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

May 31, 2019

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 &#64258;udarabine-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 &#64257;rst 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

Studies of rituximab alone followed by maintenance therapy with the same agent have reported apparently conflicting results, although differences in patient populations may be a factor. In the Swiss Group for Clinical Cancer Research (SAKK) trial, patients with relapsed/refractory FL were administered once-weekly doses of single-agent rituximab for 4 weeks, followed by 4 cycles of maintenance therapy every 2 months. A significant 2-fold increase in event-free survival was reported among patients in the prolonged exposure group, who received rituximab maintenance treatment, compared with those in the observation group, who were treated with only 4 weeks of rituximab (24 months vs 13 months, respectively; P < .001).32 In the Rituximab Extended Schedule of Re-Treatment Trial study, which enrolled patients with low-tumor-burden, previously untreated FL, rituximab followed by rituximab maintenance therapy did not demonstrate a meaningful benefit in terms of response or time to treatment failure among patients who would otherwise be observed.25

Treatment of Relapsed or Refractory FL

Multiple options have been studied in patients with relapsed or refractory FL, with varying degrees of success. Generally, the prior treatment and its duration of use, patient age, comorbid illnesses, and goals of therapy are factors involved in determining a treatment approach.33

Use of single-agent rituximab in patients with relapsed FL is supported by the SAKK trial, in which patients who responded to an initial 4-week regimen of rituximab were randomized either to observation or to maintenance therapy.32 In this study, 35% of responders remained in remission at 8 years. One potential limitation with the utilization of these data to guide treatment decisions is that since current induction therapeutic paradigms often include use of chemotherapy plus rituximab, it is thus unknown whether response to single-agent rituximab is as durable or as complete among patients who did not receive rituximab-backbone chemotherapy induction.23 Additionally, the frequent dependence on rituximab in frontline treatment and in maintenance therapy comes with a price, as patients are becoming increasingly refractory to the agent.33

Several chemotherapy regimens may be considered for use in patients with relapsed or refractory FL. In a study comparing CHOP and R-CHOP among patients not previously treated with anthracycline or a rituximab-containing regimen, R-CHOP significantly improved overall response rates and CR rates, as well as PFS.34

A recent update has suggested that rituximab maintenance therapy further improved PFS and was associated with greater 5-year OS.23 Rituximab has also been combined with fludarabine-cyclophosphamide-mitoxantrone (R-FCM) for the treatment of relapsed disease, which increased response rates and prolonged survival compared with the use of chemotherapy alone.35 The use of fludarabine in heavily pretreated and elderly patients is not advisable, however, because of immunosuppression.33

Bendamustine is approved for use in the United States in patients with rituximab-refractory B-cell lymphoma; a pivotal trial reported an objective response rate of 75% and a median PFS of 9.3 months.33 Approximately two-thirds of patients in this study required dose modifications or delays, however, primarily because of myelosuppression.33 Combination bendamustine and obinutuzumab has been suggested as an option for patients who are refractory to rituximab. In a randomized clinical trial, the combination therapy was superior to bendamustine alone and yielded significant improvement in PFS.36

Use of immunomodulators, such as lenalidomide, in combination with rituximab has also been studied for the treatment of patients with relapsed or refractory FL. Findings from the randomized Cancer and Leukemia Group B (CALBG) 50401 (Alliance) trial reported a higher overall response rate with lenalidomide plus rituximab compared with lenalidomide alone (76% vs 53%, respectively), as well as extended time to disease progression.37 Finally, radioimmunotherapy has also been shown to be a good treatment option for patients with nonbulky, indolent B-cell non-Hodgkin lymphoma (NHL) if the bone marrow is minimally involved.33 Studies of 90Y ibritumomab tiuxetan have demonstrated response rates of approximately 70%, with a duration of response (DoR) of 11 to 15 months.33

More recently, several novel agents have entered clinical trials, with the promise of inducing a greater response, less toxicity, and improved convenience for patients (Table 2).38

