497–506.
41. Jain P, Keating M, Wierda W, Estrov Z, Ferrajoli A, Jain N, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125(13):2062–7.