Follicular Lymphoma: Current Management and Future Directions

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1 Treatment decisions and outcomes for patients with follicular lymphoma may be improved with newer diagnostic tests and novel targeted agents. George Van Hook. Barns in Summer. Oil on linen, Follicular Lymphoma: Current Management and Future Directions Celeste Bello, MD, MSPH, Ling Zhang, MD, and Mojdeh Naghashpour, MD, PhD Background: Follicular lymphomas (FLs) are a heterogeneous group of lymphomas. No standard of care exists, and the management of these patients is highly individualized. Methods: After reviewing the scientific literature pertaining to the prognosis and management of FLs, we describe recent developments in treatment and discuss future trends in the care of patients with this disease. Results: With the exception of a subset of patients with limited-stage FL treated with radiation therapy, no curative treatment exists for the majority of patients with FL. The decision on when to start treatment is based on the presence of symptoms, bulky disease, or abnormalities in hematologic parameters that can be attributed to FL. Prognostic scoring systems such as the Follicular Lymphoma International Prognostic Index help in assessing prognosis but do not contribute to the decision on when to start treatment. There are numerous effective chemotherapeutic regimens for the treatment of advanced-stage FL, but none show a definitive improvement in overall survival. Maintenance and consolidation regimens have also been shown to be effective treatments of FL, with significant improvements in progression-free survival and possibly overall survival. Conclusions: Newer prognostic tests are in development that may help to guide the decision on which patients may benefit from early treatment. In addition, newer targeted agents that may improve on existing outcomes with less toxicity are currently being evaluated. From the Departments of Malignant Hematology (CB) and Hematopathology (LZ, MN) at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida. Submitted July 6, 2011; accepted January 29, Address correspondence to Celeste Bello, MD, MSPH, Department of Malignant Hematology, Moffitt Cancer Center, Magnolia Drive, FOB-3 HEM PROG, Tampa, FL Celeste Bello@ moffitt.org No significant relationship exists between the authors and the companies/organizations whose products or services may be referenced in this article. The authors have disclosed that this article discusses unlabeled/ unapproved uses of the drugs ofatumumab, epratuzumab, and lenalidomide for follicular lymphoma. Introduction For the most part, follicular lymphoma (FL) is considered an indolent type of non-hodgkin lymphoma (NHL). It comprises about 20% of all NHLs and is the most common subtype of indolent NHL. 1 The disease is characterized by a relapsing and remitting pattern, with mainly nodal and bone marrow involvement. This results in a chronic illness, which is managed with close observation and chemotherapy when appropriate. No consensus on the optimal treatment of FL exists, and it remains essentially an incurable disease. Much heterogeneity exists within the FL category. World Health Organization (WHO) histologic grades 1 and 2 are considered the indolent subtypes, and grade 3 is considered the more aggressive subtype (both 3a July 2012, Vol. 19, No. 3 Cancer Control 187

2 and 3b). 2 These categories are defined by the presence and histologic appearance of centroblasts (Figs 1 and 2). Variability in the behavior of the lymphoma exists even within a specific grade. Several prognostic features have been evaluated to better categorize the disease, with varied results. With no gold standard of therapy, several treatment regimens can be considered when determining which chemotherapy to use for patients with FL. Some of the more common regimens include cyclophosphamide-based treatments (such as cyclophosphamide, vincristine, and prednisone plus rituximab [R-CVP] and cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab [R-CHOP]), rituximab alone or in combination chemotherapy, bendamustine, and fludarabine-based treatments. Radioimmunotherapy A B Fig 1A-B. (A) Low-powered view of abnormal follicular proliferation arranged in a back-to-back pattern. (B) Low-grade follicular lymphoma (< 15 centroblasts/high-powered fi eld). CD10 A B BCL2 BCL6 C Fig 2A-D. Follicular lymphoma grade 3. (A) Neoplastic follicles of varying size with diminished mantle zones, lacking tingible body macrophages and composed of small and large centrocytes and centroblasts, > 15/high-powered fi eld (inset). (B) Neoplastic follicles positive for CD10, (C) BCL2, and (D) BCL6. D 188 Cancer Control July 2012, Vol. 19, No. 3

