Annual Clinical Updates in Hematological Malignancies

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Follicular lymphoma: 2014 update on diagnosis and management

Corresponding Author

Arnold Freedman

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts

Correspondence to: Arnold Freedman, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. E-mail :[email protected]Search for more papers by this author

Arnold Freedman,

Corresponding Author

Arnold Freedman

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts

Correspondence to: Arnold Freedman, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. E-mail :[email protected]Search for more papers by this author

First published: 29 March 2014

https://doi.org/10.1002/ajh.23674

Citations: 47

Conflict of interest: Nothing to report

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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 lymphoadenopathy, 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 <12 g/dL, serum LDH > 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. 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. Am. J. Hematol. 89:430–436, 2014. © 2014 Wiley Periodicals, Inc.

Disease Overview and Clinical Presentation

Follicular lymphoma (FL) is the second most common lymphoma diagnosed in the United States and western Europe, approximately 35 percent of all non-Hodgkin lymphomas (NHLs), and 70 percent of indolent lymphomas 1. The median age at diagnosis of 60 years 2. The incidence is slightly increased among relatives of persons with FL 3.

FLs are malignant counterparts of normal germinal center B-cells 4. Approximately 85 percent 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 percent of FLs 5. More recent studies suggest that altered normal T cell function within the malignant microenvironment play a role in the pathobiology of the disease 6. This includes altered expression of genes, specifically upregulated PMCH, ETV1, and TNFRSF9, and altered T cell motility in vitro 7.

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 8.

Diagnosis

FL recapitulates normal germinal centers (GC) of secondary lymphoid follicles 4. 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 4 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 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 9.

Bone marrow involvement is very common with paratrabecular lymphoid aggregates 4. 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 10-12.

Risk Stratification

The two best measures of outcome are the FL international prognostic index (FLIPI) and tumor grade 13. There is also evidence that the characteristics 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 5 prognostic factors patient age, stage, number of involved nodal areas, serum lactate dehydrogenase, and hemoglobin 17. 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 18. Presently the current utility of the FLIPI2 model remains uncertain. Since the incorporation of rituximab into the mainsteam therapy of FL the FLIPI has continued to be a useful prognostic model (Table 2) 19, 20. The GELF criteria 21 includes parameters of tumor burden and clinical findings, is another model for risk stratification.

Table 1. Prognostic Models for Follicular Lymphoma

Follicular lymphoma International Prognostic Index (FLIPI)) 17

Age > 60

Serum LDH > ULN

Hgb < 12 g/dl

Stage III or IV

Number of nodal sites > 4

FLIPI2 18

Age >60 years

Bone marrow involvement

Hemoglobin level <12.0 g/dL

Greatest diameter of the largest involved node more than 6 cm

Serum beta-2 microglobulin level greater than the upper limit of normal

GELF (Groupe d'Etude des Lymphomes Folliculaires) criteria for high tumor burden 21

Any site > 7cm

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

Table 2. Follicular Lymphoma International Prognostic Index (FLIPI) [20]

Risk group	# Risk factors	2 year OS	2 year PFS
Low risk	0–1	98%	84%
Intermediate risk	2	94%	70%
High risk	3 or more	87%	42%

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 Grades 1 and 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 4, 22.

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) 23-25 In contrast to DLBCL, the relapse rate of FL Grade 3b is in some series is higher, but survival is longer 26. A recent series suggested similar outcome of Grades IIIa and IIIb cases, and no benefit for the inclusion of anthracyclines in the treatment regimen 27.

Investigation of the cellular microenvironment of FL has provided interesting insights into prognosis 14, 16, 28-35. 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.

Risk-Adapted Therapy

Early stage

Less than 10% of patients with FL have stage I/II disease 36. 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 ∼19 years 37. A dose of 24 Gy appears to be highly effective, with no benefit of higher doses 38. However, most patients with Stage I disease treated in the United States do not receive radiation therapy 36. Adjuvant chemotherapy has not been demonstrated to add additional benefit after local radiotherapy 39. 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 40.

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 disease-specific survival at 5 (90 versus 81%), 10 (79 versus 66%), 15 (68 versus 57%), and 20 (63 versus 51%) years 41. A recent retrospective analysis suggested an improved PFS outcome with chemoimmunotherapy or systemic therapy plus RT as compared with RT alone, with no impact on OS 42. This will require additional study. Selected early stage 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 40.