Targeting PI3K: Rationale and Overview

PI3K proteins are classified according to their structure and function, with the class 1 family most closely associated with human cancer.6,39 Class 1 is further subdivided into Class 1A and Class 1B, based on their mode of activation—either via the regulatory subunit p85 (Class 1A) or G-protein coupled receptors (Class 1B).39 The 4 known catalytic isoforms of class 1 PI3K are p110α, p110β, and p110δ (Class 1A), as well as p110γ (Class 1B).6,39 The 3 Class 1A p110 isoforms are each ubiquitously expressed in human cells, including in leukocytes, whereas the p110γ isoform of Class 1B is found in leukocytes, as well as in cells in the thymus, heart, and endothelium.39 The isoforms are associated with different physiologic functions: Class 1A p110 isoforms play a role in proliferation, differentiation, survival, migration, chemotaxis, phagocytosis, and metabolism, whereas the p110 γ isoform is functional in cell migration, chemotaxis, and inflammation.39

The PI3K/AKT/mTOR pathway plays a central role in orchestrating a complex set of metabolic processes in multicellular organisms.40 PI3K family member proteins participate in multiple regulatory processes, including cell growth and proliferation, metabolism, migration, and secretion, whereas aberrations in PI3K signaling have been widely linked to a broad spectrum of human diseases, such as cancer, immunologic disorders, diabetes, neurologic disorders, localized tissue overgrowth, and cardiovascular disease.40 As such, inappropriate co-option of PI3K signaling has been implicated in playing a critical role in cancer progression.6

Upon activation by receptor tyrosine kinases, p110 subunits of Class 1A are relieved of their intermolecular inhibition mechanism (ie, interaction with the p85 subunit of PI3K), and PI3K is localized to the plasma membrane where its substrate, phosphatidylinositol 4,5-bisphosphate (PI[4,5]P2)—that is, PIP2—resides.6 At this point, PI3K phosphorylates PIP2 to PIP3, setting in motion conditions for activation of AKT (via phosphoinositide-dependent kinase 1[PDK1]).6,40 In turn, AKT phosphorylation results in activation of substrates involved in cell proliferation, metabolism, survival, and motility.40 Conversely, the PI3K signal pathway may be shut down at this point if the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) dephosphorylates PIP3 to PIP2.6,39 Loss of PTEN function with associated constitutive activation of PI3K is noted as a frequent underlying protumor factor in many types of cancer, although it is uncommon in lymphoma.39,40 When activated, however, PI3K-AKT signaling promotes cell growth and survival by several mechanisms,6 and indirectly activates mTOR, which is well known to play a central role in cell growth, proliferation, and survival.39,40

Several mechanisms for upregulation of PI3K signaling in human cancers have been described, including somatic mutations and PI3K activation via the receptor tyrosine kinase and RAS pathways.6 To date, a limited number of studies have investigated these events specifically in the context of FL. Using direct sequencing methods in 38 biopsy samples from human FL cases, Yahiaoui and colleagues reported finding no activating mutations in PIK3CA at exons 9 and 20 (which are hot spot loci common to many forms of human cancer), and loss of PTEN in only 3 samples (previously identified as an activator of the PI3K/AKT pathway in such cancers as mantle cell lymphoma). These findings thus provide suggestive evidence that PI3K/AKT activation may result from other events, such as mutation or gene amplifications of membrane receptors, overexpression of growth factors, or AKT gene amplification.41 PI3K-δ may also play a role in activating AKT in FL.41 Indeed, the oncogenic potential of p110 catalytic isoforms has been demonstrated in several studies.6

Nevertheless, studies using proteomic analysis have confirmed AKT phosphorylation in FL samples, which is indicative of PI3K pathway activation.39,40,42,43 Additional evidence for the relevance of the PI3K pathway in FL may be inferred from treatment trials of agents that specifically target mechanisms within this signal cascade and that exhibit ample evidence of antitumor activity.


Idelalisib, an oral agent that targets the δ isoform of PI3K, was the first PI3K-inhibitor to gain approval for the treatment of patients with FL.10,33,38,44 The approval was based on a phase 2 study conducted in 125 patients with indolent NHL who had not experienced a response to rituximab and an alkylating agent or who had had a relapse within 6 months.45 The study included 72 patients (58%) with FL, of whom 79% had a FLIPI score indicating intermediate- or high-risk disease, and 17% had grade 3a disease.45 In this study, the response rate among all patients across all NHL subtypes was 57%, with a median DoR of 12.5 months. Similar findings were noted in the subset of patients with FL.45 In the safety analysis, diarrhea (43%), fatigue (30%), nausea (30%), cough (29%), and pyrexia (28%) all occurred in >20% of patients; grade 3 or higher toxicities included neutropenia (27%), transaminase elevations (13%), diarrhea (13%), and pneumonia (7%).45

