Freedman 2018 american journal of hematology (1)

Received: October 2017 | Accepted: October 2017 DOI: 10.1002/ajh.24937 A JH ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES Follicular lymphoma: 2018 update on diagnosis and management Arnold Freedman Department of Medical Oncology, DanaFarber Cancer Institute, Boston, Massachusetts Correspondence Arnold Freedman, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA Email: afreedman@partners.org Abstract Disease overview: Follicular lymphoma is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells Follicular lymphoma (FL) is characterized by diffuse lymphadenopathy, bone marrow involvement, splenomegaly and less commonly other extranodal sites of involvement In general, cytopenias can occur but constitutional symptoms of fever, nightsweats, and weight loss are uncommon Diagnosis: Diagnosis is based on histology of preferably a biopsy of a lymph node Immunohistochemical staining is positive in virtually all cases for cell surface CD19, CD20, CD10, and monoclonal immunoglobulin, as well as cytoplasmic expression of bcl-2 protein The overwhelming majority of cases have the characteristic t(14;18) translocation involving the IgH/bcl-2 genes Risk stratification: The Follicular Lymphoma International Prognostic Index prognostic model for FL uses five independent predictors of inferior survival: age >60 years, hemoglobin normal, Ann Arbor stage III/IV, number of involved nodal areas > The presence of 0, 1, 2, and  adverse factors defines low, intermediate, and high-risk disease With the use of more modern therapies, outcomes have improved Risk-adapted therapy: Observation continues to be adequate for asymptomatic patients with low bulk disease and no cytopenias, with no survival advantage for early treatment with either chemotherapy or rituximab alone For patients needing therapy, most patients are treated with chemotherapy plus rituximab, which has improved response rates, duration of response and overall survival Randomized studies have shown additional benefit for maintenance rituximab both following chemotherapy-rituximab and single agent rituximab Experimental therapies as well as stem cell transplantation (SCT) are considered for recurrent disease | DISEASE OVERVIEW AND CLINICAL PRESENTATION genetic events are required for the development of FL since the t (14;18) translocation can be identified in the B cells from normal individuals and patients with diffuse large B-cell lymphoma Gain of func- Follicular lymphoma (FL) is the second most common lymphoma diag- tion mutations in the H3K27 methyltransferase EZH2 have been nosed in the United States and Western Europe,1 approximately 35 reported in 27 percent of FLs.5 More recent studies suggest that percent of all non-Hodgkin lymphomas (NHLs), and 70 percent of indo- altered normal T cell function within the malignant microenvironment lent lymphomas.2 The median age at diagnosis of 65 years.3 The inci- play a role in the pathobiology of the disease.6 This includes altered dence is slightly increased among relatives of persons with FL FLs are malignant counterparts of normal germinal center B-cells.2 expression of genes, specifically upregulated PMCH, ETV1, and TNFRSF9, and altered T cell motility in vitro.7 Approximately 85 percent of patients with FL have t(14;18) which Patients with FL generally present with asymptomatic lymphade- results in the overexpression of the BCL-2 protein, a member of a fam- nopathy, with waxing and waning sometimes present for years Bone ily of proteins that blocks apoptosis However, it is likely that multiple marrow involvement is present in 70 percent of patients, whereas 296 | C 2017 Wiley Periodicals, Inc V wileyonlinelibrary.com/journal/ajh Am J Hematol 2018;93:296–305 A JH FREEDMAN 297 time, with a risk of 2–3 percent per year, and is associated with rapid Prognostic models for follicular lymphoma T AB LE | progression of lymphadenopathy, extranodal disease (besides the mar- Follicular lymphoma International Prognostic Index (FLIPI))17 Age > 60 Serum LDH > ULN Hgb < 12 g/dL Stage III or IV Number of nodal sites > row), B symptoms, hypercalcemia, and elevated serum LDH.11,12 | PROGNOSIS FLIPI218 Age >60 years Bone marrow involvement Hemoglobin level cm or more sites greater than cm B symptoms Spleen below umbilical line Compressive symptoms Pleural or peritoneal effusions teristics of the associated cells in the tumor microenvironment of FL influences disease behavior and prognosis.14–16 Several prognostic models for FL have evolved (Table 1) The Follicular Lymphoma International Prognostic Index (FLIPI) includes prognostic factors patient age, stage, number of involved nodal areas, serum lactate dehydrogenase, and hemoglobin.17 The FLIPI was devel-  5000 tumor cells/mm3 Absolute neutrophil count < 1000/mm3 Platelet count < 100,000/mm3 oped out of an international study of survival data in 4167 patients with FL diagnosed between 1985 and 1992 A modified version, of this score, the FLIPI2, evaluates five parameters, with some overlap of the involvement of other normal organs is uncommon Less than 20 per- FLIPI.18 The utility of the FLIPI2 model remains uncertain Since the cent of patients present with B symptoms and also less than 20 per- incorporation of rituximab into the mainsteam therapy of FL, the FLIPI cent lactate has continued to be a useful prognostic model (Table 2).19,20 A study of dehydrogenase (LDH) Involvement of the intestine is a unique site of mutation status of 74 genes in 151 patients with previously untreated presentation of this disease, usually early stage, and with a favorable follicular lymphoma found that including the mutational status of of patients present with an increased serum prognosis Pediatric FL is a distinct entity The disease present with genes with FLIPI score, led to better prognostication of five-year failure localized disease, grade histology, and absence of bcl-2 rearrange- free survival.21 The GELF criteria 22 includes parameters of tumor bur- den and clinical findings, is another model for risk stratification An ments Pediatric FL is highly curable analysis of patients receiving R-CHOP as initial treatment, reported that relapse within years of completing therapy is associated with a | DIAGNOSIS poor prognosis (50% versus 90% year survival).23 FL recapitulates normal germinal centers (GC) of secondary lymphoid FL tumors are graded from to and this grade has some prog- follicles The neoplastic cells consist of a mixture of centrocytes (small nostic utility There has generally been suboptimal consensus of pathol- to medium sized cells) and centroblast (large