Table 4 Studies of venetoclax with or without anti-CD20 antibodies or chemotherapy in B-NHL

Mantle cell lymphoma

Davids et al.[35, 38]

NCT01328626

n = 28

R/R MCL (median 3 prior lines of therapy)

Lenalidomide and ibrutinib naïve

18% bortezomib exposed

Phase 1 dose escalation venetoclax monotherapy 200-1200 mg daily

ORR 75% CRR 21%

Median PFS 11 months

Median DOR 16 months

12-month OS: 82%

Overall cohort

Anemia 15%

Neutropenia 11%

RP2D 800 mg

Eyre et al.[79]

n = 20

R/R MCL (median 3 prior lines of therapy)

BTKi exposed (90% resistant)

Retrospective analysis of venetoclax at doses of 200-1200 mg daily

ORR 53% CRR 18%

Median PFS 3 months

Median OS 9 months

Pneumonia 15%

Zhao et al.[80]

n = 24

R/R MCL (median 5 prior lines of therapy)

BTKi resistant: 67%

Retrospective analysis of venetoclax-based regimens:

Monotherapy: n = 12

 + anti-CD20 antibody: n = 8

 + BTKi: n = 3

 + chemotherapy: n = 1

ORR 50% CRR 21%

Median PFS 8 months

Median OS 13.5 months

NA

Sawalha et al.[81]

n = 81

R/R MCL (median 3 prior lines of therapy)

Retrospective analysis of venetoclax-based regimens:

Monotherapy: n = 50

 + anti-CD20 antibody: n = 11

 + BTKi: n = 16

 + other: n = 4

ORR 42% CRR 18%

Median duration of venetoclax treatment 3 months

Median OS 13 months

NA

Follicular lymphoma

Davids et al.[35, 38]

NCT01328626

n = 29

R/R FL

Phase 1 dose escalation venetoclax monotherapy 200-1200 mg daily

ORR 38% CRR 17%

Median PFS 11 months

Median DOR 27 months

12-month OS: 100%

Overall cohort

Anemia 15%

Neutropenia 11%

RP2D 1200 mg

de Vos et al.[86]

NCT01594229

n = 32

R/R FL

Phase 1b dose escalation of venetoclax 50-1200 mg daily plus bendamustine–rutiximabx6

ORR 75% CR 38%

Median PFS and OS not reached

Overall cohort

Neutropenia 60%

Lymphopenia 38%

RP2D 800 mg in combination with bendamustine–rituximab

CAVALLI Ib [87]

NCT02055820

n = 24

R/R FL: n = 4

TN FL: n = 20

Phase 1b dose escalation of venetoclax 200-800 mg in combination with R/G-CHOP

ORR 83% CRR 75%

12-month PFS 100% Ven-R-CHOP and 90% Ven-G-CHOP

Overall cohort

Neutropenia 54%

Febrile neutropenia 33%

Thrombocytopenia 17%

Anemia 13%

RP2D 800 mg C1D4-10 and D1-10 for subsequent cycles

Stathis et al.[84]

NCT02877550

n = 25

TN FL

Phase I trial of venetoclax 600-800 mg daily plus obinutuzumab for 6 cycles, followed by obinutuzumab maintenance [2 years]

ORR 88% CRR 68%

12-month PFS 77%

Neutropenia 28%

RP2D 800 mg in combination with obinutuzumab

PrECOG 0403 [89]

NCT03113422

n = 56

TN FL with high tumor burden

Phase II trial of venetoclax 800 mg plus bendamustine–rituximabx6

CRR 73%

24-month PFS 86%

24-month OS 94%

Neutropenia 16%

Thrombocytopenia 14%

TLS 14%

Opportunistic infections, combination considered unacceptably immunosuppressive

Zinzani et al.[90]

NCT02187861

n = 163

R/R FL

Arm A: n = 52

Arm B: n = 51

Arm C: n = 51

Safety run-in: n = 9

Phase II study of:

Arm A: Venetoclax 800 mg daily for 1 year plus rituximab C1D1,8,15,22 & D1 of C4, C6, C8, C12