Idelalisib was subsequently studied in combination with lenalidomide and rituximab; however, 4 of the first 8 patients experienced dose-limiting toxicities, including grade 4 sepsis syndrome, grade 4 hypotension with grade 3 rash and fevers, grade 4 transaminase elevation with fevers, and grade 3 pulmonary infection with grade 3 maculopapular rash. This study thus did not meet its primary safety and tolerability endpoint.8 Investigators from a separate multiarm, phase 1 study also reported unacceptable toxicities associated with a triplet combination of idelalisib, lenalidomide, and rituximab.9 At least 2 other phase 3 trials involving idelalisib were terminated.10


The intravenously administered PI3K inhibitor copanlisib targets all 4 PI3K isoforms,5 although its primary activity involves inhibiting the catalytic activity of the PI3Kα and PI3Kδ isoforms.44 Copanlisib was approved in 2017 for the treatment of relapsed FL, based on the phase 2 CHRONOS-1 study program. In part A of the trial, 33 patients with indolent lymphoma (FL, n=16) and 51 with aggressive lymphoma (transformed indolent FL, n = 6; grade 3b FL, n = 1) who had received ≥2 prior lines of therapy received intravenous copanlisib on days 1, 8, and 15 of a 28-day cycle, with a median treatment duration of 23 weeks in the indolent group and 8 weeks in the aggressive group.11 The objective response rate was 43.8% and 29.4% in the indolent and aggressive cohorts, respectively, and 40% among patients with FL.

CR/unconfirmed CR was noted in 3 of 15 patients with FL, with partial responses in an additional 3 patients.11 PFS was 294 days and 70 days in the indolent and aggressive groups, respectively, whereas the rate of PFS at 12 months for these groups was 45% and 13%. Median DoR was 390 days and 166 days, respectively, in the indolent and aggressive arms.11 The most common treatment-emergent adverse events (TEAEs) reported included hyperglycemia (59.5%), hypertension (54.8%), fatigue (48.8%), and diarrhea (40.5%). Serious grade 3 or 4 TEAEs occurring in ≥2 patients included grade 3 lung infection (10.7%), grade 3 diarrhea (3.6%), grade 3 febrile neutropenia (3.6%), grade 4 decreased neutrophil count (2.4%), grade 3 hyperglycemia (2.4%), grade 3 pneumonitis (2.4%), grade 3 pancreatitis (2.4%), and grade 3 cardiac disorders (2.4%). By the time the study results were published, 10 deaths had occurred, 4 of which were considered to be possibly drug-related.11

Part B of the study reported on an additional 142 patients with relapsed or refractory indolent lymphoma (73% FL grade 1-3a) who had received a median of 3 lines of therapy. In part B, the objective response rate was 59% (same in FL subset) and the rate of CR was 12% (14% in FL subset). The median DoR was 22.6 months (12.2 months in FL) and the median PFS was 11.2 months; the median OS had not been reached.12 Findings regarding the safety profile were consistent with those reported in part A of the study.

Copanlisib is currently being studied in 3 phase 3 trials (CRONOS-2, NCT02369016; CHRONOS-3, NCT02367040; and CHRONOS-4, NCT02626455).5


Duvelisib is a second-generation dual δ/γ PI3K inhibitor that gained accelerated approval in 2018 for the treatment of relapsed/refractory FL after ≥2 prior lines of therapy.46 Duvelisib is an oral medication46—a route of administration that may be favored by some patients47—and thus differentiates the agent from other drugs in this class.

The phase 2 Duvelisib in Subjects With Refractory Indolent Non-Hodgkin Lymphoma (DYANMO) study enrolled 129 patients with indolent NHL (median age, 65 years; median 3 prior lines of therapy), who were double refractory to rituximab (monotherapy or in combination) and to either chemotherapy or radioimmunotherapy, to treatment with duvelisib 25 mg administered orally twice daily in 28-day cycles, until progression, unacceptable toxicity, or death.13 The overall response rate as assessed by an independent review committee, which was the primary endpoint, was 42.2% in patients with FL. Among all patients evaluated, the estimated median DoR was 10 months. The median PFS was 9.5 months, the median OS was 28.9 months, and the estimated OS at 1 year was 77%.13

