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Anti-CD20 Antibodies in CLL
Anti-CD20 Antibodies in CLL: What to Do in Regular Practice

Released: July 09, 2015

Expiration: July 07, 2016

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For many years after its initial approval for non-Hodgkin’s lymphoma (NHL) in 1997, rituximab was the only anti-CD20 antibody available. In chronic lymphocytic leukemia (CLL), rituximab found a role in both previously treated and previously untreated patients. In the past few years, 2 additional anti-CD20 monoclonal antibodies, ofatumumab and obinutuzumab, have been developed and are available in the US for the treatment of patients with CLL, and additional anti-CD20 antibodies are currently under investigation in clinical trials.

Ofatumumab
Ofatumumab differs from rituximab in that it is humanized (not chimeric), binds to a different epitope on the CD20 molecule, and elicits higher levels of antibody-dependent cellular cytotoxicity (ADCC). Studies and regulatory approvals have established a role for ofatumumab in both frontline and relapsed/refractory disease; ofatumumab is approved in combination with chlorambucil, for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate and for the treatment of patients with CLL refractory to fludarabine and alemtuzumab. In the frontline setting, the combination of ofatumumab and chlorambucil produced superior PFS compared with single-agent chlorambucil. In patients with disease refractory to both fludarabine and alemtuzumab, ofatumumab produced a response rate of 42%. In a recently presented abstract, adding idelalisib to ofatumumab increased the efficacy considerably.

Obinutuzumab
Obinutuzumab is a humanized anti-CD20 antibody that has been “glycoengineered” to remove fucose molecules from the Fc portion of the antibody. Obinutuzumab causes increased ADCC and direct cell death compared with rituximab. In previously untreated patients who were unfit for more intensive regimens like FCR or BR, the combination of obinutuzumab and chlorambucil produced improved outcomes compared with rituximab/chlorambucil and with chlorambucil alone. Based on these outcomes, obinutuzumab received FDA approval in December 2013 for use in combination with chlorambucil for the treatment of CLL. In the GADOLIN trial, obinutuzumab and bendamustine were associated with a significant reduction in the risk of progression or death compared with bendamustine alone in patients with rituximab-refractory indolent NHL.

Options for Frontline Therapy in Previously Untreated Patients
Putting all this information together, I think the best options for patients with CLL in need of initial chemoimmunotherapy that includes an anti-CD20 antibody are:

  • Fit, good renal function
    • FCR, for patients willing to accept a risk of higher toxicity for the potential benefit of improved PFS
    • BR, for patients who prefer a regimen with less toxicity and similar OS (at the cost of lower rates of PFS)
  • Elderly, unfit for chemotherapy
    • Obinutuzumab/chlorambucil, preferred over ofatumumab/chlorambucil due to proven survival advantage

Selected Options for Patients With Relapsed Disease

  • Many patients with relapsed disease should receive ibrutinib. At the present time, there is no known advantage to adding an anti-CD20 antibody to ibrutinib. Studies to determine whether there is value to this practice are ongoing.
  • Idelalisib/rituximab: At the present time, there are no data to suggest that obinutuzumab or ofatumumab should be substituted for rituximab when combining with idelalisib, so rituximab is the preferred anti-CD20 antibody to use in combination with idelalisib.
  • Ofatumumab, but single-agent use will be limited because of its inferiority to both ibrutinib and combination with idelalisib.

Of note, deletion of 17p and TP53 mutations in CLL confer a high risk and suggest a poor outcome with chemoimmunotherapy. Such patients should be treated in clinical trials or, if clinical trials are not an option, with ibrutinib or idelalisib/rituximab whenever possible, as outcomes with the newer agents targeting the B-cell receptor pathway appear better than outcomes seen with chemotherapy-based regimens.

Your Thoughts?
I’d like to hear from you. For which patients do you prefer to use rituximab? For which do you prefer ofatumumab or obinutuzumab/chlorambucil? I invite readers to post their thoughts and experiences in the comments section below.

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Which chemoimmunotherapy regimen would you choose for first-line treatment of an elderly patient (older than 75 years of age) with CLL and significant comorbidities?
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