Note to affiliates: This update to the venetoclax CLL AbbVie Pro site includes a homepage headline, updated CLL14 6-year and MURANO 7-year data sets, and other streamlined content updates. The CLL14 6-year and MURANO 7-year data have been updated based on the EHA 2023 abstracts. For countries that cannot use these data sets, please follow local regulations and MRLO guidance, and revert to CLL14 5-year and MURANO 5-year published data from the product label.
Primary analysis in ITT population for VEN+O vs O+Clb1:
INV-assessed PFS†: Reduced risk of progression or death (HR=0.35; 95% CI: 0.23–0.53 [P<0.0001]).
| • | Median follow-up of 28 months |
Additional analyses:
6-year PFS estimate (INV-assessed)2‡: 53% vs 22% (HR=0.40; 95% CI: 0.31–0.52) after 5 years off treatment.
| • | Median PFS of 76.2 months with VEN+O vs 36.4 months with O+Clb |
INV-assessed complete remission (CR/CRi)1: 50% vs 23% (P<0.0001).
| • | ORR: 85% (95% CI: 79.2–89.2) vs 71% (95% CI: 64.8–77.2 [P=0.0007]) |
Primary analysis in ITT population for VEN+R vs BR:
INV-assessed PFS†: Reduced risk of progression or death (HR=0.17; 95% CI: 0.11–0.25 [P<0.0001]).
| • | Median follow-up of 23.8 months |
Additional analyses:
7-year PFS estimate (INV-assessed)3‡: 23% (95% CI: 16.1–29.9) vs NE after ~5 years off treatment.
| • | Median PFS of 54.7 months with VEN+R (95% CI: 52.3–59.9) vs 17.0 months with BR (95% CI: 15.5–21.7) |
INV-assessed complete remission (CR/CRi)1‡: 27% vs 8%.
| • | ORR: 93% (95% CI: 88.8–96.4) vs 68% (95% CI: 60.6–74.2) |
*See full dosing information for VEN+O and for VEN+R in the dosing and administration section.
†Primary endpoint.
‡Results are descriptive only.
1L=first line; CLL=chronic lymphocytic leukaemia; VEN+O=VENCLYXTO + obinutuzumab; ITT=intent to treat; O+Clb=obinutuzumab + chlorambucil; INV=investigator; PFS=progression-free survival; HR=hazard ratio; CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete bone marrow recovery; ORR=overall response rate; 2L+=second line + later lines of therapy; VEN+R=VENCLYXTO + rituximab; BR=bendamustine + rituximab; NE=not evaluable.
1L CLL: VENCLYXTO + OBINUTUZUMAB
test
CLL14 TRIAL WAS DESIGNED TO ALLOW PATIENTS TO COMPLETE VENCLYXTO + OBINUTUZUMAB TREATMENT IN 1 YEAR1*
CLL14 evaluated VENCLYXTO + obinutuzumab vs a standard CIT regimen (obinutuzumab + chlorambucil)
*CLL14 was a multicentre, randomised, open-label, phase 3 trial. Treatment complete after twelve 28-day cycles.
†VENCLYXTO 400 mg daily after initial dose-titration period.
‡Obinutuzumab dosing: 100 mg Cycle 1, Day 1, followed by 900 mg on Days 1 or 2; 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycles 2–6.
§Chlorambucil dosing: 0.5 mg/kg on Days 1 and 15 of each 28-day cycle.
Click here for titration protocols and full dosing information.
Select inclusion criteria
| • | Previously untreated CLL and coexisting medical conditions (total CIRS >6 or CrCl <70 mL/min), age ≥18 years |
Select clinical endpoints||¶
| • | Primary endpoint: INV-assessed PFS |
| • | Select secondary endpoints: IRC-assessed PFS, ORR, CR/CRi, PR, TTNT, and uMRD# rate at end of treatment1,2 |
Primary analysis and results (ITT population)
| Median follow-up of 28 months (range: 0–36 months; VEN+O: n=216, O+Clb: n=216). Median PFS was not reached in either arm at primary analysis. |
| • | 2-year PFS estimate: 88% (95% CI: 83.7–92.6) with VEN+O vs 64% (95% CI: 57.4–70.8) with O+Clb (HR=0.35; 95% CI: 0.23–0.53 [P<0.0001])1,4 |
||Assessed using the International Workshop for Chronic Lymphocytic Leukemia (iwCLL) updated National Cancer Institute–sponsored Working Group (NCI-WG) guidelines (2008).1
¶ORR, CR/CRi, PR, and uMRD were assessed at EoT.