Although FL is one of several NHLs explored in the DYNAMO trial, the double-refractory design of the study is significant, particularly because of the great extent of treatment refractoriness and the prevalence of high-risk clinical features in patients with FL.13 Importantly, patients with FL who received R-CHOP as their first therapy and subsequently relapsed achieved an overall response rate of 33%, a median DoR of 12.6 months, and a median PFS of 8.2 months. The investigators noted that duvelisib monotherapy might offer an alternative treatment option for patients whose disease is refractory to bendamustine or for those who cannot tolerate bendamustine.13

In a safety analysis, TEAEs included diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and cough (27.1%). The most common grade 3 or higher TEAEs were neutropenia (24.8%), diarrhea (14.7%), anemia (14.7%), and thrombocytopenia (11.6%).13 Among patients with FL, specifically, a greater incidence of grade 3 or higher aminotransferase increase was observed with idelalisib compared with duvelisib (13% vs 5.4%, respectively).

Evidence from in vitro and in vivo studies suggests that duvelisib is synergistic with multiple therapies designed to treat hematologic malignancies. Faia and colleagues reported that duvelisib exhibited growth inhibitory activity in a variety of malignant hematologic cell lines, including DOHH-2 and WSU-NHL, both of which represent transformed FL.48 Furthermore, duvelisib activity was found to synergize with both approved and emerging agents used to treat B-cell malignancies, including dexamethasone, B-cell receptor signaling pathway inhibitors (ie, ibrutinib), and the B-cell lymphoma (BCL)-2 inhibitor venetoclax.48

These suggestions were further substantiated by an evaluation of duvelisib in combination with dexamethasone, ibrutinib, or everolimus in an in vivo lymphoma xenograft model system, which demonstrated greater antitumor growth inhibitory activity compared with monotherapies. Notably, a lymphoma xenograft model using DOHH-2 demonstrated the enhanced tumor growth inhibitory activity of these combinations.48 These results provide a strong rationale for exploring such combinations of agents in clinical trials.

Duvelisib is currently being evaluated in other patient populations, including in combination with rituximab or obinutuzumab in the frontline treatment of FL (NCT02391545).49 The study included patients with previously untreated CD20+ FL, stage II with bulky disease (≥7 cm lesion) or stage III-IV disease, ≥1 measurable disease lesion >1.5 cm, adequate liver and renal function, and no clinical evidence of transformation to a more aggressive subtype of lymphoma or grade 3B FL. A preliminary analysis demonstrated an overall response rate of 87% associated with the duvelisib-rituximab combination and 91% with the duvelisib-obinutuzumab combination.49

Based on the first 28 evaluable patients, the investigators reported that 64% of those in the duvelisib-rituximab group experienced an adverse event (AE) leading to duvelisib dose modification (defined as either reduction or hold), whereas 14% discontinued duvelisib because of an AE. The most common grade 3 or greater AEs in these patients included alanine aminotransferase (ALT) increase (21%) and rash (14%). Rates of AEs in the duvelisib-obinutuzumab group were higher in the duvelisib-rituximab arm—89%—with 70% of patients experiencing grade 3 or greater AEs. In this group, 63% of patients experienced an AE that led to duvelisib dose modification (reduction or hold), and 7% discontinued duvelisib because of an AE. The most common grade 3 or higher AEs in this group included neutropenia (19%), ALT increase (15%), and aspartate aminotransferase increase (11%).49

The phase 2 FRESCO trial, which will enroll approximately 230 adult patients from around the world who progressed within 24 months after receiving an alkylator-based chemotherapy regimen, will randomize participants to treatment with duvelisib plus rituximab or R-CHOP. The study (NCT02605694) is currently enrolling patients.50 The primary endpoint is PFS, and a number of secondary endpoints will also be evaluated: CR rate, overall response rate, OS, DoR, quality of life, AEs, clinical laboratory values, and pharmacokinetic parameters for duvelisib and its major metabolite.50


Novel therapeutics for the treatment of FL have attracted considerable attention because of the ongoing need for new treatment options among certain patient populations. In particular, disease progression despite therapy within 24 months of diagnosis is associated with a particularly poor prognosis.51 Moreover, there is a need for treatment options for individuals with relapsed/refractory FL that spares patients the exposure to potentially toxic chemotherapy regimens and that may offer more convenient dosing. Data accumulated to date with respect to various PI3K inhibitors suggest improved response rates and longer survival compared with existing therapeutic options. Longer-term follow-up is essential for ultimately determining the role of these agents in the treatment paradigm, as is further investigation into the differing safety profiles of each drug in the class. These and other additional small molecules in development, which target relevant signaling pathways in FL, offer significant promise for further improving the prognosis of patients with FL.

