Back Back
CLL Therapy: Fit Patients
How I Treat My Patients With CLL Who Are Fit or Otherwise Healthy

Released: March 11, 2015

Expiration: March 09, 2016

Activity Information

Activity

Progress
1
Course Completed
Continue

Case: A 52-year-old male patient presents to medical care after not having seen a physician in more than 5 years. He reports enlarged lymph nodes in his neck. Subsequent evaluation reveals the diagnosis of chronic lymphocytic leukemia (CLL) with a white blood cell count of 2.4 x 109/L, hemoglobin of 9.0 g/dL, and platelets of 95 x 109/L. Physical examination and CT scans show widespread adenopathy and an enlarged spleen. Molecular testing reveals IgHV-mutated B-cell receptor with deletion of chromosome 13q. You and the patient both decide that starting therapy is appropriate. In light of recently approved therapies in CLL, how do you decide what therapy to choose?

The management of patients with CLL has made great strides in the past few years. With the addition of the BTK inhibitor ibrutinib, the anti-CD20 antibodies obinutuzumab and ofatumumab in the frontline setting, and ibrutinib and the PI3K delta inhibitor idelalisib in relapsed/refractory patients, the abundance of new treatment options has resulted in dramatic improvements in patient survival with agents that are well tolerated compared with their cytotoxic counterparts. Many are now asking whether it is most appropriate for previously untreated patients to initiate therapy with traditional chemoimmunotherapy or novel agents.

With the wealth of new treatment options, optimal therapy sequencing has not been established. Where does chemotherapy fit in this new order? In this context, the use of fludarabine, cyclophosphamide, and rituximab (FCR) in patients who are fit or otherwise healthy has gained additional research support from follow-up studies 15 years after its introduction into clinical practice.

Chemotherapy or Novel Agents?
A sizable fraction of patients treated on the original FCR clinical trial from the University of Texas M. D. Anderson Cancer Center remained progression free more than 10 years later in a follow-up study, with many testing negative for minimal residual disease. The plateau shape of the Kaplan-Meier curve suggests to some a possibility of a cure with FCR in some patient subsets. Similar results are seen with long-term follow-up of the multicenter German CLL8 study, which compared fludarabine plus cyclophosphamide (FC) to FCR. In molecularly defined favorable subgroups, long-term disease control—and possibly even cure—may be obtained at exceptionally high rates.

Detailed molecular analysis of patients treated on the German CLL8 study provides insight into how to identify these patients prior to initiating therapy. Although traditional risk stratification in CLL used both FISH and IgHV mutation analysis, next-generation sequencing technology has further refined patient outcomes through identification of several novel markers that may assist in therapeutic selection.

Those patients with the most favorable risk profile include those with IgHV-mutated CLL without del(17p) or del(11q) by FISH analysis and without mutations in TP53, SF3B1, and NOTCH1 by sequencing analysis. This subset represents 20% of all treated patients; when treated with FCR the progression-free survival rate in this group at 8 years approaches 70% to 80%. Although many patients with CLL are not suitable for intensive chemoimmunotherapy with FCR, this population likely derives the best outcome with this treatment.

By contrast, patients with CLL and del(17p) or TP53 gene mutations do poorly with chemoimmunotherapy. These patients likely derive optimal outcome by utilization of novel agents in the first-line setting. Ibrutinib is indicated for patients with del(17p) CLL in the United States and Europe. Idelalisib, in combination with rituximab, has a similar indication but only in Europe in the first-line setting. Although not commonly evaluated, individuals with CLL and BIRC3 mutations have similarly poor outcomes. Although they are not currently indicated, ibrutinib or idelalisib plus rituximab could be considered for these patients.

Managing Intermediate-Risk Patients
Between these 2 patient groups with the greatest difference in outcomes are those patients with intermediate-risk features, including unmutated IgHV, del(11q), or mutations in NOTCH1 or SF3B1. Ongoing studies comparing treatment with ibrutinib to either FCR or bendamustine plus rituximab (BR) will hopefully clarify the optimal strategy in such patients. However, the German CLL8 (FC vs FCR) and CLL10 (FCR vs BR) studies have shown that long-term disease eradication in these populations is rare. Although there is a progression-free survival benefit for FCR over BR, that advantage has not yet translated into an overall survival benefit. Moreover, now that such effective salvage therapies are available to treat relapsed CLL, the modest progression-free survival benefit for FCR over BR may not be worth the additional toxicity. Ongoing studies will clarify if these patients do better with novel agents.

Selection of first-line therapy in CLL for patients who are fit or otherwise healthy has been complicated by the arrival of a variety of novel treatment options. Fortunately, molecular markers beyond traditional FISH and IgHV mutation analysis can shed light on what treatment strategy may be most suitable for an individual patient. However, this also calls upon oncologists to become familiar with yet another layer of complexity.

What factors do you consider when choosing therapy for your fit or otherwise healthy patients with CLL? Share your opinion below and in the poll question!

Continue

Poll

1.
In your practice, what first-line therapy do you use most often for fit or otherwise healthy patients with CLL?
Submit