Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study

Andrew H Wei, Stephen A Strickland Jr, Jing-Zhou Hou, Walter Fiedler, Tara L Lin, Roland B Walter, Anoop Enjeti, Ing Soo Tiong, Michael Savona, Sangmin Lee, Brenda Chyla, Relja Popovic, Ahmed Hamed Salem, Suresh Agarwal, Tu Xu, Kaffa M Fakouhi, Rod Humerickhouse, Wan-Jen Hong, John Hayslip, Gail J Roboz, Andrew H Wei, Stephen A Strickland Jr, Jing-Zhou Hou, Walter Fiedler, Tara L Lin, Roland B Walter, Anoop Enjeti, Ing Soo Tiong, Michael Savona, Sangmin Lee, Brenda Chyla, Relja Popovic, Ahmed Hamed Salem, Suresh Agarwal, Tu Xu, Kaffa M Fakouhi, Rod Humerickhouse, Wan-Jen Hong, John Hayslip, Gail J Roboz

Abstract

Purpose: Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. An international phase Ib/II study evaluated the safety and preliminary efficacy of venetoclax, a selective B-cell leukemia/lymphoma-2 inhibitor, together with low-dose cytarabine (LDAC) in older adults with AML.

Patients and methods: Adults 60 years or older with previously untreated AML ineligible for intensive chemotherapy were enrolled. Prior treatment of myelodysplastic syndrome, including hypomethylating agents (HMA), was permitted. Eighty-two patients were treated at the recommended phase II dose: venetoclax 600 mg per day orally in 28-day cycles, with LDAC (20 mg/m2 per day) administered subcutaneously on days 1 to 10. Key end points were tolerability, safety, response rates, duration of response (DOR), and overall survival (OS).

Results: Median age was 74 years (range, 63 to 90 years), 49% had secondary AML, 29% had prior HMA treatment, and 32% had poor-risk cytogenetic features. Common grade 3 or greater adverse events were febrile neutropenia (42%), thrombocytopenia (38%), and WBC count decreased (34%). Early (30-day) mortality was 6%. Fifty-four percent achieved complete remission (CR)/CR with incomplete blood count recovery (median time to first response, 1.4 months). The median OS was 10.1 months (95% CI, 5.7 to 14.2), and median DOR was 8.1 months (95% CI, 5.3 to 14.9 months). Among patients without prior HMA exposure, CR/CR with incomplete blood count recovery was achieved in 62%, median DOR was 14.8 months (95% CI, 5.5 months to not reached), and median OS was 13.5 months (95% CI, 7.0 to 18.4 months).

Conclusion: Venetoclax plus LDAC has a manageable safety profile, producing rapid and durable remissions in older adults with AML ineligible for intensive chemotherapy. High remission rate and low early mortality combined with rapid and durable remission make venetoclax and LDAC an attractive and novel treatment for older adults not suitable for intensive chemotherapy.

Trial registration: ClinicalTrials.gov NCT02287233.

Figures

FIG 1.
FIG 1.
Complete remission (CR)/CR with incomplete blood count recovery (CRi) rates by patient subgroups. The graph shows the rates of CR and CRi in all patients, as well as key patient subgroups sorted by baseline characteristics. The numbers in the bars represent the percentage of patients with a given response, and the black number at the top of each bar is the total CR/CRi percentage in a given subgroup. Partial remissions are not shown, because only one patient had a partial remission. AML, acute myeloid leukemia; HMA, hypomethylating agent; intrmed, intermediate.
FIG 2.
FIG 2.
Overall survival and duration of response. Kaplan-Meier curves showing (A) duration of remission for patients who had complete remission (CR)/CR with incomplete blood count recovery (CRi); (B) overall survival of all patients; (C) overall survival broken down by the patients’ best response; (D) overall survival by prior hypomethylating agent (HMA) exposure. NOTE: Numbers in parentheses are 95% CIs. DS, discontinued prior to assessment; LDAC, low-dose cytarabine; MLFS, morphologic leukemia–free state; NA, not available; NR, not reached; PD, progressive disease; PR, partial remission; RD, resistant disease; Ven, venetoclax.