  1. Ekström-Smedby K. Epidemiology and etiology of non-Hodgkin lymphoma — a review. Acta Oncol. 2006;45(3):258-271.
  2. Huet S, Sujobert P, Salles G. From genetics to the clinic: a translational perspective on follicular lymphoma. Nat Rev Cancer. 2018;18(4):224-239.
  3. Kridel R, Sehn LH, Gascoyne RD. Pathogenesis of follicular lymphoma. J Clin Invest. 2012;122(10):3424-3431.
  4. Fowler N. Frontline strategy for follicular lymphoma: are we ready to abandon chemotherapy? Hematology Am Soc Hematol Educ Program. 2016;2016(1):277-283.
  5. Mensah FA, Blaize JP, Bryan LJ. Spotlight on copanlisib and its potential in the treatment of relapsed/refractory follicular lymphoma: evidence to date. Onco Targets Ther. 2018;11:4817-4827.
  6. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol. 2010;28(6):1075-1083.
  7. Srinivasan L, Sasaki Y, Calado DP, et al. PI3 kinase signals BCR-dependent mature B cell survival. Cell. 2009;139(3):573-586.
  8. Smith SM, Pitcher BN, Jung S-H, et al. Safety and tolerability of idelalisib, lenalidomide, and rituximab in relapsed and refractory lymphoma: the Alliance for Clinical Trials in Oncology A051201 and A051202 phase 1 trials. Lancet Haematol. 2017;4(4):e176-e182.
  9. Cheah CY, Fowler NH. Idelalisib in the management of lymphoma. Blood. 2016;128(3):331-336.
  10. Yazdy MS, Ujjani C. Current challenges in the management of follicular lymphoma. Int J Hematol Oncol. 2017;6(1):13-24.
  11. Dreyling M, Morschhauser F, Bouabdallah K, et al. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol. 2017;28(9):2169-2178.
  12. Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol. 2017;35(35):3898-3905.
  13. Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2019;37(11):912-922.
  14. Federico M, Bellei M, Marcheselli L, et al. Follicular Lymphoma International Prognostic Index 2: a new prognostic index for follicular lymphoma developed by the International Follicular Lymphoma Prognostic Factor Project. J Clin Oncol. 2009;27(27):4555-4562.
  15. Pastore A, Jurinovic V, Kridel R, et al. Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. Lancet Oncol. 2015;16(9):1111-1122.
  16. Friedberg JW, Taylor MD, Cerhan JR, et al. Follicular lymphoma in the United States: first report of the national LymphoCare Study. J Clin Oncol. 2009;27(8):1202-1208.
  17. Reagan PM, Friedberg JW. Follicular lymphoma: first-line treatment without chemotherapy for follicular lymphoma. Curr Treat Options Oncol. 2015;16(7):32.
  18. Guadagnolo BA, Li S, Neuberg D, et al. Long-term outcome and mortality trends in early-stage, Grade 1-2 follicular lymphoma treated with radiation therapy. Int J Radiat Oncol Biol Phys. 2006;64(3):928-934.
  19. Solal-Céligny P, Bellei M, Marcheselli L, 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(31):3848-3853.
  20. Ardeshna KM, Qian W, Smith P, et al. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol. 2014;15(4):424-435.
  21. Ardeshna KM, Smith P, Norton A, et al; British National Lymphoma Investigation. 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(9383):516-522.
  22. Brice P, Bastion Y, Lepage E, 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(3):1110-1117.
  23. Freedman A. Follicular lymphoma: 2018 update on diagnosis and management. Am J Hematol. 2018;93(2):296-305.
  24. Ardeshna KM, Qian W, Smith P, et al. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol. 2014;15(4):424-435.
  25. Kahl BS, Hong F, Williams ME, et al. Rituximab extended schedule or re-treatment trial for low—tumor burden follicular lymphoma: Eastern Cooperative Oncology Group protocol E4402. J Clin Oncol. 2014;32(28):3096-3102.
  26. Marcus RE, Davies AJ, Ando K, et al. Obinutuzumab-based induction and maintenance prolongs progression-free survival (PFS) in patients with previously untreated follicular lymphoma: primary results of the randomized Phase 3 GALLIUM study. Blood. 2016;128(22): Abstract 6.
