Updates in CLL Treatment: 5-Year Off-Treatment Analyses From the CLL14 and MURANO Trials

Venetoclax is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). This video presents the 5-year off-treatment analyses from the CLL14 and MURANO studies. 

Learning Objectives: 

• Review the 5-year off-treatment analyses from the CLL14 and MURANO studies
• Understand the long-term efficacy and safety data for venetoclax-based regimens  
• Learn about treatment regimens for patients with previously untreated or treated CLL

Venetoclax Prescribing Information Overview for CLL/SLL

INDICATION

• Venetoclax is a BCL-2 inhibitor indicated: For the treatment of adult patients with CLL or SLL

DOSAGE AND ADMINISTRATION

• 5-week ramp-up dosing schedule: Initiate therapy with venetoclax at 20 mg (Week 1), 50 mg (Week 2), 100 mg (Week 3), 200 mg (Week 4), 400 mg (Week 5 and beyond) once daily
• Continue venetoclax until disease progression or unacceptable toxicity
• Oral, once daily dosing: venetoclax tablets should be taken orally once daily with a meal and water. Do not chew, crush, or break tablets
• Provide prophylaxis for TLS

CONTRAINDICATION

• Strong CYP3A Inhibitors: Concomitant use with strong CYP3A inhibitors at initiation and during ramp-up phase in patients with CLL/SLL is contraindicated

WARNINGS AND PRECAUTIONS

• TLS: TLS, including fatal events and renal failure requiring dialysis, has occurred in patients treated with venetoclax. Anticipate TLS; assess risk in all patients. Premedicate with anti-hyperuricemics and ensure adequate hydration. Employ more intensive measures (IV hydration, frequent monitoring, hospitalization) as overall risk increases
• Neutropenia: Monitor blood counts. Interrupt dosing and resume at same or reduced dose. Consider supportive care measures
• Infections: Fatal and serious infections such as pneumonia and sepsis have occurred in patients treated with venetoclax. Monitor patients closely for signs and symptoms of infection and treat promptly. Withhold venetoclax for Grade 3 and 4 infection until resolution and resume at same or reduced dose
• Immunization: Do not administer live attenuated vaccines prior to, during, or after venetoclax treatment until B-cell recovery
• Embryo-Fetal Toxicity: May cause embryo-fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception
• Increased mortality in patients with MM when venetoclax is added to bortezomib and dexamethasone: In a randomized trial in patients with relapsed or refractory MM, the addition of venetoclax to bortezomib plus dexamethasone, a use for which venetoclax is not indicated, resulted in increased mortality. Treatment of patients with MM with venetoclax in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials

ADVERSE REACTIONS

• In CLL/SLL, the most common adverse reactions (≥20%) for venetoclax when given in combination with obinutuzumab or rituximab or as monotherapy were neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema

Review full prescribing information for additional information at www.rxabbvie.com, or contact AbbVie Medical Information at 1-800-633-9110 or go to abbviemedinfo.com.

Transcript 

The content of this video has been developed by AbbVie US Medical Affairs.  

Venetoclax is a BCL-2 inhibitor indicated for the treatment of adult patients with chronic lymphocytic leukemia, CLL, or small lymphocytic lymphoma, SLL. Concomitant use of venetoclax with strong CYP3A inhibitors at venetoclax initiation during ramp-up phase in patients with CLL/SLL is contraindicated.  

This video presents the 5-year off-treatment analyses from the CLL14 and MURANO studies.  

At the 2023 summer congresses, researchers presented the 5-year off-treatment analysis for venetoclax-based regimens in both the CLL14 and MURANO studies. In this video, we will discuss the long-term efficacy and safety data for venetoclax, starting with CLL14.  

CLL14 is an open-label, multicenter, randomized, active-controlled, phase III trial studying the efficacy and safety of venetoclax plus obinutuzumab for patients with previously untreated CLL.

CLL14 evaluated a 1-year fixed-duration regimen of venetoclax plus obinutuzumab compared to chemotherapy with chlorambucil plus obinutuzumab in previously untreated CLL patients with coexisting medical conditions. 

By design, the study population was representative of the general target population of CLL patients. 

To that end, the median age of the patients was 72 years. Patients had substantial coexisting medical conditions, characterized by a median Cumulative Illness Rating Scale, or CIRS, score of 8, and 58% of patients had a creatinine clearance less than 70 milliliters per minute. 

