The “FLIPI” is no “FLOPI”

Comment on Solal-Céligny et al, page 1258

The FLIPI provides an important tool to predict outcomes for patients with follicular lymphoma and may ultimately help to tailor therapy.

The management of indolent lymphoma presents a challenge to clinicians as well as to patients and their families because they are confronted with a new diagnosis of an illness that goes against many of the “rules” of cancer, particularly with respect to the role of early diagnosis and aggressive treatment. Follicular lymphoma is by far the most common indolent subtype, and it comprises approximately a quarter of non-Hodgkin lymphoma cases overall. Median survival rates have been reported in the range of 10 years,¹  although outcomes vary widely.

In many settings, particularly in those involving asymptomatic patients with low tumor burden, observation without therapy, or a “watch and wait” approach, may be reasonable. When treatment is necessary due to symptoms or substantial tumor progression, deciding on a strategy is equally difficult. Patients and clinicians have an array of options, including alkylating agents, purine analogues, antibody therapy (rituximab), combination chemotherapy alone or with rituximab, radiolabeled antibodies, and autologous and allogeneic transplantation.²  The choices are complicated by the inconsistency of the disease course, and while some data may suggest short-term advantages (such as improved progression-free survival), there is a relative paucity of randomized trials demonstrating a long-term benefit (survival) of one approach over another.³  The fact that an individual patient may reasonably receive recommendations that run the gamut from observation to allogeneic stem cell transplantation highlights the lack of clear guidelines.

A critical first step to optimizing therapy for a heterogeneous disease is the definition of patient subsets associated with favorable or unfavorable prognosis. In aggressive lymphoma, the International Prognostic Index (IPI) has been extremely helpful in this regard and has consistently identified low-, intermediate-, and high-risk individuals to evaluate novel “risk-adapted” therapeutic approaches for different populations.⁴  For indolent lymphoma, however, relatively few patients fall into the high-risk IPI group, and, therefore, its discriminatory power is limited.⁵  In an important international effort reported in this issue of Blood, Solal-Céligny and colleagues have studied a group of more than 4000 follicular lymphoma patients in order to develop the Follicular Lymphoma International Prognostic Index (FLIPI). The authors identified 5 characteristics (referred to by the acronym “NoLASH”) associated with unfavorable survival: (1) more than 4 nodal areas; (2) elevated LDH; (3) age greater than 60 years; (4) stage III or IV; and (5) hemoglobin level less than 120 g/L (12 g/dL). Patients falling into the low-risk group (0-1 risk factor; 36% of patients) had a median 10-year overall survival rate of 70.7%, whereas high-risk patients (3 or more risk factors; 27% of patients) were associated with a median 10-year overall survival rate of 35.5%.

The FLIPI provides a simple, inexpensive tool for routine use in follicular lymphoma. Where do we go from here in order to best use this important information? First, the FLIPI should be applied retrospectively where possible to populations in previous clinical trials in follicular lymphoma. This may put phase 2 studies into context and identify patient subsets from randomized trials who might particularly benefit from one treatment or another. In these smaller data sets, correlation of the FLIPI not only with overall survival but also with progression-free survival is of interest, as is its usefulness in relapsed patient populations. Second, the FLIPI should be prospectively incorporated in new trials for indolent lymphoma, including stratification criteria for randomization. Finally, when superiority of a particular regimen is determined for a specific FLIPI patient subset, one can anticipate that treatment strategies will ultimately be defined by the accurate assessment of risk.FIG1 With this important step forward in understanding follicular lymphoma outcomes, Solal-Céligny and colleagues have brought us closer to a time when we can both provide a realistic picture of what the disease has in store for a patient and individualize the therapeutic approach for this complex disease.