3 is also an effective treatment option in the upfront or relapsed setting. Despite these numerous treatment options, no one regimen has been shown to be superior with regard to overall survival (OS). As a result, management of patients with FL varies among clinical practices. Several advances in identifying prognostic markers and in treating FL have been made in the past few years. This article reviews the utility of certain prognostic markers with regard to the current management of FL as well as current and emerging therapies. Pathogenesis FL arises from germinal center B cells of lymphoid follicles. Almost all FLs carry breaks at 18q21, with approximately 85% of them having a translocation involving chromosomes 14 and 18 [t(14;18)(q32;q21)]. 3 This translocation results in the juxtaposition of the oncogene B-cell leukemia-lymphoma 2 (BCL-2) on chromosome 18, with the immunoglobulin heavy-chain locus on chromosome 14. This leads to the overexpression of BCL-2, which blocks apoptosis and gives the cells a survival advantage. 4 Although the overexpression of BCL-2 appears to play a major role in the pathogenesis of FL, it does not explain the entire pathogenesis of the disease, as demonstrated in a study showing that the t(14;18) can be detected in healthy individuals without FL. 5 Other factors such as chronic antigen stimulation, other genetic lesions, and the tumor microenvironment may play an additional necessary role in the pathogenesis of FL. 6-8 Prognostic Factors Over the past few years, several prognostic factors have been identified in FL. In 2004, observations from an international cooperative group study resulted in the formation of the Follicular Lymphoma International Prognostic Index (FLIPI). 9 The following five characteristics at diagnosis were found to correlate with a poor prognosis: age > 60 years, Ann Arbor stage III IV, hemoglobin level < 12 g/dl, more than 4 nodal areas, and serum lactate dehydrogenase (LDH) level above normal. Based on the presence or absence of these factors, patients were stratified into three risk groups (low, intermediate, or high), which correlated with OS (Table 1). The FLIPI is an effective and easy-to-use tool to categorize patients with FL, but it has limitations, the most important being that it does not predict which patients need treatment or when they need treatment. A more recent evaluation looked at a second prognostic index called the FLIPI-2. This study evaluated 942 patients with newly diagnosed FL who received immunochemotherapy. 10 The following factors were found to be significant and were included in the scoring index: age > 60 years, hemoglobin level < 12 g/dl, dimension of largest involved lymph node > 6 cm, beta-2 microglobulin level > normal, and bone marrow involvement. Based on the presence of these factors, patients were classified into one of three different risk categories for relapse: low, intermediate, or high. The FLIPI-2 was found to be predictive of treatment outcomes in patients with newly diagnosed FL who received immunochemotherapy. However, like the initial FLIPI, the FLIPI-2 does not predict when to initiate treatment and which treatment to use. Genetic alterations have been shown to predict prognosis in certain cases of FLs. Mutations involving p53 were found to correlate with survival. 11 These mutations were rare at the time of diagnosis, occurring in only 6% of the patients tested. However, this small group had an inferior OS and progression-free survival (PFS) compared with those with wild-type p53. Transformation of FL to a large-cell lymphoma has also been noted with specific genetic alterations. A recent study showed that single nucleotide polymorphisms (SNPs) on chromosome 6p can predict transformation independent of other variables, including those noted in the FLIPI. 12 In this study, patients with a variant allele of SNP rs had a shorter time from diagnosis to transformation and a higher risk of transformation compared with other genotypes. The lymphoma microenvironment has also been found to affect disease prognosis. Gene expression profiling and immunohistochemical evaluation of the nonlymphoma cells in the FL microenvironment have been shown to correlate with survival. Cells such as dendritic cells, macrophages, and T-helper/regulatory cells seem to play a major role. In a study performed by Dave et al, 8 gene expression profiling of the nonlymphoma cells in the microenvironment made it possible to categorize patients with FL into two distinct groups: immune-response 1 signature and immune-response 2 signature. Immune signature-1 en- Table 1. Follicular Lymphoma International Prognostic Index (FLIPI), Score, and 5-Year Survival Factors Age > 60 yrs LDH level > normal Hemoglobin level < 12 g/dl Ann Arbor stage III or IV Nodal sites > 4 FLIPI Score (No. of Factors) 0 1 = Low risk 2 = Intermediate risk 3 = High risk 5-Yr Overall Survival Low risk = 91% Intermediate risk = 78% High risk = 53% Adapted from Solal-Céligny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. 2004;104(5): Blood: Journal of the American Society of Hematology by American Society of Hematology; High- Wire Press Copyright Reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY (ASH) in the format Journal via Copyright Clearance Center. LDH = lactate dehydrogenase. July 2012, Vol. 19, No. 3 Cancer Control 189

