Review a discussion on VENCLEXTA plus obinutuzumab's place in 1L CLL treatment, their complementary mechanisms of action and an overview of the CLL14 study design.
CLL14 trial in detail
Review the key study details below
The CLL14 trial was a multicentre, open-label, phase 3 study that evaluated fixed-duration treatment with VENCLEXTA plus obinutuzumab versus obinutuzumab plus chlorambucil in patients with previously untreated CLL and coexisting medical conditions.†1,2
CLL14 trial study design1–3
†The daily oral VENCLEXTA regimen was initiated on Day 22 of Cycle 1, starting with a 5-week dose ramp-up (1 week each of 20, 50, 100, and 200 mg, then 400 mg daily for one week), thereafter continuing at 400 mg daily until completion of Cycle 12. Obinutuzumab was administered intravenously for 6 cycles starting with 100 mg on Day 1 and 900 mg on Day 2 (or 1000 mg on Day 1), 1000 mg on Day 8 and 1000 mg on Day 15 of Cycle 1, and subsequently 1000 mg on Day 1 of Cycles 2 through 6.1
The endpoints of the study include:1,2
‡Response and progression assessed using the International Workshop for Chronic Lymphocytic Leukemia (iwCLL) updated National Cancer Institute–sponsored Working Group (NCI-WG) guidelines (2008).
§ORR defined as CR + CRi + PR.
¥Minimal residual disease was evaluated in bone marrow and peripheral blood 3 months after the end of treatment using ASO-PCR. The cut-off for a negative (undetectable) status was <1 CLL cell per 104 leukocytes.
ASO-PCR: allele-specific oligonucleotide polymerase chain reaction. CLL: chronic lymphocytic leukaemia. IV: intravenous.
References: 1. Fischer K et al. N Engl J Med 2019: 380: 2225–36. 2. VENCLEXTA Product Information. 3. Al-Sawaf O et al. Lancet Oncol 2020; 21: 1188–200.
The CLL14 trial included patients with previously untreated CLL and coexisting medical conditions.1,2
Select inclusion criteria of the CLL14 trial:1,2
- Age ≥18 years
- Previously untreated CLL
- Coexisting medical conditions (total CIRS >6 or CrCl <70 mL/min)
CLL14 trial demographics and baseline patient characteristics1–3
*Including only patients with available information.
CIRS: Cumulative Illness Rating Scale. Clb: chlorambucil. CLL: chronic lymphocytic leukaemia. CrCl: creatinine clearance. ECOG: Eastern Cooperative Oncology Group. IQR: interquartile range. O: obinutuzumab.
References: 1. Fischer K et al. N Engl J Med 2019; 380: 2225–36. 2. VENCLEXTA Product Information. 3. Al-Sawaf O et al. Lancet Oncol 2020; 21: 1188–200.
PRIMARY ENDPOINT
Investigator-assessed progression-free survival (PFS)
Based on the primary analysis, the investigator-assessed PFS after a median follow-up of 28 months was:1
- 1-year PFS estimate: 95% (95% CI: 91.5–97.7) with VEN+O vs 92% (95% CI: 88.4–95.8) with O+Clb
- 2-year PFS estimate: 88% (95% CI: 83.7–95.1) 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)
- Median PFS was not reached in either arm
In the CLL14 trial, over 80% of patients remained progression-free after 3 years of follow-up (median 39.6 months) from enrolment.1,2 Median PFS was not reached with VEN+O (95% CI: NE–NE) vs 35.6 months (95% CI: 33.7–40.7) with O+Clb.2
INV-assessed PFS in the intention-to-treat population2
Adapted from Al-Sawaf O et al. 2020.2
SECONDARY ENDPOINTS
OVERALL SURVIVAL (OS)
At a median follow-up of 39.6 months, median OS was not reached and was similar in both treatment groups with 27 events in each arm.2
RESPONSE RATES
In the CLL14 trial, half of patients achieved complete remission (CR+CRi) 3 months after the end of treatment (EOT).1
More than twice as many patients in the VEN+O arm (50%) had complete remission (CR+CRi) vs the O+Clb arm (23%) (p<0.0001)†1,3
†Assessed 3 months after the EOT per 2008 International Workshop for Chronic Lymphocytic Leukemia (iwCLL) guidelines.1
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)1,4
‡ORR=CR+CRi+PR (secondary endpoint).1
undetectable MRD (uMRD)
In the CLL14 trial, 76% of patients in the VEN+O arm achieved uMRD in peripheral blood 3 months after the EOT.1,2
- 18 months after the EOT, 102 (47%) patients still had peripheral blood uMRD in the VEN+O group vs 16 (7%) in the O+Clb group.2
- In the VEN+O arm, patients with a PR and uMRD had similar PFS to those with CR and uMRD.2
- Rates of uMRD were higher in all risk subgroups with VEN+O as compared with those who received O+Clb.2
Figure: Landmark PFS analysis based on MRD status in peripheral blood 3 months after EOT2,5
Adapted from Al-Sawaf O et al. 20202 and Al-Sawaf O et al. 2020 (Supplementary Appendix)5
EXPLORATORY ANALYSES
The exploratory analyses included the relation between various baseline markers and clinical outcome parameters. All subgroup analyses were exploratory only without reporting any p-values from statistical testing procedures.