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 43. 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 21.

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 44. found no deleterious impact of watchful waiting. A prospective study compared observation to rituximab alone or rituximab followed by maintenance in previously untreated FL. The median time to next treatment was 34 months in the watch and wait patient but was not reached in the rituixmab treatment arm. The 3 years PFS was 33%, 80%, and 90% of the observed, rituximab, or R followed by maintenance patients, with 95% OS in all three groups. The important issues of time to second therapy, quality of life, impact on histologic transformation, cost, toxicity, and future responses to rituximab are not yet addressed 45.

Rituximab has changed the paradigm of treating FL. This improvement in survival is largely due to the use of anti-CD20 antibody based therapy 46. 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 3) 47-51. 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 52.

Table 3. Phase III Trials of Chemotherapy Versus Rituximab and Chemotherapy in Previously Untreated Patients with Follicular NHL

Study	Regimens	OS outcome
Marcus 50	CVP v CVP-R	Improved OS
Hiddemann 48	CHOP v CHOP-R	Improved OS
Herold 47	MCP v MCP-R	Improved OS
Salles 51	CHVP v CHVP-R (+ interferon)	improved OS in high 3–5 FLIPI

Other chemotherapy drugs plus rituximab have also been reported. Bendamustine plus rituximab (B-R) has been compared with CHOP-R in a randomized Phase III trial in 513 patients with advanced follicular, indolent, and mantle cell lymphoma 53. BR had superior median progression-free survival (69.5 versus 31.2 months) at 45 months, with less toxicity, including lower rates of Grades 3 and 4 neutropenia and leukopenia was observed. There was no difference in overall survival at a median follow-up of 45 months. Intensifying the schedule of R-CHOP from every 21 to every 14 days was also of no benefit 54. A randomized phase III trial compared initial treatment in previously untreated Stages II–IV FL patients with R-CHOP or R-CVP 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 55.

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 56-58. The most impressive data of single agent rituximab is the update of the SAKK trial 59. 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 versus 12 months). Now with longer follow-up 35% of responders remain in remission at 8 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 60. 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 60. At a median follow-up of 36 months from randomization, patients assigned to rituximab maintenance had a higher rates of progression-free survival (75 versus 58%). A higher percentage of patients in complete response/CRu at 24 months (72 versus 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 61. 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. 131I tositumomab was given to 76 previously untreated patients with FL. The overall and complete response rates of 95 and 75%, respectively, and at 5-years, the OS and PFS was 89 and 59%, respectively 62. 131I tositumomab is no longer commercially available. (90)Yttrium-ibritumomab-tiuxetan has also been studied as sole initial therapy with similar excellent results with limited follow up 63.

Radioimmunotherapy has also been applied as consolidation following conventional chemotherapy induction in patients with FL. Both 90Yi-ibritumomab tiuxetan and 131I-tositumomab have been studied. This approach has been associated with very high response rates, conversions of PR to CR, and well maintained responses 64-68. Results from a Phase III trial comparing 90Yi-ibritumomab tiuxetan to observation following a CR or PR to induction chemotherapy for treatment naïve patients with FL has been reported 69. 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 70.

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 yrs 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 71-75. The majority of these studies have demonstrated a significant improvement in PFS, but no impact on overall survival 76. 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 10, 11. A recent report found the risk to be 2% per year after diagnosis 12 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. More recent studies suggest that previously untreated patients with histologic transformation may experience prolonged remission with chemoimmunotherapy alone with ASCT.

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 59. Patients with either responding or stable disease at week 12 were randomized to observation or maintenance with one dose every 2 months for 4 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.

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 77, 78. 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 ∼12 months. A recent update of this study now 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 five 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) 79. 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 80-82. Single agent bendamustine has an overall response rate of 77 with a median response duration of 6.7 months 80.

Two anti-CD20 radioimmunotherapy agents are FDA approved for treatment of patients with relapsed and refractory FL 83. The response rates in this patient population is similar with both agents, with 60–80% of patients responding. The median progression-free survival is about 12 months, although the ∼20–37% of patients who achieve a CR have a median time to progression of approximately four years 84, 85. Of note, the 131I agent has been take off the market.

FL is extremely responsive to radiation therapy (RT); low dose RT (eg, 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% 86.