4 coded genes were expressed in T cells and macrophages, whereas immune signature-2 encoded genes were expressed in macrophages and dendritic cells. Patients with an increased expression of immune-response 1 appeared to have a favorable survival, with a relative risk of death of 0.15 compared with 9.35 for those with an increased expression of immune-response 2. Another study evaluating the FL microenvironment through immunohistochemistry patterns showed that the presence of certain nonlymphoma cells correlated with more aggressive clinical features. 13 The study found two specific patterns in the reactive microenvironment. The first pattern was mainly composed of T lymphocytes and macrophages and was significantly associated with a favorable clinical course. The second pattern was predominantly composed of CD57+ T cells (natural killer cells) and was associated with a significantly higher frequency of adverse features such as B symptoms and bone marrow involvement. Despite these prognostic markers and tools, the decision to treat patients with FL is still based largely on comorbidities, symptoms, and patient preference. It remains a decision that is highly individualized and based mainly on clinical judgment. Treatment Frontline Treatments Treatment of FL has evolved over the past few decades. Several regimens have demonstrated efficacy in improving PFS and time until treatment failure. In addition, maintenance and consolidation treatments have been shown to improve outcomes in patients with low-grade FLs. The decision to treat patients is based largely on histologic grade and the extent of disease. Generally, grade 3 FLs are treated like diffuse large B-cell lymphomas. For grades 1 and 2, the decision to treat is not as clear. For the purpose of this section of the article, treatments of FL refer to low-grade lymphomas. For localized disease (Ann Arbor stage I II), locoregional radiation therapy (RT) is the preferred method of treatment (Fig 3). A subset of these patients may even be cured with RT alone. A study evaluating 106 patients with localized disease who received RT had a freedom-from-treatment failure rate of 39% at 15 years. 14 Observation is also an option in patients who may develop excessive toxicities from RT due to the location of the lymphoma or patient comorbidities. Advanced disease (Ann Arbor stage III IV or extensive stage II) is not curable with conventional treat- Low-Grade (Grade 1 2) Follicular Lymphoma Stage IA or Limited Stage IIA Advanced Stage (Stage III/IV) or B symptoms Curative intent XRT Observation if asymptomatic. If symptomatic, see Advanced Stage Asymptomatic, nonbulky disease Symptomatic or bulky disease Observe Chemotherapy/ immunotherapy No response CR or PR Repeat biopsy to confi rm diagnosis Consolidation with RIT or maintenance rituximab Fig 3. Algorithm for frontline treatment of follicular lymphoma. CR = complete response, PR = partial response, RIT = radioimmunotherapy, XRT = radiotherapy. 190 Cancer Control July 2012, Vol. 19, No. 3

5 ments. For that reason, treatment is usually reserved for patients who are symptomatic or who have bulky disease (Fig 3). Systemic chemotherapy is the preferred method of treatment for advanced disease, with RT reserved for bulky refractory areas or palliation. Determining which systemic treatment is optimal and at which dose are matters of debate. Immunotherapy with rituximab alone or combined with chemotherapy has demonstrated good results with regard to PFS and, in some instances, OS. Singleagent rituximab in treatment-naive patients with FL has yielded an overall response rate (ORR) of 72% to 73%, with a median time to disease progression of just over 2 years. 15,16 In the relapsed setting, rituximab has yielded an ORR of 40%, with a median time to disease progression of about 18 months. 17 In addition to being an effective therapy for FL, rituximab has a low toxicity profile and is tolerated well, even in elderly patients. It also seems to improve the outcomes of certain chemotherapies when added to the regimen. Several chemotherapeutic regimens when combined with rituximab have shown significant efficacy in the frontline setting (Table 2) One example is a phase III study by Hiddemann et al, 19 which showed that R-CHOP was superior to CHOP alone. In this study, 428 patients with previously untreated stage III or IV FL were randomized to receive R-CHOP or CHOP for 6 cycles; the ORR was 96% and 90%, respectively. However, the time to treatment failure was significantly better in the R-CHOP group than in the CHOP group. At a median follow-up of 18 months, 12.5% of patients in the R-CHOP group experienced treatment failure compared with 30% of the CHOP group (P <.001). Another example is a study performed by Marcus et al 18 comparing R-CVP with CVP alone. Patients in the R-CVP treatment group had an ORR of 81% and a median time to disease progression of 34 months compared with 57% and 15 months, respectively, for the CVP-alone group. Several chemotherapy regimens have shown efficacy in the treatment of FL in the frontline setting, and the decision of which one to use requires a balance of risks and benefits. Regimens such as rituximab plus fludarabine, mitoxantrone, and dexamethasone (R-FND), bendamustine and rituximab (BR), R-CHOP, and R-CVP have all been shown to be effective. Since the