BCL-2 has been implicated in hematologic malignancies and associated with drug resistance and poor prognosis in acute myelogenous leukemia (AML). Patients (pts) with relapsed/refractory (R/R) AML have poor prognosis with limited overall survival. ABT-199 is a selective, potent, orally bioavailable small molecule BCL-2 inhibitor. ABT-199 has demonstrated pre-clinical efficacy inhibiting the growth of AML cell lines or AML-pt derived primary cells systemically engrafted into immunocompromised mice. The current study evaluates ABT-199 monotherapy in pts with high-risk R/R AML and those unfit for chemotherapy.


The primary objective of this phase 2, open-label, multicenter trial was to evaluate preliminary efficacy of ABT-199 in R/R AML or as frontline therapy for pts unfit for intensive therapy. Secondary objectives included safety and phamacodynamic assessments. An intra-pt dose escalation was implemented in which pts received 20 mg ABT-199 on Week (Wk) 1 Day 1, with daily escalation to a final target dose of 800 mg on Day 6 and daily thereafter. Pts without a complete response (CR) or complete response with incomplete blood count recovery (CRi) at first scheduled assessment (end of Wk 4) were able to escalate to 1200 mg. Safety analyses were performed for all pts. Adverse events (AEs) were reported according to the NCI-CTCAE version 4.0. Responses were evaluated using the revised guidelines by the International Working Group for AML. Samples were collected over 24 hours at Wk 6 to evaluate ABT-199 pharmacokinetics.


As of July 8, 2014, 32 pts enrolled with a median time on study of 81 (range 13-187) days. The median age was 71 (range 19–84) years and 16 (50%) were male. Thirty (93.8%) pts had R/R disease. Twelve (37.5%) had a history of myelodysplastic syndrome and 2 (6%) had a history of myeloproliferative neoplasms. Fourteen (44%) had received more than three prior treatments and 22 (69%) had received one or both hypomethylating agents. Isocitrate dehydrogenase (IDH) 1 and 2 mutations (mt) were reported in 2 (6%) and 9 (28%) pts, respectively. In addition, 6 (19%) were shown to have FLT3-ITD mt (2 of these also had IDH2 mt). The most common treatment-emergent AEs (in ≥25% of pts) were nausea (14/32, 44%), diarrhea (12/32, 38%), fatigue (9/32, 28%), neutropenia and vomiting (each 8/32, 25%). Grade 3/4 AEs (in ≥3 pts) were febrile neutropenia (8/32, 25%), anemia and pneumonia (each 3/32, 9%). There were no reported events of clinical or laboratory tumor lysis syndrome. There were no AEs leading to death. The median bone marrow blast count was 50% (range 5–97; n=25) at baseline. Twenty eight pts were evaluable at first assessment and the median bone marrow blast count decreased to 21% (range 1–87.5; n=25; 1 patient had marrow aplasia, 1 had hemodilute aspirate and another had clinical progression), a 36% decrease from baseline. One pt had a CR (3%) and 4 (12.5%) had a CRi at first assessment. Of the 4 CRi, 1 achieved CR by Wk 20. Of the pts with CR/CRi, 3 had IDH mt; two pts with IDH2 mt were MRD negative by flow cytometry and the third with IDH1 mt remained MRD positive. Three more pts with IDH mt experienced anti-leukemic activity that did not meet IWG response criteria due to lack of hematologic recovery. Six of 32 (19%) pts had at least 50% bone marrow blast reduction at first assessment. Ten progressed before the first assessment. Two pts with coexisting IDH2 and FLT3 mt had no evidence of antileukemic activity. The overall response rate (CR/CRi by IWG response criteria) was 15.5% (5/32). All 3 pts with IDH mt relapsed before Wk 12. Two IDH wild type (WT) pts remain in CR/CRi, respectively, and 2 additional IDH WT pts continue to show hematologic improvement without meeting IWG response criteria. Mean (CV%) ABT-199 peak concentration and AUC24 for 15 pts on 800 mg dose at Wk 6 was 3.62 (49) µg/mL and 56.7 (73) µg•h/mL, respectively, which is similar to that seen in pts with lymphoid malignancies.


These preliminary data indicate that ABT-199 employed as a single agent has considerable clinical activity in pts with poor prognosis R/R AML and that pts with IDH mt may be particularly sensitive. ABT-199 monotherapy demonstrated an acceptable safety profile in these pts. ABT-199 demonstrates promising clinical activity in R/R AML pts who have limited available treatment options. This agent is being actively developed and evaluated in AML.


Konopleva:AbbVie, Inc: Research Funding; Genentech: Research Funding. Potluri:AbbVie, Inc: Employment. Chyla:AbbVie, Inc: Employment. Busman:AbbVie, Inc: Employment. McKeegan:AbbVie, Inc: Employment. Salem:AbbVie, Inc: Employment. Zhu:AbbVie, Inc: Employment. Ricker:AbbVie, Inc: Employment. Blum:Genentech: Consultancy. Dunbar:AbbVie, Inc: Employment. Kirby:AbbVie, Inc: Employment. Falotico:AbbVie, Inc: Employment. Leverson:abbvie: Employment, Equity Ownership. Humerickhouse:AbbVie, Inc: Employment. Mabry:AbbVie, Inc: Employment. Stone:AbbVie, Inc: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy; Roche: Consultancy. Letai:AbbVie, Inc: Consultancy, Research Funding; Tetralogic: Consultancy, Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.

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