. 2020 Nov 23;10(11):122. doi: 10.1038/s41408-020-00388-x

Table 1.

Clinical studies with venetoclax-based chemotherapy in treatment naïve acute myeloid leukemia (AML).

Study	Design	Treatment arms	Toxicity	Efficacy	Survival	Correlative studies
DiNardo et al. Lancet Oncol. (2018)	Phase 1b Group A: N = 23 Group B: N = 22 Group C: N = 12	Group A (VEN + decitabine) Group B (VEN + azacitidine), Group C (VEN + decitabine+posaconazole) Dose escalation: Group A/B VEN 400 mg (cohort 1), 800 mg (cohorts 2/3), 1200 mg (cohort 4), 400 mg for group C >65 years unfit for induction therapy. ECOG 0-2, intermediate/poor cytogenetic risk	Febrile neutropenia Lung infection Nausea Vomiting Fatigue Leukopenia Thrombocytopenia Diarrhea Anorexia	RP2D 400 mg daily or 800 mg interrupted schedule. CR/CRi; 35 (61%) Median duration of response 8.4 months (group A), 12.3 months (group B), 4.3 months (group C)	Median OS; group A 15.2 months, group B 14.2 months	23/35 (66%) with intermediate-risk cytogenetics in CR/CRi vs 11/21 (52%) with poor-risk cytogenetics. Mutations and response: 10/17 (59%) with IDH1/2 mutations, 3/4 (75%) with FLT3-ITD mutations; vs 4/11 (36%) with TP53 mutations in CR/CRi
DiNardo et al. Blood (2019)	Phase 1b N = 145	Dose escalation, VEN 400, 800, or 1200 mg daily with decitabine or azacitidine. Dose expansion, 400 or 800 mg VEN with either HMA. >65 years unfit for induction therapy	Grade 3/4 AEs: febrile neutropenia (43%), leukopenia (31%), anemia (25%), thrombocytopenia (24%), pneumonia (13%)	CR/CRi 67% in all patients. CR/CRi 73% with VEN 400 mg. Median duration of CR/CRi (all patients)— 11.3 months	Median OS in all patients—17.5 months. Median OS (VEN 400 mg)—NR	CR/CRi with poor- and intermediate-risk cytogenetics 60% and 74%. CR/CRi NPM1 mutation: 91.5%, IDH1/2 mutations: 71%, FLT3 mutation: 72%, TP53 mutation: 47%
Wei et al. JCO (2019)	Phase 1b/II N = 82	VEN 600 mg po daily + LDAC 20 mg/m² S/C (days 1–10) >60 years previously untreated AML ineligible for intensive chemotherapy	Grade 3/4 AEs: febrile neutropenia (42%), thrombocytopenia (38%), leukopenia (34%)	CR/CRi 54% Median duration of response; 8.1 months (95% CI, 5.3–14.9 months)	Median OS 10.1 months (95% CI, 5.7 to 14.2)	NPM1, IDH1/2 mutations higher CR/CRi (89%/72%, respectively), TP53 or FLT3 mutations lower CR/CRi (30%/44%, respectively).
DiNardo et al. NEJM (2020)	Phase-3 placebo-controlled, randomized, VIALE-A N = 433	Azacitidine + VEN (N = 286) or azacitidine + placebo (N = 145). 2:1 ratio >75 years or >18 years with comorbidity ineligible for intensive induction therapy	Nausea, constipation, diarrhea, vomiting. SAEs febrile neutropenia (30% vs 10%), pneumonia (17% vs 22%) with and without VEN, respectively. 1% tumor lysis with VEN	CR + CRi 66.4 vs 28.3% (p < 0.001) with and without VEN, respectively	Median OS 14.7 and 9.6 months in the VEN vs placebo arm, respectively (HR, 0.66; 95% CI, 0.52–0.85; p < 0.001)	CR/CRi rate: IDH1/2 (75% vs 11%), FLT3 (72 vs 36%), NPM1 (67% vs 24%), and TP53 (55% vs 0%), with and without VEN respectively.
Wei et al. Blood (2020)	Phase-3 randomized double-blind placebo-controlled trial N = 211	VEN (n = 143) or placebo (n = 68) in 28-day cycles, + LDAC days 1–10, 2:1 ratio. ≥18 years newly diagnosed AML ineligible for intensive chemotherapy	Grade 3/4 AEs: (VEN vs LDAC alone) febrile neutropenia (32% vs 29%), neutropenia (47% vs 16%), thrombocytopenia (45% vs 37%)	CR/CRi 48%/13% for VEN + LDAC vs LDAC alone	Median OS 7.2 (VEN + LDAC) vs 4.1 (LDAC) months (p = 0.11). Additional 6-month follow-up median OS 8.4 months (VEN + LDAC) (p = 0.04)	Higher CR/CRi with TP53 mutation (18% vs 0%), IDH1/2 (57% vs 33%), NPM1 (78% vs 57%) with VEN + LDAC vs LDAC + placebo. No difference with FLT3 mutation (44% vs 45%) with VEN + LDAC vs LDAC + placebo
Winters et al. Blood Adv. (2019)	Retrospective study N = 33 treated off-trial compared to 33 pts treated on trial	VEN 400 mg daily, for 28-day cycles. AZA 75 mg/m² IV or S/C days 1–7	Neutropenia Anemia Thrombocytopenia Neutropenic fever Pneumonia Fatigue	CR/CRi 63.3% vs 84.9% for off-trial and on trial patients, respectively (p = 0.081)	Median OS for off-trial patients 381 days vs 880 days for trial patients (p = 0.041)	CR/CRi rates lower with prior HMA. Off-trial patients without prior HMA; 19/26 (73.1%) vs with prior HMA; 0/4 (0%)
Morsia et al. AJH (2020)	Retrospective study N = 44 compared to 56 elderly pts treated with HMA alone	Median dose of VEN 150 mg (50–400 mg). AZA 75 mg/m² IV or S/C days 1–7 or decitabine 20 mg/m² IV days 1–5	Infectious complications in 17/44 (38%), heart failure 5/44 (11.4%), bleeding 4/44 (9.1%), tumor lysis 2/44 (4.5%), and renal failure 2/44 patients (4.5%)	CR/CRi (56.4%) with VEN/HMA, vs 23% with HMA alone (p = 0.005).	Median OS 17 months vs 3 months with/without CR/CRi, p = 0.0009)	4/4 (100%) with CEBPA mutation achieved CR/CRi vs 18/35 (51%) in CEPBA wild type