majority of these regimens have not been compared in a head-to-head study, determining which one is superior is challenging. The exception to this is a study done by Rummel et al 20 evaluating R-CHOP vs BR. This study evaluated 549 patients with previously untreated indolent NHL or mantle cell lymphoma. Approximately 55% of these patients had FL. The ORR was essentially equal between the two groups (93.8% for BR vs 93.5% for R-CHOP). However, the PFS was significantly better in the BR group, with a median PFS of 55 months vs 35 months for the R-CHOP group (P =.0002). In addition, the tolerability profile was better in the BR group than in the R-CHOP group. Radioimmunotherapy with yttrium-90 ( 90 Y)-ibritumomab tiuxetan and iodine-131 ( 131 I)-tositumomab has also been shown to be effective in the frontline FL setting. 131 I-tositumomab was evaluated in 76 patients with previously untreated stages III and IV FL. 22 After a single 1-week course of treatment, the ORR was 95%, with a 75% complete remission (CR) rate. The median PFS was 6.1 years. In a follow-up analysis, after a median of 10 years of follow-up, the median duration of response was still around 6 years. 23 However, in the 57 complete responders, the median PFS was 10.9 years. A similar study evaluating 90 Y-ibritumomab tiuxetan in 59 patients with previously untreated FL is underway. 24 At 1 year, the ORR was 72%, with 52% obtaining a CR. Long-term follow-up results have not been reported yet, but at a median follow-up of 23 months, the PFS was approximately 18 months. Table 2. Summary of Studies Evaluating Frontline Chemotherapy in Follicular Lymphoma Trial No. of Patients Regimen Tested Overall Response Rate Median Response Duration Marcus et al 18 (2008) 321 R-CVP vs CVP 81% R-CVP 57% CVP (P <.0001) Hiddemann et al 19 (2005) 428 R-CHOP vs CHOP 96% R-CHOP 90% CHOP (P <.01) 34 mos TTP R-CVP 15 mos TTP CVP (P <.0001) Not reported Tsimberidou et al 21 (2002) 73 FMD with interferon-α 97% Not reported Rummel et al 20 (2009) 549 BR vs R-CHOP 93.8% BR 93.5% R-CHOP 55 mos PFS BR 35 mos PFS R-CHOP BR = bendamustine, rituximab, CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone, CVP = cyclophosphamide, vincristine, prednisone, FMD = fl udarabine, mitoxantrone, dexamethasone, PFS = progression-free survival, R-CHOP = rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone, R-CVP = rituximab-cyclophosphamide, vincristine, prednisone, TTP = time to disease progression. July 2012, Vol. 19, No. 3 Cancer Control 191

6 Consolidation and Maintenance Treatments Consolidation treatment has been shown to be beneficial in patients with advanced stages of FL. Consolidation treatment with radioimmunotherapy in previously untreated patients with FL was evaluated in a phase III study called the First-line Indolent Trial (FIT). 25 This study randomized patients who obtained CR or partial remission (PR) with a frontline regimen to receive further treatment with 90 Y-ibritumomab tiuxetan or observation. Those who received radioimmunotherapy had a median PFS of 36.5 months vs 13.3 months for the observation group. Those who obtained CR to the initial chemotherapy had an even better response to consolidation treatment with 90 Y-ibritumomab tiuxetan, with a median PFS of 54 months. An updated analysis after a median follow-up of 5.5 years showed that the median PFS for all patients who received 90 Y-ibritumomab tiuxetan improved to 49 months compared with 14 months for the control group. 26 In addition, in this updated analysis, the median PFS had not yet been reached in those patients who received 90 Y- ibritumomab tiuxetan after obtaining CR to the initial therapy. There was no difference in OS in the initial study or in the 5.5-year follow-up analysis. Only 14% of the patients in this study received rituximab as part of the frontline therapy. On a similar note, maintenance therapy with rituximab has also been shown to be beneficial in patients with FL. The Primary Rituximab and Maintenance (PRI- MA) study assessed the use of rituximab maintenance in patients with previously untreated FL. 27 These patients received an induction regimen with chemotherapy plus rituximab. Those who obtained CR or PR were randomized to either observation or rituximab (1 dose every 2 months for 2 years). The 3-year PFS rate was found to be about 75% in the rituximab maintenance group compared with approximately 58% for the observation group. At a median follow-up of 36 months, the median time to disease progression in the maintenance group had not yet been reached at the time the study was published. In addition to the PRIMA study, several other studies using maintenance rituximab at varying schedules have shown similar results (Table 3) A meta-analysis published in 2009 summarizes these findings and supports the use of maintenance rituximab, with an across-theboard improvement in PFS and an improvement in OS in a pooled analysis. 