Arm B: Venetoclax 800 mg daily for 1 year plus bendamustine–rutiximabx6

Arm C: Bendamustine–rituximabx6

Arm A: ORR 35% CRR 17%

Arm B: ORR 84% CRR 75%

Arm C: ORR 84% CRR 69%

18-month PFS

Arm A: 27%

Arm B: 62%

Arm C:59%

Arm A:

Neutropenia 25%

Arm B:

Neutropenia 59%

Thrombocytopenia 45%

Anemia 14%

Febrile neutropenia 12%

Arm C:

Neutropenia 28%

Diffuse large B cell lymphoma and aggressive B cell lymphomas

Davids et al.[35, 38]

NCT01328626

n = 34

R/R DLBCL and PMBCL [2 patients]

Phase 1 dose escalation venetoclax monotherapy 200-1200 mg daily

ORR 18% CRR 12%

Median PFS 1 month

12-month OS: 32%

Overall cohort

Anemia 15%

Neutropenia 11%

RP2D 1200 mg

de Vos et al.[86]

NCT01594229

n = 22

R/R DLBCL

Phase 1b dose escalation of venetoclax 50-1200 mg daily plus bendamustine–rutiximabx6

ORR 41% CR 14%

Median PFS 4 months

Median OS 15 months

Overall cohort

Neutropenia 60%

Lymphopenia 38%

Thrombocytopenia 28%

Anemia 17%

RP2D 800 mg in combination with bendamustine–rituximab

CAVALLI 1b [87]

NCT02055820

n = 18

TN DLBCL

Phase 1b dose escalation of venetoclax 200-800 mg in combination with R/G-CHOP

ORR 89% CRR 89%

12-month PFS 70% Ven-R-CHOP and 100% Ven-G-CHOP

Overall cohort

Neutropenia 54%

Febrile neutropenia 33%

Thrombocytopenia 17%

Anemia 13%

RP2D 800 mg C1D4-10 and D1-10 for subsequent cycles

Rutherford et al.[154]

NCT03036904

n = 30

TN aggressive B-NHL

DHL: n = 15

DLBCL: n = 9

Transformed NHL: n = 2

HGBCL-NOS: n = 2

PMBCL: n = 2

Phase 1 dose escalation of venetoclax 400-800 mg in combination with dose-adjusted-R-EPOCH

ORR 97% CRR 93%

24-month PFS: 83%

24-month OS: 90%

Neutropenia 83%

Thrombocytopenia 70%

Febrile neutropenia 63%

Anemia 60%

Serious gastrointestinal AEs 27%

RP2D 600 mg for 5 days per cycle

CAVALLI phase II [93]

NCT02055820

n = 206

TN DLBCL

IPI 2–5

Phase II study of venetoclax-Rx8 plus CHOPx6-8

ORR 83% CRR 69%

24-month PFS: 80%

24-month OS: 86%

Neutropenia 68%

Febrile neutropenia 31%

Infections 23%

Anemia 24%

Thrombocytopenia 22%

Leukopenia 10%

Improved PFS compared to historical R-CHOP control (GOYA), esp if BCL2 + by IHC

ALLIANCE A051701 [95]

NCT03984448

TN double-hit lymphoma (by FISH or expression)

n = 36

Phase II/III randomized study

DA-R-EPOCH

ORR 73% CRR 67%

Median PFS and OS not reached (median follow-up 7 months)

Neutropenia 67%

Febrile neutropenia 36%

Sepsis 14%

Early discontinuation due to excess deaths in DA-R-EPOCH + venetoclax arm

n = 73

DA-R-EPOCH + venetoclax 600 mg C1D4-8 and C2-6D1-5

ORR 58% CRR 50%

Median PFS 7 months

Median OS 9 months

Neutropenia 71%

Febrile neutropenia 40%

Sepsis 23%

Davids et al. [98]

NCT03054896

n = 27

DLBCL-RT

Phase II of C1 DA-R-EPOCH, followed by venetoclax ramp-up, then venetoclax 400 mg D1-10 of C2-6 of DA-R-EPOCH followed by alloSCT/CAR-T or venetoclax 400 mg daily maintenance

ORR 62% CRR 50%

Median PFS 10 months

Median OS 20 months

Neutropenia 58%

Anemia 62%

Thrombocytopenia 50%

Febrile neutropenia 38%

Hypophosphatemia 23%

Hyponatremia 15%

Hyperglycemia 15%