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Treating Fit Patients With CLL
How I Treat Young, Fit Patients With Newly Diagnosed Non-del(17p) CLL

Released: September 29, 2016

Expiration: September 28, 2017

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Patient Case
A 59-year-old white, otherwise healthy male without comorbid conditions was diagnosed with asymptomatic CLL during a routine blood count 1 year ago. He now comes to your office with new symptomatic lymphadenopathy, splenomegaly, and anemia. Prognostic workup reveals unmutated IGHV, and trisomy 12, with β2-microglobulin of 5 mg/dL.What would you recommend as the first-line therapy for this patient?

Based on existing data, there are several choices that can be offered to patients without del(17p), who are otherwise young and healthy, and require first-line therapy for their CLL, including chemoimmunotherapy (fludarabine/cyclophosphamide/rituximab FCR, bendamustine/rituximab BR), kinase inhibitors alone (ibrutinib), and kinase inhibitors in combination with chemoimmunotherapy (BR and ibrutinib). Here are the data I consider when making a treatment recommendation for patients like this one.

Use of FCR vs BR
The CLL8 trial established the superiority of FCR as a chemotherapeutic option for patients with non-del(17p) CLL. However, the benefit of this approach was limited to patients younger than 65 years of age due to increased treatment-related mortality in older patients. The more recent CLL10 trial recapitulates the superiority of FCR over BR albeit with higher toxicity, including severe neutropenia and infections. Long-term data from the original FCR300 phase II trial were also reported recently and show that at a median of 12.8 years of follow-up, 31.0% of the total population remained free of disease progression whereas this percentage increased to 53.9% for patients with mutated IGHV. The PFS curve plateaus in patients with mutated IGHV, and no relapses were observed in these patients beyond 10.4 years. All patients with mutated IGHV (n = 15) that had evaluable peripheral blood data were found to be negative for minimal residual disease. Moreover, these patients had a higher proportion of del(13q) and β2-microglobulin < 4 mg/dL. This raises the tantalizing possibility of long-term disease control and potentially a cure for a subset of patients who are healthy enough to tolerate chemotherapy (ie, those with mutated IGHV who achieve minimal residual disease negativity in the peripheral blood).

However, an argument can be made that patients who do well on FCR are generally those with low-risk disease who might have done just as well on other regimens that are not as intense as FCR therapy. In addition, FCR treatment results in significant infectious complications (found in 39% of the CLL10 study population) as well as persistent cytopenias seen in 12% of patients at 9 months after therapy. Fludarabine-based regimens can also result in treatment-related myeloid neoplasia in 5% to 8% of patients. Long-term follow-up from the CLL8 trial show that secondary malignancies occurred in 13.1% of patients treated with FCR.

Use of Ibrutinib
Ibrutinib is another attractive, first-line treatment option for all patients with CLL requiring therapy, particularly following the newly expanded indication to include patients without del(17p). Data from the RESONATE-2 trial on the use of ibrutinib in the treatment-naive setting confirms the activity seen in relapsed/refractory CLL: Response rates and CRs were statistically higher than with chlorambucil and improved over time. In addition, PFS and OS is significantly longer than with chlorambucil and may be comparable to other conventional chemoimmunotherapy. Ibrutinib also results in improved quality-of-life measures compared with patients receiving chemotherapy. The RESONATE-2 trial also reported excellent tolerability, with discontinuation rates secondary to adverse events less than 10%. Moreover, initiating ibrutinib earlier in the disease course may improve response and survival outcomes.

Along with the expanded indication for ibrutinib, the new prescribing information also includes data from the HELIOS trial showing improvement in ORR, CR, and PFS without significant increase in toxicity. However, there does not appear to be an added outcome benefit with the addition of BR compared with single-agent ibrutinib alone.

Summary
Although FCR might result in durable remissions in a subset of patients with low-risk disease, its use can be associated with significant toxicity. It does, however, offer the option of a defined treatment timeline compared with the indefinite timeline with ibrutinib. Ibrutinib is an option for patients who do not want to receive chemotherapy and can commit to continuous treatment over a long period of time. There is currently no evidence that adding additional agents to ibrutinib improves outcomes over ibrutinib alone. Given these data, direct comparison trials such as the E1912 trial comparing ibrutinib plus rituximab with FCR in previously untreated CLL are urgently required. In the meantime, treatment decisions should be based on an informed decision by the patient after understanding the risks and benefits of either approach.

Patient Case Conclusion
Based on the data summarized above, this patient would be a candidate for either FCR or ibrutinib as first-line therapy. His prognostic markers (unmutated IGHV, elevated β2-microglobulin) place him in the group of patients who are less likely to attain long-term disease-free remissions after FCR. Moreover, this particular patient adamantly refused chemotherapy out of concerns regarding quality of life and treatment-related morbidity and mortality. After prolonged discussion with the patient where I explained the risks and benefits of FCR, BR, and ibrutinib, the patient is pursuing treatment with single-agent ibrutinib.

A New Tool to Help Guide CLL Treatment Decisions
To help you address the challenges associated with treatment decisions for your patients with CLL, my colleagues (Steven E. Coutre, MD; Jeffrey A. Jones, MD, MPH; Michael J. Keating, MB BS; and Andrew D. Zelenetz, MD, PhD) and I are updating an Interactive Treatment Decision Tool along with other online activities and several more commentaries from CLL experts, so check back in on the CCO Web site for more information on managing your patients with CLL. An older version of this Treatment Decision Tool is available here and an updated version will be published on the CCO Web site in October 2016. This tool is designed to help you rapidly select individualized treatment options based on your patient’s specific disease characteristics and overall fitness by offering recommendations from each of the experienced faculty listed above specifically for the case you enter into the tool.

Please share your questions or thoughts on your current management approaches for patients with CLL in the comment box below.

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Which of the following therapies would you recommend for the patient described in this commentary?
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