#MRD was evaluated using ASO-PCR. In PB or bone marrow, the cutoff for an undetectable (negative) status was <1 CLL cell per 104 leukocytes.1
CIT=chemoimmunotherapy; IV=intravenous; CIRS=Cumulative Illness Rating Scale; CrCl=creatinine clearance; IRC=independent review committee; PR=partial remission; TTNT=time to next anti-leukaemic treatment; uMRD=undetectable minimal residual disease; EoT=end of treatment; ASO-PCR=allele-specific oligonucleotide polymerase chain reaction; PB=peripheral blood.
VENCLYXTO + OBINUTUZUMAB INDUCED DEEP RESPONSES,* INCLUDING uMRD, IN THE MAJORITY OF PATIENTS1
Unparalleled rates of uMRD for VEN+O vs O+Clb in 1L CLL
| • | Rates of uMRD in PB at EoT were 2 times higher in the VEN+O arm than in the O+Clb arm |
| • | Rates of uMRD in bone marrow at EoT were 3 times higher in the VEN+O arm (57% [95% CI: 50.1–63.6]) than in the O+CIb arm (17% [95% CI: 12.4–22.8]) (P<0.0001) |
uMRD (secondary endpoint) results in ITT population are presented. The cutoff for an undetectable (negative) status was <1 CLL cell per 104 leukocytes.
More than twice as many patients achieved complete remission with VEN+O (50%) vs O+Clb (23%)
COMPLETE REMISSION (CR/CRi) RATE†
| • | ORR‡ was 85% (95% CI: 79.2–89.2) in the VEN+O arm vs 71% (95% CI: 64.8–77.2) in the O+Clb arm (P=0.0007) |
*Deep response as measured by uMRD or CR.
†CR/CRi were assessed in the ITT population.2
‡ORR=CR/CRi+PR (secondary endpoint).
Note to affiliates: This page contains 6-year follow-up PFS data from an abstract presented by Al-Sawaf et al at EHA 2023. For countries that cannot yet promote these data, please use the 5-year follow-up data.
PFS FOR VENCLYXTO + OBINUTUZUMAB PATIENTS: RESULTS AT 6 YEARS2*
Updated 6-year analysis
Median follow-up of 76.4 months (interquartile range: 52.5–80.5 months).
Median PFS was 76.2 months with VEN+O vs 36.4 months with O+Clb (HR=0.40; 95% CI: 0.31–0.52) (P<0.0001).
INV-ASSESSED PFS IN THE ITT POPULATION
PFS benefit was sustained in patients off treatment for at least 5 years
*Results are descriptive.
Note to affiliates: This OPTIONAL content below is for regions with local regulations that do not allow 6-year follow-up PFS data. This content contains 5-year PFS data from a follow-up analysis published by Al-Sawaf et al in Nat Commun in 2023.
LONGER LASTING PFS: 63% PFS ESTIMATE FOR VENCLYXTO + OBINUTUZUMAB VS 27% FOR O+Clb AT 5 YEARSX*
Updated 5-year analysis
Median follow-up of 65.4 months (interquartile range: 52.6–69.4).
Median PFS was not reached with VEN+O vs 36.4 months with O+Clb (HR=0.35; 95% CI: 0.26–0.46).
INV-ASSESSED PFS IN THE ITT POPULATION
PFS benefit was sustained in patients off treatment for 4 years
*Results are descriptive.
Reference: X. Al-Sawaf O, Zhang C, Jin HY, et al. Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia. Nat Commun. 2023;14(1):2147.
Note to affiliates:
This page contains TTNT data from a 6-year follow-up analysis from an abstract presented by Al-Sawaf et al at EHA 2023. For countries that cannot promote congress abstracts, please revert to a previous version using the 5-year TTNT data published by Al-Sawaf et al in Nat Commun in 2023, or delete this page.
TIME TO NEXT TREATMENT FOR VENCLYXTO + OBINUTUZUMAB PATIENTS: RESULTS AT 6 YEARS2
Results of a 6-year analysis
5 years after treatment completion, 65% of VEN+O patients did not require next treatment vs 37% of O+Clb patients (HR=0.44; 95% CI: 0.33–0.58). Results are descriptive; not tested for statistical significance.3
PERCENTAGE OF PATIENTS FREE OF NEXT ANTI-LEUKAEMIC TREATMENT (NLT) AT FOLLOW-UP ANALYSIS
Note to affiliates: Data published by Al-Sawaf et al in J Clin Oncol in 2021 (see the reference list for full citation information).