33 Treatment for Relapsed/Refractory Disease Relapsed FL does not necessarily require immediate treatment. The principles on when to initiate treatment in the frontline setting apply in the relapsed setting as well, and the majority of asymptomatic patients can be observed. When feasible, a rebiopsy should be performed to rule out transformation, especially in symptomatic patients. Since there is no standard of therapy, numerous treatment options exist, and patients who require treatment should be encouraged to enroll in a clinical trial if available. The regimens previously mentioned in the frontline setting are all options in the relapsed/refractory setting. Based on prior response to therapy, rechallenging with the initial therapy can be considered. In general, treatment of relapsed/refractory disease is based on patient and tumor characteristics and must be individualized on a patient-by-patient case. Stem Cell Transplantation The benefit of high-dose therapy followed by autologous stem cell transplant (HDT/ASCT) in FL is debatable. Several studies have shown an improvement in PFS and OS, but these studies were conducted prior to the rituximab era. A study by the Groupe d Etude des Lymphomes de l Adulte (GELA) evaluating HDT/ASCT after salvage chemotherapy with or without rituximab Table 3. Summary of Studies Evaluating Maintenance Rituximab Trial No. of Patients Type of Lymphoma Type of Induction Response to Induction Maintenance Rituximab Hainsworth et al 28 (2005) 90 Relapsed FL, SLL Rituximab SD/CR/PR Weekly 4 every 6 mos 2 yrs Hochster et al 29 (2005) 304 Untreated FL, SLL CVP CR/PR Weekly 4 every 6 mos 2 yrs Forstpointner et al 30 (2006) 195 Relapsed FL, mantle cell FMC ± R SD/CR/PR Weekly 4 at 3 and 9 mos Ghielmini et al 31 (2004) 151 Untreated and relapsed FL Rituximab SD/CR/PR One dose every 2 mos 4 van Oers et al 32 (2006) 334 Relapsed FL CHOP ± R CR/PR One dose every 3 mos 2 yrs CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone, CR = complete remission, CVP = cyclophosphamide, vincristine, prednisone, FL = follicular lymphoma, FMC = fl udarabine, mitoxantrone, cyclophosphamide, PR = partial remission, R = rituximab, SD = stable disease, SLL = small lymphocytic lymphoma. 192 Cancer Control July 2012, Vol. 19, No. 3

7 in patients with FL in first relapse found that HDT/ASCT seemed to benefit most the group that received rituximab as part of the salvage chemotherapy. 34 Patients who did not receive rituximab as part of the salvage regimen had a 5-year event-free survival (EFS) of 30% vs 55% for those who received rituximab. The 5-year EFS in the rituximab group improved to 67% in those who also received HDT/ASCT, with a nonstatistically significant increase in OS. These results suggest a benefit to HDT/ASCT in the relapsed FL setting, but how much is due to the effects of rituximab vs the HDT/ ASCT is unclear. Allogeneic stem cell transplant is also an option in patients with FL and may even be curative in select cases. However, allogeneic transplants are associated with significant treatment-related mortality (TRM). 35 A report by the International Bone Marrow Transplant Registry noted a TRM rate of 30% in patients undergoing myeloablative transplants. However, at 5 years, only 21% of the patients receiving an allogeneic transplant had relapsed compared with 43% of those undergoing HDT/ASCT. To reduce the high incidence of TRM, nonmyeloablative approaches have been evaluated. The downside is concern that the relapse rate is higher with nonmyeloablative approaches. 36 However, a study performed by Khouri et al 37 shows that this concern may not necessarily be the case. This study evaluated 47 patients with relapsed FL treated with a nonmyeloablative conditioning regimen followed by a matched-sibling allogeneic transplant. At a median follow-up of 5 years, the OS and PFS were 85% and 83%, respectively. Allogeneic transplant remains an option for long-term disease-free survival in patients with relapsed/refractory FL, but the morbidity and TRM make this an option that requires a serious risk/benefit discussion with the patient. Emerging Therapies Monoclonal Antibodies Due to the success of rituximab, several monoclonal antibodies are now in development for the treatment of FL. They are an especially attractive group of drugs, offering a targeted form of therapy with minimal toxicities. Although rituximab is currently the only US Food and Drug Administration (FDA)-approved monoclonal antibody for FL, the compounds discussed here are currently in development and have shown activity in FL. Ofatumumab is a fully humanized monoclonal antibody against CD20. Previously referred to as HuMax- CD20, it targets a novel epitope of the CD20 molecule. 38 Ofatumumab has similar antibody-dependent cellular cytotoxicity when compared with rituximab, but it delivers stronger complement-dependent cytotoxicity in in vitro models. The first in-human study evaluating patients with relapsed/refractory FL treated with ofatumumab reported modest results. 39 This small phase I study reported an ORR of 20% to 60%. However, a small subset of patients who received rituximab in a prior treatment regimen reported an ORR of 64%. Due to these findings, a larger phase II study was performed with 116 patients with low-grade FL refractory to rituximab. 