Follicular Lymphoma: Past, Present, and Future Melody R. Becnel, MD * Loretta J. Nastoupil, MD

Transcription

1 Curr. Treat. Options in Oncol. (2018) 19:32 DOI /s Lymphoma (DO Persky, Section Editor) Follicular Lymphoma: Past, Present, and Future Melody R. Becnel, MD * Loretta J. Nastoupil, MD Address * Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429, Houston, TX, 77030, USA MRBecnel@mdanderson.org * Springer Science+Business Media, LLC, part of Springer Nature 2018 This article is part of the Topical Collection on Lymphoma Keywords Non-Hodgkin lymphoma I Indolent lymphoma I Follicular lymphoma treatment I Sequencing therapy in follicular lymphoma I Novel therapy in follicular lymphoma Opinion statement Even in the modern era, follicular lymphoma (FL) remains largely an incurable but treatable disease with both standard and novel treatment modalities. Despite the abundance of efficacious treatment modalities currently available, there is no universally agreed upon standard approach to treatment for patients with FL, particularly in the relapsed/refractory (R/R) setting. There is an increasing need for better tools to risk-stratify patients and to identify those likely to experience relapse early. Additionally, the use of gene expression profiling and next-generation sequencing techniques in recent years has led to a wealth of knowledge regarding the molecular drivers of lymphomagenesis; however, much of this knowledge is not currently applicable on a day to day basis in the clinic setting. Further studies are needed to determine a validated, clinically relevant predictive model that incorporates patient factors and molecular factors that will guide clinicians on the most effective treatment strategy. With many questions left unanswered, it is our opinion that the treatment of FL and sequencing of therapy in the R/R setting should be a personalized approach that balances patient-specific factors such as preferences and comorbidities with treatment-related factors such as known response rates and toxicity profiles. Introduction Follicular lymphoma (FL) is the second most common B-cell non-hodgkin lymphoma (NHL) and the most common indolent B-cell NHL [1 3]. On average, there are 13,000 to 15,000 new cases per year in the USA [2, 4, 5]. The incidence of FL increases with age; the average age of presentation is between ages years of age [2, 6]. Most patients present with advanced disease (stages III or IV per the Ann Arbor Staging System)

2 32 Page 2 of 16 Curr. Treat. Options in Oncol. (2018) 19:32 at diagnosis; however, despite extensive disease, many patients are asymptomatic at presentation [3, 7]. The significant heterogeneity of disease presentation is one among many factors that accounts for variations in management strategies of FL [1, 6, 8 ]. To date, FL remains fundamentally a treatable but not curable disease with currently available treatment modalities [3, 5 7]. The natural history of FL is indolent in nature, with most patients developing several relapses over their lifetime. As the disease progresses, subsequent relapses can become progressively aggressive and refractory, and some cases may transform into aggressive lymphoma [1, 3, 4, 5, 7]. Despite the many advances in the management of FL in recent years, there are still questions that remain unanswered. Given the chronicity and relapsing nature of this disease, clinicians are tasked with balancing efficacy of treatment with quality of life and limited toxicities. With the increasing number of novel agents available, there remains debate regarding optimal management strategies or appropriate sequencing of therapy. To date, there is no universally accepted standard approach to treatment. Herein, we present our approach to tackling the often challenging decision of treatment sequencing in patients with FL. Risk stratification and prognostic systems With the heterogeneity in both disease presentation and response to treatment among patients with FL, various models have been developed to assist in the pretreatment assessment of prognosis. The widely used Follicular Lymphoma International Prognostic Index (FLIPI) [9, 10] and later FLIPI2[11] are prognostication tools that encompass clinical features to stratify patients into low-, intermittent-, and high-risk groups that correlate with overall survival (OS) or progression-free survival (PFS), respectively (Table 1). Patients classified as high-risk experience worse outcomes [9, 10]. FLIPI and FLIPI2 are not useful in determining which patients need treatment and which treatment to select or in predicting response to treatment [1, 8, 12]. Another limitation of the FLIPI and FLIPI2 models, particularly with the emphasis on targeted treatments, is the failure of these tools to incorporate molecular data into the assessment [8, 13, 14]. The recently developed m7-flipi score is a clinicogenetic model that incorporates the Eastern Cooperative Oncology Group (ECOG) performance status, FLIPI, and the mutational status of seven commonly affected genes in FL (EZH2, ARID1A, MEF2B, EP300, FOX01, CREBBP,and CARD11) to better assess prognosis in patients with high tumor burden receiving first-line chemoimmunotherapy [1, 8, 12, 13]. Interestingly, patients with mutations in EZH2 were likely to have better outcomes with chemoimmunotherapy treatment, had a low-risk m7-flipi (high-risk patients per FLIPI with EZH2 mutation were able to be downgraded), and improved OS and failure-free survival (FFS) [1, 8, 13]. Despite these promising results, however, the m7- FLIPI remains primarily a research tool not applicable to routine clinical practice [1, 12, 13]. To date, no validated prediction model has been sufficiently able to predict those patients at risk for early relapse [1, 4, 13]. Though not currently clinically useful, the m7-flipi is promising gateway towards the incorporation of a more clinicomolecular approach to risk stratification. Gene expression profiling techniques are currently being explored to develop more clinically relevant models. For example, a recently reported 23-gene expression panel is able to predict PFS in FL patients with high tumor burden [15]. Despite these advances, there remains an unmet need for the use of clinically meaningful biomarkers to guide the management of FL.