cells) The clinical aggres- ogists on grading FL There is no evidence to support a different siveness of the tumor increases with increasing numbers of centro- treatment approach between grade and grade FL Differences in blasts The WHO Classification has adopted grading from to molecular genetics as well as clinical behavior suggest that FL grade IIIa based on increased numbers of centroblasts counted per high power is often an indolent disease whereas grade IIIb is an aggressive field: Grade I with to centroblasts/high power field (hpf) (follicular disease.2,24 small cleaved), Grade II with to 15 centroblasts/hpf (follicular mixed) FL grade has been historically referred to as follicular large cell Grade III with more than 15 centroblasts/hpf (follicular large cell) lymphoma Since many studies likely include both grade IIIa and IIIb, Grade III has been subdivided into grade IIIa, in which centrocytes are this heterogeneity may affect interpretation of the outcomes Although 10 present, and grade IIIb, in which there are sheets of centroblasts the follicular architecture is intact, the clinical presentation, behavior, Bone marrow involvement is very common with paratrabecular lymphoid aggregates.2 FL cells express monoclonal immunoglobulin light chain, CD19, CD20, CD10, and BCL-6 and are negative for CD5 T AB LE Follicular Lymphoma International Prognostic Index (FLIPI)20 and CD23 In virtually all cases FL cells overexpress BCL-2, due to t Risk group # Risk factors year OS year PFS (14;18) Clonal Ig gene rearrangements are also present and most cases Low risk 0–1 98% 84% Intermediate risk 94% 70% High risk or more 87% 42 have extensive somatic mutations Histologic transformation of FL from an indolent disease to a diffuse large B cell lymphoma occurs in 10 to 70 percent of patients over 298 A JH | FREEDMAN and outcome with treatment in many patients with FL grade IIIb more treatment unless they have symptomatic nodal disease, compromised closely lymphoma end organ function B symptoms; symptomatic extranodal disease, or (DLBCL).25–27 In contrast to DLBCL, the relapse rate of FL grade 3b is cytopenias This approach is supported by randomized prospective tri- in some series is higher, but survival is longer.28 A recent series sug- als of observation versus immediate treatment One of the largest trials gested similar outcome of grade IIIa and IIIb cases, and no benefit for compared immediate treatment with chlorambucil to observation.48 At approximates that of diffuse large B-cell 29 the inclusion of anthracyclines in the treatment regimen a median follow-up of 16 years, no difference in overall survival and Investigation of the cellular microenvironment of FL has provided cause-specific survival was seen between the two approaches Similar interesting insights into prognosis.14,16,30–37 It has been suggested that results have been noted in other prospective trials of initial treatment FL is an immunologically functional disease in which an interaction versus observation.22 between the tumor cells and the microenvironment determines overall A major question is whether rituximab might change this approach clinical behavior These studies which have observed an impact on in early treatment in asymptomatic patients A retrospective analysis of prognosis of the normal infiltrate of macrophages, T cells, and T cell good risk patients who were either observed or received single agent subsets will need additional study in larger data sets, and prospectively rituximab found no deleterious impact of watchful waiting.49 A pro- with uniformly treated patient populations spective study compared observation to rituximab alone or rituximab In the 2016 version of the WHO classification, there are four addi- followed by maintenance in previously untreated FL No difference in tional entities: pediatric FL; FL in situ; primary intestinal FL; and pre- overall survival or incidence of histologic transformation was seen.50 1,38,39 The important issues of time to second therapy, cost, toxicity, and dominantly diffuse follicular lymphoma with IRF-4 rearrangement future responses to rituximab were not addressed.51 A trial in a similar | INITIAL TREATMENT OF EARLY STAGE DISEASE patient population randomized patients following doses of weekly rituximab to either observation and retreatment at progression, or rituximab maintenance for years, known as the RESORT trial No Less than 10% of patients with FL have stage I/II disease.40 Radiation difference in time to treatment failure, histologic transformation, or therapy is generally the treatment of choice for limited stage FL and overall survival was seen, but more rituximab was administered to the results in 10-year overall survival rates of 60 to 80 percent; with a maintenance arm There was a difference in time to cytotoxic therapy, median survival is approximately 19 years.41 A dose of 24 Gy appears in favor of the maintenance rituximab receiving patients.52 42 A recent Rituximab has changed the paradigm of treating FL This improve- phase III study showed 24 Gy to be superior to Gy in disease con- ment in survival is largely due to the use of anti-CD20 antibody based trol.43 However most patients with stage I disease treated in the therapy.53 The benefit of adding rituximab to combination chemother- United States not receive radiation therapy, instead they receive apy for the initial treatment has been demonstrated in multiple single agent rituximab or chemoimmunotherapy.40 Adjuvant chemo- randomized trials of chemotherapy with or without rituximab.54–58 All therapy has not been demonstrated to add additional benefit after local of these trials have demonstrated improved response rates time to pro- to be highly effective, with no benefit of higher doses 44 radiotherapy If significant morbidity is possible from radiotherapy gression in the rituximab plus chemotherapy arms, as well as improve- based on the location of the disease area or if the patient chooses to ment in overall survival [(18)F]Fluorodeoxyglucose positron emission not receive radiation, observation may be a reasonable alternative, tomography (PET) scanning has been employed to evaluate responses especially for stage II patients.45 to CHOP-R in previously untreated patients PET scanning was predic- In a large study of over 6000 patients with stage I or stage II FL tive when performed after cycles, and at end of therapy The year diagnosed from 1973 to 2004, 34 percent of whom were initially PFS was significantly higher for PET negative than PET positive treated with RT, patients who received initial RT had higher rates of patients when employed as an interim