Rethinking Prognosis and Therapy for Follicular Lymphoma

In the article that accompanies this editorial, Casulo et al report an analysis of data from the National LymphoCare Study that demonstrates that patients with follicular lymphoma (FL) who relapse within 2 years of therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone have a poor prognosis, independent of that predicted by the FL International Prognostic Index (FLIPI). This accounts for approximately 20% of patients with FL. Specifically, the 5-year overall survival (OS) in this group is only 50% compared with 90% for patients who have a longer treatment response. This corroborates an earlier analysis that was performed in the prerituximab era that identified older age and a response duration of 1 year or less as factors associated with a shortened survival. These analyses raise important questions regarding the biology of these lymphomas and approaches to their therapy. Specifically, what is the biologic and genetic make-up of these high-risk lymphomas, and should their treatment be tailored to these findings, as opposed to more traditional chemotherapeutic approaches? Several studies have correlated both circulating immune cells and immunologic components of the tumor microenvironment with prognosis in FL. An elevated absolute lymphocyte count at diagnosis ( 890-1,000 cells/ L) has been associated with longer time to progression and survival, independent of the FLIPI score, in both the prerituximab and rituximab eras (median OS, 14.6 v 6.1 years; P .001, before rituximab; median time to progression, 36.5 v 8.1 months, with rituximab). Conversely, an elevated absolute monocyte count has been associated with a poor prognosis, with a median progressionfree survival after several different rituximab-containing regimens of approximately 27 months versus not yet reached (P .001). Casulo et al review the findings of gene expression profiles of FL biopsies, which identify two major clusters of genes that correlate with prognosis. These clusters, named immune-response 1 (IR-1) and immuneresponse 2 (IR-2), were enriched for genes encoding certain T-cell markers and those expressed in macrophages, and genes expressed in macrophages and/or dendritic cells, respectively. IR-1 was associated with a decreased risk of death compared with IR-2 (risk ratio for death, 0.15 [95% CI, 0.05 to 0.46] v 9.35 [95% CI, 3.02 to 28.90]). Similarly, increased numbers of CD8 T cells in FL biopsies are associated with longer survival, whereas higher numbers of tumor-associated CD68 macrophages are associated with poor outcomes. These findings suggest that markers of immune response and inflammation are important determinants of prognosis in this disease. An antitumor adaptive immune response may lead to improved outcomes. However, increased numbers and activation of monocytes and macrophages, perhaps a result of tumor-induced inflammatory cytokines, lead to, among other things, the suppression of this important host antitumor immune response. Genetic evaluation of tumor cells in FL biopsies has yielded important information regarding the pathogenesis of this disease. Oligonucleotide arrays identified several genes, including cyclin B1, CDC2, CDKN3A, CKS1B, ANP32E, and KIAA0101, the expression of which was associated with improved outcomes. Deep sequencing analysis allows for the identification of recurrent somatic mutations in FL, and their incorporation into prognostic tools to determine a more biologically relevant, genetically annotated prognostic index. Mutations in epigenetic regulators including EZH2, CREBBP, EP300, and MLL2, and less frequently linker histone genes and ARID1A, transcriptions factor genes such as OCT2, IRF8, EBF1, and PAX5, and cell cycle regulatory genes like CDKN2A and TP53, have been described, with frequencies ranging from as high as 60% to 90% for MLL2 and CREBBP (suggesting that these are early driver mutations) to 5% to 10% for genes like ARID1A, IRF8, and OCT2. Understanding the interaction between the accumulation of these recurrent, somatic mutations and the biology and prognosis of follicular lymphoma will help to both distinguish patients expected to do poorly from those whose disease will have a long natural history, and to investigate differential therapeutic approaches tailored to the underlying genetic and biologic determinants of tumor growth and survival. If, in studying the immunologic and inflammatory host response to, and the genetic landscape of, these lymphomas, we are able to define this high-risk subgroup of patients with FL, the question becomes whether we could use this information to effectively treat these patients differently. Although high-dose chemotherapy and autologous stem-cell transplantation (HDC-ASCT) in first remission seems to have no effect on OS in all comers, results might be different for this cohort of high-risk patients. To study this would require an ability to identify these patients at diagnosis. Given that the efficacy of HDC-ASCT is maintained in the case of chemosensitive relapse, reserving HDC-ASCT for patients who relapse within the first 2 years of their initial therapy may be a more prudent strategy. However, it may be that this is a particularly chemoresistant population and that, instead, attention should be paid to targeting JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 23 AUGUST 1