3 Curr. Treat. Options in Oncol. (2018) 19:32 Page 3 of Table 1. Prognostic assessment tools in the management of follicular lymphoma [10, 11, 18, 19] FLIPI FLIPI2 GELF criteria BNLI criteria Age 9 60 years Elevated serum lactate dehydrogenase Hemoglobin G 12 g/dl Ann Arbor stage III or IV disease 9 4 involved nodal sites Age 9 60 years Hemoglobin G 12 g/dl Elevated beta-2 microglobulin Any node 9 6cm Bone marrow involvement Any node 9 7cm 3 or more nodes each 9 3cm Splenomegaly (9 16 cm per imaging) B symptoms Increased lactate dehydrogenase or Beta-2 microglobulin Leukemia ( /L malignant cells) Compression syndrome (ureteral, gastrointestinal) Effusions (pleural or peritoneal) Cytopenias Leukocytes G /L Platelets G /L Hemoglobin G 10 g/dl Rapid disease progression within 3 months B symptoms Life-endangering organ involvement (or impending involvement) Osseous lesions Renal infiltration Cytopenias related to bone marrow involvement: Leukocytes G /L Platelets G /L Hemoglobin G 10 g/dl FLIPI, Follicular Lymphoma Involvement Prognostic Index; GELF, Grouped Etude des Lymphomes Folliculaires; BNLI, British National Lymphoma Investigation First-line treatment Though FL is not currently curable with currently available treatment options, it remains a very treatable disease that is responsive to various treatment modalities

4 32 Page 4 of 16 Curr. Treat. Options in Oncol. (2018) 19:32 such as radiation, chemotherapy, immunotherapy, and targeted therapies. Treatment decisions must be individualized according to both disease-specific and patient-specific factors. Clinicians should discuss the pros and cons of these various options with the patient. It is also important to note that aside from traditional approaches described below, clinical trials can be considered at any point during the course of treatment in appropriately selected patients. Role of radiation in limited stage disease Though most patients present with advanced disease at diagnosis, for those who present with localized disease and a low tumor burden, localized external beam radiation is a reasonable approach. Long-term follow-up of patients with localized disease treated with radiation alone (35 60 Gy) suggests 10-year OS rates up to 80% and median OS of nearly 20 years [6, 16, 17]. Limited stage with high tumor burden and advanced stage Determining the need for treatment Once the diagnosis of FL is made, the next step is to determine if the patient requires immediate treatment. Given the indolent and heterogeneous disease course, not all patients with FL require treatment immediately. Interestingly, not only is there no consensus within the lymphoma community regarding standard first-line treatment, but there is also no consensus on which patients need immediate therapy versus a watch and wait approach [13, 18]. The Groupe d Etude des Lymphomes Folliculaires (GELF) criteria (Table 1) are often used to determine those patients who would benefit from immediate therapy rather than observation. The GELF criteria are a measure of tumor burden, and to date, patients with high tumor burden are often treated with an upfront chemoimmunotherapy approach, and those with low tumor burden can be observed or treated with single-agent rituximab [6, 13, 18]. The British National Lymphoma Investigation (BNLI) criteria, listed in Table 1, are another validated tool that is often used to assess the optimal timing of initial treatment in patients undergoing observation [19, 20]. In appropriately selected low tumor burden patients, a delayed treatment approach is reasonable and does not affect prognosis, survival, or response to treatment. Additionally, delayed treatment can spare patients long-term treatment-related toxicities [18, 19]. Rituximab monotherapy As with other chronic, incurable diseases, quality of life is also an important aspect in deciding treatment in FL. Patients comorbidities, performance status, and their preferences are also factors that should be considered when determining the timing of treatment initiation and in selection of first-line agents. Ardeshna et al. have reported that the incidence of severe anxiety among patients managed with watch and wait is lower than previously expected [20]. However, severe anxiety may be an indication for treatment in a patient with low tumor burden who may otherwise be reasonably managed the observation [7, 20]. In our experience, in patients with low tumor burden who cannot cope with the thought of an untreated diagnosis despite discussions of the rationale of watch and wait, single-agent rituximab weekly 4 can be considered [7, 17].

