1. The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou 450003, China 2. Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla, NY 10595, USA
Conventional combination therapies have not resulted in considerable progress in the treatment of acute myeloid leukemia (AML). Elderly patients with AML and poor risk factors have grave prognosis. Midostaurin has been recently approved for the treatment of FLT-3-mutated AML. Venetoclax, a BCL-2 inhibitor, has been approved for the treatment of relapsed and/or refractory chronic lymphoid leukemia. Clinical trials on applying venetoclax in combination with cytarabine and other agents to treat various hematological malignancies are currently underway. Here, we present a case of a male patient with poor performance status and who developed AML following allogeneic hematopoietic stem cell transplant for high-risk myelodysplasia. The patient with high risk AML achieved complete response to the combined treatment regimen of low-dose cytarabine and venetoclax. Furthermore, we reviewed current clinical trials on the use of venetoclax for hematological malignancies.
Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, Potter NE, Heuser M, Thol F, Bolli N, Gundem G, Van Loo P, Martincorena I, Ganly P, Mudie L, McLaren S, O’Meara S, Raine K, Jones DR, Teague JW, Butler AP, Greaves MF, Ganser A, Döhner K, Schlenk RF, Döhner H, Campbell PJ; Chronic Myeloid Disorders working group of the International Cancer Genome Consortium. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 2016; 374(23): 2209–2221 https://doi.org/10.1056/NEJMoa1516192
3
Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P, Yoon CJ, Ellis P, Wedge DC, Pellagatti A, Shlien A, Groves MJ, Forbes SA, Raine K, Hinton J, Mudie LJ, McLaren S, Hardy C, Latimer C, Della Porta MG, O’Meara S, Ambaglio I, Galli A, Butler AP, Walldin G, Teague JW, Quek L, Sternberg A, Gambacorti-Passerini C, Cross NC, Green AR, Boultwood J, Vyas P, Hellstrom-Lindberg E, Bowen D, Cazzola M, Stratton MR, Campbell PJ. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 2013; 122(22): 3616–3627 https://doi.org/10.1182/blood-2013-08-518886
4
Linder K, Iragavarapu C, Liu D. SETBP1 mutations as a biomarker for myelodysplasia /myeloproliferative neoplasm overlap syndrome. Biomark Res 2017; 5(1): 33 https://doi.org/10.1186/s40364-017-0113-8
5
Taylor J, Xiao W, Abdel-Wahab O. Diagnosis and classification of hematologic malignancies on the basis of genetics. Blood 2017; 130(4): 410–423 https://doi.org/10.1182/blood-2017-02-734541
6
Shimoni A, Labopin M, Savani B, Volin L, Ehninger G, Kuball J, Bunjes D, Schaap N, Vigouroux S, Bacigalupo A, Veelken H, Sierra J, Eder M, Niederwieser D, Mohty M, Nagler A. Long-term survival and late events after allogeneic stem cell transplantation from HLA-matched siblings for acute myeloid leukemia with myeloablative compared to reduced-intensity conditioning: a report on behalf of the acute leukemia working party of European group for blood and marrow transplantation. J Hematol Oncol 2016; 9(1): 118 https://doi.org/10.1186/s13045-016-0347-1
7
