By William B. Ershler, MD
Synopsis: In an analysis of a well-characterized dataset capturing outcomes for patients with asymptomatic, low-burden follicular lymphoma, those managed by initial watchful waiting had outcomes similar to comparable patients who were treated at the time of diagnosis with regimens including rituximab. Thus, delayed initial therapy remains a reasonable approach for selected follicular lymphoma patients.
Source: Solal-Celigny P, et al. Watchful waiting in low-tumor burden follicular lymphoma in the rituximab era: Results of an F2-study database. J Clin Oncol 2012;30:3848-3853.
It has long been held that follicular lymphoma (FL) is typically indolent but incurable. However, it’s not indolent for every patient. Progression, either shortly after diagnosis or months to years later, is observed in most patients and transformation to a more malignant variant with all the features of aggressive lymphoma occurs in a small subset. Furthermore, with the advent of new and targeted therapies, the “incurable” moniker also may be challenged. It has been speculated that therapies such as rituximab may change the natural history of this disease, and, if not resulting in cure, at least prolonging survival beyond that seen for patients treated with chemotherapy alone.
Accordingly, the practice of delaying initial treatment (watch and wait, W&W) for those with low-burden FL needs careful reexamination. The premise for such an approach has been based on studies initially published from Stanford in which a W&W approach was compared with chemotherapy demonstrating no significant differences in terms of overall survival.1-3 These conclusions have been confirmed in additional studies in which selected FL patients were randomized to observation (W&W) or treatment with chemotherapy (either single or multiple agents) or interferon with no significant difference in overall survival observed.4-6 Yet, the question is whether early treatment with rituximab would provide results that would change the current sentiment or whether there is no disadvantage to delaying initial therapy.
To address this, investigators participating in the International Follicular Lymphoma Prognostic Factor Project examined data derived from more current FL patients (i.e., in the rituximab era) registered in the F2-study and initially managed without treatment to describe the presentation and outcome of a W&W strategy. The goal was to identify parameters for initiating treatment and to evaluate whether initial W&W could have deleterious effects on treatment efficacy after progression or relapse when compared to those receiving current management including rituximab.
Between 2003 and 2005, 120 patients selected from the 1093 treatment-naive patients with FL in the F2-study cohort initially were managed expectantly (W&W), and 107 patients were assessed. Most of these patients (80%) had disseminated disease with a low tumor burden, according to Groupe d’Etudes des Lymphomes Folliculaires criteria.5 After a median follow-up of 64 months, treatment was initiated in 54 patients (50%), with a median delay of 55 months for the entire cohort. In a univariate analysis, involvement of more than four nodal areas (hazard ratio [HR], 2.26) and serum albumin < 3.5 g/dL (HR, 3.51) were predictive of a shorter time to lymphoma treatment initiation. In a multivariate analysis, only involvement of more than four nodal areas remained significant (HR, 2.32). The 4-year freedom from treatment failure (FFTF) rate of W&W patients (79%; 95% CI, 69% to 85%) was not inferior to that of a subgroup of 242 patients from the F2-study cohort with good prognosis characteristics who were initially treated with a rituximab-based regimen (69%; 95% CI, 61%-76%; P = 0.103).
Clinical oncologists (like me) may not be too familiar with the FFTF endpoint, but it is indeed an outcome of relevance when comparing delayed vs initial therapy. The issue is best exemplified by the intriguing findings presented at the American Society of Hematology annual meeting in 2010 by Ardeshna and colleagues.7 They presented preliminary results from a trial in which 450 asymptomatic FL patients were randomly assigned to either W&W or to four weekly doses of rituximab followed either by observation or by 2 years of maintenance rituximab. They found the time to initiation of chemotherapy or radiotherapy was significantly prolonged in the early intervention arms — findings that would argue against delaying treatment, even in asymptomatic low-burden patients. That conclusion, however, has raised some controversy as articulated both by the authors of the current study and by Dr. Cheson who provided the accompanying editorial.8 They emphasized that rather than compare the time to initial treatment for the W&W patients with the time to second-line therapy for the treated patients, it would be more appropriate to compare the FFTF or the time to second lymphoma therapy and, of course, when the data are sufficiently mature, the overall survival for each of the cohorts.
The currently presented careful analysis of a well-constructed dataset would suggest patients with asymptomatic, low-burden FL can still be managed safely with W&W as such an approach, even in the rituximab era, does not have apparent detrimental effects on FFTF and overall survival rates.
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4. Ardeshna KM, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: A randomised controlled trial. Lancet 2003; 362:516-522.
5. Brice P, et al. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: A randomized study from the Groupe d’Etude des Lymphomes Folliculaires. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 1997; 15:1110-1117.
6. Young RC, et al. The treatment of indolent lymphomas: Watchful waiting v aggressive combined modality treatment. Semin Hematol 1988; 25(2 Suppl 2):11-16.
7. Ardeshna KM, et al. An intergroup randomised trial ofrituximab versus a watch and wait strategy in patients with stage II, III, IV asymptomatic, non-bulky follicular lymphoma (grades 1, 2, 3a): A preliminary analysis. Blood 2010; 116:abstr 6.
8. Cheson BD. Waiting is the hardest part. J Clin Oncol 2012; 30:3781-3782.