5 Curr. Treat. Options in Oncol. (2018) 19:32 Page 5 of The anti-cd20 monoclonal antibody rituximab has been the backbone of NHL treatment since its development in the late 1990s. When compared to surveillance, single-agent rituximab improves time to next treatment and PFS. It does not however affect the rate of histologically aggressive transformation and does not improve OS [20]. The Rituximab Extended Schedule or Retreatment Trial (RESORT) examined extended dosing rituximab (maintenance) versus observation with retreatment (rituximab weekly for 4 weeks at the time of progression). The median time to treatment failure was 3.9 years in the retreatment group versus 4.3 years in the rituximab maintenance (RM) group. These results suggest that shorter courses of rituximab provide adequate disease control compared to longer maintenance strategies in low tumor burden FL [21]. Rituximab + chemotherapy Obinutuzumab The addition of chemotherapy to rituximab has become a standard approach in patients with high tumor burden or high-risk disease; however, there is no consensus among experts in the field regarding the selection of chemotherapy. What is agreed upon is that there is an OS benefit with combination chemotherapy and rituximab (chemoimmunotherapy) compared to chemotherapy alone [3, 22]. The regimens most commonly selected include rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP); and bendamustine and rituximab (BR) [3, 7, 23 27]. In the past, R-CHOP was the regimen most commonly selected by clinicians as frontline treatment; however, practice patterns have changed in recent years with BR becoming the preferred treatment [22, 28]. Rummel et al. reported improved PFS and CR rates in untreated indolent NHL patients treated with BR compared to those treated with R-CHOP. Additionally, the toxicity profile favored BR over R-CHOP [28]. Although these results are promising, in practice, it remains reasonable to choose first-line R-CHOP for select patients including those in whom a more aggressive histology is of concern. The GALLIUM study compared rituximab versus obinutuzumab (a type II monoclonal antibody to CD20) in combination with chemotherapy followed by maintenance in previously treated high tumor burden FL. Untreated patients with FL were randomized to obinutuzumab-based chemotherapy (G-chemo) or rituximab-based chemotherapy (R-chemo). Responders then received 2 years of maintenance therapy with the same anti-cd20 antibody used in induction. PFS was significantly improved in the G-chemo arm; however, this arm also had a significantly increased rate of serious (grades 3 to 5) adverse effects (AEs) [29 ]. This now provides a novel antibody approach in combination with chemotherapy for untreated high tumor burden FL patients. Novel immunomodulatory agents Lenalidomide Although high initial responses are seen with chemotherapy combinations, the relapsing nature of this disease and desire to avoid chemotherapy-

