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Supplements Targeting the PI3K Pathway in Follicular Lymphoma

The PI3K Pathway: The Benefits of Dual Inhibition in Follicular Lymphoma

Follicular lymphoma (FL) is associated with considerable clinical heterogeneity, along with etiologic and pathologic diversity.1 Although the hallmark transformation t(14;18) is identified in the majority of cases,1,2 it is considered insufficient on its own to drive B-cell transformation or to perpetuate follicular lymphomagenesis.3 Fortunately, the complex, multifaceted biology and pathogenesis of FL, which function to drive oncogenic signaling pathway, are coming into focus.4 

Over the past decade, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway has emerged as a point of emphasis in FL research, with this signaling cascade appearing to confer survival advantages for malignant B cells.5-7 To date, 3 PI3K inhibitors have been approved for the treatment of patients with FL, although they all are characterized by significantly different safety and toxicity profiles. Unfortunately, one of these agents, idelalisib, proved extremely toxic in combination with chemotherapy regimens, leading to the discontinuation of clinical trials.8-10 Nevertheless, active clinical trial programs involving the next-generation, isoform-specific PI3K inhibitors copanlisib (an intravenous agent that inhibits the PI3K α and δ isoforms) and duvelisib (an oral agent that targets the catalytic activity associated with the δ and γ isoforms) have thus far demonstrated positive results in historically difficult-to-treat patients, with a more favorable safety profile compared with idelalisib.11-13 This article examines the treatment of patients with FL, with an emphasis on the role of the PI3K pathway.

Treatment Challenges in Patients With FL

Although significant progress has been made in the treatment and management of patients with FL, several challenges remain, including the need to develop better prognostic models and markers for suggested therapeutic response, to incorporate the safe, effective use of targeted therapies, and to improve outcomes for relapsed and refractory patients.10

Regarding prognostic and predictive models, the Follicular Lymphoma International Prognostic Index (FLIPI) is the most widely studied and used clinical tool, which is often supplemented with histologic grading.10 FLIPI-2 was designed with 5 parameters: age >60 years, bone marrow involvement, hemoglobin level <12.0 g/dl, greatest diameter of the largest involved node >6 cm, and an elevated serum β-2 microglobulin level.14 Although clinically validated, the exact utility of the FLIPI-2 is uncertain.10 A later version, called the M7-FLIPI, incorporates the mutation status of 7 genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11); FLIPI; and Eastern Cooperative Oncology Group (ECOG) performance status.15 Similar to the FLIPI-2, the feasibility and practical application of M7-FLIPI is unclear.10 In the absence of a validated, reliable predictive model, treatment choices must be individualized for each patient, while also considering available data on the various approaches that have been studied to date in clinical trials.

Frontline Treatment Options

Early-Stage FL

FL is most commonly diagnosed in later stages of the disease. It is estimated that only about 10% of patients are diagnosed during stage I or II.10 The National LymphoCare Study, which prospectively enrolled and followed 2728 patients from 265 academic and nonacademic sites, found that 17.4% of participants had stage I FL.16 Notably, this study, which included 80% of patients from community-based (ie, nonacademic) centers, reported that a variety of treatment approaches were used in the initial treatment of stage I FL: observation (17.7%), rituximab monotherapy (13.9%), treatment in clinical trials (6.1%), external-beam radiotherapy (5.6%), chemotherapy only (3.2%), and chemotherapy plus rituximab (51.9%). The chemotherapy-plus-rituximab regimens included the following:  rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), 55.0%); rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP, 23.1%); rituximab plus fludarabine-based regimen (15.5%); and other (6.4%).16

Despite the infrequent use of radiation in frontline settings, some practice guidelines recommend this approach for patients with limited-stage disease in whom treatment is initiated. Some investigators have argued that among patients with limited-stage and/or low-tumor-burden FL, radiation therapy may be considered as a chemotherapy-sparing option with curative potential.17 Indeed, results from a study from the pre-rituximab era, which was published in 2006, demonstrated that the use of radiation therapy among patients with limited-stage FL was associated with a 10-year overall survival (OS) rate of approximately 75% and median survival of about 19 years.18 In contrast, a report from the same group in 2009 questioned the presumptive use of radiation in this setting after finding no difference in OS among patients with stage I disease treated with rituximab-based chemotherapy, radiation alone, observation, systemic therapy plus radiation, rituximab monotherapy, or other approaches.16 Observation of patients who are in the early stages of FL is a viable strategy in light of studies reporting no OS benefit compared with the use of early treatment.17 Evidence suggests that observation confers no deleterious effect on freedom from treatment failure as an initial strategy compared with the use of initial regimens that incorporate rituximab,19 whereas initial therapy with single-agent rituximab, with or without maintenance therapy, improves progression-free survival (PFS) and time to next treatment compared with the use of  observation.20