Saraceni F, Labopin M, Gorin NC, Blaise D, Tabrizi R, Volin L, Cornelissen J, Cahn JY, Chevallier P, Craddock C, Wu D, Huynh A, Arcese W, Mohty M, Nagler A. Matched and mismatched unrelated donor compared to autologous stem cell transplantation for acute myeloid leukemia in first complete remission: a retrospective, propensity score-weighted analysis from the ALWP of the EBMT. J Hematol Oncol 2016; 9(1): 79 https://doi.org/10.1186/s13045-016-0314-x
8
Ruggeri A, Battipaglia G, Labopin M, Ehninger G, Beelen D, Tischer J, Ganser A, Schwerdtfeger R, Glass B, Finke J, Michallet M, Stelljes M, Jindra P, Arnold R, Kröger N, Mohty M, Nagler A. Unrelated donor versus matched sibling donor in adults with acute myeloid leukemia in first relapse: an ALWP-EBMT study. J Hematol Oncol 2016; 9(1): 89 https://doi.org/10.1186/s13045-016-0321-y
9
Montalban-Bravo G, Takahashi K, Garcia-Manero G. Decitabine in TP53-mutated AML. N Engl J Med 2017; 376(8): 796–798 (Correspondence) https://doi.org/10.1056/NEJMc1616062
10
Welch JS, Petti AA, Ley TJ. Decitabine in TP53-mutated AML. N Engl J Med 2017; 376(8): 797–798 (Correspondence)
11
Guerenne L, Beurlet S, Said M, Gorombei P, Le Pogam C, Guidez F, de la Grange P, Omidvar N, Vanneaux V, Mills K, Mufti GJ, Sarda-Mantel L, Noguera ME, Pla M, Fenaux P, Padua RA, Chomienne C, Krief P. GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways. J Hematol Oncol 2016; 9(1): 5 https://doi.org/10.1186/s13045-016-0235-8
12
Ivey A, Hills RK, Simpson MA, Jovanovic JV, Gilkes A, Grech A, Patel Y, Bhudia N, Farah H, Mason J, Wall K, Akiki S, Griffiths M, Solomon E, McCaughan F, Linch DC, Gale RE, Vyas P, Freeman SD, Russell N, Burnett AK, Grimwade D. Assessment of minimal residual disease in standard-risk AML. N Engl J Med 2016; 374(5): 422–433 https://doi.org/10.1056/NEJMoa1507471
13
Boddu P, Takahashi K, Pemmaraju N, Daver N, Benton CB, Pierce S, Konopleva M, Ravandi F, Cortes J, Kantarjian H, DiNardo CD. Influence of IDH on FLT3ITD status in newly diagnosed AML. Leukemia 2017; 31(11): 2526–2529 https://doi.org/10.1038/leu.2017.244
14
Kelly AD, Kroeger H, Yamazaki J, Taby R, Neumann F, Yu S, Lee JT, Patel B, Li Y, He R, Liang S, Lu Y, Cesaroni M, Pierce SA, Kornblau SM, Bueso-Ramos CE, Ravandi F, Kantarjian HM, Jelinek J, Issa JP. A CpG island methylator phenotype in acute myeloid leukemia independent of IDH mutations and associated with a favorable outcome. Leukemia 2017; 31(10): 2011–2019 https://doi.org/10.1038/leu.2017.12
Tvedt TH, Nepstad I, Bruserud O. Antileukemic effects of midostaurin in acute myeloid leukemia — the possible importance of multikinase inhibition in leukemic as well as nonleukemic stromal cells. Expert Opin Investig Drugs 2017; 26(3): 343–355 https://doi.org/10.1080/13543784.2017.1275564
de Vos S, Flowers CR, Wang D, Swinnen LJ, Fowler N, Reid E, Gifford M, D’Amico D, Dunbar M, Zhu M, Yang J, Enschede SH, Ricker JL, Chien D, Humerickhouse RA, Kozloff M. The BCL-2 inhibitor ABT-199 (GDC-0199) in combination with bendamustine and rituximab in patients with relapsed or refractory non-Hodgkin’s lymphoma. Blood 2014; 124(21): 1722
24
