CLL - Episode 6

ASH 2020: Updated Results from the Murano Five-Year Analysis in R/R CLL

April 23, 2021

FOR YOUR REFERENCE: What Are Clinical Trials?

Clinical trials determine if a drug works in humans and if it is safe and effective. To determine if a drug can be approved for use, the Food and Drug Administration (FDA) requires 4 phases of a clinical trial. The number of participants increases in each phase, starting from 20 to 80 people for a phase 1 trial to up to 3,000 for a phase 3 trial (Figure 1).1

  • Phase 1: tests an experimental treatment on a small group of often healthy people to judge its safety and side effects and to find the correct drug dosage.
  • Phase 2: focuses primarily of effectiveness and obtains preliminary data on whether the drug works in people who have a certain disease or condition.
  • Phase 3: gathers more information about safety and effectiveness, studies different populations and different dosages, and examines use of the drug in combination with other drugs.
  • Phase 4: occurs after FDA approval, monitors safety and effectiveness in large, diverse populations, and collects information on long-term side effects.

FOR YOUR REFERENCE: What is Chronic Lymphocytic Leukemia?

Chronic lymphocytic leukemia (CLL) is a form of cancer that starts in the blood-forming cells in bone marrow that become certain white blood cells, called lymphocytes. In CLL, cancer occurs in B cells, a type of lymphocyte, which defends your body against infection. These cells change and become cancer cells, or leukemia cells, that can grow out of control and spread by traveling into the blood to other parts of the body.2

Patients with CLL may experience symptoms such as weakness, feeling tired, weight loss, chills, fever, night sweats, swollen lymph nodes, pain or a sense of fullness in the belly. While these signs and symptoms can point to CLL, tests are needed for a diagnosis. Many people with CLL do not have any symptoms at the time they are diagnosed; in fact, their leukemia is found during blood tests for unrelated health issues or routine check-ups.3 CLL is usually recognized when blood counts performed for unrelated reasons reveal lymphocytosis, or higher-than-normal amount of lymphocytes in the body.

There are different treatment options for patients with CLL4:

  • Watchful waiting.
  • Radiation therapy.
  • Chemotherapy.
  • Immunotherapy.
  • Targeted therapy.
  • Clinical trials.

Patients undergoing CLL treatment often experience a complete or partial response to initial therapy, however this is not always the case. Consequently, CLL can be classified as relapsed or refractory (R/R) depending on how the disease responds to treatment. Some patients who have been previously treated with CLL agents have disease that doesn’t respond to treatment or a worsening of the disease within six months of the last treatment (refractory CLL) or disease that responds initially and goes away for six months or more, but comes back (relapsed CLL).5

FOR YOUR REFERENCE: What Agents Were Investigated in the MURANO Trial?

Bendamustine plus rituximab is a standard-of-care chemoimmunotherapy combination often given for the treatment of R/R CLL. Chemoimmunotherapy refers to the use of drugs to directly kill or affect the growth of cancer cells (chemotherapy) together with substances to activate the body’s immune system to fight cancer cells (immunotherapy).6

Venetoclax is an orally administered inhibitor of BCL-2, a protein involved in regulating a cell’s life cycle. Venetoclax is used for the treatment of patients with CLL in combination with rituximab or obinutuzumab.6,7 Venetoclax and rituximab are often used in combination as continuous therapy for the treatment of R/R CLL.6-8

ASH 2020: Updated Results from the Murano Five-Year Analysis in R/R CLL

The MURANO trial was an open-label, multicenter, randomized phase three study that evaluated the efficacy, safety and tolerability of venetoclax given in combination with rituximab versus bendamustine given with rituximab as treatments for adult patients with R/R CLL.9

Patients included in the study were those who had received up to 3 prior treatment regimens, including at least one regimen that included standard chemotherapy.9

A group of 389 patients from the original MURANO study who experienced disease progression (their CLL continued to worsen) after treatment with venetoclax plus rituximab or bendamustine plus rituximab were enrolled in a sub study, in which researchers had patients either continue with venetoclax plus rituximab (if they were already taking this combination) or switch patients to venetoclax plus rituximab (if they had been taking bendamustine plus rituximab initially). These patients were monitored for a median of five years as part of the sub study.10

Researchers monitored patients to see how much time would pass before the patients experienced disease progression (progression-free survival [PFS]) and also conducted blood work to monitor for the presence of a reduced number of cancer cells after treatment (minimal residual disease [MRD]).6,10 


The Table illustrates the benefits in PFS and overall survival (OS) observed in this sub study.10

After a median follow-up of 59.2 months in the sub study, median PFS was 53.6 months among patients who received venetoclax plus rituximab, compared with 17.0 months in the bendamustine plus rituximab group.

Researchers estimated that the five-year OS was 82.1% in the venetoclax plus rituximab group and 62.2% in the bendamustine plus rituximab group.

OS was improved among patients who did not experience disease progression after receiving venetoclax plus rituximab and had undetectable MRD, compared with those with MRD. A total of 118 patients completed venetoclax plus rituximab treatment without experiencing disease progression. In patients with undetectable MRD (83 of 118 patients), researchers estimated that the three-year survival rate after treatment was 95.3%, compared with 85.0% in those with MRD (35 of 118 patients).