6 32 Page 6 of 16 Curr. Treat. Options in Oncol. (2018) 19:32 Ibrutinib associated toxicity has led to the investigation of novel agents to improve outcomes for these patients. The pathogenesis of FL and other NHLs is heavily dependent on the interplay between the tumor microenvironment, B-cell receptor (BCR) signaling pathways, and the immune system [30, 31]. Therapeutic agents that target these pathways such as immune modulators, immune checkpoint inhibitors, and BCR signaling pathway inhibitors have become attractive alternative treatment approaches, particularly given the increasing interest in the development of efficacious targeted therapies with favorable toxicity profiles. In a phase II study, the immune-modulating agent lenalidomide in combination with rituximab (R2) was efficacious and well tolerated in indolent NHL [32, 33]. The phase III RELEVANCE trial compared R-chemo followed by RM to R2 followed by RM. Preliminary results suggest there is no difference in CR rate at 30 months, but this may provide an immune therapy-based approach if PFS or toxicity advantages are seen. Ibrutinib, an irreversible, oral Bruton tyrosine kinase (BTK) inhibitor, has been effective in the treatment of various B cell lymphomas through inhibition of BCR-dependent pathways and chemokine-directed homing of B cells [30, 34 39]. In a recent phase II study, the combination of first-line ibrutinib and rituximab (IR) was well tolerated and efficacious with an ORR of 82%. Interestingly, response rates improved over long-term followup suggesting this combination is both durable and well tolerated. The PERSPECTIVE phase III trial comparing IR to R + placebo is currently underway [40]. Though additional phase III trials and follow-up of long-term data of these studies are warranted, these novel, non-cytotoxic combinations may be reasonable frontline treatment options for elderly patients or patients with poor performance status or comorbidities in whom traditional chemotherapy approaches may not be appropriate. Role of maintenance therapy There is no consensus regarding the use of maintenance therapy in FL. The PRIMA study evaluated the role of RM for 2 years versus observation in patients previously treated with R-chemo first line. Maintenance therapy was found to improve PFS but had no OS benefit [41]. However, updates from this study are notable in that over 50% of patients in the RM arm have no evidence of disease to date and have not required retreatment with 10 years of follow-up [42 ]. These newly released updates to the PRIMA trial may now impact practice changes favoring RM in select patients in whom a 10-year remission would be very attractive such as the young or very elderly subgroups [21]. The safety and efficacy of maintenance rituximab following frontline BR are not well understood. The PRIMA study did not include BR as an induction regimen. The GALLIUM study included maintenance following frontline BR or obinutuzumab and bendamustine; however, this was not compared to observation following induction. The fatal adverse event rate in the bendamustine containing arms (4.7 and 5.9%) of the GALLIUM study and the lack of

7 Curr. Treat. Options in Oncol. (2018) 19:32 Page 7 of randomized prospective data demonstrating a clear benefit of maintenance rituximab following frontline BR have generated controversy regarding the role of RM following frontline BR. A recent multi-center retrospective analysis evaluated outcomes of patients with FL treated with frontline BR who subsequently underwent observation or RM. The results suggest that RM following BR induction was associated with a significant improvement in PFS with an acceptable safety profile; however, the improvement was observed in patients who achieved a PR following BR induction but not in those who achieved CR [43]. This suggests that RM following frontline BR is most impactful in patients that fail to achieve a CR at the end of induction in the real-world setting. Prognostic features at the end of treatment Despite prior response to therapy, 20% of patients with FL relapse within 2 years. Casulo et al. reported that in patients previously treated with R-CHOP, those who progressed within 2 years of diagnosis had an increased risk of death within 5 years of diagnosis and worse OS [4 ]. Next-generation sequencing studies of these patients will be useful to better understand this observation. Additional studies are also needed to better assess outcomes in early relapsers treated with frontline non-chemotherapy regimens. Recent studies have demonstrated that end-of-therapy positron emission tomography computed tomography (PET-CT) in patients treated with chemotherapy/immunotherapy strongly predicts outcome. Negative end-of-treatment PET is associated with improved OS and longer durations of remission [44, 45]. This suggests that PET-CT rather than CT with iodinated contrast should be considered as standard mode of response evaluation in FL [45]. We have the tools available to identify high-risk patients that warrant referral for consideration for clinical trials and closer monitoring. What we need are tools to inform the next treatment selection. Second-line treatment When deciding upon treatment in patient with evidence of relapse, it is imperative to first confirm the histological diagnosis, as patients with FL have a 3% annual risk of transformation to aggressive NHL [46]. Currently, there is no standard of care approach to the management of disease relapse. A significant concern in the relapsed setting is rituximab-refractory disease. As previously mentioned, the GADOLIN study, which compared BG followed by G maintenance to B monotherapy in rituximab-refractory patients, favored the BG arm with respect to PFS. This study suggests that obinutuzumab in combination with bendamustine may be a reasonable option to overcome refractoriness to rituximab in relapsed FL [47 ]. Where the GADOLIN study falls short is defining the preferred approach to patients refractory to chemotherapy or those with early relapse following frontline chemoimmunotherapy. Immune modulators A phase II trial of lenalidomide monotherapy in relapsed/refractory (R/R) FL patients noted modest responses with an ORR 23% and median PFS of 4.4 months [48, 49]. The combination of lenalidomide with a monoclonal