DiNardo C, Pollyea D, Pratz K, Thirman MJ, Letai A, Frattini M, Jonas B, Leverson J, Zhu M, Dunbar M, Falotico N, Kirby R, Agarwal S, Mabry M, Potluri J, Humerickhouse RA, Kantarjian HM, Konopleva M. 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
25
Fischer K, Al-Sawaf O, Fink AM, Dixon M, Bahlo J, Warburton S, Kipps TJ, Weinkove R, Robinson S, Seiler T, Opat S, Owen C, López J, Humphrey K, Humerickhouse R, Tausch E, Frenzel L, Eichhorst B, Wendtner CM, Stilgenbauer S, Langerak AW, van Dongen JJM, Böttcher S, Ritgen M, Goede V, Mobasher M, Hallek M. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood 2017; 129(19): 2702–2705 https://doi.org/10.1182/blood-2017-01-761973
26
Flinn I, Brunvand M, Dyer MJ, Hillman P, Jones J, Lymp J, Elhamy M, Vosganian G, Huang J, Kipps TJ. Preliminary results of a phase 1b study (GP28331) combining GDC-0199 (ABT-199) and obinutuzumab in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia. Blood 2014; 124(21): 4687
27
Lin T, Strickland SA, Fiedler W, Walter RB, Hou J-Z, Roboz GJ, Enjeti A, Fakhoui KM, Darden DE, Dunbar M, Zhu M, Hayslip JW and Wei AH. Phase Ib/2 study of venetoclax with low-dose cytarabine in treatment-naive patients age≥65 with acute myelogenous leukemia. J Clin Oncol 2016; 34(15_suppl): 7007
28
Ma S, Seymour JF, Lanasa MC, Kipps TJ, Barrientos JC, Davids MS, Mason-Bright T, Rudersdorf N, Yang J, Munasinghe W, Zhu M, Cerri E, Enschede SH, Humerickhouse R, Roberts AW. ABT-199 (GDC-0199) combined with rituximab (R) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): interim results of a phase 1b study. ASCO Meeting Abstracts 2014; 32(15_suppl): 7013
29
Moreau P, Chanan-Khan AAA, Roberts AW, Agarwal A, Facon T, Kumar S, Touzeau C, Diehl S, Cordero J, Ross JA, Munasinghe W, Zhu M, Salem AH, Leverson J, Maciag PC, Verdugo ME and Harrison SJ. Phase Ib venetoclax combined with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. J Clin Oncol 2016; 34(15_suppl): 8011
30
Portell CA, Axelrod M, Brett LK, Gordon VL, Capaldo B, Xing JC, Bekiranov S, Williams ME, Weber MJ. Synergistic cytotoxicity of ibrutinib and the BCL2 antagonist, ABT-199(GDC-0199) in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL): molecular analysis reveals mechanisms of target interactions. Blood 2014; 124(21): 509
31
Roberts AW, Ma S, Brander DM, Kipps TJ, Barrientos JC, Davids MS, Anderson MA, Tam C, Mason-Bright T, Rudersdorf NK, Gressick L, Yang J, Munasinghe W, Zhu M, Cerri E, Enschede SH, Humerickhouse RA, Seymour JF. Determination of recommended phase 2 dose of ABT-199 (GDC-0199) combined with rituximab (R) in patients with relapsed / refractory (R/R) chronic lymphocytic leukemia (CLL). Blood 2014; 124(21): 325
32
Zelenetz AD, Salles GA, Mason KD, Casulo C, Gouill SL, Sehn LH, Tilly H, Cartron G, Chamuleau MED, Goy A, Tam C, Lugtenburg PJ, Elstrom RL, Hsu W, Mobasher M and Morschhauser F. Phase 1b study of venetoclax plus R- or G-CHOP in patients with B-cell non-Hodgkin lymphoma. J Clin Oncol 2016; 34(15_suppl): 7566
33
Zhao X, Bodo J, Sun D, Durkin L, Lin J, Smith MR, Hsi ED. Combination of ibrutinib with ABT-199: synergistic effects on proliferation inhibition and apoptosis in mantle cell lymphoma cells through perturbation of BTK, AKT and BCL2 pathways. Br J Haematol 2015; 168(5): 765–768 https://doi.org/10.1111/bjh.13149
34
Gao L, Sun Y, Meng F, Han M, Huang H, Wu D, Yu L, Ren H, Huang X, Zhang X. Antifungal prophylaxis of patients undergoing allogenetic hematopoietic stem cell transplantation in China: a multicenter prospective observational study. J Hematol Oncol 2016; 9(1): 97 https://doi.org/10.1186/s13045-016-0305-y
35
Agarwal SK, DiNardo CD, Potluri J, Dunbar M, Kantarjian HM, Humerickhouse RA, Wong SL, Menon RM, Konopleva MY, Salem AH. Management of venetoclax-posaconazole interaction in acute myeloid leukemia patients: evaluation of dose adjustments. Clin Ther 2017; 39(2): 359–367 https://doi.org/10.1016/j.clinthera.2017.01.003
36
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 2016; 56(11): 1335–1343 https://doi.org/10.1002/jcph.730
37
Agarwal SK, Salem AH, Danilov AV, Hu B, Puvvada S, Gutierrez M, Chien D, Lewis LD, Wong SL. Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in patients with non-Hodgkin lymphoma. Br J Clin Pharmacol 2017; 83(4): 846–854 https://doi.org/10.1111/bcp.13175
38
Salem AH, Agarwal SK, Dunbar M, Nuthalapati S, Chien D, Freise KJ, Wong SL. Effect of low- and high-fat meals on the pharmacokinetics of venetoclax, a selective first-in-class BCL-2 inhibitor. J Clin Pharmacol 2016; 56(11): 1355–1361 https://doi.org/10.1002/jcph.741
39
Salem AH, Hu B, Freise KJ, Agarwal SK, Sidhu DS, Wong SL. Evaluation of the pharmacokinetic interaction between venetoclax, a selective BCL-2 Inhibitor, and warfarin in healthy volunteers. Clin Drug Investig 2017; 37(3): 303–309 https://doi.org/10.1007/s40261-016-0485-9
40
Wei A, Strickland SA, Roboz GJ, Hou JZ, Fiedler W, Lin TL, Martinelli G, Walter RB, Enjeti A, Fakouhi K, Darden DE, Dunbar M, Zhu M, Agarwal S, Salem AH, Mabry M, Hayslip J. Safety and efficacy of venetoclax plus low-dose cytarabine in treatment-naive patients aged≥65 years with acute myeloid leukemia. Blood 2016; 128(22): 102
41
Wei A, Strickland SA, Roboz GJ, Hou JZ, Fiedler W, Lin TL, Walter RB, Enjeti A, Chyla B, Popovic R, Fakouhi K, Shah P, Dunbar M, Xu T, Mabry M, Hayslip J. Phase 1/2 study of venetoclax with low-dose cytarabine in treatment-naive, elderly patients with acute myeloid leukemia unfit for intensive chemotherapy: 1-year outcomes. Blood 2017; 130(Suppl 1): 890
42
Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, McKeegan E, Salem AH, Zhu M, Ricker JL, Blum W, DiNardo CD, Kadia T, Dunbar M, Kirby R, Falotico N, Leverson J, Humerickhouse R, Mabry M, Stone R, Kantarjian H, Letai A. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov 2016; 6(10): 1106–1117 https://doi.org/10.1158/2159-8290.CD-16-0313
43
Bogenberger JM, Kornblau SM, Pierceall WE, Lena R, Chow D, Shi CX, Mantei J, Ahmann G, Gonzales IM, Choudhary A, Valdez R, Camoriano J, Fauble V, Tiedemann RE, Qiu YH, Coombes KR, Cardone M, Braggio E, Yin H, Azorsa DO, Mesa RA, Stewart AK, Tibes R. BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies. Leukemia 2014; 28(8): 1657–1665 https://doi.org/10.1038/leu.2014.44
