Treatments for chronic lymphocytic leukemia (CLL) have experienced significant progress over the past 3-5 years. Survival is markedly improving with new small molecule inhibitors, especially for high-risk patients, such as del(17p) CLL. Standards of care are rapidly evolving with expanding options, and forthcoming results of several phase III trials will amplify this. Having numerous treatment options could make first-line and salvage management of CLL very challenging for the general oncologist.
First treatment is the best opportunity to use the most effective agents to achieve the deepest and most durable remission. This holds for chemoimmunotherapy (CIT)-based treatments and oral small molecule inhibitors of the B-cell receptor signaling pathway, such as the Bruton's tyrosine kinase inhibitor ibrutinib. High-risk cytogenetic abnormalities like del(17p) and complex karyotype are less common in untreated patients and emerge as a more common occurrence among patients with relapsing disease. Reasonable and effective salvage options must also be available, since none of the standard treatments is curative.
The median age at diagnosis is 72, and most patients don't need treatment until years after diagnosis, so age is a significant consideration in selecting first-line therapy. Older patients don't tolerate myelosuppressive or immunosuppressive CIT well; have increased risk for ibrutinib-associated toxicities; and have geographic, financial, and access limitations.
There are few absolutes regarding first-line therapy, but one applies to patients with del(17p) or mutated TP53 (M-TP53) CLL, which account for 5-8 percent of untreated patients. Ibrutinib-based therapy is standard for these patients; chemotherapy should be avoided. CIT may transiently de-bulk disease for some, but it is ineffective in achieving deep and durable remissions. If the patient is not able to tolerate ibrutinib, then the Bcl-2 inhibitor venetoclax is next choice. Venetoclax is not currently approved in the first-line setting but offers an oral treatment option that results in deep and durable remission, including in high-risk relapsed del(17p) CLL. First-line and salvage phase III trials with venetoclax are ongoing and will likely alter standards-of-care options in the near future.
Outcomes with first-line CIT are best for young, fit patients with mutated immunoglobulin heavy chain variable gene (M-IGHV) treated with fludarabine, cyclophosphamide, rituximab (FCR). For the majority of these patients, progression-free survival is greater than 10 years, and there is the possibility of cure. Options for young, fit patients with unmutated (UM)-IGHV, older patients with CLL, or those with comorbidities include ibrutinib and CIT. The choice should be based on physician and patient preference. CIT options include FCR, bendamustine and rituximab, and a CD20 monoclonal antibody (mAb) with or without chlorambucil.
Ibrutinib-based therapy has the advantage of significant activity across all risk groups in first-line and salvage, including del(17p)/M-TP53, del(11q), and UM-IGHV CLL. It is highly effective at disease control, and deeper remissions are possible after several years on first-line therapy. It is unclear whether the addition of a CD20 mAb or CIT to ibrutinib has any impact on long-term outcomes of remission duration or survival. Improved survival was demonstrated for ibrutinib monotherapy over chlorambucil in first-line patients.
Disadvantages of first-line ibrutinib include commitment to long-term treatment; high cost; side effects and toxicities, which increased in elderly and are a common reason for discontinuation; unknown long-term effects; physician and patient compliance; concern for treatment options post-ibrutinib; and persistent immune dysfunction with this non-curative therapy.
First-line CIT-based therapy typically has a defined duration with likely remission and treatment-free interval. Therefore, cost is less than for ibrutinib.
Patients with UM-IGHV respond to CIT, but have a shorter progression-free survival, and virtually all will relapse. For patients with UM-IGHV, preference may be to delay exposure to CIT, especially for younger patients. When CIT is given first-line, ibrutinib is then available as a salvage treatment option. For patients with a long first remission post-CIT, it may be reasonable to retreat with the expectation of another durable response and a long treatment-free interval.
There is limited data on efficacy of CIT after first-line ibrutinib. Disadvantages of CIT include the need for IV administration; regimen-dependent myelosuppression with associated risk for infection; genotoxicity with associated risk for long-term bone marrow damage, including MDS and AML; and Richter's transformation.
CD20 mAb-based treatment (with or without chlorambucil or bendamustine) is less myelosuppressive, is better tolerated by older patients with CLL, and offers a treatment option of defined duration. However, it has limited efficacy and shorter response duration, has to be administered IV, and has associated cost and toxicity issues.
In recent years, many new agents have become available for the treatment of CLL that confer marked improvement in survival. Progress in first-line treatment will be appreciated by achieving deep remissions and making treatment-free intervals possible with non-chemotherapy-based treatments. Reducing cost and toxicities are also crucially important considerations. Developmental work on effective combinations, sequencing, and maintenance strategies with the small molecule inhibitors will likely establish the next standards of care.
In addition, predictive markers and studies of mechanisms of resistance to small molecule inhibitors are needed. Curative treatment strategies must be an objective, and there is optimism that the newer agents will make this possible
WILLIAM G. WIERDA, MD, PHD, is the D.B. Lane Cancer Research Distinguished Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston.