A JH CME Information: Follicular lymphoma: 2015 update on diagnosis and management CME Editor: Ayalew Tefferi, M.D. Author: Arnold S. Freedman, M.D. If you wish to receive credit for this activity, please refer to the website: www.wileyhealthlearning.com
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䊏 Educational Objectives Upon completion of this educational activity, participants will be better able to: 1. To correctly make the diagnosis of follicular lymphoma and assess the prognosis the patient 2. To understand the treatment options for previously untreated patients as well as for patients with recurrent and refractory disease
䊏 Activity Disclosures No commercial support has been accepted related to the development or publication of this activity. CME Editor: Ayalew Tefferi, M.D. has no relevant financial relationships to disclose. Author: Arnold S. Freedman, M.D. has no relevant financial relationships to disclose. This activity underwent peer review in line with the standards of editorial integrity and publication ethics maintained by American Journal of Hematology. The peer reviewers have no conflicts of interest to disclose. The peer review process for American Journal of Hematology is single blinded. As such, the identities of the reviewers are not disclosed in line with the standard accepted practices of medical journal peer review. Conflicts of interest have been identified and resolved in accordance with Blackwell Futura Media Services’ Policy on Activity Disclosure and Conflict of Interest. The primary resolution method used was peer review and review by a non-conflicted expert.
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American Journal of Hematology, Vol. 90, No. 12, December 2015
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AJH Educational Material
Follicular lymphoma: 2015 update on diagnosis and management Arnold Freedman* 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 lymphoadenopathy, bone marrow involvement, splenomegaly, and less commonly other extranodal sites of involvement. In general, cytopenias can occur but constitutional symptoms of fever, night sweats, 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 > 4. The presence of 0, 1, 2, and 3 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. C 2015 Wiley Periodicals, Inc. Am. J. Hematol. 90:1172–1178, 2015. V
䊏 Disease Overview and Clinical Presentation Follicular lymphoma (FL) is the second most common lymphoma diagnosed in the United States and Western Europe, approximately 35% of all non-Hodgkin lymphomas (NHLs), and 70% of indolent lymphomas . The median age of diagnosis is at 65 years . The incidence is slightly increased among relatives of persons with FL . FLs are malignant counterparts of normal germinal center B-cells . Approximately 85% of patients with FL have t(14;18) which results in the overexpression of the BCL-2 protein, a member of a family of proteins that blocks apoptosis. However, it is likely that multiple 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 function mutations in the H3K27 methyltransferase EZH2 have been reported in 27% of FLs . More recent studies suggest that altered normal T cell function within the malignant microenvironment play a role in the pathobiology of the disease . This includes altered expression of genes, specifically upregulated PMCH, ETV1, and TNFRSF9, and altered T cell motility in vitro . Patients with FL generally present with asymptomatic lymphadenopathy, with waxing and waning present for years. Bone marrow involvement is present in 70% of patients, whereas involvement of other normal organs is uncommon. Less than 20% of patients present with B symptoms and also less than 20% of patients present with an increased serum lactate dehydrogenase (LDH). Involvement of the intestine is a unique site of presentation of this disease, usually early stage, and with a favorable prognosis .
䊏 Diagnosis FL recapitulates normal germinal centers (GC) of secondary lymphoid follicles . The neoplastic cells consist of a mixture of centrocytes (small to medium sized cells) and centroblast (large cells). The clinical aggressiveness of the tumor increases with increasing numbers of centroblasts. The WHO Classification  has adopted grading from 1 to 3 based on increased numbers of centroblasts counted per high power field: Grade I with 0 to 5 centroblasts/high power field (hpf) (follicular small cleaved), Grade II with 6 to 15 centroblasts/hpf (follicular mixed) Grade
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
Conflict of interest: Nothing to report *Correspondence to: Arnold Freedman, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. E-mail: [email protected]
Received for publication: 21 September 2015; Accepted: 23 September 2015 Am. J. Hematol. 90:1172–1178, 2015. Published online: in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.24200 C 2015 Wiley Periodicals, Inc. V
American Journal of Hematology, Vol. 90, No. 12, December 2015
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES TABLE I. Prognostic Models for Follicular Lymphoma
FLIPI  Age > 60 Serum LDH > ULN Hgb < 12 g/dL Stage III or IV Number of nodal sites > 4 FLIPI2  Age >60 years Bone marrow involvement Hemoglobin level 7 cm 3 or more sites greater than 3 cm B symptoms Spleen below umbilical line Compressive symptoms Pleural or peritoneal effusions 5,000 tumor cells/mm3 Absolute neutrophil count < 1,000/mm3 Platelet count < 100,000/mm3
III with more than 15 centroblasts/hpf (follicular large cell). Grade III has been subdivided into grade IIIa, in which centrocytes are present, and grade IIIb, in which there are sheets of centroblasts . Bone marrow involvement is very common with paratrabecular lymphoid aggregates . FL cells express monoclonal immunoglobulin light chain, CD19, CD20, CD10, and BCL-6 and are negative for CD5 and CD23. In virtually all cases FL cells overexpress BCL-2, due to t(14;18). Clonal Ig gene rearrangements are also present and most cases have extensive somatic mutations. Histologic transformation of FL from an indolent disease to a diffuse large B cell lymphoma occurs in 10–70% of patients over time, with a risk of 2–3% per year, and is associated with rapid progression of lymphadenopathy, extranodal disease (besides the marrow), B symptoms, elevated serum LDH [9–11].
䊏 Prognosis The overall survival of patient with FL has improved significantly since the introduction of rituximab. Data from the Swedish Lymphoma Registry, has reported 10 year overall survivals from: 2000 to 2002; 2003 to 2007; and 2008 to 2010, to be 92%, 83%, 78%, and 64% by the age groups 18–49, 50–59, 60–69, and70, respectively . Two measures of outcome are the FL international prognostic index (FLIPI) and tumor grade . There is also evidence that the characteristics of the associated cells in the tumor microenvironment of FL influence disease behavior and prognosis [13–15]. Several prognostic models for FL have evolved (Table I). The FLIPI includes five prognostic factors patient age, stage, number of involved nodal areas, serum lactate dehydrogenase, and hemoglobin . The FLIPI was developed out of an international study of survival data in 4,167 patients with FL diagnosed between 1985 and 1992. A modified version, of this score, the FLIPI2, evaluates five parameters, with some overlap of the FLIPI . The utility of the FLIPI2 model remains uncertain. Since the incorporation of rituximab into the mainstream therapy of FL, the FLIPI has continued to be a useful prognostic model (Table II) [19,20]. A study of mutation status of 74 genes in 151 patients with previously untreated follicular lymphoma found that including the mutational status of seven genes with FLIPI score, led to better prognostication of five-year failure free survival doi:10.1002/ajh.24200
Follicular Lymphoma TABLE II. FLIPI  Risk group Low risk Intermediate risk High risk
# Risk factors
2 year OS
2 year PFS
0–1 2 3 or more
98% 94% 87%
84% 70% 42%
. The GELF criteria  includes parameters of tumor burden and clinical findings, is another model for risk stratification. A recent analysis of patients receiving R-CHOP as initial treatment, reported that relapse within 2 years of completing therapy is associated with a poor prognosis (50% vs. 90% 5 year survival) . FL tumors are graded from 1 to 3 and this grade has some prognostic utility. There has generally been suboptimal consensus of pathologists on grading FL. There is no evidence to support a different treatment approach between grade 1 and grade 2 FL. Differences in molecular genetics as well as clinical behavior suggest that FL grade IIIa is an indolent disease whereas IIIb is an aggressive disease [1,23]. FL grade 3 has been historically referred to as follicular large cell lymphoma. Since many studies likely include both grade IIIa and IIIb, this heterogeneity may affect interpretation of the outcomes. Although the follicular architecture is intact, the clinical presentation, behavior, and outcome with treatment in many patients with FL grade IIIb more closely approximates that of diffuse large B-cell lymphoma (DLBCL) [24–26]. In contrast to DLBCL, the relapse rate of FL grade 3b is in some series is higher, but survival is longer . A recent series suggested similar outcome of grade IIIa and IIIb cases, and no benefit for the inclusion of anthracyclines in the treatment regimen . Investigation of the cellular microenvironment of FL has provided interesting insights into prognosis [13,15,29–36]. It has been suggested that FL is an immunologically functional disease in which an interaction between the tumor cells and the microenvironment determines overall clinical behavior. These studies which have observed an impact on prognosis of the normal infiltrate of macrophages, T cells, and T cell subsets will need additional study in larger data sets, and prospectively with uniformly treated patient populations.
䊏 Treatment Early stage Less than 10% of patients with FL have stage I/II disease . Radiation therapy is generally the treatment of choice for limited stage FL and results in 10-year overall survival rates of 60–80%; with a median survival is approximately 19 years . A dose of 24 Gy appears to be highly effective, with no benefit of higher doses . A recent phase III study showed 24 Gy to be superior to 2 Gy in disease control . However, most patients with stage I disease treated in the United States do not receive radiation therapy . Adjuvant chemotherapy has not been demonstrated to add additional benefit after local radiotherapy . If significant morbidity is possible from radiotherapy based on the location of the disease area or if the patient chooses to not receive radiation, observation may be a reasonable alternative, especially for stage II patients . In a large study of over 6,000 patients with stage I or stage II FL diagnosed from 1973 to 2004, 34% of whom were initially treated with RT, patients who received initial RT had higher rates of diseasespecific survival at 5 (90 vs. 81%), 10 (79 vs. 66%), 15 (68 vs. 57%), and 20 (63 vs. 51%) years . A recent retrospective analysis suggested an improved PFS outcome with chemoimmunotherapy or systemic therapy plus RT as compared to RT alone, with no impact on OS . This will require additional study. Selected early stage American Journal of Hematology, Vol. 90, No. 12, December 2015
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Freedman TABLE III. Phase III Trials of Chemotherapy versus Rituximab and Chemotherapy in Previously Untreated Patients with Follicular NHL Study Marcus  Hiddemann  Herold  Salles 
CVP vs. CVP-R CHOP vs. CHOP-R MCP vs. MCP-R CHVP vs. CHVP-R (1 interferon)
Improved OS Improved OS Improved OS Improved OS in high 3-5 FLIPI
patients can be observed without initial treatment with radiation. In one report, the median overall survival of selected untreated patients was 19 years. At a median follow-up of 7 years, 63% of patients had not required treatment .
Advanced stage The overwhelming majority of patients have advanced stage disease at diagnosis. Patients with asymptomatic FL do not require immediate treatment unless they have symptomatic nodal disease, compromised end organ function B symptoms; symptomatic extranodal disease, or cytopenias. This approach is supported by randomized prospective trials of observation versus immediate treatment. One of the largest trials compared immediate treatment with chlorambucil to observation . At a median follow-up of 16 years, no difference in overall survival and cause-specific survival was seen between the two approaches. Similar results have been noted in other prospective trials of initial treatment versus observation . A major question is whether rituximab might change this approach in early treatment in asymptomatic patients. A retrospective analysis of good risk patients who were either observed or received single agent rituximab  found no deleterious impact of watchful waiting. A prospective study compared observation to rituximab alone or rituximab followed by maintenance in previously untreated FL. No difference in overall survival or incidence of histologic transformation was seen . The important issues of time to second therapy, cost, toxicity, and future responses to rituximab are not yet addressed . A trial in a similar patient population randomized patients following four doses of weekly rituximab to either observation and retreatment at progression, or rituximab maintenance for 2 years. No difference in time to treatment failure, histologic transformation, or overall survival was seen, but more rituximab was administered to the maintenance arm. There was a difference in time to cytotoxic therapy, in favor of the maintenance rituximab receiving patients . Rituximab has changed the paradigm of treating FL. This improvement in survival is largely due to the use of anti-CD20 antibody based therapy . The benefit of adding rituximab to combination chemotherapy for the initial treatment has been demonstrated in multiple randomized trials of chemotherapy with or without rituximab (Table III) [51–55]. All of these trials have demonstrated improved response rates time to progression in the rituximab plus chemotherapy arms, as well as improvement in overall survival. [(18)F]Fluorodeoxyglucose positron emission tomography (PET) scanning has been employed to evaluate responses to CHOP-R in previously untreated patients. PET scanning was predictive when performed after 4 cycles, and at end of therapy. The 2 year PFS was significantly higher for PET negative than PET positive patients when employed as an interim or end of therapy scan. The 2 year overall survival was also significantly higher for PET negative than PET positive patients. This will require further study but may be change management in the future [56,57]. Although controversial, a recent study reported minimal residual disease detection and long-term outcome.
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The marker that was followed was the BCL-2/IGH translocation in the bone marrow . Other chemotherapy drugs plus rituximab have been reported and have changed the landscape of upfront treatment. Bendamustine plus rituximab (B-R) has been compared to CHOP-R in a randomized phase III trial in 513 patients with advanced follicular, indolent, and mantle cell lymphoma . BR had superior median progression-free survival (69.5 vs. 31.2 months) at 45 months, with less toxicity, including lower rates of grade 3 and 4 neutropenia and leukopenia was observed. There was no difference in overall survival at a median follow-up of 45 months. The BRIGHT study found BR to be noninferior to CHOP-R and CVP-R, with BR having a similar complete and overall response rates to the other regimens . These studies provide support for BR as the primary therapy for indolent follicular lymphoma. A randomized phase III trial compared initial treatment in previously untreated stage II-IV FL patients with R-CHOP or RCVP or R-fludarabine-mitoxantrone. Both R-FM and R-CHOP were superior to R-CVP in 3 year PFS and TTF but there was no difference in OS. The current impact of this study is uncertain given the results of the BR versus R-CHOP study . Rituximab alone has been used as the first therapy in patients with indolent lymphoma, with overall response rates of around 70% and CR rates of over 30% reported [62–64]. The most impressive data of single agent rituximab is the update of the SAKK trial . Patients received 4 weekly doses and then patients with stable disease or better were randomized to observation or 4 doses of maintenance with one dose every 2 months. In this study, 202 patients with previously untreated or relapsed/refractory FL administered 4 weekly doses of single agent rituximab has been reported. The 151 patients with responding or stable disease at week 12 were randomized to no further treatment or prolonged rituximab maintenance every 2 months for 4 doses. At a median follow-up of 35 months, patients who received the prolonged rituximab maintenance had a two fold increase in event-free-survival (23 vs. 12 months). Now with longer follow-up 35% of responders remain in remission at eight years with 45% of newly diagnosed patients in this study in remission at eight years with the additional maintenance rituximab. The use of maintenance rituximab after chemoimmunotherapy in patients with FL has been examined in a large randomized trial . While maintenance rituximab appears to improve progression-free survival rates, toxicities, albeit tolerable, are increased and the effect on overall survival is to date unclear. The Primary Rituximab and Maintenance (PRIMA) phase III intergroup trial in 1,018 patients with previously untreated FL responded to chemoimmunotherapy (CVP-R, CHOP-R, or FCM-R) randomly assigned maintenance with rituximab (375 mg/m2 every 8 weeks for 24 months) or placebo . At a median follow-up of 36 months from randomization, patients assigned to rituximab maintenance had a higher rates of progressionfree survival (75 vs. 58%). A higher percentage of patients in complete response/CRu at 24 months (72 vs. 52%) 2 years post randomization. There was a significantly higher percentage of patients with grade III/IV adverse events and infections in the rituximab maintenance group. At this time, overall survival is the same in both groups. Another randomized phase III trial using fludarabine, cyclophosphamide and mitoxantrone examined whether abbreviated maintenance with rituximab had clinical benefit in patients ages 60–75 with previously untreated FL . Rituximab maintenance did not have a statistically significant PFS benefit. Therefore, the role for maintenance with regimens besides CHOP-R or CVP-R remains uncertain. Radioimmunotherapy alone has been used as the initial treatment in a limited number of patients with FL . Two radioimmunotherapy agents have been studied; however, 131I tositumomab is no longer commercially available. (90)Yttrium-ibritumomab-tiuxetan has
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES also been studied as sole initial therapy with similar excellent results with limited follow up . Radioimmunotherapy has also been applied as consolidation following conventional chemotherapy induction in patients with FL. Results from a phase III trial comparing 90Yi-ibritumomab tiuxetan to observation following a CR or PR to induction chemotherapy for treatment na€ıve patients with FL has been reported . Of note, the majority of patients did not receive rituximab along with the induction chemotherapy. At 8 years, both the PR and CR patients who received Yi90-ibritumomab tiuxetan had significantly longer median progression-free survival with improvement of about 36 months. In contrast to this study a randomized trial of CHOP plus rituximab to CHOP followed by 131I tositumomab did not see any differences in PFS between the two arms . High dose therapy and autologous stem cell transplantation has been used to consolidate first remission for patients with FL. These studies generally preceded the widespread use of rituximab. Generally about 50% of patients are disease free at 10 or more years following ASCT, but the risk of second malignancies both MDS, AML, and solid tumors has been observed with long follow up of these patients. Several randomized trials have examined the role of ASCT in previously untreated patients with FL following an induction therapy [72–76]. The majority of these studies have demonstrated a significant improvement in PFS, but no impact on overall survival . One reason for the lack of impact on overall survival has been the excess number of second malignancies. Although allogeneic stem cell transplantation (HCT) can potentially lead to cure for patients with FL, due to the significant treatment related mortality, this is largely reserved for patients with relapsed and more refractory disease. Part of the natural history of indolent NHL is progression to a higher grade histologic subtype, such as diffuse large B-cell lymphoma [9,78]. A recent report found the risk to be 2% per year after diagnosis . A subgroup of patients with indolent NHL who transform to a more aggressive histology may attain complete remission following treatment with CHOP-like chemotherapy and some may be cured by high dose chemotherapy followed by autologous hematopoietic cell transplantation . Retrospective studies of patients with histologic transformation suggests that consolidation of remission following chemoimmunotherapy leads to a better outcome than chemoimmunotherapy alone, with 5 year overall survival of 55% versus 40% .
Treatment of relapsed FL 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 4 weekly doses of rituximab . Patients with either responding or stable disease at week 12 were randomized to observation or maintenance with one dose every 2 months for four doses. With long follow-up, 35% of responders remain in remission at 8 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. The combination of chemotherapy and rituximab has enhanced the efficacy of treatment of relapsed FL. Probably the largest study treated selected patients with relapsed FL who were previously not treated with an anthracycline or rituximab containing regimen .
Patients were randomized to CHOP or CHOP-R and responding patients were randomized to 2 years of maintenance rituximab or observation. The overall and CR rates were significantly improved in the CHOP-R group, and the median PFS was improved by approximately 12 months. A recent update of this study with a median follow-up of 6 years reported that maintenance rituximab also improved median progression-free survival by 2.4 years. The overall survival at 5 years following maintenance was 74% versus 64% with observation alone. Another regimen in which a benefit for the addition of rituximab was seen for relapsed disease in a randomized trial employing fludarabine, cyclophosphamide, and mitoxantrone (FCM) . A number of phase II trials of other agents plus rituximab associated with quite high response rates included bendamustine plus rituximab with 90% RR and median PFS of 2 years [83–85]. Single agent bendamustine has an overall response rate of 77 with a median response duration of 6.7 months . Anti-CD20 radioimmunotherapy agents have been used for treatment of patients with relapsed and refractory FL . The response rates in this patient population is 60–80%. 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 4 years [87,88]. 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 (e.g., total dose of 4 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% . The use of either autologous or allogeneic hematopoietic cell transplantation (HCT) in FL is controversial and the subject of numerous clinical trials . 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 experience prolong progression-free and overall survival rates [91–95]. Prior to the widespread use of rituximab for in vivo purging many strategies were taken to render the autologous stem cell collections free of lymphoma cells. Although single institution studies suggested that reinfusion of tumor free stem cells led to a decreased relapse rate, it remains controversial as to whether there is a benefit particularly now in the rituximab era. The only phase III randomized trial (the CUP trial) comparing ASCT to conventional chemotherapy in relapsed FL patients demonstrated a higher PFS and OS for ASCT, and no benefit for purging the stem cell graft . An retrospective analysis of patients undergoing ASCT following rituximab based salvage therapy did not suggest a benefit of ASCT as compared to conventional therapy. Unfortunately as has been seen in ASCT in first remission, second malignancies both solid tumors and MDS/AML are reported post ASCT. A recent phase III trial in patients with relapsed FL has investigated the inclusion of rituximab for in vivo purging pre-ASCT and 2 years of maintenance post-ASCT . There was an improvement in PFS for patients receiving rituximab for in vivo purging, maintenance and the combination of both as compared to no rituximab but no OS benefit. 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% . Enthusiasm for RIC allogeneic has lower treatment related mortality [99–101], but some reports suggest that the relapse rate may be higher than conventional myeloablative conditioning. The role of allogeneic SCT versus autologous SCT for American Journal of Hematology, Vol. 90, No. 12, December 2015
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FL remains uncertain. A recent NCCN database retrospective analysis found significantly higher 3 year OS for autologous SCT versus allogeneic SCT (87% versus 61%) . Certainly for younger patients with more resistant disease, allogeneic SCT remains a potentially curative option for relapsed FL.
䊏 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. Several new anti-CD20 monoclonal antibodies are being evaluated in patients with FL who are refractory to rituximab. These include several humanized antibodies which are designed to have less infusion toxicity and better ADCC effector function [103–105]. The other mAb that has been of interest is obinutuzumab, the first type II, glycoengineered and humanized monoclonal anti-CD20 antibody . In rituximab refractory pts in the high dose cohort, the RR was 55% with median PFS of 11.9 months. Studies of in obinutuzumab combination with chemotherapy, have shown 93–98% response rates in relapsed and refractory FL patients . A number of immunostimulatory agents have been studied to enhance the activity of rituximab [108–110]. To date, although having
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immunomodulatory effects, the impact on enhancing the therapeutic effect of rituximab has been limited. A phase II study of lenilidomide plus rituximab has reported high response rates, but phase III study will be needed to demonstrate superiority over rituximab alone . 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 [112,113]. 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 . 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, 3 kinase inhibitors, idelalisib, ibrutinib, and R788 which target PI3 kinase p110d, btk, and syk, respectively. In relapsed and refractory FL patients, idelalisib is the most active of these kinase inhibitors with overall response rate of 57%, and median duration of response was 12.5 months [115,116]. 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 currently being studied.
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