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Ibrutinib + Rituximab
Ibrutinib Plus Rituximab and the Expanding Therapeutic Toolbox for Previously Untreated CLL

Released: June 26, 2020

Expiration: June 25, 2021

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We are fortunate to have several highly active, well-tolerated, targeted therapy regimens approved as initial therapy for patients with chronic lymphocytic leukemia (CLL), including acalabrutinib with or without obinutuzumab, ibrutinib, and venetoclax plus obinutuzumab. Recently, the indication for ibrutinib was expanded in this setting to include its combination with rituximab, providing another therapeutic option. In this commentary, I discuss the evidence supporting this new approval and outline how I expect to fit this combination into an increasingly complex therapeutic landscape.

Ibrutinib With or Without Rituximab
Ibrutinib is an oral BTK inhibitor approved as monotherapy for patients with CLL in both the frontline and relapsed/refractory settings. As described above, the FDA recently approved an expanded indication for ibrutinib in combination with the anti‑CD20 antibody rituximab for adult patients with previously untreated CLL. This was based on the phase III ECOG 1912 study, which randomized treatment-naive patients with CLL to ibrutinib plus rituximab or fludarabine/cyclophosphamide/rituximab (N = 529). Of note, this was a younger, fit patient population (younger than 70 years of age, ECOG PS ≤ 2) and the comparator arm was a clinically relevant standard chemotherapy combination. Ibrutinib was given as continuous therapy, whereas rituximab was provided as a limited course of 6 cycles. The primary endpoint of the trial was met, in that the combination of ibrutinib plus rituximab was superior in terms of PFS (HR: 0.39, P < .0001). There was also an OS advantage with ibrutinib plus rituximab. The combination was well tolerated; rituximab generally did not add to the adverse event profile generally associated with ibrutinib monotherapy.

One question we face in the clinic is whether rituximab adds significantly to the efficacy of ibrutinib. This is a difficult question to answer because the ECOG 1912 trial did not include an ibrutinib monotherapy comparator arm. The phase III ALLIANCE trial assessed ibrutinib with or without rituximab vs bendamustine plus rituximab in previously untreated patients with CLL, showing again that ibrutinib alone or with rituximab is superior to chemoimmunotherapy in terms of PFS. Of note, this trial demonstrated comparable PFS benefit with ibrutinib monotherapy vs ibrutinib plus rituximab. 

In my practice, I tend to administer ibrutinib as a monotherapy based on the data showing limited additive value of rituximab to ibrutinib. However, if I am being a purist, I would say that one could select the combination of ibrutinib plus rituximab for patients who are similar to those in the ECOG 1912 trial: younger, fit patients with no previous therapy who are candidates for fludarabine/cyclophosphamide/rituximab.

Selecting Among Approved Therapies
Given the wealth of targeted therapies available for frontline CLL treatment, how does one select one drug vs another in the absence of head-to-head comparison data for each of these agents?

The second-generation BTK inhibitor acalabrutinib was recently approved in the frontline setting based on the phase III ELEVATE TN trial, which demonstrated a significant PFS benefit with acalabrutinib alone or in combination with the anti‑CD20 antibody obinutuzumab when compared with obinutuzumab plus chlorambucil. This is another regimen with the potential to use the BTK inhibitor alone or in combination with an anti‑CD20 antibody. A notable difference with ELEVATE TN is that this trial did show a benefit with the addition of obinutuzumab to acalabrutinib (albeit in a post hoc analysis that was not powered to detect statistical significance). However, in my practice, I generally give acalabrutinib as a monotherapy as well.

The major reason I have hesitated to incorporate anti‑CD20 antibodies in combination with BTK inhibitors in my practice is that the BTK inhibitors are given as continuous therapies regardless of the addition of an antibody. Although the anti-CD20 antibody likely deepens the response, we do not yet have data to determine whether or not we could shorten exposure to the BTK inhibitor in the setting of combination therapy.

The BCL-2 inhibitor venetoclax is also approved for frontline CLL in combination with obinutuzumab, based on the phase III CLL‑14 trial. In that study, venetoclax plus obinutuzumab led to significant improvement in PFS and higher MRD negativity vs chlorambucil plus obinutuzumab. The major advantage of this combination is that it is a time‑limited 12‑month therapy where venetoclax is given for 12 months and obinutuzumab is given for a total of 6 months.

Selecting among regimens can be challenging, and one must consider the patients, including their age, fitness, past medical history, active comorbidities, and treatment preferences.

Are they more in favor of receiving a continuous therapy that is relatively well tolerated? Or are they more interested in an active combination that will be time limited? Together with the provider’s clinical experience, accounting for patient-specific characteristics and preferences can lead to the best treatment decision.

Your Thoughts?
How are you choosing among approved therapies for patients with previously untreated CLL? When do you consider adding an anti-CD20 antibody to BTK inhibitor therapy? Please answer the polling question and join the discussion by posting a comment.

In addition, click here to use CCO’s Interactive Decision Support Tool: Expert Guidance for the Treatment of CLL to receive management recommendations from a panel of 5 experts for a wide variety of patient presentations. For easy access to this and several other patient management tools from CCO, download the CCO Decision Support app from the app store on your phone!

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Is there a scenario in which you would consider the addition of rituximab to ibrutinib for frontline treatment of your patients with CLL?
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