or end of therapy scan The disease-specific survival at (90 versus 81 percent), 10 (79 versus 66 year overall survival was also significantly higher for PET negative than percent), 15 (68 versus 57 percent), and 20 (63 versus 51 percent) PET positive patients This will require further study but may be change years.46 A recent retrospective analysis suggested an improved PFS management in the future.59,60 Although controversial, a recent study outcome with chemoimmunotherapy or systemic therapy plus RT as reported minimal residual disease detection and long-term outcome compared to RT alone, with no impact on OS.47 Selected early stage The marker that was followed was the BCL-2/IGH translocation in the patients can be observed without initial treatment with radiation In bone marrow.61 one report, the median overall survival of selected untreated patients Subcutaneous administration of rituximab has been shown to be was 19 years At a median follow-up of years, 63 percent of patients as effective with less adverse events than intravenous This is likely to had not required treatment.45 once again change the paradigm of the use of rituximab.62 | INITIAL TREATMENT OF ADVANCED STAGE DISEASE have changed the landscape of upfront treatment Bendamustine plus Other chemotherapy drugs plus rituximab have been reported and rituximab (B-R) has been compared to CHOP-R in a randomized phase III trial in 513 patients with advanced follicular, indolent, and mantle The overwhelming majority of patients have advanced stage disease at cell lymphoma.63 BR had superior median progression-free survival diagnosis Patients with asymptomatic FL not require immediate (69.5 versus 31.2 months) at 45 months, with less toxicity, including A JH FREEDMAN | 299 lower rates of grade and neutropenia and leukopenia was observed FCM-R) randomly assigned maintenance with rituximab (375 mg/m2 There was no difference in overall survival at a median follow-up of 45 every weeks for 24 months) or placebo.71 At a median follow-up of months The BRIGHT study found BR to be noninferior to CHOP-R 36 months from randomization, patients assigned to rituximab mainte- and CVP-R, with BR having a similar complete and overall response nance had higher rates of progression-free survival (75 versus 58 per- 64 rates to the other regimens These studies provide support for BR as cent) A higher percentage of patients in complete response/CR the primary therapy for indolent follicular lymphoma A randomized unconfirmed at 24 months (72 versus 52 percent) yrs post random- phase III trial compared initial treatment in previously untreated stage ization There was a significantly higher percentage of patients with II-IV FL patients with R-CHOP or R-CVP or R-fludarabine- grade III/IV adverse events and infections in the rituximab maintenance mitoxantrone Both R-FM and R-CHOP were superior to R-CVP in group At this time, overall survival is the same in both groups Another year PFS and TTF but there was no difference in OS The current randomized phase III trial using fludarabine, cyclophosphamide and impact of this study is uncertain given the results of the BR versus mitoxantrone examined whether abbreviated maintenance with rituxi- 65 mab had clinical benefit in patients ages 60–75 with previously R-CHOP study Several other anti-CD20 monoclonal antibodies have being eval- untreated FL.72 Rituximab maintenance did not have a statistically sig- uated in patients with FL who are refractory to rituximab One66 of nificant PFS benefit Therefore the role for maintenance with regimens these antibodies, obinutuzumab has been evaluated in a phase III study besides CHOP-R or CVP-R remains uncertain comparing chemoimmunotherapy with either obinutuzumab or rituxi- Radioimmunotherapy alone has been used as the initial treatment mab for previously untreated patients with FL.67 The chemotherapy in a limited number of patients with FL.73 Two radioimmunotherapy options were either bendamustine, CHOP or CVP This is known as the agents have been studied, however, 131I tositumomab is no longer GALLIUM study, which also included years of maintenance with commercially available (90)Yttrium-ibritumomab-tiuxetan has also either obinutuzumab or rituximab The response rates and overall were been studied as sole initial therapy with similar excellent results with similar with either obinutuzumag or rituximab, however the progression limited follow up.74 free survival was higher for patients receiving obinutuzumab No differ- Radioimmunotherapy has also been applied as consolidation fol- ence was seen in overall survival Adverse events were greater in num- lowing conventional chemotherapy induction in patients with FL ber in the obinutuzumab arms Results from a phase III trial comparing 90Yi-ibritumomab tiuxetan to Rituximab alone has been used as the first therapy in patients with observation following a CR or PR to induction chemotherapy for treat- indolent lymphoma, with overall response rates of around 70% and CR ment naïve patients with FL has been reported.75 Of note, the majority 68–70 rates of over 30% reported The most impressive data of single 66 of patients did not receive rituximab along with the induction chemo- Patients received therapy At years, both the PR and CR patients who received Yi90- weekly doses, and then patients with stable disease or better were ibritumomab tiuxetan had significantly longer median progression-free randomized to observation or doses of maintenance with one dose survival with improvement of about 36 months In contrast to this every months In this study, 202 patients with previously untreated study a randomized trial of CHOP plus rituximab to CHOP followed by or relapsed/refractory FL administered weekly doses of single agent 131I tositumomab did not see any differences in PFS between the two rituximab has been reported The 151 patients with responding or sta- arms.76 agent rituximab is the update of the SAKK trial ble disease at week 12 were randomized to no further treatment or High dose therapy and autologous stem cell transplantation has prolonged rituximab maintenance every months for doses At a been used to consolidate first remission for patients with FL These median follow-up of 35 months, patients who received the prolonged studies generally preceded the widespread use of rituximab Generally rituximab maintenance had a twofold increase in event-free-survival speaking, about 50% of patients are disease free at 10 or more yrs fol- (23 versus 12 months) Now with longer follow-up 35 percent of all lowing ASCT, but the risk of second malignancies both MDS, AML, and responders remain in