Venetoclax and low-dose cytarabine induced complete remission in a patient with high-risk acute myeloid leukemia: a case report

Abstract

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.

Keywords

venetoclax / cytarabine / AML / leukemia

Introduction

Acute myeloid leukemia (AML) is the most common type of leukemia in adults aged 60 years and above. The treatment of AML largely depends on the age, performance status, and pre-existing comorbid conditions of the patient, as well as prior myelodysplasia (MDS) and cytotoxic therapy [¹]. Molecular and cytogenetic abnormalities are important prognostic indicators of AML [²–⁵]. In general, elderly patients aged>65 years receive induction therapy given its proven benefit over supportive and palliative chemotherapy. However, conventional combination therapies have not resulted in significant progress in the treatment of AML. Allogeneic hematopoietic stem-cell transplantation (HSCT), including cord-blood stem cell and haploidentical HSCT, remains a major curative approach for high-risk AML [⁶–⁸]. Next-generation sequencing has enabled the identification of common mutations associated with AML, thus allowing the development of therapies that target mutant proteins in AML [²,⁹–¹²]. Extensive clinical trials have been conducted on targeted therapy for AML [¹³–¹⁵]. Midostaurin has been recently approved for the treatment of FLT-3-mutated AML [¹⁶–¹⁹]. Venetoclax, a BCL-2 inhibitor, has also been recently approved for the treatment of relapsed and/or refractory (R/R) chronic lymphoid leukemia [²⁰–²²]. Clinical trials on the treatment of various hematological malignancies with venetoclax in combination with cytarabine and other agents are currently underway [²³–³³].

Here, we present a case of a male patient who developed AML following allogeneic HSCT for high-risk MDS. The patient exhibited complete response to the combined treatment regimen of low-dose cytarabine (LDAC) and venetoclax. We also review current clinical trials on the treatment of hematological malignancies with venetoclax.

Case presentation

In August 2014, a 67-year-old Caucasian male presented with fatigue and was found to have a low platelet (PLT) count of 50 × 1000 /mm³ (k/mm³), white blood cell (WBC) count of 8.4 k/mm³, and hemoglobin (HgB) level of 12.3 g/dL. A bone marrow biopsy conducted in February 2015 revealed markedly hypercellular marrow with dysplastic features and 7% myeloblasts. The patient was diagnosed with refractory anemia with excessive blasts-1 (RAEB-1). Karyotyping showed 46, XY, del(6)(p21.3) [²⁰]. The patient subsequently received 5 cycles of decitabine, and his cytopenia progressed to pancytopenia. He received induction chemotherapy with one cycle of 7+3 regimen of cytarabine and idarubicin. He achieved complete response with normal cytogenetics after a cycle of chemotherapy in July 2015.

In January 2016, the patient received an allogeneic stem cell transplant from a 10/10 HLA-matched unrelated female donor. The graft comprised T-cell-depleted peripheral blood stem cells. The conditioning regimen included melphalan, alemtuzumab, and fludarabine. The patient did not exhibit any clear evidence of GVHD post-transplantation and was maintained on tacrolimus for GVHD prophylaxis for 6 months. Antibiotic prophylaxis was provided as previously reported [³⁴]. A bone marrow biopsy conducted after transplantation was negative for leukemia or significant dysplasia. The patient remained transfusion-dependent in the meantime. In December 2016, he exhibited persistent pancytopenia and an increased need for transfusion support despite treatment with growth factors. His blood parameters at the time were as follows: WBC count of 0.8 k/mm³, HgB level of 8.5 g/dL, HCT of 23.8%, platelet count of 21 k/mm³. Bone marrow biopsy showed acute undifferentiated leukemia with 60% myeloblasts. Karyotyping analysis revealed 47, XX, del(6)(p21) and +8[3]/46, XY[⁵]. MDS FISH analysis showed trisomy 8. The molecular profiling of a 175-gene panel by Geneoptix Laboratory showed mutations of the ASXL1, FAT1, FGFR4, PLCG2, SRSF2, and STAG2 genes (Table 1).