The use of either autologous or allogeneic hematopoietic cell transplantation (HCT) in FL is controversial and the subject of numerous clinical trials 87. A large number of Phase II studies prior to the availability of rituximab, involving high dose therapy and autologous HCT have shown that for ∼40% of patients with good performance status and chemosensitive relapsed disease may experience prolong progression-free and overall survival rates 88-92. 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 93. An retrospective analysis of patients undergoing ASCT following rituximab-based salvage therapy did not suggest a benefit of ASCT as compared with 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 94. 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% 95. Enthusiasm for RIC allogeneic has lower treatment related mortality 96-98, 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 3 year OS for autologous SCT versus allogeneic SCT (87% versus 61%) 99. 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.

Monoclonal antibodies directed against other B cell associated antigens as well as new anti-CD20 mAbs are being investigated in FL. The anti-CD40 mAb HCD122 has a ORR of 33% in relapsed FL patients 100. This antibody blocks the CD40-CD40 ligand signal from T cells and mediated ADCC. 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 101-103. The other mAb that has been of interest is obinutuzumab, the first Type II, glycoengineered and humanized monoclonal anti-CD20 antibody 104. 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 105.

A number of immunostimulatory agents have been studied to enhance the activity of rituximab 106-108. To date, although having 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 109.

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. The Favrille trial used rituximab for induction therapy. The median time to progression (TTP) was 9 months for the Idiotype-KLH vaccinated patients and 12.6 months in the control group (P = 0.019) 110. The Biovax study reported showing a 14 month improvement in PFS for the Id-KLH vaccinated patients as compared to control; however, the induction chemotherapy was intense and remissions had to be sustained for 12 months prior to initiation of vaccination 111. The final trial using the MyVax Id-KLH conjugate following CVP induction awaits final reporting, but preliminary reports found no advantage for idiotype vaccination. On the basis of these studies it is unlikely that 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, PCI-ibrutinib and R788 which target PI3 kinase p110δ, btk, and syk, respectively. In relapsed and refractory FL patients, the response rates to idelalisib 112, ibrutinib 113, and R788 114 were 62% (including other indolent NHLs besides FL, 27%, and 10%, respectively. 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.