remission at eight years with 45 percent of newly solid tumors has been observed with long follow up of these patients diagnosed patients in this study in remission at eight years with the Several randomized trials have examined the role of ASCT in previously additional maintenance rituximab untreated patients with FL following an induction therapy.77–81 The The North American study known as the RESORT trial looked at majority of these studies have demonstrated a significant improvement the role for maintenance rituximab following weekly doses of rituxi- in PFS, but no impact on overall survival.82 One reason for the lack of 52 mab The patient population was low tumor burden patients with previously untreated FL Maintenance rituximab in this study was not of meaningful benefit for patients who would otherwise be observed impact on overall survival has been the excess number of second malignancies Although allogeneic stem cell transplantation (HCT) can potentially The use of maintenance rituximab after chemoimmunotherapy in lead to cure for patients with FL, due to the significant treatment patients with FL has been examined in a large randomized trial.71 While related mortality, this is largely reserved for patients with relapsed and maintenance rituximab appears to improve progression-free survival more refractory disease rates, toxicities, albeit tolerable, are increased and the effect on overall Part of the natural history of indolent NHL is progression to a survival is to date unclear The Primary Rituximab and Maintenance higher grade histologic subtype, such as diffuse large B-cell lym- (PRIMA) phase III intergroup trial in 1018 patients with previously phoma.11,83 A recent report found the risk to be 2% per year after diag- untreated FL responded to chemoimmunotherapy (CVP-R, CHOP-R or nosis.84 A subgroup of patients with indolent NHL who transform to a 300 A JH | FREEDMAN more aggressive histology may attain complete remission following phase II trials of other agents plus rituximab associated with quite high treatment with CHOP-like chemotherapy, particularly if treatment response rates included bendamustine plus rituximab with 90% RR and naive Some 30 to 50 percent of patients may be cured by high dose median PFS of years.94–96 Single agent bendamustine has an overall chemotherapy response rate of 77 with a median response duration of 6.7 months.94 followed by autologous hematopoietic cell 85 Bendamustine plus obinutuzumab for cycles followed by years of transplantation Retrospective studies of patients with histologic transformation maintenance obinutuzzumab was superior to cycles of bendamustine suggests that consolidation of remission following chemoimmunother- alone, leading to the US FDA approval for the combination in relapsed apy leads to a better outcome than chemoimmunotherapy alone, with FL patients.97 86 year overall survival of 55% versus 40% Immunomodulators have been examined in combination with rituximab to enhance activity The most impressive of these is the combi- | TREATMENT OF RELAPSED FL nation of lenalidomide plus rituximab The overall response rate is higher with the combination (70 versus 53 percent), and the time to When patients with relapsed FL require treatment, there are many options, ranging from rituximab alone to combination chemotherapy plus rituximab, radioimmunotherapy and for selected patients stem cell transplantation A recent update of single agent rituximab therapy in patients with relapsed FL is from the SAKK trial In that study patients with either newly diagnosed, relapsed or refractory FL were treated with weekly doses of rituximab.66 Patients with either responding or stable disease at week 12 were randomized to observation or maintenance with one dose every months for doses With long follow-up, 35% of responders remain in remission at eight years However in the context of current induction therapy that includes chemotherapy and rituximab in the majority of patients, it is uncertain if the response data to single agent rituximab is as high or durable as in patients who did not receive rituximab plus chemotherapy induction Several humanized anti-CD20 monoclonal antibodies have been studied in patients with relapsed FL These were designed to have perhaps less infusion toxicity and better ADCC effector function.87–89 Obinutuzumab, is the first type II, glycoengineered and humanized monoclonal anti-CD20 antibody.90 In rituximab refractory pts in the progression was year longer for the combination.98 A phase III randomized trial of lenalidomide plus rituximab versus chemoimmunotherapy is ongoing in patients with previously untreated FL Anti-CD20 radioimmunotherapy agents have been used for treatment of patients with relapsed and refractory FL.99 The response rates in this patient population is 60 to 80 percent The median progressionfree survival is about 12 months, although the approximately 20–37% of patients who achieve a CR have a median time to progression of approximately four years.100,101 These radioimmunoconjugates have not received widespread use, and the 131I agent has been taken off the market FL is extremely responsive to radiation therapy (RT) Low dose RT (eg, total dose of Gy) can be used for the palliation of patients who have symptoms related to a single disease site, with CR rates of 57% and ORR of 82%.102 The use of either autologous or allogeneic hematopoietic cell transplantation (HCT) in FL is controversial and the subject of numerous clinical trials.103 A large number of phase II studies prior to the availability of rituximab, involving high dose therapy and autologous HCT have shown that for approximately 40% of patients with good performance status and chemosensitive relapsed disease may experi- high dose cohort, the response rate was 55% with median PFS of 11.9 ence prolong progression-free and overall survival rates.104–108 Prior to months.90 Studies of obinutuzumab combination with chemotherapy, the widespread use of rituximab for in vivo purging, many strategies have shown 93–98% response rates in relapsed and refractory FL were taken to render the autologous stem cell collections free of lym- patients.91 phoma cells Although single institution studies suggested that reinfu- The combination of chemotherapy and rituximab has enhanced sion of tumor free stem cells led to a decreased relapse rate, it remains the efficacy of treatment of relapsed FL Probably the largest study controversial as to whether there is a benefit particularly now in the rit- treated selected patients with relapsed FL who were previously not uximab era The only phase III randomized trial (the CUP