40 Refractoriness to rituximab was defined as failure to achieve at least PR or disease progression following a response within 6 months of the last treatment with single-agent rituximab or a rituximab-containing regimen. Patients received 8 weekly infusions of ofatumumab, at either a 500-mg dose (n = 30) or a 1,000-mg dose (n = 86); dose 1 was 300 mg, while doses 2 through 8 were 500 or 1,000 mg. The ORR in the total population was 11%. In those patients whose disease was refractory to treatment with rituximab as monotherapy, the ORR was 22%. Although modest, these results demonstrated that ofatumumab is effective in some patients with low-grade FL despite prior treatment failure with rituximab. Further studies evaluating ofatumumab alone or combined with other chemotherapeutic agents in the treatment of FL are underway. One study of interest will evaluate rituximab vs ofatumumab in relapsed FL after prior treatment with rituximab. Another planned study will evaluate the combination of bendamustine with ofatumumab vs bendamustine alone. Another anti-cd20 monoclonal antibody is GA101. This is a humanized type II monoclonal antibody. Type II anti-cd20 monoclonal antibodies (also referred to as tositumomab-like) differ from type I (rituximab-like) in that they do not activate complement dependent cytotoxicity and more potently evoke direct programmed cell death. 41 In a phase II study in patients with relapsed/refractory indolent NHL, 40 patients were treated with GA101 on days 1, 8, and 22, and then every 21 days, for a total of 9 treatments. 42 Of these 40 patients, 22 received what was referred to as a high-dose regimen. In the high-dose group, 55% had a response (CR or PR) to therapy, with half of them occurring in patients whose disease was considered refractory to rituximab. A randomized phase II study comparing GA101 and rituximab in relapsed indolent NHL is currently underway. Epratuzumab is another monoclonal antibody in development. It is fully humanized and targets CD22, a transmembrane protein found on B cells, which is thought to play a role in activation and adhesion. Its mechanism of action appears to be through antibodydependent cytotoxicity and also possibly through a second mechanism involving the internalization of the antibody receptor complex, which leads to activation of nonreceptor tyrosine kinases. 43 A small phase I/II study evaluated patients with relapsed or refractory NHL treated with epratuzumab. 44 The subset of patients with FL had an ORR of 43% at the 360-mg/m 2 dose. To improve the ORR, a second study combined epratuzumab with rituximab in patients with July 2012, Vol. 19, No. 3 Cancer Control 193

8 relapsed/refractory FL. 45 A total of 49 patients received 4 weekly doses of both drugs. The ORR was 54%, with 10 CRs and a median duration of response of 13.4 months. A more extended dosing regimen combining both epratuzumab and rituximab was tested in the frontline FL setting. 46 This study evaluated 60 patients with previously untreated FL. The patients received both drugs weekly for 4 doses, then every 2 months for 4 doses. An interim analysis showed the ORR to be 84%, with 33% obtaining CR. Final results from this study are pending. Another monoclonal antibody in development is an antibody against CD19. CD19 is a component of the B-cell receptor complex and functions to control the signaling threshold for B-cell development and humoral immunity. A few different compounds are in the pipeline, and they appear to exert their cytotoxicity through antibody-dependent cellular cytotoxicity. Ongoing clinical trials of these agents are in the early phases. Drugs That Alter the Microenvironment The immunomodulatory agent lenalidomide is the drug in this category that is farthest along in development for the treatment of FL. Lenalidomide has been approved by the FDA for treatment of myelodysplastic syndrome and multiple myeloma. Recent studies have demonstrated that it appears to have an effect on the cells in the microenvironment in NHL. 47 The exact mechanism is not known but appears to involve the downregulation of several key cytokines as well as activation of T and NK cells. 48 A phase II study evaluating the combination of lenalidomide, dexamethasone, and rituximab in patients with relapsed or refractory NHL whose disease was refractory to rituximab showed an ORR of 57%. 49 These results are encouraging, but the exact role of lenalidomide in FL is unclear. Numerous studies evaluating lenalidomide in the frontline, relapsed, and maintenance settings are underway. Phosphatidylinositol-3-kinase (PI3K) inhibitors are also thought to interact with the microenvironment in NHL. PI3K is part of a cell-signaling pathway that promotes cell growth and survival. It appears to be commonly activated in B-cell malignancies through constitutive activation of the B-cell receptor, which is thought to be from exposure to survival factors present in the microenvironment. Lymphoma cell lines were stimulated with various cytokines and chemokines mimicking signaling from the microenvironment, resulting in phosphorylation of Akt. This phosphorylation was inhibited by the use of a PI3K inhibitor known as CAL- 101 and resulted in decreased cell growth and survival. 