8 32 Page 8 of 16 Curr. Treat. Options in Oncol. (2018) 19:32 Third line and novel agents CD20 antibody may enhance the efficacy of targeting the microenvironment in FL. The ongoing phase III AUGMENT trial is comparing lenalidomide + rituximab (R2) to rituximab + placebo in R/R FL to determine the safety and efficacy of this combination [50]. In the ongoing MAGNIFY trial, R/R patients are treated with induction R2. Responders are then randomized to R2 maintenance versus RM. Preliminary data are promising, with a 1-year PFS of 70%, 65% for double-refractory patients, and 49% for early progressors. An early look at this data supports its efficacy and tolerability. Though additional phase III studies are needed, R2 is an attractive option in the R/R setting, particularly in the double-refractory and early relapse setting [51]. A phase II study evaluating the efficacy of single-agent ibrutinib in R/R FL has yielded modest results with ORR of 37%. This study noted that in the R/R setting, responses to ibrutinib were significantly higher (52%) in rituximabsensitive patients compared to those in rituximab-resistant patients (16%). Additionally, patients with somatic CARD11 mutations had exceedingly poor responses to single-agent ibrutinib [52]. The ongoing SELENE study seeks to address if the addition of ibrutinib to either R-CHOP or BR will improve PFS [53]. At the present time, without compelling biomarkers such as CARD11 mutational status to better guide treatment, ibrutinib monotherapy should not routinely be recommended for R/R FL. Despite prolonged remissions following frontline treatment, decreased efficacy and shorter remission durations have historically been observed with successive treatment courses in most patients with FL, which highlights the need for novel therapies [54]. PI3K inhibitors Phosphatidylinositol-3-kinase (PI3K) delta is an important mediator of B-cell receptor signaling and has thus been an attractive target for novel therapies in NHL [54, 55, 56, 57]. There are currently two Food and Drug Administration (FDA)-approved PI3K inhibitors for the treatment of R/R FL in patients who have failed two prior lines of therapy: idelalisib and copanlisib. Copanlisib is a pan-class I PI3K inhibitor with an activity against both the alpha and delta isoforms, whereas idelalisib is active against the delta isoform alone. In a phase II trial in rituximab-refractory and alkylating agent-refractory heavily pretreated patients, idelalisib had an ORR of 54% with a median PFS of 11 months [56]. A retrospective analysis of this patient population noted that idelalisib was active in early relapsers (relapse within 2 years of first chemoimmunotherapy) with an ORR of 56%. Of note, there was no difference in responses between patients who experienced progressive disease (PD) within 1 year and those with PD within 2 years [58 ]. Copanlisib was administered to heavily pretreated patients with FL in a phase II trial. TheORRwas59%,andthemedianPFSwas11months[55, 59]. These agents are efficacious, particularly in the often challenging heavily pretreated population [5, 6, 54, 56, 58, 59, 60].