trial) compar- treated with an anthracycline or rituximab containing regimen.92 ing ASCT to conventional chemotherapy in relapsed FL patients Patients were randomized to CHOP or CHOP-R and responding demonstrated a higher PFS and OS for ASCT, and no benefit for purg- patients were randomized to years of maintenance rituximab or ing the stem cell graft.109 An retrospective analysis of patients under- observation The overall and CR rates were significantly improved in going ASCT following rituximab based salvage therapy did not suggest the CHOP-R group, and the median PFS was improved by approxi- a benefit of ASCT as compared to conventional therapy Unfortunately mately 12 months A recent update of this study with a median follow- as has been seen in ASCT in first remission, second malignancies both up of six years reported that maintenance rituximab also improved solid tumors and MDS/AML are reported post ASCT median progression-free survival by 2.4 years The overall survival at A recent phase III trial in patients with relapsed FL has investi- five years following maintenance was 74% versus 64% with observa- gated the inclusion of rituximab for in vivo purging pre-ASCT and tion alone yrs of maintenance post-ASCT.110 There was an improvement in PFS Another regimen in which a benefit for the addition of rituximab for patients receiving rituximab for in vivo purging, maintenance and was seen for relapsed disease in a randomized trial employing fludara- the combination of both as compared to no rituximab but no OS bine, cyclophosphamide, and mitoxantrone (FCM).93 A number of benefit A JH FREEDMAN Allogeneic SCT has been investigated in patients with relapsed FL Both myeloablative and reduced intensity conditioning (RIC) approaches have been employed Unfortunately myeloablative conditioning has a treatment related mortality of up to 40%, however the relapse rate is less than 20%.111 Enthusiasm for RIC allogeneic has lower treatment related mortality,112–114 but some reports suggest that the relapse rate may be higher than conventional myeloablative conditioning The role of allogeneic SCT versus autologous SCT for FL remains uncertain A recent NCCN database retrospective analysis found significantly higher year OS for autologous SCT versus alloge115 neic SCT (87% versus 61%) Certainly for younger patients with more resistant disease, allogeneic SCT remains a potentially curative option for relapsed FL | NEWER AGENTS There are a multitude of new approaches that have been studied in patients with FL This includes monoclonal antibodies, idiotype vaccines, immunomodulatory agents and novel drugs such as kinase inhibitors Immunostimulatory agents, including IL2 and CpGs have been studied to enhance the activity of rituximab.116–118 To date, although having immunomodulatory effects, the impact on enhancing the therapeutic effect of rituximab has been limited The other area of interest has been in active immunization, focusing largely on the idiotype protein as the antigen To date there have been three randomized studies employing idiotype proteins coupled to KLH following induction of remission in patients with follicular NHL 119,120 Only one trial has shown an improvement in PFS However the induction chemotherapy was intense and remissions had to be sustained for 12 months prior to initiation of vaccination.121 Based on these studies idiotype vaccination will be pursued further in follicular NHL B cell kinases are logical targets for therapy in FL To date, kinase inhibitors, idelalisib, ibrutinib and R788 which target PI3 kinase p110id, btk, and syk, respectively In relapsed and refractory FL patients, idelalisib is the most active of these kinase inhibitors with overall response 122,123 rate of 57%, and median duration of response was 12.5 months Another PI3 kinase inhibitor copanlisib has been recently approved in patients with relapsed FL, with similar responses to idelalisib This intravenously delivered agent targets PI3 kinase alpha and delta isoforms.124 These agents are undergoing additional study, in combination with chemotherapy and as consolidation following remission induction to better define their role They represent novel approaches to lymphoma therapy, and are perhaps some of the more exciting agents cur- | 301 [3] Junlen HR, Peterson S, Kimby E, et al Follicular lymphoma in Sweden: nationwide improved survival in the rituximab era, particularly in elderly women: a Swedish Lymphoma Registry study Leukemia 2015;29:668–676 [4] Goldin LR, Bjorkholm M, Kristinsson SY, et al Highly increased familial risks for specific lymphoma subtypes Br J Haematol 2009; 146:91–94 [5] Bodor C, Grossmann V, Popov N, et al EZH2 mutations are frequent and represent an early event in follicular lymphoma Blood 2013;122:3165–3168 [6] Ansell SM Malignant B cells at the helm in follicular lymphoma J Clin Oncol 2013;31:2641–2642 [7] Kiaii S, Clear AJ, Ramsay AG, et al Follicular lymphoma cells induce changes in T-cell gene expression and function: potential impact on survival and risk of transformation J Clin Oncol 2013; 31:2654–2661 [8] Schmatz AI, Streubel B, Kretschmer-Chott E, et al Primary follicular lymphoma of the duodenum is a distinct mucosal/submucosal variant of follicular lymphoma: a retrospective study of 63 cases J Clin Oncol 2011;29:1445–1451 [9] Louissaint A, Jr,., Schafernak KT, Geyer JT, et al Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations Blood 2016;128:1093–1100 [10] Ott G, Katzenberger T, Lohr A, et al Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: types of follicular lymphoma grade Blood 2002;99:3806–3812 [11] Freedman AS Biology and management of histologic transformation of indolent lymphoma Hematol Am Soc Hematol Educ Prog 2005;314–320 [12] Montoto S, Davies AJ, Matthews J, et al Risk and clinical implications of transformation of follicular lymphoma to diffuse large Bcell lymphoma J Clin Oncol 2007;25:2426–2433 [13] Relander T, Johnson NA, Farinha P, et al Prognostic factors in follicular lymphoma J Clin Oncol 2010;28:2902–2913 [14] Dave SS, Wright G, Tan B, et al Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells N Engl J Med 2004;351:2159–2169 [15] Glas AM, Kersten MJ, Delahaye LJ, et al Gene expression profiling in follicular lymphoma to assess clinical aggressiveness and to guide the choice of treatment Blood 2005;105:301–307 [16] Carreras J, Lopez-Guillermo A, Fox BC, et al High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma Blood 2006; 108:2957–2964 [17] Solal-Celigny P, Roy P, Colombat P, et al Follicular lymphoma international prognostic index Blood 2004;104:1258–1265 [18] 