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 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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