50 These results suggest that PI3K may play an important role in regulating signals between malignant B cells and their microenvironment. Inhibition may enhance the effect of cytotoxic drugs by inhibiting the protective signals of the microenvironment. Further studies to evaluate the role of these drugs in FL are ongoing. Conclusions Low-grade follicular lymphoma is an indolent but incurable lymphoma. Its heterogeneous clinical course complicates decisions on which patients to treat and when. Existing prognostic scores as well as novel ones help in making treatment decisions, but for the most part, treatment is addressed on a patient-by-patient basis. Newer molecular tests have shown promise in predicting which patients will require treatment, but these tests are in the early phases of development. When a patient is deemed in need of therapy, several effective treatment options exist. None of them has been shown to be curative, but the addition of maintenance and consolidation treatments has demonstrated an improvement in progression-free survival and has shown a trend in improvement in overall survival. As the data in these maintenance and consolidation trials mature, the effects of these agents on overall survival will become clearer. Novel therapies have also shown promise in the treatment of follicular lymphoma. The development of new monoclonal antibodies is an expanding and promising field. These drugs provide an effective targeted therapy with minimal toxicities. In addition, novel approaches addressing the follicular lymphoma microenvironment may hold the key to improving outcomes. Continued research in these areas is paramount to our understanding and treatment of follicular lymphoma. References 1. Glass AG, Karnell LH, Menck HR. The National Cancer Data Base report on non-hodgkin s lymphoma. Cancer. 1997;80(12): Swerdlow SH, Campo E, Harris NL, et al. World Health Organization Classifi cation of Tumours of Haematopoietic and Lymphoid Tissues. Vol 2. Lyon, France: IARC Press; Weiss LM, Warnke RA, Sklar J, et al. Molecular analysis of the t(14;18) chromosomal translocation in malignant lymphomas. N Engl J Med. 1987;317(19): Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-b cells. Nature. 1988;335(6189): Roulland S, Navarro JM, Grenot P, et al. Follicular lymphoma-like B cells in healthy individuals: a novel intermediate step in early lymphomagenesis. J Exp Med. 2006;203(11): Bentz M, Werner CA, Döhner H, et al. High incidence of chromosomal imbalances and gene amplifi cations in the classical follicular variant of follicle center lymphoma. Blood. 1996;88(4): Roulland S, Lebailly P, Lecluse Y, et al. Long-term clonal persistence and evolution of t(14;18)-bearing B cells in healthy individuals. Leukemia. 2006;20(1): Dave SS, Wright G, Tan B, et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infi ltrating immune cells. N Engl J Med. 2004;351(21): Solal-Céligny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. 2004;104(5): 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(27): O Shea D, O Riain C, Taylor C, et al. The presence of TP53 mutation at diagnosis of follicular lymphoma identifi es a high-risk group of patients with shortened time to disease progression and poorer overall survival. Blood. 2008;112(8): Wrench D, Leighton P, Skibola CF, et al. SNP rs in the HLA region on chromosome 6p is predictive of the transformation of follicular lymphoma. Blood. 2011;117(11): Alvaro T, Lejeune M, Salvadó MT, et al. Immunohistochemical patterns of reactive microenvironment are associated with clinicobiologic 194 Cancer Control July 2012, Vol. 19, No. 3

9 behavior in follicular lymphoma patients. J Clin Oncol. 2006;24(34): 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(3): Colombat P, Salles G, Brousse N, et al. Rituximab (anti-cd20 monoclonal antibody) as single fi rst-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood. 2001;97(1): 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(6): Davis TA, Grillo-López AJ, White CA, et al. Rituximab anti-cd20 monoclonal antibody therapy in non-hodgkin s lymphoma: safety and effi cacy of re-treatment. J Clin Oncol. 2000;18(17): 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(28): Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) signifi cantly 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(12): Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as fi rst-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: fi nal results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood (ASH Annual Meeting Abstracts). 2009;114: Tsimberidou AM, McLaughlin P, Younes A, et al. Fludarabine, mitoxantrone, dexamethasone (FND) compared with an alternating triple therapy (ATT) regimen in patients with stage IV indolent lymphoma. Blood. 2002;100(13): Kaminski MS, Tuck M, Estes J, et al. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med. 2005;352(5): Kaminski MS, Tuck M, Estes J, et al. Tositumomab and iodine I-131 tositumomab for previously untreated, advanced-stage, follicular lymphoma: median 10 year follow-up results. Blood (ASH Annual Meeting Abstracts). 