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;27:4555–4562 [1] Swerdlow SH, Campo E, Pileri SA, et al The 2016 revision of the World Health Organization classification of lymphoid neoplasms Blood 2016;127:2375–2390 [19] Buske C, Hoster E, Dreyling M, et al The Follicular Lymphoma International Prognostic Index (FLIPI) separates high-risk from intermediate- or low-risk patients with advanced-stage follicular lymphoma treated front-line with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) with respect to treatment outcome Blood 2006;108: 1504–1508 [2] Campo E, Swerdlow SH, Harris NL et al The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications Blood 2011;117:5019–5032 [20] Nooka AK, Nabhan C, Zhou X, et al Examination of the follicular lymphoma international prognostic index (FLIPI) in the National LymphoCare study (NLCS): a prospective US patient cohort rently being studied R E FER E NCE S 302 | A JH treated predominantly in community practices Ann Oncol 2013; 24:441–448 [21] 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;16:1111–1122 [22] Brice P, Bastion Y, Lepage E, et al Comparison in low-tumorburden 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;15:1110–1117 [23] 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; 33:2516–2522 [24] Wahlin BE, Yri OE, Kimby E, et al Clinical significance of the WHO grades of follicular lymphoma in a population-based cohort of 505 patients with long follow-up times Br J Haematol 2012; 156:225–233 [25] Anderson JR, Vose JM, Bierman PJ, et al Clinical features and prognosis of follicular large-cell lymphoma: a report from the Nebraska Lymphoma Study Group J Clin Oncol 1993;11:218–224 [26] Hans CP, Weisenburger DD, Vose JM, et al A significant diffuse component predicts for inferior survival in grade follicular lymphoma, but cytologic subtypes not predict survival Blood 2003;101:2363–2367 [27] Rodriguez J, McLaughlin P, Hagemeister FB, et al Follicular large cell lymphoma: an aggressive lymphoma that often presents with favorable prognostic features Blood 1999;93(7):2202 [28] Chau I, Jones R, Cunningham D, et al Outcome of follicular lymphoma grade 3: is anthracycline necessary as front-line therapy? Br J Cancer 2003;89:36–42 [29] Shustik J, Quinn M, Connors JM, et al Follicular non-Hodgkin lymphoma grades 3A and 3B have a similar outcome and appear incurable with anthracycline-based therapy Ann Oncol 2011;22: 1164–1169 [30] Alvaro T, Lejeune M, Salvado MT, et al Immunohistochemical patterns of reactive microenvironment are associated with clinicobiologic behavior in follicular lymphoma patients J Clin Oncol 2006; 24:5350–5357 [31] Canioni D, Salles G, Mounier N, et al High numbers of tumorassociated macrophages have an adverse prognostic value that can be circumvented by rituximab in patients with follicular lymphoma enrolled onto the GELA-GOELAMS FL-2000 trial J Clin Oncol 2008;26:440–446 [32] Farinha P, Masoudi H, Skinnider BF, et al Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL) Blood 2005;106:2169–2174 [33] Glas AM, Knoops L, Delahaye L, et al Gene-expression and immunohistochemical study of specific T-cell subsets and accessory cell types in the transformation and prognosis of follicular lymphoma J Clin Oncol 2007;25:390–398 [34] Klapper W, Hoster E, Rolver L, et al Tumor sclerosis but not cell proliferation or malignancy grade is a prognostic marker in advanced-stage follicular lymphoma: the German Low Grade Lymphoma Study Group J Clin Oncol 2007;25:3330–3336 [35] Kuppers R Prognosis in follicular lymphoma–it’s in the microenvironment N Engl J Med 2004;351:2152–2153 FREEDMAN [36] Lee AM, Clear AJ, Calaminici M, et al Number of CD41 cells and location of forkhead box protein P3-positive cells in diagnostic follicular lymphoma tissue microarrays correlates with outcome J Clin Oncol 2006;24:5052–5059 [37] Wahlin BE, Sander B, Christensson B, et al CD81 T-cell content in diagnostic lymph nodes measured by flow cytometry is a predictor of survival in follicular lymphoma Clin Cancer Res 2007;13: 388–397 [38] Mamessier E, Song JY, Eberle FC, et al Early lesions of follicular lymphoma: a genetic perspective Haematologica 2014;99:481– 488 [39] Schmidt J, Gong S, Marafioti T, et al Genome-wide analysis of pediatric-type follicular lymphoma reveals low genetic complexity and recurrent alterations of TNFRSF14 gene Blood 2016;128: 1101–1111 [40] Friedberg J, Huang J, Dillon H, et al: Initial therapeutic strategy in follicular lymphoma: An analysis from the National LymphoCare Study 24 428s; 2006 [41] 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; 64:928–934 [42] Lowry L, Smith P, Qian W, et al Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial Radiother Oncol 2011;100:86–92 [43] Hoskin PJ, Kirkwood AA, Popova B, et al Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase non-inferiority trial Lancet Oncol 2014;15:457– 463 [44] Kelsey SM, Newland AC, Hudson GV, et al A British National Lymphoma Investigation randomised trial of single agent chlorambucil plus radiotherapy versus radiotherapy alone in low grade, localised non-Hodgkins lymphoma Med Oncol 1994;11:19–25 [45] Advani R, Rosenberg SA, Horning SJ Stage I and II follicular nonHodgkin’s lymphoma: long-term follow-up of no initial therapy J Clin Oncol 2004;22:1454–1459 [46] Pugh TJ, Ballonoff A, Newman F, et al Improved survival in patients with early stage low-grade follicular lymphoma treated with radiation: a Surveillance, Epidemiology, and End Results database analysis Cancer 2010;116:3843–3851 [47] Friedberg JW, Byrtek M, Link BK, et al Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study J Clin Oncol 2012;30:3368– 3375 [48] Ardeshna KM, Smith P, Norton A, et al 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;362:516–522 [49] Solal-Celigny 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;30:3848–3853 [50] Ardeshna KM, Qian W, Smith P, et al Rituximab versus a watchand-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase trial Lancet Oncol 2014;15:424–435 [51] Ardeshna K, Smith P, Qian W, et al An intergroup randomised trial of rituximab versus a watch and wait strategy in patients with stage II, III, IV, asymptomatic, non-bulky follicular lymphoma (Grades 1, and 3a) A preliminary analysis Blood 2010;116: abstract 6, FREEDMAN A JH | 303 [52] 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;32:3096–3102 [66] Martinelli G, Schmitz SF, 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; 28:4480–4484 [53] Fisher RI, LeBlanc M, Press OW, et al New treatment options have changed the survival of patients with follicular lymphoma J Clin Oncol 2005;23:8447–8452 [67] Marcus R Obinutuzumab-based