References

1 A clinical evaluation of the International Lymphoma Study Group classification of non- Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 1997; 89: 3909–3918.
PubMed Web of Science® Google Scholar
2 Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: Clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 1998; 16: 2780–2795.
10.1200/JCO.1998.16.8.2780
CAS PubMed Web of Science® Google Scholar
3 Goldin LR, Bjorkholm M, Kristinsson SY, et al. Highly increased familial risks for specific lymphoma subtypes. Br J Haematol 2009; 146: 91–94.
10.1111/j.1365-2141.2009.07721.x
PubMed Web of Science® Google Scholar
4WHO Classification of tumours of haematopoietic and lymphoid tissues, IARC, 2008.
Google Scholar
5 Bodor C, Grossmann V, Popov N, et al. EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood 2013; 122: 3165–168.
10.1182/blood-2013-04-496893
CAS PubMed Web of Science® Google Scholar
6 Ansell SM. Malignant B cells at the helm in follicular lymphoma. J Clin Oncol 2013; 31: 2641–2642.
10.1200/JCO.2013.49.2165
CAS PubMed Web of Science® Google Scholar
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.
10.1200/JCO.2012.44.2137
CAS PubMed Web of Science® Google Scholar
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.
10.1200/JCO.2010.32.9193
PubMed Web of Science® Google Scholar
9 Ott G, Katzenberger T, Lohr A, et al. Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3. Blood 2002; 99: 3806–3812.
10.1182/blood.V99.10.3806
CAS PubMed Web of Science® Google Scholar
10 Freedman AS. Biology and management of histologic transformation of indolent lymphoma. Hematol Am Soc Hematol Educ Program 2005; 314–320.
10.1182/asheducation-2005.1.314
PubMed Google Scholar
11 Montoto S, Fitzgibbon J. Transformation of Indolent B-Cell Lymphomas. J Clin Oncol 2011; 29: 1827–1834.
10.1200/JCO.2010.32.7577
PubMed Web of Science® Google Scholar
12 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.
10.1200/JCO.2012.48.3990
PubMed Web of Science® Google Scholar
13 Relander T, Johnson NA, Farinha P, et al. Prognostic factors in follicular lymphoma. J Clin Oncol 2010; 28: 2902–2913.
10.1200/JCO.2009.26.1693
CAS PubMed Web of Science® Google Scholar
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 351: 2159–69, 2004.
10.1056/NEJMoa041869
CAS PubMed Web of Science® Google Scholar
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.
10.1182/blood-2004-06-2298
CAS PubMed Web of Science® Google Scholar
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.
10.1182/blood-2006-04-018218
CAS PubMed Web of Science® Google Scholar
17 Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood 2004; 104: 1258–1265.
10.1182/blood-2003-12-4434
CAS PubMed Web of Science® Google Scholar
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.
10.1200/JCO.2008.21.3991
PubMed Web of Science® Google Scholar
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 (R-CHOP) with respect to treatment outcome. Blood 2006; 108: 1504–108.
10.1182/blood-2006-01-013367
CAS PubMed Web of Science® Google Scholar
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 treated predominantly in community practices. Ann Oncol 2013; 24: 441–448.
10.1093/annonc/mds429
CAS PubMed Web of Science® Google Scholar
21 Brice P, Bastion Y, Lepage E, et al. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: A randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 1997; 15: 1110–1117.
10.1200/JCO.1997.15.3.1110
CAS PubMed Web of Science® Google Scholar
22 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.
10.1111/j.1365-2141.2011.08942.x
PubMed Web of Science® Google Scholar
23 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.
10.1200/JCO.1993.11.2.218
CAS PubMed Web of Science® Google Scholar
24 Hans CP, Weisenburger DD, Vose JM, et al. A significant diffuse component predicts for inferior survival in grade 3 follicular lymphoma, but cytologic subtypes do not predict survival. Blood 2003; 101: 2363–2367.
10.1182/blood-2002-07-2298
CAS PubMed Web of Science® Google Scholar
25 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: 2202–2207.
10.1182/blood.V93.7.2202
CAS PubMed Web of Science® Google Scholar
26 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.
10.1038/sj.bjc.6601006
CAS PubMed Web of Science® Google Scholar
27 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.
10.1093/annonc/mdq574
CAS PubMed Web of Science® Google Scholar
28 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.
10.1200/JCO.2006.06.4766
PubMed Web of Science® Google Scholar
29 Canioni D, Salles G, Mounier N, et al. High numbers of tumor-associated 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.
10.1200/JCO.2007.12.8298
CAS PubMed Web of Science® Google Scholar
30 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.
10.1182/blood-2005-04-1565
CAS PubMed Web of Science® Google Scholar
31 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.
10.1200/JCO.2006.06.1648
CAS PubMed Web of Science® Google Scholar
32 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.