The primary endpoint in the original analysis for CLL14 was progression-free survival, or PFS, as assessed by an independent review committee.  

In the primary analysis, with a median follow-up of 28 months, venetoclax plus obinutuzumab significantly reduced the risk of progression or death by 67% vs obinutuzumab plus chlorambucil. Median PFS was not reached in either arm. 

The CLL14 5-year off-treatment analysis had a median follow-up time of 76.4 months after randomization. The estimated 6-year PFS was 53.1% in the venetoclax arm compared to 21.7% in the chlorambucil-treated patients. 

The median PFS in the venetoclax plus obinutuzumab treatment arm was reached at 76.2 months versus 36.4 months in the chlorambucil plus obinutuzumab arm.

Among the secondary endpoints results, also assessed were the time-to-next-treatment results. Overall, 65.2% of patients in the venetoclax plus obinutuzumab arm did not need to start another line of CLL therapy 5 years after completing treatment, versus 37.1% of patients in the chlorambucil plus obinutuzumab arm. This demonstrates that most patients had a prolonged treatment-free period.

In the primary analysis, the most common Any Grade adverse events, or AEs, greater than or equal to 20% for venetoclax plus obinutuzumab were neutropenia (60%), diarrhea (28%), and fatigue (21%), while the most frequent Grade 3 or greater AE (≥20%) was neutropenia (56%). Tumor lysis syndrome, or TLS, occurred in 3 patients (1%) in the venetoclax arm, with all occurring during treatment with obinutuzumab and before venetoclax treatment was initiated. None of the events met the Howard criteria for clinical TLS.

The incidence of select Grade 3 to 4 AEs decreased over time from the venetoclax plus obinutuzumab combination to the venetoclax single-agent treatment period. No new safety signals were identified at the 5-years off-treatment analysis. 

In summary, in the CLL14 primary analysis, we see a 67% reduction in risk of disease progression or death with venetoclax when compared to patients treated with chlorambucil, both in combination with obinutuzumab. At the primary analysis, median PFS was not yet reached in either arm. 

In the 5-year off-treatment analysis, the median PFS was 76.2 months and 36.4 months for venetoclax plus obinutuzumab and chlorambucil plus obinutuzumab, respectively.  

Additionally, 5 years after treatment completion, an estimated 65% of patients in the venetoclax plus obinutuzumab arm had not yet received a subsequent treatment compared to 37% for chlorambucil plus obinutuzumab. 

Again, the most common any-grade AEs, defined as ≥20%, for venetoclax plus obinutuzumab were neutropenia, diarrhea, and fatigue, while the most frequent Grade ≥3 AE was neutropenia. 

Incidence of Grade 3 to 4 AEs decreased over time from the combination period to the single-agent treatment period, and no new safety signals were identified at the 5-year off-treatment analysis. 

Now we will provide an overview of the 5-year off-treatment analysis of the MURANO study. 

MURANO was a multicenter, open-label, phase 3 randomized study of venetoclax plus rituximab versus bendamustine plus rituximab in patients with CLL who had received at least 1 line of prior therapy. 

Study patients were required to have had 1 to 3 prior lines of therapy, including at least 1 chemotherapy-containing regimen. 

Three hundred eighty-nine patients were randomized 1 to 1 to receive either venetoclax plus rituximab for 6 cycles or bendamustine plus rituximab for 6 cycles followed by venetoclax orally once daily for 24 months from Cycle 1 Day 1 of rituximab. 

Of these patients, the median age was 65 years, and the median number of prior therapies was 1. 

The primary endpoint was independent review committee-assessed PFS. 

In the primary analysis, with a median follow-up of 23.4 months, venetoclax plus rituximab significantly reduced the risk of progression or death by 81% vs bendamustine plus rituximab; median PFS was not reached for venetoclax plus rituximab and was 18.1 months for bendamustine plus rituximab. 

With the patients that were off venetoclax plus rituximab treatment for 5 years, the estimated 7-year PFS rate was 23%. This was not evaluable in the bendamustine plus rituximab treatment arm. 

The median PFS was 54.7 months in the venetoclax plus rituximab arm, compared to 17 months in the bendamustine plus rituximab arm.

In an analysis of time-to-next-treatment, the median time-to-next-treatment was 63 months in the venetoclax plus rituximab arm and 24 months in the bendamustine plus rituximab arm, indicating that about half of the patients in the venetoclax plus rituximab arm did not need next-line anti-CLL treatment for at least 3 years after completing treatment.