VENCLYXTO + OBINUTUZUMAB PFS BENEFIT WAS CONSISTENT ACROSS MULTIPLE SUBGROUPS AT 4-YEAR FOLLOW-UP5*
Results of a 4-year analysis
Median follow-up of 52 months (interquartile range: 49.5–56.2). Median PFS was not reached for the VEN+O arm vs 36.4 months in the O+Clb arm.
| • | 4-year PFS estimate: 74% with VEN+O vs 35% with O+Clb (HR=0.33; 95% CI: 0.25–0.45) |
INV-ASSESSED PFS BY SUBGROUP AT 4 YEARS6
Data cutoff: 11 September 2020.5
*Results are descriptive.
Del=deletion; TP53=tumour protein p53; IGHV=immunoglobulin heavy-chain variable gene.
Note to affiliates: This page contains 5-year OS data from the October 2022 EU,as well as 6-year OS data from a follow-up analysis presented by Al-Sawaf et al at EHA 2023.
OS FOR VENCLYXTO + OBINUTUZUMAB PATIENTS: RESULTS AT 5 AND 6 YEARS1,2
Results of a 5-year analysis1*
There were 40 (19%) events in the VEN+O arm compared with 57 (26%) events in the O+Clb arm (HR=0.72; 95% CI: 0.48–1.09).
Results of a 6-year analysis2*
HR=0.69 (0.48–1.01).
Note to affiliates: This page reflects the CLL13 data published by Eichhorst et al in the N Engl J Med in 2023 and by Eichhorst et al in Blood in 2021 (see the reference list for full citation information).
UPDATED PHASE 3 STUDY RESULTS FROM CLL13 IN 1L CLL7
VENCLYXTO + obinutuzumab vs CIT (FCR/BR) arms
CLL13 was a multicentre, open-label, phase 3, four-arm trial of treatment-naive, fit (CIRS ≤6, normal creatinine clearance ≥70 mL/min) patients with CLL. Patients were randomised to receive CLL therapy, including CIT (FCR for patients ≤65 years; BR for patients >65 years) or a VENCLYXTO regimen, including VENCLYXTO + obinutuzumab (further details for the study NCT02950051 are available at clinicaltrials.gov). Only those arms on-label for VENCLYXTO are detailed below.
DOSING SCHEMA FOR VENCLYXTO + OBINUTUZUMAB AND CIT ARMS
*VENCLYXTO 400 mg daily after initial dose-titration period for 12 cycles. Each cycle was 28 days.
†Obinutuzumab dosing: 100 mg on Day 1, 900 mg on Day 2, and 1000 mg on Days 8 and 15 of Cycle 1. 1000 mg on Day 1 of Cycles 2–6. Each cycle was 28 days.
‡Fludarabine dosing: 25 mg/m2 on Days 1–3 of Cycles 1–6. Each cycle was 28 days.
§Cyclophosphamide dosing: 250 mg/m2 on Days 1–3 of Cycles 1–6. Each cycle was 28 days.
IIRituximab dosing: 375 mg/m2 on Day 1, Cycle 1, and 500 mg/m2 on Day 1, Cycles 2–6. Each cycle was 28 days.
¶Bendamustine dosing: 90 mg/m2 on Days 1–2 of Cycles 1–6. Each cycle was 28 days.
Co-primary endpoints
| • | uMRD in peripheral blood at Month 15 assessed by flow cytometry (VEN+O vs CIT). uMRD was defined as <1 CLL cell per 104 leukocytes |
| • | PFS (for unapproved regimen not shown) |
Select secondary endpoints
| • | PFS (VEN+O vs CIT)8 |
| • | ORR# and CR/CRi# |
| • | uMRD in bone marrow, determined by bone marrow biopsy performed at final restaging in patients with clinical CR7 |
Select inclusion criteria
| • | Creatinine clearance ≥70 mL/min |
Select exclusion criteria
| • | Del(17p) or TP53 mutation |
#Assessed at Month 15 according to iwCLL 2008 guidelines.
FCR=fludarabine + cyclophosphamide + rituximab.
AT MONTH 15, 87% OF VENCLYXTO + OBINUTUZUMAB-TREATED PATIENTS ACHIEVED uMRD IN PERIPHERAL BLOOD VS 52% FOR CIT7,8
At Month 15, a significantly higher percentage of patients in the VEN+O arm than in the CIT arm achieved uMRD in peripheral blood (the primary endpoint); median follow-up was 27.9 months.