10.1200/JCO.2006.10.5833
PubMed Web of Science® Google Scholar
33 Kuppers R. Prognosis in follicular lymphoma—It's in the microenvironment. N Engl J Med 2004; 351: 2152–2153.
10.1056/NEJMp048257
PubMed Web of Science® Google Scholar
34 Lee AM, Clear AJ, Calaminici M, et al. Number of CD4+ 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.
10.1200/JCO.2006.06.4642
CAS PubMed Web of Science® Google Scholar
35 Wahlin BE, Sander B, Christensson B, et al. CD8+ 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.
10.1158/1078-0432.CCR-06-1734
CAS PubMed Web of Science® Google Scholar
36 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.
10.1200/JCO.2011.40.6546
CAS PubMed Web of Science® Google Scholar
37 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.
10.1016/j.ijrobp.2005.08.010
PubMed Web of Science® Google Scholar
38 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.
10.1016/j.radonc.2011.05.013
PubMed Web of Science® Google Scholar
39 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.
10.1007/BF02990087
CAS PubMed Web of Science® Google Scholar
40 Advani R, Rosenberg SA, Horning SJ. Stage I and II follicular non-Hodgkin's lymphoma: long-term follow-up of no initial therapy. J Clin Oncol 2004; 22: 1454–1459.
10.1200/JCO.2004.10.086
PubMed Web of Science® Google Scholar
41 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.
10.1002/cncr.25149
PubMed Web of Science® Google Scholar
42 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.
10.1200/JCO.2011.40.6546
CAS PubMed Web of Science® Google Scholar
43 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.
10.1016/S0140-6736(03)14110-4
CAS PubMed Web of Science® Google Scholar
44 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.
10.1200/JCO.2010.33.4474
PubMed Web of Science® Google Scholar
45 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, 2 and 3a). A preliminary analysis. Blood 2010; 116:abstract 6.
10.1182/blood.V116.21.6.6
Web of Science® Google Scholar
46 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.
10.1200/JCO.2005.03.1674
CAS PubMed Web of Science® Google Scholar
47 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.
10.1200/JCO.2006.06.4618
CAS PubMed Web of Science® Google Scholar
48 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.
10.1182/blood-2005-01-0016
CAS PubMed Web of Science® Google Scholar
49 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.
10.1182/blood-2004-08-3175
CAS PubMed Web of Science® Google Scholar
50 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.
10.1200/JCO.2007.13.5376
CAS PubMed Web of Science® Google Scholar
51 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.
10.1182/blood-2008-04-153189
CAS PubMed Web of Science® Google Scholar
52 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.
10.1200/JCO.2012.43.0934
CAS PubMed Web of Science® Google Scholar
53 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 3 non-inferiority trial. Lancet 2013; 381: 1203–1210.
10.1016/S0140-6736(12)61763-2
CAS PubMed Web of Science® Google Scholar
54 Watanabe T, Tobinai K, Shibata T, et al. Phase II/III study of R-CHOP-21 versus R-CHOP-14 for untreated indolent B-cell non-Hodgkin's lymphoma: JCOG 0203 trial. J Clin Oncol 2011; 29: 3990–3998.
10.1200/JCO.2011.34.8508
PubMed Web of Science® Google Scholar
55 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.
10.1200/JCO.2012.45.0866
CAS PubMed Web of Science® Google Scholar
56 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.
10.1182/blood.V97.1.101
CAS PubMed Web of Science® Google Scholar
57 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 4 schedule. Blood 2004; 103: 4416–4423.
10.1182/blood-2003-10-3411
CAS PubMed Web of Science® Google Scholar
58 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.
10.1200/JCO.2005.12.052
CAS PubMed Web of Science® Google Scholar
59 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.
10.1200/JCO.2010.28.4786
CAS PubMed Web of Science® Google Scholar
60 Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): A phase 3, randomised controlled trial. Lancet 2011; 377: 42–51.
10.1016/S0140-6736(10)62175-7
CAS PubMed Web of Science® Google Scholar
61 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.
10.1200/JCO.2012.44.8290
CAS PubMed Web of Science® Google Scholar
62 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.
10.1056/NEJMoa041511
CAS PubMed Web of Science® Google Scholar
63 Scholz CW, Pinto A, Linkesch W, et al. (90)Yttrium-ibritumomab-tiuxetan 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.
10.1200/JCO.2011.41.1553
CAS PubMed Web of Science® Google Scholar
64 Zinzani PL, Tani M, Pulsoni A, et al. Fludarabine and mitoxantrone followed by yttrium-90 ibritumomab tiuxetan in previously untreated patients with follicular non-Hodgkin lymphoma trial: a phase II non-randomised trial (FLUMIZ). Lancet Oncol 2008; 9: 352–358.
10.1016/S1470-2045(08)70039-1
CAS PubMed Web of Science® Google Scholar