  27. Rummel MJ, Niederle N, Maschmeyer G, et al; Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381(9873):1203-1210.
  28. Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014;123(19):2944-2952.
  29. Federico M, Luminari S, Dondi A, et al. R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol. 2013;31(12):1506-1513.
  30. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011;377(9759):42-51.
  31. Vitolo U, Ladetto M, Boccomini C, et al. Rituximab maintenance compared with observation after brief first-line R-FND chemoimmunotherapy with rituximab consolidation in patients age older than 60 years with advanced follicular lymphoma: a phase III randomized study by the Fondazione Italiana Linfomi. J Clin Oncol. 2013;31(27):3351-3359.
  32. Martinelli G, Schmitz S-FH, Utiger U, et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol. 2010;28(29):4480-4484.
  33. Kahl BS, Yang DT. Follicular lymphoma: evolving therapeutic strategies. Blood. 2016;127(17):2055-2063.
  34. van Oers MH, Klasa R, Marcus RE, et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood. 2006;108(10):3295-3301.
  35. Forstpointner R, Dreyling M, Repp R, et al; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004;104(10):3064-3071.
  36. Sehn LH, Chua NS, Mayer J, et al. GADOLIN: primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2015;33(18 suppl): Abstract LBA8502.
  37. Leonard JP, Jung SH, Johnson J, et al. Randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (Alliance). J Clin Oncol. 2015;33(31):3635-3640.
  38. Sutamtewagul G, Link BK. Novel treatment approaches and future perspectives in follicular lymphoma. Ther Adv Hematol. 2019;10:2040620718820510.
  39. Westin JR. Status of PI3K/Akt/mTOR pathway inhibitors in lymphoma. Clin Lymphoma Myeloma Leuk. 2014;14(5):335-342.
  40. Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K pathway in human disease. Cell. 2017;170(4):605-635.
  41. Yahiaoui OI, Nunès JA, Castanier C, et al. Constitutive AKT activation in follicular lymphoma. BMC Cancer. 2014;14:565.
  42. Fang X, Zhou X, Wang X. Clinical development of phosphatidylinositol 3-kinase inhibitors for non-Hodgkin lymphoma. Biomarker Research. 2013;1(1):30.
  43. Gulmann C, Espina V, Petricoin E, III, et al. Proteomic analysis of apoptotic pathways reveals prognostic factors in follicular lymphoma. Clin Cancer Res. 2005;11(16):5847-5855.
  44. Anastasia A, Rossi G. Novel drugs in follicular lymphoma. Mediterr J Hematol Infect Dis. 2016;8(1):e2016061.
  45. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008-1018.
  46. Copiktra [prescribing information]. Needham, MA: Verastem, Inc; 2018. Accessed May 29, 2019.
  47. Eek D, Krohe M, Mazar I, et al. Patient-reported preferences for oral versus intravenous administration for the treatment of cancer: a review of the literature. Patient Prefer Adherence. 2016;10:1609-1621.
  48. Faia K, White K, Murphy E, et al. The phosphoinositide-3 kinase (PI3K)-δ,γ inhibitor, duvelisib shows preclinical synergy with multiple targeted therapies in hematologic malignancies. PLoS One. 2018;13(8):e0200725.
  49. Casulo C, Sancho J-M, Van Eygen K, et al. CONTEMPO: preliminary results in first-line treatment of follicular lymphoma with the oral dual PI3K-δ,γ inhibitor, duvelisib, in combination with rituximab or obinutuzumab. Blood. 2016;128(22):2979.
  50. Fowler NH, Pearlberg J, Brail LH, et al. FRESCO: a phase 2, randomized study of duvelisib plus rituximab vs R-CHOP in patients with relapsed/refractory follicular lymphoma who have progressed within 24 months of receiving an alkylator-based chemotherapy regimen. J Clin Oncol. 2016;34(15 suppl): Abstract TPS7578.
  51. Casulo C, Byrtek M, Dawson KL, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study. J Clin Oncol. 2015;33(23):2516-2522.