Volume 1, Number 2 (Spring 2007)
Volume 1, Number 2 (Spring 2007)
The University of Chicago Medical Center, Chicago, Illinois
Follicular lymphoma is second only to diffuse large B-cell lymphoma as the most common subtype of non-Hodgkin’s lymphoma. The introduction of immunotherapy using rituximab and radioimmunotherapy has improved progression-free and overall survival in follicular lymphoma patients, making the value of previously recognized clinical prognostic models used before rituximab’s availability questionable. Clinical prognostic models and molecular markers (eg, those based on immunohistochemistry, karyotype, or gene expression profiling) are useful for elucidating disease biology and therapeutic outcomes, yet they currently cannot be used to stratify follicular lymphoma therapy. Current clinical indices and molecular markers in follicular lymphoma must be re-evaluated and incorporated actively into prospective trials to allow development of risk-adapted treatment guidelines and novel targeted therapies. The results of such studies will help to further recommendations regarding the effective timing of therapeutic intervention (ie, watchful waiting versus active treatment) and the efficacy of various chemotherapeutic regimens in different patient populations.
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| Dr. Rosenbaum is a Hematology/Oncology Fellow at The University of Chicago Medical Center, Chicago, Illinois. |
Follicular lymphoma comprises 22% of all non-Hodgkin’s lymphoma (NHL) cases and 70% of all indolent lymphomas, making it the second most common NHL subtype after diffuse large B-cell lymphoma (-DLBCL).1 The disease typically presents in an advanced stage (stage III/IV), and often patients are asymptomatic on presentation. Although a median survival of 8–10 years has been reported among follicular lymphoma patients, the overall survival times range from years to decades. This indolent lymphoma typically is incurable using conventional chemotherapy, and approximately 3% of patients undergo transformation to aggressive large-cell lymphoma each year.2
The immunophenotype of follicular lymphoma is typically composed of CD10+, CD20+, CD22+, and CD79a+ cells.3 The chromosomal translocation t(14;18)(q32;q21) characterizes the disease in over 80% of patients in whom the anti-apoptotic gene BCL2 is juxtaposed to the immunoglobulin heavy-chain locus.
There are three histologic grades of follicular lymphoma, and they are defined by the number of centroblasts observed per high power field. Two grading subtypes (3a and 3b) together comprise grade 3 follicular lymphomas. Grade 3b disease defines a large-cell histology characterized by solid sheets of centroblasts effacing the nodal architecture normally seen in grades 1 and 2 follicular lymphomas and exhibits a clinically aggressive behavior similar to that of DLBCL.
An educational program session on NHL was held during the 48th Annual Meeting of the American Society of Hematology (ASH) in Orlando, Florida. A primary focus of this session was the management of follicular lymphoma, as experts on its epidemiology and treatment discussed prognostic risk factors of the disease and controversies about its treatment.
Adapted from a presentation by Laurie H. Sehn, MD, MPH, Associate Professor of Medicine, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
The introduction of immunotherapy using rituximab and radioimmunotherapy with 90Y-ibritumomab and 131I-tositumo-mab has improved both progression-free survival (PFS) and overall survival (OS) in follicular lymphoma. This development, in turn, has made the value of clinical prognostic models used before rituximab’s availability, such as the Follicular Lymphoma International Prognostic Index (FLIPI), questionable.4
For decades, no treatment for follicular lymphoma significantly changed the natural history of the disease; thus, no standard first-line therapy was universally accepted. In 1993, Horning5 analyzed the survival of indolent lymphoma patients from 1960 to 1996, noting that various single and multiagent chemotherapy regimens and combined-modality therapies yielded no differences in survival. Gallagher et al6 first demonstrated that monotherapy using the anti-CD20 monoclonal antibody rituximab yielded prolonged median response durations of 11–12 months in the setting of third and fourth relapse, whereas other therapies of the time resulted in shorter response durations when given during first and second relapse.
