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Individualized Frontline CLL Therapy
How I Individualize Frontline CLL Therapy in My Practice

Released: March 29, 2016

Expiration: March 28, 2017

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I recently worked with a group of CLL experts to develop an online treatment decision aid to help clinicians select optimal therapy for their own patients with CLL. This interactive tool allows you to enter a specific patient’s characteristics through simple pull-down menus and then see what treatment the 5 of us would select for your patient.

Selecting First-line Treatment for Patients With CLL
For treatment‑naive patients with CLL and del(17p), it is pretty simple—ibrutinib is optimal for almost every patient. Ibrutinib is very effective in patients with del(17p) cytogenetic lesions, and patients can achieve a long remission. You review my previous ClinicalThought commentary for a discussion of some of the potential issues with ibrutinib and how I handle them in my practice.

If you look at patients with other cytogenetic profiles, the choice of frontline treatment is not as clear-cut. I recently had a 58-year-old patient diagnosed with CLL, and cytogenetics came back with del(13q). This patient had an ECOG PS of 1 and CIRS score of 10 but no renal dysfunction. If you input these patient characteristics into the online CLL Interactive Decision Support Tool, you see a range of treatment recommendations from the experts (Figure).

Figure. Expert selections for young patient with comorbidities.

Based on the CLL10 trial, FCR is likely optimal for younger patients without comorbidities. However, this regimen can be difficult to tolerate. For this patient, I would possibly consider “FCR‑light,” but patients with an unfavorable ECOG PS or CIRS, like our patient here, usually do not tend to do well on FCR.

BR is also an option for these patients and is what I would choose for the patient case described here. Although there was a PFS benefit for FCR vs BR in the CLL10 trial, there was not an OS benefit, and the modest PFS benefit for FCR over BR may not be worth the additional toxicity. For patients who are older than 65 years of age, the efficacy outcomes were identical, and patients with unfavorable ECOG PS or CIRS or renal impairment were excluded from that trial. Due to the unfavorable CIRS for this patient, I think FCR might be too harsh even though he is younger. Patients who are less fit typically require more dose adjustments, require less dose intensity, and only receive 3-4 cycles of FCR instead of 6 full cycles. But, for your ideal patient for FCR—no comorbidities, younger than 65 years of age, and del(13q) or no higher risk cytogenetics (even if they are IGHV unmutated)—FCR will give them a chance to experience a long treatment-free interval.

Ofatumumab or obinutuzumab with chlorambucil are also options for patients with less fit patients (an unfavorable ECOG PS or CIRS). Furthermore, until recently, we did not have ibrutinib approved for frontline treatment. However, the FDA has now approved ibrutinib for frontline therapy, regardless of cytogenetics, based on the RESONATE-2 trial of ibrutinib vs chlorambucil in treatment-naive patients with CLL without del(17p) who were older than 65 years of age. Many clinicians, therefore, may extrapolate based on these data from patients older than 65 years of age to patients with multiple comorbidities and/or unfavorable ECOG PS and CIRS.

Right now, it is difficult for me to justify giving a young patient without significant comorbidities a long‑term therapy like ibrutinib when FCR and BR have been shown to be effective with only 6 cycles of treatment. Even with the recent approval, I do not think many clinicians are choosing ibrutinib for frontline for a young patient because you are committing your patient to lifelong therapy. We learned from our experience with imatinib in CML that, after 2 years of an oral therapy, only 40% of people are still compliant with their regimen. This consideration can also impact choice of therapy: It may be better to schedule infusions and know that your patient is receiving appropriate therapy rather than prescribing an oral, long-term agent that they may not be compliant with over time.

There is currently an intergroup phase III clinical trial that is enrolling patients to compare FCR with ibrutinib plus rituximab for younger patients with untreated CLL or SLL, Hopefully, this trial will give us some insight as to the best treatment approach for this patient population. Another intergroup phase III trial is currently ongoing to compare BR vs ibrutinib vs ibrutinib plus rituximab for older patients with previously untreated CLL, and these data are expected soon.

Final Thoughts
With multiple options available for frontline treatment of CLL, it is sometimes difficult to select the optimal therapy for individual patients in this setting. Consideration of each patient’s disease characteristics and general fitness is essential in selecting the best therapy, and the NCCN treatment guidelines along with expert recommendations and decision aids such as the online treatment selection tool for CLL can help guide your treatment selection.

Let me know in the comments what you use when deciding on treatment for your patients with CLL. Have recent clinical trial data changed your treatment approach?

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Which treatment would you select in your current clinical practice for the patient case mentioned in this commentary?
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