Study

Design

Treatment arms

Toxicity

Efficacy

Survival

Correlative studies

DiNardo et al.

Lancet Oncol. (2018)

Phase 1b

Group A: N = 23

Group B: N = 22

Group C: N = 12

Group A

(VEN + decitabine)

Group B

(VEN + azacitidine),

Group C (VEN + decitabine+posaconazole)

Dose escalation: Group A/B VEN 400 mg (cohort 1), 800 mg (cohorts 2/3), 1200 mg (cohort 4),

400 mg for group C

>65 years unfit for induction therapy.

ECOG 0-2,

intermediate/poor cytogenetic risk

Febrile neutropenia

Lung infection

Nausea

Vomiting

Fatigue

Leukopenia

Thrombocytopenia

Diarrhea

Anorexia

RP2D

400 mg daily or 800 mg interrupted schedule.

CR/CRi; 35 (61%)

Median duration of response

8.4 months (group A), 12.3 months (group B), 4.3 months (group C)

Median OS; group A 15.2 months, group B 14.2 months

23/35 (66%) with intermediate-risk cytogenetics in CR/CRi vs 11/21 (52%) with poor-risk cytogenetics.

Mutations and response:

10/17 (59%) with IDH1/2 mutations, 3/4 (75%) with FLT3-ITD mutations; vs 4/11 (36%) with TP53 mutations in CR/CRi

DiNardo et al.

Blood (2019)

Phase 1b

N = 145

Dose escalation, VEN 400, 800, or 1200 mg daily with decitabine or azacitidine.

Dose expansion, 400 or 800 mg VEN with either HMA.

>65 years unfit for induction therapy

Grade 3/4 AEs: febrile neutropenia (43%), leukopenia (31%), anemia (25%), thrombocytopenia (24%),

pneumonia (13%)

CR/CRi 67% in all patients.

CR/CRi 73% with VEN 400 mg.

Median duration of CR/CRi (all patients)— 11.3 months

Median OS in all patients—17.5 months.

Median OS (VEN 400 mg)—NR

CR/CRi with poor- and intermediate-risk cytogenetics 60% and 74%.

CR/CRi

NPM1 mutation: 91.5%,

IDH1/2 mutations: 71%,

FLT3 mutation: 72%,

TP53 mutation: 47%

Wei et al.