9 Curr. Treat. Options in Oncol. (2018) 19:32 Page 9 of BCL-2 inhibitors Despite the promising efficacy, the unique toxicities have been a concern and may be a hindrance to their routine use in clinical practice [54, 55, 56, 58, 59, 60]. Their toxicity profiles differ, possibly related to their route of administration and selectivity against the PI3K isoforms. Idelalisib is an oral agent while copanlisib is parenteral and may explain less gastrointestinal toxicity observed with copanlisib. The schedules are also different with continuous dosing of idelalisib and intermittent dosing of copanlisib. Idelalisib has been associated with reactivation of opportunistic infections and with often severe immune-mediated toxicities such as colitis, hepatitis, and pneumonitis [54]. Copanlisib has been associated with hyperglycemia and hypertension. With increasing experience using these agents, we are better educated on early identification and management of these unique adverse effects. With the use of antimicrobial prophylaxis against opportunistic infections and with diligent monitoring of toxicities, particularly delayed diarrhea, these agents remain sound options in appropriately selected R/R patients who have failed at least two prior therapies [5, 55, 59]. B-cell leukemia/lymphoma-2 (BCL-2) dysregulation is integral to the pathogenesis of FL and is therefore an attractive target for novel therapeutic agents [5, 61]. Venetoclax (ABT-99) is a highly selective inhibitor of BCL-2. As BCL-2 alterations represent the hallmark of FL, there was significant hope for these agents; however, results have been modest with ORR of 38% and median PFS of 11 months in R/R patients with FL. The most common adverse effects of these agents are cytopenias [5, 61, 62]. Though these results are modest, additional trials are underway to assess combination approaches to improve efficacy. Epigenetic alterations: HDAC and EZH2 inhibitors Modulation of histone acetylation is important in the regulation of transcription and, with respect to FL, of tumor suppressor genes. Histone deacetylase (HDAC) inhibitors such as vorinostat and the pan-hdac inhibitor abexinostat have been evaluated in phase I and II studies as monotherapy and in combination with rituximab. Interestingly, the ORR (47%) of vorinostat was similar in trials of single agent or in combination with rituximab. Median PFS was also similar with PFS of months [5, 63, 64]. A phase I trial of abexinostat in R/R patients noted an ORR of 64% and median PFS of 20.5 months [65, 66]. These agents are generally well tolerated, with cytopenias and fatigue the most commonly reported AEs. EZH2 (enhancer of zeste homolog 2) mutations have found to be important in the pathogenesis of various B-cell NHLs. Transformation to aggressive lymphoma has been associated with aberrations in genetic modifiers such as EZH2 [67]. Three EZH2 inhibitors are undergoing evaluation in phase I and II trials. Tazemetostat has recently been given Fast Track FDA designation for R/R FL and diffuse large cell lymphoma (DLBCL) based on phase I/II data demonstrating ORR of 92% in R/R FL with EZH2 mutations. There are also ongoing studies of these agents in combination with chemotherapy in treatment-naïve patients. Preliminary data suggests that these agents are generally well tolerated, with nausea and cytopenias as the commonly reported AEs [67, 68]. EZH2 and other epigenetic modifiers are components of the m7-flipi. Though only useful in

10 32 Page 10 of 16 Curr. Treat. Options in Oncol. (2018) 19:32 Immune checkpoint inhibitors Chimeric antigen receptor T cell therapy the research setting currently, these agents offer promise of a targeted approach using a risk stratification model such as the m7-flipi. These agents offer exciting new options for a non-cytotoxic, efficacious, and well-tolerated treatment in FL and other malignancies [67, 68, 69 ]. As is the case with many other malignancies, immune checkpoint inhibitors offer an appealing option for NHL treatment. Alteration in the PD-1 and PD-L1 axis is a well-known mechanism by which tumors evade the immune system. The interaction between PD-1 and PD-L1 down-regulates T-cell-mediated immunity. Over-expression of PD-L1 by cancer cells leads to enhanced activation of PD-1 on T-cell, which eventually leads to immune tolerance and T-cell exhaustion [70 72]. Blocking PD-1 enhances the function of antitumor T-cell in FL. In addition, blocking PD-1 on NK cells has been shown to enhance the ADCC effect of NK cells [73, 74]. In a recent phase II study, the combination of pembrolizumab, an anti-pd-1 antibody, and rituximab in R/R FL reported an ORR of 65%, CR rate of 50%, and median PFS of 11 months [75]. Though this study demonstrated a meaningful response rate, several trials assessing the efficacy of immune checkpoint inhibitors have demonstrated only modest activity as single agents in FL suggesting only combination approaches are worth exploring. These agents have been associated with immune-mediated adverse effects and combination approaches may be associated with increase in these unique toxicities. It is imperative that clinicians are vigilant and up to date on the management of these AEs to reduce morbidity [70, 73 82]. A particularly exciting area of interest in R/R NHL is chimeric antigen receptor T- cell (CAR-T) therapy, which utilizes genetically modified autologous T-cell to express the pan-b-cell antigen CD-19. Ongoing studies in various B-cell malignancies have led to highly efficacious and durable responses [83, 84]. Currently, CAR-T therapy is an FDA approved for patients with DLBCL that have failed at least two prior lines of therapy. CAR-T therapy is currently under evaluation in clinical trials for the treatment of R/R FL. Schuster et al. evaluated the efficacy of CAR-T therapy in R/R FL patients, with 10 of 14 (71%) achieving a CR, with a median duration of remission of 29 months [83]. Despite exciting results of these trials, CAR-T therapy must be balanced with its unique and potentially life-threatening toxicities, specifically cytokine release syndrome (CRS) and neurotoxicity. [83, 84]. Studies are currently underway to determine biomarkers predictive of response to CAR-T and the risk of developing CRS [85, 86]. This exciting new therapy may be most appropriate for high-risk patients such as those with transformed FL and the early relapse patients who are failing subsequent lines of therapy. Pleotropic pathway modifier A novel cereblon-modulating agent, CC-122, has recently been discovered as an efficacious and well-tolerated agent in combination with obinutuzumab in R/R FL. In this trial of heavily pretreated patients with FL, the ORR was 80% [87 ]. The most commonly reported AEs attributed to CC-122 were hematologic. CC- 122 appears to be an attractive agent in R/R FL.