induction and maintenance prolongs progression-free survival (PFS) in patients with previously untreated follicular lymphoma: primary results of the randomized Phase III GALLIUM study (abstract 6) Blood 2016 [54] Herold M, Haas A, Srock S, et al Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study J Clin Oncol 2007;25:1986–1992 [55] Hiddemann W, Kneba M, Dreyling M, et al Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group Blood 2005;106:3725–3732 [56] Marcus R, Imrie K, Belch A, et al CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma Blood 2005;105:1417–1423 [57] Marcus R, Imrie K, Solal-Celigny P, et al Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma J Clin Oncol 2008;26:4579–4586 [58] Salles G, Mounier N, de Guibert S, et al Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study Blood 2008;112: 4824–4831 [59] Dupuis J, Berriolo-Riedinger A, Julian A, et al Impact of [(18)F]fluorodeoxyglucose positron emission tomography response evaluation in patients with high-tumor burden follicular lymphoma treated with immunochemotherapy: a prospective study from the Groupe d’Etudes des Lymphomes de l’Adulte and GOELAMS J Clin Oncol 2012;30:4317–4322 [60] Luminari S, Biasoli I, Versari A, et al The prognostic role of postinduction FDG-PET in patients with follicular lymphoma: a subset analysis from the FOLL05 trial of the Fondazione Italiana Linfomi (FIL) Ann Oncol 2014;25:442–447 [61] Galimberti S, Luminari S, Ciabatti E, et al Minimal residual disease after conventional treatment significantly impacts on progressionfree survival of patients with follicular lymphoma: the FIL FOLL05 trial Clin Cancer Res 2014;20:6398–6405 [62] Davies A, Merli F, Mihaljevic B, et al Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase trial Lancet Haematol 2017;4:e272–e282 [63] Rummel MJ, Niederle N, Maschmeyer G, et al 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 non-inferiority trial Lancet 2013;381:1203–1210 [68] Colombat P, Salles G, Brousse N, et al Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation Blood 2001;97:101–106 [69] Ghielmini M, Schmitz SF, Cogliatti SB, et al Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x schedule Blood 2004;103:4416–4423 [70] Witzig TE, Vukov AM, Habermann TM, et al Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkin’s lymphoma: a phase II trial in the North Central Cancer Treatment Group J Clin Oncol 2005;23:1103–1108 [71] Salles G, Seymour JF, Offner F, et al Rituximab maintenance for years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial Lancet 2011;377:42–51 [72] 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;31:3351–3359 [73] Kaminski MS, Tuck M, Estes J, et al 131I-tositumomab therapy as initial treatment for follicular lymphoma N Engl J Med 2005;352: 441–449 [74] Scholz CW, Pinto A, Linkesch W, et al 90)Yttrium-ibritumomabtiuxetan as first-line treatment for follicular lymphoma: 30 months of follow-up data from an international multicenter phase II clinical trial J Clin Oncol 2013;31:308–313 [75] Morschhauser F, Radford J, Van Hoof A, et al 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the International, Randomized, Phase III First-LineIndolent trial J Clin Oncol 2013;31:1977–1983 [76] Press OW, Unger JM, Rimsza LM, et al Phase III randomized intergroup trial of CHOP plus rituximab compared with CHOP chemotherapy plus (131)iodine-tositumomab for previously untreated follicular non-Hodgkin lymphoma: SWOG S0016 J Clin Oncol 2013;31:314–320 [77] Deconinck E, Foussard C, Milpied N, et al High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by GOELAMS Blood 2005;105:3817–3823 [64] 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: 2944–2952 [78] Lenz G, Dreyling M, Schiegnitz E, et al Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German LowGrade Lymphoma Study Group Blood 2004;104:2667–2674 [65] 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;31:1506–1513 [79] Sebban C, Mounier N, Brousse N, et al Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study 304 | A JH from the Groupe d’Etude des Lymphomes de l’Adulte (GELA) Blood 2006;108:2540–2544 [80] Ladetto M, De Marco F, Benedetti F, et al Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of RHDS does not translate into an overall survival advantage Blood 2008;111:4004–4013 [81] Gyan E, Foussard C, Bertrand P, et al High-dose therapy followed by autologous purged stem cell transplantation and doxorubicinbased chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS with final results after a median follow-up of years Blood 2009;113: 995–1001 [82] Al Khabori M, de Almeida JR, Guyatt GH, et al Autologous stem cell transplantation in follicular lymphoma: a systematic review and meta-analysis J Natl Cancer Inst 2012;104:18–28 [83] Montoto S, Fitzgibbon J Transformation of Indolent B-Cell Lymphomas J Clin Oncol 2011;29:1827–1834 [84] Link BK, Maurer MJ, Nowakowski GS, et al Rates and outcomes of follicular lymphoma transformation in the immunochemotherapy era: a report from the University of Iowa/MayoClinic Specialized Program of Research Excellence Molecular Epidemiology Resource J Clin Oncol 2013;31:3272–3278 FREEDMAN [94] Friedberg JW, Cohen P, Chen L, et al Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin’s lymphoma: results from a phase II multicenter, single-agent study J Clin Oncol 2008;26:204–210 [95] Robinson KS, Williams ME, van der Jagt RH, et al Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-hodgkin’s lymphoma J Clin Oncol 2008;26:4473–4479 [96] Rummel MJ, Al-Batran SE, Kim SZ, et al Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin’s lymphoma J Clin Oncol 2005;23:3383–3389 [97] Sehn LH, Chua N, Mayer J, et al Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximabrefractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase trial Lancet Oncol 2016;17:1081–1093 [98] 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;33:3635–3640 [99] Cheson BD Radioimmunotherapy of non-Hodgkin lymphomas Blood 2003;101:391–398 [85] Madsen C, Pedersen MB, Vase MO, et al Outcome determinants for transformed indolent lymphomas treated with or without autologous stem-cell transplantation Ann Oncol 2015;26:393–399 [100] Fisher RI, Kaminski MS, Wahl RL, et al Tositumomab and iodine131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin’s lymphomas JCO 2005;23:7565–7573 [86] Villa D, Crump M, Panzarella T, et al Autologous and allogeneic stem-cell transplantation for transformed follicular lymphoma: a report of the Canadian blood and marrow transplant group J Clin Oncol 2013;31:1164–1171 [101] Witzig TE, Molina A, Gordon LI, et al Long-term responses in patients with recurring