Out of 34 patients with progressive disease who entered the retreatment sub-study, 25 patients were retreated with venetoclax plus rituximab.

Retreated patients received a second 2-year fixed-duration venetoclax plus rituximab regimen after relapse with qualifying indications for treatment, and crossover patients received a first regimen.  

The venetoclax retreatment subgroup achieved a best overall response rate of 72%.

In the primary analysis, the most common Any Grade adverse events, or AEs (≥10%) for venetoclax plus rituximab were neutropenia (65%), diarrhea (40%), nausea (21%), upper respiratory tract infection (39%), and fatigue (22%), while the most frequent Grade ≥3 AE (≥10%) was neutropenia (62%). 

The incidence of TLS was 3%, or 6 patients, in the venetoclax plus rituximab arm. After the protocol was changed to incorporate the current TLS prophylaxis and monitoring measures, including extending the dose ramp-up to 5 weeks, no clinical TLS events were reported with venetoclax plus rituximab. 

The incidence of select Grade 3 to 4 AEs decreased over time from the venetoclax plus rituximab combination to the venetoclax single-agent treatment period. No new safety signals were identified at the 5-year off-treatment analysis. 

In summary, at the primary analysis, venetoclax plus rituximab reduced the risk of progression or death by 81% when compared with bendamustine plus rituximab.     

We see that in the 5-year off treatment analysis, the median PFS was 54.7 months for the venetoclax plus rituximab arm versus 17.0 months for the bendamustine plus rituximab arm. Median time-to-next treatment was 63.0 months versus 24.0 months for venetoclax versus bendamustine, respectively, both combined with rituximab. 

The most common any-grade AEs, defined as ≥20%, for venetoclax plus rituximab were neutropenia, diarrhea, nausea, upper respiratory tract infection, and fatigue, while the most frequent Grade ≥3 AE was neutropenia. 

Additionally, the venetoclax retreatment subgroup achieved a best overall response rate of 72%.

-

Venetoclax is a BCL-2 inhibitor indicated for the treatment of adult patients with chronic lymphocytic leukemia, CLL, or small lymphocytic lymphoma, SLL.

Important safety information. Concomitant use of Venetoclax with strong CYP3A inhibitors at venetoclax initiation during ramp-up phase in patients with CLL/SLL is contraindicated.

Warnings and precautions. TLS: Tumor lysis syndrome, including fatal events and renal failure requiring dialysis, has occurred in patients treated with venetoclax. Anticipate TLS; assess risk in all patients. Premedicate with anti-hyperuricemics and ensure adequate hydration. Employ more intensive measures (intravenous hydration, frequent monitoring, and hospitalization), as overall risk increases. 

Neutropenia: Monitor blood counts. Interrupt dosing and resume at the same or a reduced dose. Consider supportive care measures. 

Infections: Fatal and serious infections such as pneumonia and sepsis have occurred in patients treated with venetoclax. Monitor patients for signs and symptoms of infection and treat promptly. Withhold venetoclax for grade 3 and 4 infections until resolution and resume at the same or a reduced dose. 

Immunization: Do not administer live attenuated vaccines prior to, during, or after venetoclax treatment until B-cell recovery.  

Embryo-fetal toxicity: May cause embryo-fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. 

Increased mortality in patients with multiple myeloma, or MM, when venetoclax is added to bortezomib and dexamethasone: In a randomized trial in patients with relapsed or refractory MM, the addition of venetoclax to bortezomib plus dexamethasone, a use for which venetoclax is not indicated, resulted in increased mortality. Treatment of patients with MM with venetoclax in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials. 

Adverse reactions: In CLL and SLL, the most common adverse reactions (≥20%) for venetoclax when given in combination with obinutuzumab or rituximab or as monotherapy were neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema. 

Review full prescribing information for additional information at www.rxabbvie.com, or contact AbbVie Medical Information at 1-800-633-9110 or go to abbviemedinfo.com.

This content is intended for US/PR Healthcare Professionals.

AbbVie US Medical Affairs is the sole author and copyright owner of this presentation and has paid Oncology Learning Network to host this content. AbbVie is solely responsible for all written and oral content within this presentation.
©2024 AbbVie Inc. All rights reserved.

BCL2-US-00088-MC
V1.0, Approved 03/2024