65 Jacobs SA, Swerdlow SH, Kant J, et al. Phase II trial of short-course CHOP-R followed by 90Y-ibritumomab tiuxetan and extended rituximab in previously untreated follicular lymphoma. Clin Cancer Res 2008; 14: 7088–7094.
10.1158/1078-0432.CCR-08-0529
CAS PubMed Web of Science® Google Scholar
66 Leonard JP, Coleman M, Kostakoglu L, et al. Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma. J Clin Oncol 2005; 23: 5696–5704.
10.1200/JCO.2005.14.803
CAS PubMed Web of Science® Google Scholar
67 Press OW, Unger JM, Braziel RM, et al. Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin's lymphoma: Five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol 2006; 24: 4143–4149.
10.1200/JCO.2006.05.8198
CAS PubMed Web of Science® Google Scholar
68 Link BK, Martin P, Kaminski MS, et al. Cyclophosphamide, vincristine, and prednisone followed by tositumomab and iodine-131-tositumomab in patients with untreated low-grade follicular lymphoma: Eight-year follow-up of a multicenter phase II study. J Clin Oncol 2010; 28: 3035–3041.
10.1200/JCO.2009.27.8325
CAS PubMed Web of Science® Google Scholar
69 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.
10.1200/JCO.2012.45.6400
CAS PubMed Web of Science® Google Scholar
70 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.
10.1200/JCO.2012.42.4101
CAS PubMed Web of Science® Google Scholar
71 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.
10.1182/blood-2004-10-3920
CAS PubMed Web of Science® Google Scholar
72 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 Low-Grade Lymphoma Study Group. Blood 2004; 104: 2667–2674.
10.1182/blood-2004-03-0982
CAS PubMed Web of Science® Google Scholar
73 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 from the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood 2006; 108: 2540–2544.
10.1182/blood-2006-03-013193
CAS PubMed Web of Science® Google Scholar
74 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 R-HDS does not translate into an overall survival advantage. Blood 2008; 111: 4004–4013.
10.1182/blood-2007-10-116749
CAS PubMed Web of Science® Google Scholar
75 Gyan E, Foussard C, Bertrand P, 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 the GOELAMS with final results after a median follow-up of 9 years. Blood 2009; 113: 995–1001.
10.1182/blood-2008-05-160200
CAS PubMed Web of Science® Google Scholar
76 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.
10.1093/jnci/djr450
PubMed Web of Science® Google Scholar
77 van Oers MH, Klasa R, Marcus RE, et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: Results of a prospective randomized phase 3 intergroup trial. Blood 2006; 108: 3295–3301.
10.1182/blood-2006-05-021113
CAS PubMed Web of Science® Google Scholar
78 van Oers MH, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: Long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol 2010; 28: 2853–2858.
10.1200/JCO.2009.26.5827
CAS PubMed Web of Science® Google Scholar
79 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.
10.1182/blood-2004-04-1323
CAS PubMed Web of Science® Google Scholar
80 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.
10.1200/JCO.2007.12.5070
CAS PubMed Web of Science® Google Scholar
81 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.
10.1200/JCO.2008.17.0001
CAS PubMed Web of Science® Google Scholar
82 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.
10.1200/JCO.2005.08.100
CAS PubMed Web of Science® Google Scholar
83 Cheson BD. Radioimmunotherapy of non-Hodgkin lymphomas. Blood 2003; 101: 391–398.
10.1182/blood-2002-06-1793
CAS PubMed Web of Science® Google Scholar
84 Fisher RI, Kaminski MS, Wahl RL, et al. Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin's lymphomas. J Clin Oncol 2005; 23: 7565–7573.
10.1200/JCO.2004.00.9217
CAS PubMed Web of Science® Google Scholar
85 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.
10.1002/cncr.22617
CAS PubMed Web of Science® Google Scholar
86 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.
10.1016/j.ijrobp.2012.12.024
PubMed Web of Science® Google Scholar
87 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.
10.3324/haematol.2013.084723
PubMed Web of Science® Google Scholar
88 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.
10.1200/JCO.2006.09.8327
PubMed Web of Science® Google Scholar
89 Bierman PJ, Vose JM, Anderson JR, et al. High-dose therapy with autologous hematopoietic rescue for follicular low-grade non-Hodgkin's lymphoma. J Clin Oncol 1997; 15: 445–450.
10.1200/JCO.1997.15.2.445
CAS PubMed Web of Science® Google Scholar
90 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.
10.1053/bbmt.2001.v7.pm11400952
CAS PubMed Web of Science® Google Scholar
91 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: 183.
Web of Science® Google Scholar
92 Bastion Y, Brice P, Haioun C, et al. Intensive therapy with peripheral blood progenitor cell transplantation in 60 patients with poor-prognosis follicular lymphoma. Blood 1995; 86: 3257–3262.
10.1182/blood.V86.8.3257.3257
CAS PubMed Web of Science® Google Scholar
93 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.
10.1200/JCO.2003.10.023