No additional safety concerns were identified in the sub study. Among patients in the venetoclax plus rituximab group, two additional cases of second primary malignancies (acute myeloid leukemia and multiple myeloma) among patients in the venetoclax plus rituximab group were noted beyond those reported in a previous MURANO trial update.10 A similar number of patients in each group experienced a change from CLL to a fast-growing form of lymphoma — seven treated with venetoclax and rituximab in combination and six treated with bendamustine and rituximab.6,10

In this analysis of data from a subset of patients from the MURANO trial who experienced disease progression, treatment with venetoclax plus rituximab resulted in continued improvements in PFS and OS after a median of five years of follow up.10

As not all patients can qualify for certain clinical trials, talk to your doctor about possible treatment options available to you.

FOR YOUR REFERENCE: Glossary of Terms4-8

Acute myeloid leukemia: a type of cancer of the blood and bone marrow

B cells: one type of white blood cell that is an important part of your immune system (the body’s defense against infection).

Chemotherapy: treatment that uses drugs to stop the growth of cancer cells either by killing the cells or by stopping them from dividing. These drugs are taken by mouth or injected and enter the bloodstream so they can help cancers that spread throughout the body (like CLL). This can affect cancer cells and normal cells

Chronic lymphocytic leukemia (CLL): cancer that develops into a particular white blood cell

Clinical trials: research investigations in which people volunteer to test new treatments

Complete response (also called complete remission): the disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured.

Efficacy: the ability to produce a desired outcome; in the case of cancer treatments, the desired outcome is a decrease in the number of cancer cells or the disappearance of cancer cells

Hypertension: a blood pressure reading of 140/90 mm Hg or higher; also called high blood pressure

Immunotherapy: type of therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection and other diseases. Some types of immunotherapy only target certain cells of the immune system. Others affect the immune system in a general way

Leukemia: cancer that starts in blood-forming tissue, such as bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the bloodstream

Lymphocytes: a type of white blood cell that is made in the bone marrow and is found in the blood and lymph tissue

Lymphocytosis: a higher-than-normal amount of lymphocytes in the body

Median follow-up: the time between treatment and the time when data outcomes are gathered

Median: the middle value of a sorted list of numbers placed in value order from highest to lowest

Minimal residual disease (MRD): the small number of cancer cells that remain in the body after treatment

Multiple myeloma: a type of cancer of the plasma cells, a type of white blood cell

Neutropenia: a condition in which there is a lower-than-normal number of neutrophils (a type of white blood cell) in the blood

Objective response rate: the proportion of patients with a decrease of cancer over a predefined amount

Overall survival: the length of time from either the date of diagnosis or the start of treatment for a disease that patients diagnosed with the disease are still alive

Partial response: A decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. Also called partial remission

Phase 1: tests an experimental treatment on a small group of often healthy people

Phase 2: uses more people and emphasizes effectiveness

Phase 3: gathers more information about safety and effectiveness, studying different populations and different dosages, using the drug in combination with other drugs

Phase 4: usually occurs after FDA approval

Progression free survival: the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse

Progressive Disease: cancer that is growing, spreading or getting worse

Refractory: a disease state or condition that does not respond to treatment or medication. Refers to when the lymphoma does not respond to treatment (the cancer cells continue to grow) or when the response to treatment does not last very long.

Relapsed: a return of signs and symptoms of cancer after a period of treatment or medication. Relapsed is the disease that returns or grows again after a period of remission following one or more treatments. Marked by an initial response to treatment that is no longer present after six months or more

Rituxan: a treatment indicated for the treatment of adult patients CCL or SLL

Side effect: An unintended reaction to, or result of, a treatment

Small lymphocytic lymphoma (SLL): a slow-growing type of lymphoma in which too many immature lymphocytes (white blood cells) are found mostly in the lymph nodes

Venetoclax: is a treatment indicated for the treatment of adult patients CCL or SLL

White blood cells: a type of cell that is found in the blood and lymph tissue that helps fight infections and other diseases. Lymphocytes (T and B cells) are a type of white blood cell


1. What are clinical trials and studies? National Cancer Institute. Accessed March 15, 2021.

2. What is chronic lymphocytic leukemia? American Cancer Society. Revised May 10, 2018. Accessed March 15, 2021.

3. Signs and symptoms of chronic lymphocytic leukemia. American Cancer Society. Updated May 10, 2018. Accessed March 15, 2021.

4. Chronic lymphocytic leukemia treatment (PDQ®)–patient version. National Cancer Institute. Updated November 25, 2020. Accessed March 15, 2021.

5. Chronic Lymphocytic Leukemia. Leukemia and Lymphoma Society. Updated 2014. Accessed March 15, 2021.

6. NCI Dictionary of Cancer Terms. National Cancer Institute. Accessed April 17, 2021.

7. Venclexta. Prescribing information. AbbVie Inc; 2020. Accessed March 17, 2021.

8. Rituxan. Prescribing information. Genentech, Inc.; 2020. Accessed March 19, 2021.

9. A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) (MURANO). Updated February 17, 2021. Accessed March 19, 2021.

10. Kater AP, Kipps TJ, Eichhorst B, et al. Five-Year Analysis of Murano Study Demonstrates Enduring Undetectable Minimal Residual Disease (uMRD) in a Subset of Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Patients (Pts) Following Fixed-Duration Venetoclax-Rituximab (VenR) Therapy (Tx). Presented at: The 62nd Annual Meeting and Exposition of the American Society for Hematology; December 2-10, 2020; Virtual. Presentation 125