Andre Goy, MD, MS
Chief, Lymphoma Division, Professor and Chairman
John Theurer Cancer Center at Hackensack University Medical Center
This article offers highlights from some of the advances we’ve seen in hematological and solid tumors over the past 2 decades. The first report by Janssens and colleagues focuses on the changes in chronic lymphocytic leukemia (CLL) outcomes and the benefits of chemoimmunotherapy, namely rituximab, using a meta-analysis to compare regimens used in the United States and Europe. The second paper by Popek and Tsikitis reviews the broad changes that have occurred in the treatment and management of metastatic colon cancer.
CLL is the most common form of leukemia and the second most common blood cancer after lymphomas. CLL has long been regarded as an incurable disease of the elderly, treated mainly by symptom palliation. While some patients can have a very indolent course (ie, never require treatment and have the same life expectancy as normal control groups), others can have a much more rapid course. In some cases, the disease can even transform into large cell lymphoma (eg, Richter syndrome). Prior generations of chemotherapy resulted in improved response rates but did not change the natural history of the disease. However, prolonged remissions and improvements in survival are now possible, owing to therapeutic advances in the use of purine analogs as frontline treatment and the emergence of monoclonal antibody-containing chemoimmunotherapy combinations.
As is the case with indolent non-Hodgkin lymphoma (NHL), clinical criteria have been developed to help determine when to initiate therapy in patients with CLL. However, the criteria are somewhat subjective and tend to lead to heterogeneous treatment, which might affect comparisons from one trial to another. Moreover, as in indolent NHL, using overall survival (OS) as an endpoint can be a challenge due to the long natural history of the disease. Therefore, surrogate markers of outcome, such as overall response rate (ORR), complete response rate (CRR), and progression-free survival (PFS), have often been used. Over the past 3 decades, trials have looked at a number of regimens—from chlorambucil single agent to purine analogs (fludarabine and to a lesser degree pentostatin) to combinations with fludarabine and cyclophosphamide (FC)—based on significant synergistic cytotoxicity in preclinical models. Combination FC was shown to be superior to fludarabine alone, and fludarabine/cyclophosphamide/rituximab (FCR), which was developed at MD Anderson Cancer Center, has been shown to be superior by all parameters (ie, ORR, CRR, duration of response [DOR], and PFS).
Rituximab, a chimeric anti-CD20 monoclonal antibody that targets the cell-surface antigen CD20 expressed on more than 90% of mature B-cell malignancies, has proven to be a game changer in B-cell NHL. However, rituximab has limited single-agent activity in CLL (ORR 12% at 375 mg/m2) which may be attributed in part to the reduced tumor expression of CD20 and the presence of soluble CD20 serving as a decoy receptor in CLL.
The addition of rituximab to FC (ie, FCR) doubles the proportion of patients entering complete remission, and significantly prolongs remission duration and OS. The quality of the responses has led to the emergence of minimal residual disease (MRD), and patients with no MRD had the best outcome. Strategies of consolidation and maintenance therapies have been developed for patients to reach negative MRD. This includes more rituximab or better alemtuzumab, an anti-CD52 antibody. Unfortunately, FCR is not always a treatment option (eg, in elderly, “nonfit” patients), and patients with poor risk factors, especially those with p53 abnormalities (mutation/deletion), still have a poor outcome. Ongoing studies are looking at FCR plus alemtuzumab in these patients, but issues related to toxicity, myelosuppression, and immunosuppression (especially infection, pneumocystis pneumonia, and cytomegalovirus reactivation) are an obvious concern with this combination regimen.
In the relapse setting, an increasing number of patients are fludarabine-resistant and represent a clear challenge to the clinician. A growing list of new salvage options has been developed, again showing a benefit from the combination with rituximab. Not surprisingly, some of these new options are being implemented in the frontline setting as well. Bendamustine, approved in relapsed CLL, is now being tested in the frontline setting in the CLL10 trial (bendamustine/rituximub vs FCR). Results of this trial are still pending. In addition, a number of new monoclonal antibodies have been developed or are currently in development for the treatment of CLL. For example, ofatumumab, which targets another epitope of CD20 and induces greater complement-dependent cytotoxicity, has shown activity in CLL double failures (fludarabine and alemtuzumab).