Given the significant comorbidity and poor performance status of the patient, he received daily treatments of subcutaneously administered LDAC at the dose of 20 mg/m² for 10 days and venetoclax over a 28-day cycle. Ventoclax dose was escalated daily from 100 mg to 600 mg in accordance with the published regimen [²⁷]. The post-chemotherapy course of the patient was complicated by febrile neutropenia, transaminitis, aspergillosis, and severe orthostatic hypotension. Venetoclax was initially discontinued to resolve transaminitis, which was resolved by lowering venetoclax dose to 300 mg. The patient also received isavuconazole for probable pulmonary aspergillosis. The patient exhibited significant orthostatic hypotension. Extensive investigation revealed no clear cause for the orthostatic hypotension of the patient. Orthostatic hypotension was resolved after the venetoclax dose was decreased. The blood parameters of the patient on day 40 of cycle 1 were as follows: WBC count of 5.5 k/mm³, HgB level of 10.7 g/dL, HCT of 30.5%, and platelet count of 12 k/mm³. Post-treatment bone marrow biopsy on day 40 of cycle 1 showed 3% myeloblasts in the bone marrow aspirate and 0.5% through flow cytometry. Karyotyping showed 46, XY. The MDS FISH panel was normal. Molecular profiling by Geneoptix Laboratory showed mutations of the FAT1 and FGFR4 genes (Table 1). This result is consistent with complete response with thrombocytopenia (CRp). The patient completed his second cycle of subcutaneous LDAC and was discharged to the acute rehabilitation program. The patient was maintained on a daily dose of 200 mg of venetoclax. The patient passed away on May 2017 as a result of AML relapse and septic shock.

Discussion

This case report describes a MDS patient who developed secondary AML after receiving T-cell-depleted allogenic HSCT. Surprisingly, this high-risk patient with poor performance status exhibited CRp after 1 cycle of venetoclax with LDAC. The patient presented significant orthostatic hypotension without a clear etiology. Moreover, whether the occurrence of orthostatic hypotension in this patient is correlated with venetoclax treatment is unclear. No report is available on the relationship of orthostatic hypotension with venetoclax. In our case, the patient had significant transaminitis that rapidly improved and remained stable after his venetoclax dose was decreased. The patient was simultaneously receiving isavuconazole which is a strong CYP3A4 inhibitor. Recent studies have shown that venetoclax dose should be reduced by 50%–75% in patients treated concomitantly with CYP3A4 inhibitors because these drugs increase venetoclax levels [³⁵–³⁹].

Venetoclax (ABT-199) is an oral selective B-cell lymphoma-2 (BCL-2) inhibitor. Venetoclax, a BH-3 mimetic, inhibits the antiapoptotic action of other proteins, including BCL-2, BCL-xL, and BCL-w, by occupying the BH3-binding groove domain. Venetoclax has been approved for R/R chronic lymphocytic leukemia therapy. Its application as a single agent (Table 2) or in combination regimens (Table 3) in the treatment of various hematological malignancies is currently being studied.

A phase 1b/2 dose escalation/expansion trial has been conducted to evaluate the effects of orally administered venetoclax (600 and 800 mg) concomitantly given with subcutaneously administered LDAC (20 mg/m²) during days 1 to 10 of the chemotherapy cycle [²⁷]. Venetoclax dose is gradually increased and is given during days 1 to 28 of each cycle. The subjects are treatment-naïve elderly patients with AML who are≥65 years of age and who are unfit for intensive therapy. Grade 3 thrombocytopenia has been associated with a venetoclax dose of 800 mg. Hence, the dose of 600 mg is recommended for use in phase-2 trials. Complete response has been noted in 4 out of 18 patients, with another 4 patients showing partial response. Febrile neutropenia (33%) is the most common adverse event noted. Moreover, no evidence of tumor lysis syndrome has been found in the study subjects.

An update on this frontline study on combined LDAC and venetoclax therapy has been presented [⁴⁰,⁴¹]. A total of 14 out of the 20 patients (70%) enrolled in the study exhibited CR/CRp. Approximately 86% of the patients exhibited a reduction in bone marrow blasts of<5%. Nevertheless, the response rate of patients with R/R AML to this combination regimen remains unknown.

A phase-2 trial on venetoclax monotherapy with 800 mg as the target dose is ongoing in patients with R/R AML who are>65 years of age and are unfit for intensive chemotherapy [⁴²]. Objectives are evaluated on the basis of various biomarkers, such as the expression levels of BCL-2 and myeloid cell line-1 (MCL-1) proteins. BH3 profiling is also used to identify the mechanisms underlying resistance. The study reported an overall response rate of 19% with an additional 19% showing partial count recovery. The median time to disease progression is 2.5 months, and the estimated overall survival is 36%. The median overall survival is 4.7 months. This study demonstrated the activity of venetoclax monotherapy for R/R AML.

Venetoclax has synergistic activity with hypomethylating agents [⁴³–⁴⁵]. In 2015, a phase-1b trial on venetoclax in combination with either decitabine or azacytidine was conducted in treatment-naïve elderly patients who are>65 years old and are unsuitable for intensive chemotherapy (NCT02203773) [²⁴]. The study has two arms, as follows: over a 28-day cycle, patients in arm A received 20 mg/m² decitabine from days 1 to 5, whereas those in arm B received 75 mg/m² azacytidine from days 1 to 7. Patients in each arm received a daily dose of venetoclax. Venetoclax dose was gradually escalated to the maximum dose of 1200 mg. The study primarily aimed to characterize the safety and pharmacokinetic profile of venetoclax when administered with other agents. The secondary outcomes included overall efficacy. The overall response rate (CR/CR with incomplete marrow recovery/partial remission) is 75% (9 out of 12 patients) in the decitabine arm and 70% (7 out of 10 patients) in the azacytidine arm. Neutropenia and thrombocytopenia are the most common adverse events. A phase-3 double-blind, randomized study on azacytidine treatment with or without venetoclax is being conducted in treatment-naïve patients with AML who are ineligible for standard induction regimens (NCT02993523).