IN PERIPHERAL BLOOD
| • | Rates of uMRD in bone marrow were 73% in the VEN+O arm vs 37% in the CIT arm* |
RATES OF CR/CRi IN VEN+O VS CIT7,8†
| • | INV-assessed ORR (CR/CRi+PR) was 96% in the VEN+O arm vs 81% in the CIT arm |
*Bone marrow biopsy and measurement of MRD were requested only for patients with a clinical CR.
†Assessed at Month 15 according to iwCLL 2008 guidelines.
PFS RESULTS FOR VENCLYXTO + OBINUTUZUMAB IN 1L FIT PATIENTS7
A pre-planned interim analysis of PFS was conducted at Month 61. At the cutoff date (20 January 2022), the median observation time was 38.8 months. Because the PFS co-primary endpoint includes an unapproved regimen, these results are not shown.
Secondary endpoint: PFS for VEN+O vs CIT
Median follow-up of 38.8 months. (HR=0.42; 97.5% CI: 0.26–0.68, P<0.0001).
INV-ASSESSED PFS ANALYSIS
*CIT was given for a total of 6 cycles.
Data cutoff: 20 January 2022.
SAFETY INFORMATION FROM THE CLL13 TRIAL7
| • | The most common Grade 3/4 treatment-emergent AEs (incidence ≥5%) in the VEN+O and CIT arms were: |
- VEN+O (Grade 3; Grade 4): neutropaenia (22%; 23%), thrombocytopaenia (11%; 4%), infusion-related reactions (11%; 0), tumour lysis syndrome (8%; 1%), neutrophil count decreased (8%; 7%), leukopaenia (5%; 0.4%), and pneumonia (5%; 0), respectively
| |
- CIT (Grade 3; Grade 4): neutropaenia (16%; 30%), febrile neutropaenia (11%; 1%), leukopaenia (9%; 3%), thrombocytopaenia (7%; 2%), anaemia (7%; 1%), pneumonia (6%; 0), infusion-related reactions (6%; 0), neutrophil count decreased (3%; 6%), and second primary malignancy solid tumours (5%; 1%), respectively
| |
| • | Incidence of CTC Grade 3-4 infections was 13% in the VEN+O arm and 19% in the CIT arm |
| • | Secondary neoplasia occurred in 10% of patients in the VEN+O arm and 17% in the CIT arm |
| • | Fatal AEs occurred in 3.9% and 4.6% of the VEN+O- and CIT-treated patients, respectively. There were no fatal cases of TLS |
AE=adverse event; TLS=tumour lysis syndrome; CTC=common toxicity criteria.
[Placeholder for safety balance required by local regulations]
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References: 1. VENCLYXTO Summary of Product Characteristics. Ludwigshafen, Germany: AbbVie Deutschland GmbH & Co. KG. 2. AI-Sawaf O, Robrecht S, Zhang C, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized CLL14 study. HemaSphere. 2023;7(S3):1-3. 3. Kater A, Harrup R, Kipps TJ, et al. Final 7-year follow up and retreatment substudy analysis of MURANO: venetoclax-rituximab (VENR)-treated patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Abstract presented at the European Hematology Association Congress 2023; June 8-11, 2023; Frankfurt, Germany. 4. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. 5. Al-Sawaf O, Zhang C, Lu T, et al. Minimal residual disease dynamics after venetoclax-obinutuzumab treatment: extended off-treatment follow-up from the randomized CLL14 study. J Clin Oncol. 2021;39(36):4049-4060. 6. Al-Sawaf O, Zhang C, Lu T, et al. Minimal residual disease dynamics after venetoclax-obinutuzumab treatment: extended off-treatment follow-up from the randomized CLL14 study. J Clin Oncol. 2021;39(36):4049-4060(suppl). 7. Eichhorst B, Niemann CU, Kater AP, et al. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388(19):1739-1754. 8. Eichhorst B, Niemann C, Kater AP, et al. Blood. 2021;138(Supplement 1):71-74.
ALL-VNCCLL-220060 May 2024
A randomized phase Ill study of venetoclax-based time-limited combination treatments (RVe, GVe, GIVe) vs standard chemoimmunotherapy (CIT: FCR/BR) in frontline chronic lymphocytic leukemia (CLL) of fit patients: first co-primary endpoint analysis of the International Intergroup GAIA (CLL13) trial.