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Maintenance Therapy in CLL
What Is the Role of Maintenance Therapy in CLL?

Released: May 16, 2017

Expiration: May 15, 2018

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A 64-year-old man was diagnosed with del(13q), IGHV-mutated CLL 15 years ago. He was followed with watchful waiting initially before requiring treatment 10 years ago for symptomatic progressive disease. This patient was initially treated with 6 cycles of FCR without any major issues and had a long, uneventful remission for approximately 7 years. During the last 3 years, he has had slowly progressive disease and, based on ongoing cytopenias night sweats, and painful lymphadenopathy, he was treated with BR for 6 cycles. He tolerated this additional chemotherapy well and achieved a CR. Now, he is currently in your office 2 months after completing therapy for follow-up and inquires if there are any options that will prolong his remission.

History of Maintenance Therapy in CLL
Maintenance therapy has typically been considered redundant for the management of patients with CLL after chemotherapy-based or chemoimmunotherapy-based regimens. This practice persisted despite the fact that similar regimens have shown clinical benefit for other indolent lymphoid malignancies like FL and MCL. Early efforts to study maintenance options in CLL included the CD52 antibody alemtuzumab, whose use was associated with unacceptable toxicity, primarily infections, despite the fact that there was improvement in PFS.

Multiple other studies with better-tolerated therapies demonstrated significant improvements in PFS with manageable toxicities. These therapies include flavopiridol, lenalidomide, and the anti-CD20 antibodies rituximab and ofatumumab.

New Indication for Ofatumumab
In the phase III PROLONG study, maintenance ofatumumab for 2 years for patients who achieved CR or PR after second-line or third-line therapy improved PFS by 14 months over observation alone. Based on these data, the FDA approved ofatumumab for maintenance therapy in patients with CLL who are in CR or PR following at least 2 lines of therapy. However, OS was not improved, suggesting that ofatumumab was probably more helpful in delaying relapse rather than affecting deeper remissions, since ofatumumab also increased time to subsequent therapy by around 7 months vs observation alone. In addition, 33% of patients experienced serious AEs, with pneumonia, pyrexia, and neutropenia being the most common serious AEs observed.

Additional Maintenance Trials
Similarly, the phase III AGMT CLL-8a trial enrolled patients who achieved a CR, CR with incomplete bone marrow recovery, or PR to first-line or second-line therapy with rituximab-containing chemotherapy. Median PFS was improved by almost 12 months after rituximab maintenance for 2 years vs observation, but OS remained similar. Rituximab maintenance was associated with an increased rate of infection, but there was no excess in infection mortality.

Likewise, lenalidomide has also recently been shown to improve PFS. The phase III CLL M1 study of the German CLL Study Group enrolled patients who achieved PR or better after at least 4 cycles of first-line chemoimmunotherapy and were at high risk for progression. Maintenance lenalidomide achieved a relative risk reduction for disease progression of 80% (P < .00001) in this patient population vs placebo, although no OS benefit has been observed at this time. However, of the initial 468 patients enrolled in the trial who received first-line chemoimmunotherapy, only 89 patients qualified as “high risk,” defined as having MRD levels of ≥ 10-2 or MRD levels of ≥ 10-4 to < 10-2 along with unmutated IGHV gene status or a del(17p) or TP53 mutation at baseline, and were eligible to continue on the trial to receive maintenance therapy.

The phase III CONTINUUM trial assessed the utility of maintenance lenalidomide after second-line therapy and showed a 24-month improvement in PFS with lenalidomide vs placebo (33.0 vs 9.2 months, respectively). There was a trend toward an OS improvement in this trial, but it was not statistically significant; however, many patients went on to receive subsequent therapy, which may help explain the lack of survival advantage. Most common AEs with lenalidomide therapy include neutropenia (66%) and diarrhea (41%), with 17% of patients experiencing grade 3/4 infection (vs 10% with placebo). There was no difference in the rate of second primary malignancies between arms in this study.

View of Maintenance Therapy for CLL
In the PROLONG trial, the most significant improvement in outcomes were observed for patients with generally accepted good risk features like mutated IGHV and del(13q)—patients who would ordinarily be expected to have a good response to chemoimmunotherapy regardless. Moreover, maintenance therapy is generally associated with increased risk of infectious complications but quality-of-life measures in the trials mentioned above appeared to be unaffected.

Based on these existing data, an argument can be made that maintenance therapy might allow for a longer disease-free interval at a modestly higher risk of infectious complications. However, given the rapid development of alternative, extremely effective and well-tolerated therapies like ibrutinib, idelalisib, and venetoclax and a lack of improvement in OS, an argument can be made to use maintenance therapies only in selected patients who are expected to tolerate these without any major issues.

Patient Case Conclusion
Based on the data summarized above, in this particular patient, after a prolonged discussion about the advantages and disadvantages of the various available therapies and especially after considering the excellent outcome with initial therapies, the patient elected to proceed with lenalidomide treatment as maintenance treatment.

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; Jeff P. Sharman, MD; and Andrew D. Zelenetz, MD, PhD) and I have developed an updated interactive treatment decision tool. 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. Use this tool, along with several other online activities and additional commentaries on CLL to optimize the care of your patients with CLL.

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

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