11 Curr. Treat. Options in Oncol. (2018) 19:32 Page 11 of Selecting agents With so many promising novel treatment options offering a favorable toxicity profile and durable responses, the future of stem cell transplant in R/R FL is in question. Though there has been debate about the use of transplant in FL in the past, long-term results of studies with these novel agents will help us better understand where transplant fits into the sequence of treatment in the future of FL. Currently, transplant remains a viable option for treatment in appropriately selected young patients in the third-line setting. With so many novel agents that have already demonstrated durable responses in FL and many additional novel agents currently in development, selection of the optimal treatment for each patient must be individualized and must take into account patients comorbidities or unique circumstances. Cardiac Hematologic Pulmonary Gastrointestinal Endocrine In patients with known cardiac disease, anthracyclines should be used with caution or omitted. Atrial fibrillation is a well-documented adverse effect related to ibrutinib therapy; therefore, clinicians may opt to avoid this agent in patients with uncontrolled atrial fibrillation. Ibrutinib is associated with an increased risk of bleeding; therefore, caution should be used in patients who require anticoagulation. If a patient requires both antiplatelet and anticoagulation, it is perhaps best to avoid ibrutinib in this setting. Cytopenias are a possible side effect with most currently available treatment options for FL; however, in patients with profound cytopenias, though results are promising, CC-122 may not be the optimal choice in the R/R setting. However, with respect to selection of agents appropriate for patients with cytopenias, one should remember that if these cytopenias are related to the underlying lymphoma, this may actually improve with treatment. Both checkpoint inhibitors and oral PI3K inhibitors are associated with an increased risk of pneumonitis; therefore, these agents are not optimal in the treatment of patients with known pulmonary disease such as COPD or asthma. Checkpoint inhibitors and PI3K inhibitors are associated with severe colitis or hepatitis; therefore, these agents should be avoided in patients with known Crohn s disease/ulcerative colitis or known liver disease. Hyperglycemia is the most widely reported AE in patients treated with copanlisib; therefore, caution or avoidance should be used in patients with poorly controlled diabetes mellitus.

12 32 Page 12 of 16 Curr. Treat. Options in Oncol. (2018) 19:32 Infectious disease/immune Checkpoint inhibitors commonly lead to aberrations in thyroid function, both hyperthyroidism and hypothyroidism. However, these agents can be safely used in patients with thyroid disease, but thyroid function studies should be monitored closely. Patients with HIV and lymphoma have historically had decreased survival compared to patients without HIV, and as a result may be potentially undertreated, possibly out of physicians fear of worsening the patient s immunocompromised state [88, 89]. Additionally, the treatment of HIV-infected patients can be challenging given drug-drug interactions that may exist with HAART and chemotherapy [88, 90]. Recent studies have demonstrated that in patients with HIV in whom further cytopenias or drug-drug interactions is a concern, immune checkpoint inhibitors can be safely and effectively used [79, 91]. Infectious disease specialists should also be involved in the care of these patients. The role of the immune system in lymphomagenesis is complex, with both immunosuppression and autoimmunity linked to an increased risk of lymphoma. In general, immune checkpoint inhibitors are relatively contraindicated in patients with known autoimmune diseases, with the exception of immunemediated thyroid disease, as there is concern for disease flare. Careful monitoring of patients and close comanagement with a rheumatologist is important if these agents are considered in patients with autoimmune diseases. Compliance with Ethical Standards Conflict of Interest Melody R. Becnel declares that she has no conflict of interest. Loretta J. Nastoupil has received research support from Celgene, Genentech, and TG Therapeutics, and she has also received compensation from Celgene, Genentech, Gilead Sciences, Novartis, and TG Therapeutics for service as a consultant. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Casulo C, Nastoupil L, Fowler NH, Friedberg JW, Flowers CR. Unmet needs in the first-line treatment of follicular lymphoma. Ann. Oncol. 2017;28(9): Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin. 2016;

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