Evaluating venetoclax and its potential in treatment-naïve acute myeloid leukemia

Figures & data

Table 1 Completed studies of venetoclax in the treatment of AML

Intervention	Population	Major findings	Reference
Venetoclax (variable dosing) plus either low-dose cytarabine or decitabine or azacitidine. Retrospective analysis.	Adult (25–83 years), 43 total patients, with R/R AML (39), MDS (2), or BPDCN (2). Heavily pretreated, 2–8 preceding lines of treatment, including HMAs	9 patients (21%) responded including 8 with R/R AML to venetoclax 100–800 mg (all doses other than 400–800 mg administered in combination with azole antifungal). Median OS 3 months, 4.8 months for responders (range: 1–8 months); 2 responders able to proceed to allogeneic HSCT.	DiNardo et al, 2018.^Citation71
Venetoclax monotherapy (800 mg daily). Phase II, open label, single arm.	Adult (19–84 years), 32 total patients with AML; 2 treatment naïve, 30 with R/R disease. Among R/R patients, all heavily pretreated.	6 patients (19%) responded; additional 6 patients (19%) demonstrated antileukemic activity not meeting IWG response criteria. Among responders, 2 (6%) achieved CR. Median OS 4.7 months (range: 2.3–6.0 months)	Konopleva et al, 2016.^Citation72
Venetoclax (variable dosing, 600–800 mg daily goal) plus low-dose cytarabine. Phase I/Phase II, open label, single arm.	Adult (≥65 years or unfit for intensive chemotherapy), 71 total patients, all treatment naïve.	Overall response rate was 75% (5% PR, 70% response CR or Cri). OS at 12 months was 74.7%. One-year follow-up: 64% CR/CRi/PR (26% CR and 2% PR), median duration of 14.9 months, with total median OS of 11.4 months (and median OS of 18.4 months in those achieving CR/Cri). Those with unfavorable cytogenetics all achieved CR/CRi of over 75%.	Wei et al, 2016.^Citation38 Lin et al, 2016.^Citation39 Wei et al, 2017.^Citation40
Venetoclax (variable dosing, up to 1200 mg daily) plus either azacitidine or decitabine. Phase 1/Phase II, open label, non-randomized.	Adult (≥65 years or unfit for intensive chemotherapy), 145 total patients, all treatment naïve.	Overall response rate 68% (7% PR, 61% CR/CRi). OS at 12 months was 59%. At one-year follow-up 67% CR/CRi, median response duration of 11.3 months, with total median OS of 17.5 months. Those with unfavorable cytogenetics achieved CR/CRi of 60% .	DiNardo et al, 2018.^Citation42 DiNardo et al, 2019.^Citation43

Abbreviations: AML, acute myeloid leukemia; BPDCN, blastic plasmacytoid dendritic cell neoplasm; CR, complete response; CRi, complete response with incomplete hematological recovery; HMAs, hypomethylating agents; HSCT, hematopoietic stem cell transplant; IWG, International Working Group; MDS, myelodysplastic syndrome; OS, overall survival; PR, partial response; R/R, relapsed/refractory