JCO (2019)

Phase 1b/II

N = 82

VEN 600 mg po daily + LDAC 20 mg/m² S/C (days 1–10)

>60 years previously untreated AML ineligible for intensive chemotherapy

Grade 3/4 AEs:

febrile neutropenia (42%), thrombocytopenia (38%),

leukopenia (34%)

CR/CRi 54%

Median duration of response; 8.1 months (95% CI, 5.3–14.9 months)

Median OS 10.1 months (95% CI, 5.7 to 14.2)

NPM1, IDH1/2 mutations higher CR/CRi (89%/72%, respectively), TP53 or FLT3 mutations lower CR/CRi (30%/44%, respectively).

DiNardo et al.

NEJM (2020)

Phase-3

placebo-controlled, randomized,

VIALE-A

N = 433

Azacitidine +

VEN (N = 286) or azacitidine + placebo (N = 145).

2:1 ratio >75 years or >18 years with comorbidity ineligible for intensive induction therapy

Nausea, constipation, diarrhea, vomiting.

SAEs febrile neutropenia (30% vs 10%), pneumonia (17% vs 22%) with and without

VEN, respectively. 1% tumor lysis with VEN

CR + CRi 66.4 vs 28.3% (p < 0.001) with and without VEN, respectively

Median OS 14.7 and 9.6 months in the VEN vs placebo arm, respectively (HR, 0.66; 95% CI, 0.52–0.85; p < 0.001)

CR/CRi rate: IDH1/2 (75% vs 11%),

FLT3 (72 vs 36%),

NPM1 (67% vs 24%), and TP53 (55% vs 0%), with and without VEN respectively.

Wei et al.

Blood (2020)

Phase-3 randomized double-blind placebo-controlled trial

N = 211

VEN (n = 143) or placebo (n = 68) in 28-day cycles, + LDAC days 1–10, 2:1 ratio.

≥18 years newly diagnosed AML ineligible for intensive chemotherapy

Grade 3/4 AEs: (VEN vs LDAC alone)

febrile neutropenia (32% vs 29%), neutropenia (47% vs 16%), thrombocytopenia (45% vs 37%)

CR/CRi 48%/13% for VEN + LDAC vs LDAC alone

Median OS 7.2 (VEN + LDAC) vs 4.1 (LDAC) months (p = 0.11).

Additional 6-month follow-up median OS 8.4 months (VEN + LDAC) (p = 0.04)

Higher CR/CRi with

TP53 mutation (18% vs 0%),

IDH1/2 (57% vs 33%),

NPM1 (78% vs 57%) with VEN + LDAC vs LDAC + placebo.

No difference with FLT3 mutation (44% vs 45%) with VEN + LDAC vs LDAC + placebo

Winters et al.

Blood Adv. (2019)

Retrospective study

N = 33 treated off-trial compared to 33 pts treated on trial

VEN 400 mg daily, for 28-day cycles. AZA 75 mg/m² IV or S/C days 1–7

Neutropenia

Anemia

Thrombocytopenia

Neutropenic fever

Pneumonia

Fatigue

CR/CRi 63.3% vs 84.9% for off-trial and on trial patients, respectively (p = 0.081)

Median OS for off-trial patients 381 days vs 880 days for trial patients (p = 0.041)

CR/CRi rates lower with prior HMA.

Off-trial patients without prior HMA; 19/26 (73.1%) vs with prior HMA; 0/4 (0%)

Morsia et al.

AJH (2020)

Retrospective study

N = 44 compared to 56 elderly pts treated with HMA alone

Median dose of VEN 150 mg (50–400 mg). AZA 75 mg/m² IV or S/C days 1–7 or decitabine 20 mg/m² IV days 1–5

Infectious complications in 17/44 (38%),

heart failure 5/44 (11.4%), bleeding 4/44 (9.1%), tumor lysis 2/44 (4.5%), and

renal failure 2/44 patients (4.5%)

CR/CRi (56.4%) with VEN/HMA, vs 23% with HMA alone

(p = 0.005).

Median OS 17 months vs 3 months with/without CR/CRi, p = 0.0009)

4/4 (100%) with CEBPA mutation achieved CR/CRi vs 18/35 (51%) in CEPBA wild type

VEN venetoclax, ORR overall response rate, CR complete remission, CRi complete remission with incomplete hematological recovery, RP2D recommended phase 2 dose, OS overall survival, HMA hypomethylating agent, NR not reached, AE adverse event, SAE serious adverse event, HR hazard ratio, CI confidence interval, LDAC low-dose ara-C, AZA azacitidine.