References

    1. Juliusson G, Antunovic P, Derolf A, et al. Age and acute myeloid leukemia: Real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood. 2009;113:4179–4187.
    1. US Department of Health and Human Services, National Institutes of Health. National Cancer Institute: Surveillance, Epidemiology, and End Results Program: Cancer Stat Facts: Leukemia – Acute Myeloid Leukemia (AML). 2018 .
    1. Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007;109:1114–1124.
    1. Dennis M, Hills RK, Russell NH, et al: An evaluation of 17 years of low dose cytarabine as therapy for AML patients not fit for intensive treatment, including patients with adverse cytogenetics, shows improving survival, potential underutilisation and highlights the need for new therapy. Blood 2017; 130:3874.
    1. Kantarjian HM, Thomas XG, Dmoszynska A, et al. 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. 2012;30:2670–2677.
    1. Amadori S, Suciu S, Selleslag D, et al. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: Results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016;34:972–979.
    1. Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015;126:291–299.
    1. Ma E, Bonthapally V, Chawla A, et al: An evaluation of treatment patterns and outcomes in elderly patients newly diagnosed with acute myeloid leukemia: A retrospective analysis of electronic medical records from US community oncology practices. Clin Lymphoma Myeloma Leuk 16:625-636.e3, 2016.
    1. Del Poeta G, Venditti A, Del Principe MI, et al. Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML) Blood. 2003;101:2125–2131.
    1. Lagadinou ED, Sach A, Callahan K, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12:329–341.
    1. Fischer K, Al-Sawaf O, Fink AM, et al. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood. 2017;129:2702–2705.
    1. Kumar S, Kaufman JL, Gasparetto C, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017;130:2401–2409.
    1. Moreau P, Chanan-Khan A, Roberts AW, et al. Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood. 2017;130:2392–2400.
    1. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:311–322.
    1. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378:1107–1120.
    1. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: A multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17:768–778.
    1. Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6:1106–1117.
    1. Bogenberger JM, Delman D, Hansen N, et al. Ex vivo activity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-azacytidine in myeloid malignancies. Leuk Lymphoma. 2015;56:226–229.
    1. Niu X, Zhao J, Ma J, et al. Binding of released Bim to Mcl-1 is a mechanism of intrinsic resistance to ABT-199 which can be overcome by combination with daunorubicin or cytarabine in AML cells. Clin Cancer Res. 2016;22:4440–4451.
    1. Teh TC, Nguyen NY, Moujalled DM, et al. Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1. Leukemia. 2018;32:303–312.
    1. DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: A non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19:216–228.
    1. Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21:4642–4649.
    1. Agarwal SK, DiNardo CD, Potluri J, et al. Management of venetoclax-posaconazole interaction in acute myeloid leukemia patients: Evaluation of dose adjustments. Clin Ther. 2017;39:359–367.
    1. US Department of Health and Human Services, National Institutes of Health , National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE) v4.03. 2018.
    1. Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 2011;364:1844–1854.
    1. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood. 2009;114:937–951.
    1. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–2221.
    1. Papaemmanuil E, Döhner H, Campbell PJ. Genomic classification in acute myeloid leukemia. N Engl J Med. 2016;375:900–901.
    1. Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood. 2006;107:3481–3485.
    1. Breems DA, Van Putten WL, De Greef GE, et al. Monosomal karyotype in acute myeloid leukemia: A better indicator of poor prognosis than a complex karyotype. J Clin Oncol. 2008;26:4791–4797.
    1. Kantarjian H, O’brien S, Cortes J, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: Predictive prognostic models for outcome. Cancer. 2006;106:1090–1098.
    1. Prébet T, Gore SD, Esterni B, et al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011;29:3322–3327.
    1. Kantarjian H, Ravandi F, O’Brien S, et al. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood. 2010;116:4422–4429.
    1. Gardin C, Turlure P, Fagot T, et al. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy: Results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood. 2007;109:5129–5135.
    1. Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36:2684–2692.
    1. Oran B, Weisdorf DJ. Survival for older patients with acute myeloid leukemia: A population-based study. Haematologica. 2012;97:1916–1924.
    1. Al-Ali HK, Jaekel N, Niederwieser D. The role of hypomethylating agents in the treatment of elderly patients with AML. J Geriatr Oncol. 2014;5:89–105.
    1. Cashen AF, Schiller GJ, O’Donnell MR, et al. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol. 2010;28:556–561.
    1. Döhner H, Lübbert M, Fiedler W, et al. Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy. Blood. 2014;124:1426–1433.
    1. Chyla B, Daver N, Doyle K, et al. Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. Am J Hematol. 2018;93:E202–E205.
    1. Agarwal SK, Salem AH, Danilov AV, et al. 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;83:846–854.

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