Table 2 Active clinical trials of venetoclax in acute myeloid leukemia

NCT Number	Name	Status	Disease	Drug(s)	Phase	Design	Population
NCT02287233	A study evaluating venetoclax in combination with low-dose cytarabine in treatment-naïve subjects with AML.	Active, not recruiting	AML	Venetoclax, cytarabine	Phase I Phase II	Open-label, single group	Age: 60 years to 99 years
NCT03466294	Azacitidine and venetoclax as induction therapy with venetoclax maintenance in the elderly with AML	Recruiting	AML	Venetoclax, azacitidine	Phase II	Open-label, single group	60 years and older
NCT03484520	A study of venetoclax and dinaciclib (MK7965) in patients with relapsed/refractory AML	Recruiting	AML	Venetoclax, dinaciclib	Phase I	Open-label, single group	18 years and older
NCT03441555	A study of venetoclax and alvocidib in patients with relapsed/refractory AML	Recruiting	AML	Venetoclax, alvocidib	Phase I	Open-label, single group	18 years and older
NCT03625505	A study to assess safety and efficacy of venetoclax in combination with gilteritinib in subjects with relapsed/refractory AML	Recruiting	AML	Venetoclax, gilteritinib	Phase I	Open-label, single group	18 years and older
NCT02993523	A study of venetoclax in combination with azacitidine versus azacitidine in treatment naïve subjects with AML who are ineligible for standard induction therapy	Recruiting	AML	Venetoclax, azacitidine	Phase III	Randomized, double-blind.	18 years and older
NCT03709758	Venetoclax in combination with intensive induction and consolidation chemotherapy in treatment naïve AML	Recruiting	AML	Venetoclax, daunorubicin, cytarabine	Phase I	Open-label, single group	18 years to 75 years
NCT03069352	A study of venetoclax in combination with low dose cytarabine versus low dose cytarabine alone in treatment naive patients with AML who are ineligible for intensive chemotherapy	Recruiting	AML	Venetoclax, cytarabine	Phase III	Randomized, double-blind.	18 years and older
NCT03214562	Study of the BCL-2 inhibitor venetoclax in combination with standard intensive AML induction/consolidation therapy with FLAG-IDA in patients with newly diagnosed or relapsed/refractory AML	Recruiting	AML	Venetoclax, fludarabine, cytarabine, idarubicin, filgrastim	Phase I Phase II	Nonrandomized, parallel assignment, open-label	18 years and older
NCT03613532	Venetoclax added to fludarabine + busulfan prior to transplant for AML, MDS, and MDS/MPN	Recruiting	AML, MDS, MDS/MPN	Venetoclax, fludarabine, busulfan	Phase I	Open-label, single group	18 years and older
NCT03586609	Venetoclax, cladribine, low dose cytarabine, and azacitidine in treating participants with patients previously untreated AML	Recruiting	AML	Venetoclax, azacitidine, cladribine, cytarabine	Phase II	Open-label, single group	60 years and older
NCT03629171	Liposome-encapsulated daunorubicin-cytarabine and venetoclax in treating participants with relapsed, refractory or untreated AML	Recruiting	AML	Venetoclax, liposome-encapsulated daunorubicin-cytarabine	Phase II	Open-label, single group	18 years and older
NCT03573024	Venetoclax and azacitidine for non-elderly adult patients with AML	Recruiting	AML	Venetoclax, aazacitidine	Phase II	Open-label, single group	18 years to 59 years
NCT02203773	Study of ABT-199 (GDC-0199) in combination with azacitidine or decitabine (chemo combo) in subjects with AML	Active, not recruiting	AML	Venetoclax, posaconazole, decitabine, azacitidine,	Phase I Phase II	Open-label, single group	60 years and older
NCT03662724	Venetoclax registry	Recruiting	AML	Venetoclax	N/A	Observation cohort	16 years and older
NCT03672695	Phase I dose escalation study of intravenously administered S64315 in combination with orally administered venetoclax in patients with AML	Not yet recruiting	AML	Venetoclax, S64315	Phase I	Open-label, sequential assignment	18 years and older
NCT03844815	Study of venetoclax in combination with decitabine in subjects with AML	Not yet recruiting	AML	Venetoclax, decitabine	Phase I	Open-label, single group	18 years and older
NCT03194932	Study of venetoclax in combination with chemotherapy in pediatric patients with refractory or relapsed AML or acute leukemia of ambiguous lineage	Recruiting	AML	Venetoclax, cytarabine, idarubicin, intrathecal triple therapy	Phase I	Open-label, single group	2 years to 20 years
NCT03735875	Venetoclax and quizartinib in treating patients with FLT3-mutated recurrent or refractory AML	Recruiting	AML	Venetoclax, quizartinib	Phase I Phase II	Open-label, single group	18 years and older
NCT03404193	Venetoclax in combination with 10-day decitabine in newly diagnosed elderly or relapsed/refractory AML and relapsed high-risk MDS	Recruiting	AML, MDS	Venetoclax, ddecitabine	Phase II	Open-label, single group	18 years and older
NCT03455504	Venetoclax add in combination with fludarabine, cyratabine and idarubicine in induction for AML	Not yet recruiting	AML	Venetoclax, fludarabine, cytarabine, idarubicin	Phase II	Nonrandomized, parallel assignment, open-label	18 years to 65 years
NCT02670044	A study of venetoclax in combination with cobimetinib and venetoclax in combination with idasanutlin in patients aged ≥60 years with relapsed or refractory AML who are not eligible for cytotoxic therapy	Recruiting	AML	Venetoclax, cobimetinib, idasanutlin	Phase I Phase II	Nonrandomized, parallel assignment, open-label	60 years and older
NCT03471260	Study of venetoclax with the mIDH1 inhibitor ivosidenib (AG120) in IDH1-mutated hematologic malignancies	Recruiting	AML, other	Venetoclax, ivosidenib	Phase I Phase II	Open-label, single group	18 years and older
NCT03797261	A study of venetoclax and AMG 176 in patients with relapsed/refractory hematologic malignancies	Not yet recruiting	AML, NHL, DLBCL	Venetoclax, AMG 176	Phase I	Open-label, sequential assignment	18 years and older
NCT02265731	Study evaluating venetoclax in subjects with hematological malignancies	Active, not recruiting	AML, CLL, SLL, NHL, MM	Venetoclax, azacitadine, rituximab/IDEC-C2B8	Phase I Phase II	Open-label, single group	20 years and older
NCT03236857	A study of the safety and pharmacokinetics of venetoclax in pediatric and young adult patients with relapsed or refractory malignancies	Recruiting	AML, ALL, NHL, NBL	Venetoclax	Phase I	Open-label, single group	Up to 25 years
NCT03844048	An extension study of venetoclax for subjects who have completed a prior venetoclax clinical trial	Not yet recruiting	AML	Venetoclax	Phase III	Open-label, single group	Any

Abbreviations: ABT-199, venetoclax; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; MDS, myelodysplastic syndrome; MDS/MPN, myelodysplastic syndrome/myeloproliferative neoplasm; MM, multiple myeloma; NBL, neuroblastoma; NHL, non-Hodgkin's lymphoma; SLL, small lymphocytic leukemia.

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