Clinical trials on the use of venetoclax to treat non-Hodgkin lymphoma and multiple myeloma (mantle cell lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma) are ongoing, and doses for various lymphomas are being established in phase-2 trials [²³,³¹,³²]. The use of venetoclax in the treatment of R/R multiple myeloma with prior bortezomib therapy has also been evaluated and has been shown to improve outcomes in patients with (11;14) translocation in myeloma cells [²⁹].

Recently, venetoclax resistance has been demonstrated to be secondary to elevated MCL-1 and BCL-xL levels [⁴⁶–⁴⁹]. Mutational analysis of venetoclax-resistant cells also revealed a possible new resistance mechanism that arises from a mutation of F104L in the BH3-binding groove that leads to interference within venetoclax binding [⁵⁰]. This resistance mechanism suggests that the design of new BCL-2 inhibitors that can target F104L-mutated BCL2 will be necessary. Similar approaches have been applied in designing new generations of tyrosine kinase inhibitors for EGFR and ibrutinib [⁵¹–⁵⁶].

The combination of venetoclax with additional agents, such as ibrutinib, idelalisib, bortezomib, and entospetinib, may be helpful in overcoming resistance [²³,²⁹,³¹–³³,⁵⁷,⁵⁸].

Additional mechanisms of venetoclax resistance are being actively explored through reverse-phase protein arrays, whole genome sequencing, and methylation array profiling [⁵⁹,⁶⁰]. Recurrent genomic changes, including deletions, missense mutations, or genetic alterations, that affect CDKN2A/B (p16^Ink4a/p14^Arf), BTG1, and BRAF have recently been reported [⁶⁰]. These new discoveries will guide further therapeutic strategies against venetoclax resistance.

Conclusions

Venetoclax combined with LDAC may be a feasible therapeutic option for high-risk patients with AML and who are unfit for intensive chemotherapy.

References

[1] Ossenkoppele G, Löwenberg B. How I treat the older patient with acute myeloid leukemia. Blood 2015; 125(5): 767–774

[2] 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

[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

[4] Linder K, Iragavarapu C, Liu D. SETBP1 mutations as a biomarker for myelodysplasia /myeloproliferative neoplasm overlap syndrome. Biomark Res 2017; 5(1): 33

[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

[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

[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

[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

[9] Montalban-Bravo G, Takahashi K, Garcia-Manero G. Decitabine in TP53-mutated AML. N Engl J Med 2017; 376(8): 796–798 (Correspondence)

[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

[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

[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

[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

[15] Saygin C, Carraway HE. Emerging therapies for acute myeloid leukemia. J Hematol Oncol 2017; 10(1): 93

[16] 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. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017; 377(5): 454–464

[17] Levis M. Midostaurin approved for FLT3-mutated AML. Blood 2017; 129(26): 3403–3406

[18] 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

[19] Patnaik MM. Midostaurin for the treatment of acute myeloid leukemia. Future Oncol 2017; 13(21): 1853–1871

[20] Brower V. Venetoclax targets BCL2 in chronic lymphocytic leukaemia. Lancet Oncol 2016; 17(1): e11

[21] Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 2016; 374(4): 311–322

[22] Davids MS. Targeting BCL-2 in B-cell lymphomas. Blood 2017; 130(9): 1081–1088

[23] 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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[44] Wei A. ABT-199 partners with azacitidine to contest myeloid malignancies. Leuk Lymphoma 2015; 56(1): 8–9

[45] 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

[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

[48] Bose P, Gandhi V, Konopleva M. Pathways and mechanisms of venetoclax resistance. Leuk Lymphoma 2017; 58(9): 2026–2039

[49] 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

[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

[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

[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

[54] Wu J, Liu C, Tsui ST, Liu D. Second-generation inhibitors of Bruton tyrosine kinase. J Hematol Oncol 2016; 9(1): 80

[55] Wu J, Zhang M, Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol 2016; 9(1): 21

[56] Wang S, Song Y, Liu D. EAI045: the fourth-generation EGFR inhibitor overcoming T790M and C797S resistance. Cancer Lett 2017; 385: 51–54

[57] Liu D, Mamorska-Dyga A. Syk inhibitors in clinical development for hematological malignancies. J Hematol Oncol 2017; 10(1): 145

[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

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