CAS PubMed Web of Science® Google Scholar
94 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.
10.1200/JCO.2012.47.1862
CAS PubMed Web of Science® Google Scholar
95 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.
10.1182/blood-2003-04-1205
CAS PubMed Web of Science® Google Scholar
96 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.
10.1182/blood-2008-01-136242
CAS PubMed Web of Science® Google Scholar
97 Hari P, Carreras J, Zhang MJ, et al. Allogeneic transplants in follicular lymphoma: Higher risk of disease progression after reduced-intensity compared to myeloablative conditioning. Biol Blood Marrow Transplant 2008; 14: 236–45.
10.1016/j.bbmt.2007.11.004
PubMed Web of Science® Google Scholar
98 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: 1051–1057.
10.1016/j.bbmt.2010.11.004
PubMed Web of Science® Google Scholar
99 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.
10.1002/cncr.28243
CAS PubMed Web of Science® Google Scholar
100 Fanale M, Assouline S, Kuruvilla J, et al. Phase IA/II, multicentre, open-label study of the CD40 antagonistic monoclonal antibody Lucatumumab in adult patients with advanced non-Hodgkin or Hodgkin lymphoma. Br J Haematol 2014; 164: 258–265.
10.1111/bjh.12630
CAS PubMed Web of Science® Google Scholar
101 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 1/2 trial. Blood 2008; 111: 5486–5495.
10.1182/blood-2007-10-117671
CAS PubMed Web of Science® Google Scholar
102 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.
10.1200/JCO.2008.19.9117
CAS PubMed Web of Science® Google Scholar
103 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.
10.1093/annonc/mdq027
CAS PubMed Web of Science® Google Scholar
104 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.
10.1200/JCO.2012.46.9718
CAS PubMed Web of Science® Google Scholar
105 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.
10.1182/blood-2013-01-481341
CAS PubMed Web of Science® Google Scholar
106 Friedberg JW, Neuberg D, Gribben JG, et al. Combination immunotherapy with rituximab and interleukin 2 in patients with relapsed or refractory follicular non-Hodgkin's lymphoma. Br J Haematol 2002; 117: 828–834.
10.1046/j.1365-2141.2002.03535.x
CAS PubMed Web of Science® Google Scholar
107 Friedberg JW, Kelly JL, Neuberg D, et al. Phase II study of a TLR-9 agonist (1018 ISS) with rituximab in patients with relapsed or refractory follicular lymphoma. Br J Haematol 2009; 146: 282–291.
10.1111/j.1365-2141.2009.07773.x
CAS PubMed Web of Science® Google Scholar
108 Friedberg JW, Kim H, McCauley M, et al. Combination immunotherapy with a CpG oligonucleotide (1018 ISS) and rituximab in patients with non-Hodgkin lymphoma: Increased interferon-alpha/beta-inducible gene expression, without significant toxicity. Blood 2005; 105: 489–495.
10.1182/blood-2004-06-2156
CAS PubMed Web of Science® Google Scholar
109 Friedberg JW. Treatment of follicular non-Hodgkin's lymphoma: The old and the new. Semin Hematol 2008; 45: S2–S6.
10.1053/j.seminhematol.2008.07.003
CAS PubMed Web of Science® Google Scholar
110 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.
10.1200/JCO.2008.19.8903
CAS PubMed Web of Science® Google Scholar
111 Schuster SJ, Neelapu SS, Gause BL, et al. Vaccination with patient-specific tumor-derived antigen in first remission improves disease-free survival in follicular lymphoma. J Clin Oncol 2011; 29: 2787–2794.
10.1200/JCO.2010.33.3005
CAS PubMed Web of Science® Google Scholar
112 Kahl B, Byrd J, Flinn I, et al. Clinical safety and activity in a phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110δ, in patients with relapsed or refractory non-hodgkin lymphoma. Blood 2010; 116:abstract 1777.
CAS PubMed Web of Science® Google Scholar
113 Fowler F, Porte Sharman J, Smith S, et al. The Btk inhibitor, PCI-32765, induces durable responses with minimal toxicity in patients with relapsed/refractory B-cell malignancies: Results from a phase I STUDY. Blood 2010; 116:abstract 964.
PubMed Web of Science® Google Scholar
114 Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010; 115: 2578–2585.
10.1182/blood-2009-08-236471
CAS PubMed Web of Science® Google Scholar

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Volume89, Issue4

April 2014

Pages 429-436

Follicular lymphoma: 2014 update on diagnosis and management

Abstract

Disease overview

Diagnosis

Risk stratification

Risk-adapted therapy

Disease Overview and Clinical Presentation

Diagnosis

Risk Stratification

Risk-Adapted Therapy

Early stage

Advanced stage

Treatment of relapsed FL

Newer agents

References

Citing Literature

References

Information

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Follicular lymphoma: 2014 update on diagnosis and management

Abstract

Disease overview

Diagnosis

Risk stratification

Risk-adapted therapy

Disease Overview and Clinical Presentation

Diagnosis

Risk Stratification

Risk-Adapted Therapy

Early stage

Advanced stage

Treatment of relapsed FL

Newer agents

References

Citing Literature

References

Related

Information