PFS with VEN+O remained longer to O+Clb in all subgroups.5
Figure: Investigator-assessed PFS benefit with VEN+O vs O+Clb across subgroups of interest5
Adapted from Al-Sawaf O et al. 2020.5
Undetectable MRD is defined as <1 CLL cells/10,000 leukocytes. Low MRD+ defined as 1 to 100 CLL cells/10,000 leukocytes. High MRD+ defined as >100 CLL cells/10,000 leukocytes.
CI: confidence interval. Clb: chlorambucil. CR: complete response. CRi: complete response with incomplete marrow recovery. HR: hazard ratio. MRD: minimal residual disease. NE: not estimable. O: obinutuzumab. ORR: overall response rate. PR: partial response. VEN: VENCLEXTA.
References: 1. VENCLEXTA Product Information. 2. Al-Sawaf O et al. Lancet Oncol 2020; 21: 1188–200. 3. Fischer K et al. N Engl J Med 2019; 380(23): 2225–36. 4. Fischer K et al. N Engl J Med 2019; 380(23): 2225–36 (Supplementary Appendix). 5. Al-Sawaf O et al. Lancet Oncol 2020; 21: 1188–200 (Supplementary Appendix).
VENCLEXTA offers your patients with CLL a well-characterised safety profile.1
The common adverse events reported in the phase 3 CLL14 trial are listed in the table below.
Please refer to the product information for full safety information.
Adverse events reported at total frequency of ≥10% (based on Grades 1–2 frequency ≥10% & Grades 3–5 frequency ≥1%)2
Adapted from Al Sawaf O et al. 2020.2 Median follow-up of 39.7 months.2
NEUTROPENIA AND SERIOUS INFECTION
Neutropenia is an identified risk with VENCLEXTA treatment and was the most common adverse reaction that led to dose interruption in the CLL14 trial.1
Serious infection is an identified risk associated with VENCLEXTA treatment.1
Neutropenia and infections observed in the CLL14 trial1
Adapted from VENCLEXTA Product Information.1
TUMOUR LYSIS SYNDROME (TLS)
TLS is an important identified risk when initiating VENCLEXTA1
- TLS, including life-threatening or fatal events and renal failure requiring dialysis, has occurred in patients treated with VENCLEXTA.1
- The risk of TLS is a continuum based on multiple factors including comorbidities, particularly reduced renal function (creatinine clearance [CrCl] <80mL/min) and tumour burden. Splenomegaly may contribute to the overall TLS risk.1
- All patients should be assessed for risk and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricaemics.1
- Blood chemistries should be monitored and abnormalities managed promptly.1
- Employ more intensive measures (intravenous hydration, frequent monitoring, and hospitalisation) as overall risk increases.1
Refer to the VENCLEXTA Product Information for recommendations for TLS prophylaxis and monitoring during initiation and dose ramp-up phase.
In the CLL14 trial, TLS occurred in 1% (3/212) of patients in the VEN+O arm1:
- All TLS events resolved and did not lead to withdrawal from the study.1
- Obinutuzumab administration was delayed in two cases in response to the TLS events.1
- No clinical TLS was observed.3
CLL: chronic lymphocytic leukaemia. O: obinutuzumab. VEN: VENCLEXTA.
References: 1. VENCLEXTA Product Information. 2. Al-Sawaf O et al. Lancet Oncol 2020; 21: 1188–200. 3. Fischer K et al. N Engl J Med 2019; 380(23): 2225–36.
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PBS Information
Venclexta: VENCLEXTA (venetoclax) in combination with rituximab is PBS listed for relapsed or refractory chronic lymphocytic leukaemia (CLL). VENCLEXTA in combination with obinutuzumab is PBS listed for first line treatment of CLL or small lymphocytic lymphoma (SLL). VENCLEXTA in combination with azacitidine is PBS listed for treatment of acute myeloid leukaemia (AML). General Schedule listing. Authority required (telephone). Refer to PBS schedule for full authority information. VENCLEXTA monotherapy is not listed on the PBS. VENCLEXTA in combination with low-dose cytarabine is not listed on the PBS for treatment of AML.
Please review the full Product Information (PI) before prescribing, available below.
1L: first line. CLL: chronic lymphocytic leukaemia.
Reference: 1. Fischer K et al. N Engl J Med 2019; 380: 2225–36.
AU-VENC-210076 Last revised October 2022