2009;114: Scholz CW, Pinto A, Linkesch W, et al. 90Yttrium ibritumomab tiuxetan as fi rst line treatment for follicular lymphoma: fi rst results from an international phase II clinical trial. Blood (ASH Annual Meeting Abstracts). 2010;116: Morschhauser F, Radford J, Van Hoof A, et al. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after fi rst remission in advanced follicular lymphoma. J Clin Oncol. 2008;26(32): Hagenbeek A, Radford J, Van Hoof A, et al. 90 Y-ibritumomab tiuxetan (Zevalin ) consolidation of fi rst remission in advanced-stage follicular Non-Hodgkin s lymphoma: updated results after a median follow-up of 66.2 months from the international, randomized, phase III fi rst-line indolent trial (FIT) in 414 patients. Blood (ASH Annual Meeting Abstracts). 2010;116: 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(9759): Hainsworth JD, Litchy S, Shaffer DW, et al. Maximizing therapeutic benefi t of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-hodgkin s lymphoma a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2005;23(6): Hochster HS, Weller E, Gascoyne RD, et al. Maintenance rituximab after CVP results in superior clinical outcome in advanced follicular lymphoma (FL): results of the E1496 phase III trial from the Eastern Cooperative Oncology Group and the Cancer and Leukemia Group B. Blood (ASH Annual Meeting Abstracts). 2005;106: Forstpointner R, Unterhalt M, Dreyling M, et al. Maintenance therapy with rituximab leads to a signifi cant prolongation of response duration after salvage therapy with a combination of rituximab, fl udarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006;108(13): Ghielmini M, Schmitz SF, Cogliatti SB, et al. Prolonged treatment with rituximab in patients with follicular lymphoma signifi cantly increases event-free survival and response duration compared with the standard weekly 4 schedule. Blood. 2004;103(12): 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(10): Vidal L, Gafter-Gvili A, Leibovici L, et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst. 2009;101(4): Sebban C, Brice P, Delarue R, et al. Impact of rituximab and/or high-dose therapy with autotransplant at time of relapse in patients with follicular lymphoma: a GELA study. J Clin Oncol. 2008;26(21): 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(10): 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(2): Khouri IF, McLaughlin P, Saliba RM, et al. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fl udarabine, cyclophosphamide, and rituximab. Blood. 2008;111(12): Teeling JL, French RR, Cragg MS, et al. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-hodgkin lymphomas. Blood. 2004;104(6): 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(12): Hagenbeek A, Fayad L, Delwail V, et al. Evaluation of ofatumumab, a novel human CD20 monoclonal antibody, as single agent therapy in rituximab-refractory follicular lymphoma. Blood (ASH Annual Meeting Abstracts). 2009;114: Mössner E, Brünker P, Moser S, et al. Increasing the effi cacy of CD20 antibody therapy through the engineering of a new type II anti-cd20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010;115(22): Salles GA, Morschhauser F, Thieblemont C, et al. Promising effi cacy with the new anti-cd20 antibody GA101 in heavily pre-treated NHL patients: updated results with encouraging progression free survival (PFS) data from a phase II study in patients with relapsed/refractory indolent NHL (inhl). Blood (ASH Annual Meeting Abstracts). 2010;116: Sato S, Tuscano JM, Inaoki M, et al. CD22 negatively and positively regulates signal transduction through the B lymphocyte antigen receptor. Semin Immunol. 1998;10(4): Leonard JP, Coleman M, Ketas JC, et al. Phase I/II trial of epratuzumab (humanized anti-cd22 antibody) in indolent non-hodgkin s lymphoma. J Clin Oncol. 2003;21(16): Leonard JP, Schuster SJ, Emmanouilides C, et al. Durable complete responses from therapy with combined epratuzumab and rituximab: fi nal results from an international multicenter, phase 2 study in recurrent, indolent, non-hodgkin lymphoma. Cancer. 2008;113(10): Grant B, Leonard JP, Johnson JL, et al. Combination biologic therapy as initial treatment for follicular lymphoma: initial results from CALGB 50701: a phase II trial of extended induction epratuzumab (anti- CD22) and rituximab (anti-cd20). Blood (ASH Annual Meeting Abstracts). 2010;116: Ramsay AG, Clear AJ, Kelly G, et al. Follicular lymphoma cells induce T-cell immunologic synapse dysfunction that can be repaired with lenalidomide: implications for the tumor microenvironment and immunotherapy. Blood. 2009;114(21): Chang DH, Liu N, Klimek V, et al. Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood. 2006;108(2): Ahmadi T, Chong EA, Gordon A, et al. Phase II trial of lenalidomide - dexamethasone - rituximab in relapsed or refractory indolent B-cell or mantle cell lymphomas resistant to rituximab. Blood (ASH Annual Meeting Abstracts). 2010;116: Lannutti BJ, Meadows SA, Herman SE, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B- cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117(2):591. July 2012, Vol. 19, No. 3 Cancer Control 195