DiNardo CD, Pollyea DA, Jonas BA, Konopleva M, Pullarkat V, Wei A, Kantarjian HM, Pigneux A, Recher C, Seymour JF, Dunbar M, Xu T, Mabry M, Potluri J, Pratz K, Letai A. Updated safety and efficacy of venetoclax with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 2017; 130(Suppl 1): 2628
46
Bodo J, Zhao X, Durkin L, Souers AJ, Phillips DC, Smith MR, Hsi ED. Acquired resistance to venetoclax (ABT-199) in t(14;18) positive lymphoma cells. Oncotarget 2016; 7(43): 70000–70010 https://doi.org/10.18632/oncotarget.12132
47
Bodo J, Zhao X, Smith MR, Hsi ED. Activity of ABT-199 and acquired resistance in follicular lymphoma cells. Blood 2014; 124(21): 3635
Zhang Q, Pan R, Han L, Shi C, Kurtz SE, Mu H, Ma H, Andreeff M, Leverson J, Tyner JW, Mi Y, Konopleva M. Mechanisms of acquired resistance to venetoclax in preclinical AML models. Blood 2015; 126(23): 328
50
Tahir SK, Smith ML, Hessler P, Rapp LR, Idler KB, Park CH, Leverson JD, Lam LT. Potential mechanisms of resistance to venetoclax and strategies to circumvent it. BMC Cancer 2017; 17(1): 399 https://doi.org/10.1186/s12885-017-3383-5
51
Wang S, Cang S, Liu D. Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer. J Hematol Oncol 2016; 9(1): 34 https://doi.org/10.1186/s13045-016-0268-z
52
Wang S, Song Y, Yan F, Liu D. Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors. Front Med 2016; 10(4): 383–388 https://doi.org/10.1007/s11684-016-0488-1
53
Wang S, Tsui ST, Liu C, Song Y, Liu D. EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M-positive non-small cell lung cancer. J Hematol Oncol 2016; 9(1): 59 https://doi.org/10.1186/s13045-016-0290-1
Wu J, Zhang M, Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol 2016; 9(1): 21 https://doi.org/10.1186/s13045-016-0250-9
56
Wang S, Song Y, Liu D. EAI045: the fourth-generation EGFR inhibitor overcoming T790M and C797S resistance. Cancer Lett 2017; 385: 51–54 https://doi.org/10.1016/j.canlet.2016.11.008
57
Liu D, Mamorska-Dyga A. Syk inhibitors in clinical development for hematological malignancies. J Hematol Oncol 2017; 10(1): 145 https://doi.org/10.1186/s13045-017-0512-1
58
Jain N, Thompson PA, Ferrajoli A, Burger JA, Borthakur G, Takahashi K, Bose P, Estrov Z, Jabbour EJ, Konopleva M, Alvarado Y, Kadia T, Yilmaz M, DiNardo CD, Ohanian M, Cortes JE, Kanagal-Shamanna R, Patel K, Garg N, Wang X, Fru N, Cruz N, Gandhi V, Plunkett W, Kantarjian HM, Keating MJ, Wierda WG. Combined venetoclax and ibrutinib for patients with previously untreated high-risk CLL, and relapsed/refractory CLL: a phase II trial. Blood 2017; 130(Suppl 1): 429
59
Huang S, Jiang C, Guo H, Wang J, Liu Y, Li C, Lopez E, Zhang H, Lorence EA, Merolle M, Balaji S, Ahmed M, Nomie K, Zhang L, Wang M. Resistance mechanisms underlying venetoclax resistance in mantle cell lymphoma. Blood 2017; 130(Suppl 1): 2749
60
Frenzel LP, Herling CD, Abedpour N, Weiss J, Mayer P, Cartolano M, Berg V, Kutsch N, Cramer P, Wendtner CM, Persigehl T, Saleh A, Altmüller J, Nürnberg P, Pallasch C, Achter V, Lang U, Eichhorst BF, Castiglione R, Schaefer SC, Buettner R, Kreuzer KA, Reinhardt HC, Hallek MJ, Peifer M. Mechanisms of venetoclax resistance in chronic lymphocytic leukemia. Blood 2017; 130(Suppl 1): 263