Advanced-Stage FL

Decisions regarding the initiation of treatment in patients with advanced-stage FL are highly individualized, and are based largely on age, performance status, comorbidities, symptoms, and tumor burden.10 The role of observation in asymptomatic patients is supported by prospective clinical trials that demonstrated no difference in OS after 16 years of follow-up of patients recruited to a watch-and-wait policy or systemic therapy with oral chlorambucil.21 Other studies among patients with advanced-stage, but low-tumor-burden FL have reported similar results.22

Various randomized, prospective trials have demonstrated no benefit for OS and cause-specific survival with chemotherapy compared with observation among patients with asymptomatic FL.22,23 Studies investigating the addition of rituximab to chemotherapy in asymptomatic patients have noted no difference compared with watchful waiting,19 as well as no observable difference in OS or incidence of histologic transformation with the use of rituximab therapy versus observation.23,24 Small differences in time to cytotoxic therapy in patients receiving maintenance rituximab versus rituximab administered on an as-need basis have been observed in some studies.23,25 Similar benefits have been reported with other anti-CD20 monoclonal antibodies, such as obinutuzumab. In the GALLIUM study, similar response rates and OS rates were observed among patients treated with CHOP or CVP plus either rituximab or obinutuzumab, whereas PFS was higher in the obinutuzumab group.26

Among patients with advanced-stage FL, the presence of symptoms, including symptomatic nodal disease, compromised end-organ function B symptoms, symptomatic extranodal disease, or cytopenias, is a key factor in determining whether treatment is required.23 Choice of therapeutic approach has evolved over time, particularly with the introduction of rituximab. Data from selected clinical trials are shown in Table 1.10,26-30 In the BRIGHT study, bendamustine plus rituximab was noninferior to R-CHOP and R-CVP, with similar complete response (CR) rates (31% with bendamustine plus rituximab vs 25% with R-CHOP/R-CVP) rates and overall response rates (97% with bendamustine plus rituximab vs 91% with R-CHOP/R-CVP).28 In the FOLL05 phase 3 trial conducted among treatment-naïve patients with stage II to IV FL, treatment with rituximab-fludarabine-mitoxantrone (R-FM) and R-CHOP yielded higher 3-year PFS rates (63% and 68%, respectively) compared with R-CVP therapy (52%). In an analysis of the study’s primary endpoint—time to treatment failure—which was defined as time from date of study entry to last follow-up, or to the first of the following events: less than partial remission, shift to a different therapy for any reason after at least cycle 1, progressive disease or relapse, or death, R-FM and R-CHOP performed significantly better than R-CVP at 3 years (59%, 62%, and 46%, respectively).29

Maintenance Therapy

The phase 3 Primary Rituximab and Maintenance (PRIMA) study was an open-label, randomized clinical trial conducted in previously untreated patients with FL to determine the role of 2 years of rituximab maintenance therapy following first-line chemotherapy treatment with R-CHOP, R-CVP, or rituximab plus fludarabine-cyclophosphamide-mitoxantrone (R-FCM).30 With a median follow-up of 36 months after induction, PFS was 74.9% in patients who received rituximab maintenance, compared with 57.6% in the observation group.30  At 2 years postrandomization, rates of complete/unconfirmed CR were 71.5% in the rituximab maintenance group and 52.5% in the observation group.30  Notably, OS did not differ significantly between the 2 groups.30

A recent update on PRIMA with a median 9 years of follow-up confirmed the earlier findings, reporting a median PFS of 4.06 years in the observation arm compared with 10.49 years in the rituximab maintenance arm. Additionally, 51% and 35% of patients in the rituximab and observation arms, respectively, were estimated to be free of disease progression. OS estimates, however, were identical in the 2 arms.30

Vitolo and colleagues investigated abbreviated maintenance with rituximab (ie, for 8 months, once every 2 months) following 4 courses of R-FCM in patients 60 to 75 years of age with FL.31 No statistically significant improvement in 2-year PFS was reported with rituximab maintenance compared with observation.31

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