or refractory B-cell non-Hodgkin lymphoma treated with yttrium 90 ibritumomab tiuxetan Cancer 2007;109: 1804–1810 [87] Hagenbeek A, Gadeberg O, Johnson P, et al First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/ trial Blood 2008;111:5486–5495 [102] Russo AL, Chen YH, Martin NE, et al Low-dose involved-field radiation in the treatment of non-hodgkin lymphoma: predictors of response and treatment failure Int J Radiat Oncol Biol Phys 2013; 86:121–127 [88] Morschhauser F, Leonard JP, Fayad L, et al Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin’s lymphoma: phase I/II results J Clin Oncol 2009;27:3346–3353 [103] Montoto S, Corradini P, Dreyling M, et al Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-Lymphoma Working Party Haematologica 2013;98:1014–1021 [89] Morschhauser F, Marlton P, Vitolo U, et al Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma Ann Oncol 2010;21:1870–1876 [90] Salles GA, Morschhauser F, Solal-Celigny P, et al Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study J Clin Oncol 2013;31:2920–2926 [91] Radford J, Davies A, Cartron G, et al Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000) Blood 2013;122:1137–1143 [92] van Oers MH, Klasa R, Marcus RE, et al Rituximab maintenance improves clinical outcome of relapsed/resistant follicular nonHodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase intergroup trial Blood 2006;108:3295–3301 [93] Forstpointner R, Dreyling M, Repp R, et al 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;104:3064–3071 [104] Rohatiner AZ, Nadler L, Davies AJ, et al Myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma at the time of second or subsequent remission: long-term follow-up J Clin Oncol 2007;25:2554–2559 [105] Bierman PJ, Vose JM, Anderson JR, et al High-dose therapy with autologous hematopoietic rescue for follicular low-grade nonHodgkin’s lymphoma J Clin Oncol 1997;15:445–450 [106] Cao TM, Horning S, Negrin RS, et al High-dose therapy and autologous hematopoietic-cell transplantation for follicular lymphoma beyond first remission: the Stanford University experience Biol Blood Marrow Transplant 2001;7:294–301 [107] Safar V, Gastinne T, Milpied N, et al Very long term follow-up of autologous stem cell transplantation in follicular lymphoma: a retrospective single-institution experience Ann Oncol 2008;19(19): 183 [108] Bastion Y, Brice P, Haioun C, et al Intensive therapy with peripheral blood progenitor cell transplantation in 60 patients with poorprognosis follicular lymphoma Blood 1995;86:3257–3262 [109] Schouten HC, Qian W, Kvaloy S, et al High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin’s lymphoma: results from the randomized European CUP trial J Clin Oncol 2003;21:3918–3927 FREEDMAN [110] Pettengell R, Schmitz N, Gisselbrecht C, et al Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized trial from the lymphoma working party of the European group for blood and marrow transplantation J Clin Oncol 2013;31:1624– 1630 [111] van Besien K, Loberiza FR, Jr,., Bajorunaite R, et al Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma Blood 2003;102:3521–3529 [112] Khouri IF, McLaughlin P, Saliba RM, et al Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab Blood 2008;111:5530–5536 [113] Hari P, Carreras J, Zhang MJ, et al Allogeneic transplants in follicular lymphoma: higher risk of disease progression after reducedintensity compared to myeloablative conditioning Biol Blood Marrow Transplant 2008;14:236–245 [114] Tomblyn MR, Ewell M, Bredeson C, et al Autologous versus reduced-intensity allogeneic hematopoietic cell transplantation for patients with chemosensitive follicular non-Hodgkin lymphoma beyond first complete response or first partial response Biol Blood Marrow Transplant 2011;17(7):1051 [115] Evens AM, Vanderplas A, LaCasce AS, et al Stem cell transplantation for follicular lymphoma relapsed/refractory after prior rituximab: a comprehensive analysis from the NCCN lymphoma outcomes project Cancer 2013;119:3662–3671 [116] Friedberg JW, Neuberg D, Gribben JG, et al Combination immunotherapy with rituximab and interleukin in patients with relapsed or refractory follicular non-Hodgkin’s lymphoma Br J Haematol 2002;117:828–834 [117] Friedberg JW, Kelly JL, Neuberg D, et al Phase II study of a TLR9 agonist (1018 ISS) with rituximab in patients with relapsed or refractory follicular lymphoma Br J Haematol 2009;146:282–291 [118] Friedberg JW, Kim H, McCauley M, et al Combination immunotherapy with a CpG oligonucleotide (1018 ISS) and rituximab in A JH | 305 patients with non-Hodgkin lymphoma: increased interferon-alpha/ beta-inducible gene expression, without significant toxicity Blood 2005;105:489–495 [119] Freedman A, Neelapu SS, Nichols C, et al Placebo-controlled phase III trial of patient-specific immunotherapy with mitumprotimut-T and granulocyte-macrophage colony-stimulating factor after rituximab in patients with follicular lymphoma J Clin Oncol 2009;27:3036–3043 [120] Levy R, Ganjoo KN, Leonard JP, et al Active idiotypic vaccination versus control immunotherapy for follicular lymphoma J Clin Oncol 2014;32:1797–1803 [121] Schuster SJ, Neelapu SS, Gause BL, et al Vaccination with patientspecific tumor-derived antigen in first remission improves diseasefree survival in follicular lymphoma J Clin Oncol 2011;29:2787– 2794 [122] Gopal AK, Kahl BS, de Vos S, et al PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma N Engl J Med 2014;370:1008–1018 [123] Kahl B, Byrd J, Flinn I, et al : Clinical Safety and Activity In a Phase Study of CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110d, In Patients with Relapsed or Refractory Non-Hodgkin Lymphoma Blood 116:abstract 1777, 2010 [124] Patnaik A, Appleman LJ, Tolcher AW, et al First-in-human phase I study of copanlisib (BAY 80–6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin’s lymphomas Ann Oncol 2016;27: 1928–1940 How to cite this article: Freedman A Follicular lymphoma: 2018 update on diagnosis and management Am J Hematol 2018;93:296–305 https://doi.org/10.1002/ajh.24937 ... and cytogenetic profiles of follicular lymphoma: types of follicular lymphoma grade Blood 2002;99:3806–3812 [11] Freedman AS Biology and management of histologic transformation of indolent lymphoma... response rates of around 70% and CR ment naïve patients with FL has been reported.75 Of note, the majority 68–70 rates of over 30% reported The most impressive data of single 66 of patients did... 29 the inclusion of anthracyclines in the treatment regimen a median follow-up of 16 years, no difference in overall survival and Investigation of the cellular microenvironment of FL has provided