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R/R CLL: Venetoclax + R
How I Use Venetoclax/Rituximab in Relapsed/Refractory CLL

Released: July 24, 2018

Expiration: July 23, 2019

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In June 2018, the FDA approved venetoclax (with priority review given for venetoclax plus rituximab) for all patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma who had received at least one previous therapy, regardless of deletion 17p status, based on positive results from the randomized phase III MURANO trial. In MURANO, patients with relapsed/refractory CLL had a significantly longer investigator-assessed PFS with 6 cycles of venetoclax/rituximab vs 6 cycles of bendamustine/rituximab (not reached vs 17 months, respectively; HR: 0.17 95% CI: 0.11-0.25; P < .0001). The benefit was consistent in patients with and without deletion 17p. Before this, venetoclax was approved only for previously treated CLL with deletion 17p. How will this broadened approval change the landscape for CLL?

Venetoclax/Rituximab in Relapsed/Refractory CLL: Longer Remission Compared to Conventional Chemotherapy Combinations
I believe that having more novel targeted options to offer patients with CLL benefits our patients. When we only had conventional cytotoxic chemoimmunotherapy treatments, the first remission was the longest and subsequent remissions were progressively shorter. Additionally, many patients were not fit enough for chemoimmunotherapy, or their CLL had evolved to become resistant to these treatments. With this approval, I anticipate the greatest change will be that more patients will attain long‑term remissions and longer symptom-free intervals. The venetoclax plus rituximab combination is also notable as a novel targeted combination for its high minimal residual disease negativity and achievement of long PFS with time limited treatment. Ibrutinib, a BTK inhibitor, and idelalisib, a PI3Kδ inhibitor, are both administered continuously until progression or intolerance.

The venetoclax approval is also important for patients who are intolerant to or progressing on ibrutinib or idelalisib. Previously, we had few options outside of clinical trials because this population usually does not have meaningful remission associated with chemotherapy. Now, venetoclax with or without rituximab is another option for these patients.

Sequencing Venetoclax/Rituximab in CLL
There is no one-size-fits-all with sequencing venetoclax/rituximab with other novel agents in CLL, in part due to lack of direct clinical trial comparisons: The best options depend on each patient’s disease characteristics, age, and comorbidities. Given the longer term experience with ibrutinib, I would anticipate using ibrutinib as the initial targeted therapy for some patients, particularly patients who are older and/or who have renal dysfunction that raise concerns about the tumor lysis syndrome (TLS) associated with venetoclax (TLS risk characteristics discussed below). In other situations, concurrent conditions and/or patient preferences may favor venetoclax plus rituximab. However, we currently lack data on whether patients’ long‑term outcomes are comparable if they sequence from venetoclax to ibrutinib vs ibrutinib to venetoclax. 

Among my patients who are intolerant to or progressing on ibrutinib, in the absence of clinical trial options, I offer treatment with venetoclax with or without rituximab. Data from a multicenter, retrospective analysis indicated that patients treated with ibrutinib had improved PFS if they switched to venetoclax rather than idelalisib or chemoimmunotherapy. Jones and colleagues reported that patients who progressed after ibrutinib and went on to venetoclax had a high ORR with patients even achieving MRD negativity.

Management of Dose Escalation and Safety
Although venetoclax is approved as monotherapy, most often we are using venetoclax in combination with rituximab based on the MURANO data, unless the patient has had severe reactions to rituximab or received rituximab within a few weeks of treatment start. To minimize the risk of TLS, it is important to follow the approved 5-week dose ramp-up schedule to reach the final target dose of venetoclax before starting rituximab monthly for 6 cycles. 

When assessing whether a patient is at high risk for TLS and should be admitted to the hospital for close monitoring during dose escalation, I use the package insert and standard consensus guidelines to assign low, medium, or high risk according to absolute lymphocyte count and/or lymph node size. However, these are general guidelines and one should also consider consider the patient’s renal function, and/or other comorbidities to determine risk for TLS and need for inpatient escalation. Patients transitioning from ibrutinib or idelalisib to venetoclax are also considered a special population, because the patient’s white blood cell count can rapidly increase or their lymph nodes can enlarge if ibrutinib or idelalisib is stopped in actively progressing disease.

Cytopenias, including neutropenia, can also be encountered in patients receiving venetoclax plus rituximab. Cytopenias tend to occur within the first weeks to months of therapy, and they often respond to brief holding of the drug and/or growth factor support, without significant infections.

Your Thoughts?
Where would you sequence venetoclax/rituximab when managing your patients with CLL? Please share your thoughts in the comments box below.

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Would you consider venetoclax/rituximab for a relapsed/refractory patient with CLL without deletion 17p?
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