Fisher et al7 reported on three sequential treatment approaches taken in consecutive Southwest Oncology Group (SWOG) trials from 1974 to 2000 that demonstrated the cumulative effect of new treatment options on PFS and OS rates: cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without nonspecific immunostimulants (SWOG 7426, 7713); prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide plus mechlorethamine, vincristine, procarbazine, and prednisone with or without interferon (ProMACE-MOPP ± IFN; SWOG 8809); and CHOP plus rituximab (R-CHOP; SWOG 9800) or 131I-tositumomab (SWOG 9911). The 4-year PFS rate increased only when the monoclonal antibody was added in the latter two studies comprising the third treatment approach (46% vs 48% vs 61%, respectively). On the other hand, the 4-year OS rate increased with each consecutive treatment approach (69% vs 79% vs 91%, respectively), supporting the hypothesis that sequential new treatment options extended OS when disease progressed in this patient subgroup.
These outcomes justify re-evaluation of current treatment paradigms. In turn, new therapies and changing paradigms require a similar re-evaluation of existing prognostic markers and models to ensure their continued applicability.
Over the past decade, two major prognostic indices specific for follicular lymphoma have been described. In 1997, the Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria sought to stratify patients by disease burden.8 Specifically, these criteria considered that the presence of at least one risk factor characteristic of high tumor burden, such as systemic symptoms, elevated lactate dehydrogenase (LDH) level, cytopenias, or splenomegaly, should prompt consideration to initiate treatment.
In 2004, the FLIPI designated prognostic groups as having low, intermediate, or high risk based on the presence or absence of five adverse prognostic factors: age ³ 60 years, Ann Arbor stage III/IV, hemoglobin level < 12 g/dL, more than four nodal sites of involvement, and elevated serum LDH level.4 The index was based on a Cox regression analysis from a large multicenter trial of 4,167 patients. The FLIPI model was based upon 1,795 patients treated on various protocols, all without the addition of rituximab. The 10-year OS rates in the low-, intermediate,- and high-risk groups were 71%, 51%, and 36%, respectively; the 5-year OS rates were 91%, 78%, and 53%, respectively.
Perea et al9 compared the International Prognostic Index (IPI) often used in follicular lymphoma patients with the FLIPI in an independent population of 411 patients and confirmed the FLIPI’s predictive capacity to classify patients with follicular lymphoma into differentiated risk groups. The FLIPI identified a larger proportion of high-risk follicular lymphoma patients than did the IPI (38% vs 31%, respectively), although it was unable to identify a poor outcome group having a 5-year OS below 50%.
As the FLIPI was developed in the pre-rituximab era, Buske et al10 examined its prognostic value in patients given rituximab-based immunochemotherapy in a prospective trial by the German Low Grade Lymphoma Study Group (GLSG) that compared CHOP with R-CHOP as front-line therapy. A 20-month median follow-up of the R-CHOP cohort showed a significant difference in the 2-year time to treatment failure (TTF) between the high- and low-/intermediate-risk groups; however, no difference in OS was seen. This suggested that the FLIPI may identify high-risk patients treated with immunochemotherapy based solely upon TTF.
Histology. The correlation of histologic grade with clinical outcome is often unclear in follicular lymphoma; generally, however, grade 1 and grade 2 disease may be indolent in behavior, whereas grade 3 disease may be more aggressive. Based upon morphology, immunohistochemistry (IHC), and cytogenetic profile, grade 3a disease is more closely associated with grade 1 and grade 2 disease, whereas grade 3b disease may be more similar to DLBCL.11 A series reported by the Nebraska Lymphoma Study Group12 examined patients with grade 3 follicular lymphoma who were treated with anthracycline-based chemotherapy and showed a similar prolongation in relapse-free survival rates among grade 3a and grade 3b patients.
Unfortunately, it is difficult to make treatment recommendations based upon grade alone, although histologic and genetic similarities between grade 3b follicular lymphoma and DLBCL usually dictate similar therapeutic strategies.
Immunohistochemistry. Expression levels of various proteins determined by IHC have been correlated with clinical outcome (Table 1).13,14 High levels of bcl-2 expression correlate with a worse outcome, whereas high levels of germinal center (GC) markers (CD10, bcl-6, PU.1) correlate with a more favorable outcome.15,16 Cyclin B1 expression is also associated with a favorable outcome.
The absolute number of lymphoma-associated macrophages (LAM score) in a biopsy specimen is an independent predictor of survival, with more than 15 CD68+ macrophages per high power field associated with a poor outcome and lower OS.17
Cytogenetics. The t(14;18) translocation leads to constitutive expression of the BCL2 anti-apoptotic oncogene and is found in approximately 85% of low-grade follicular lymphomas.
Higher Bcl-2 protein expression is associated with a worse prognosis in follicular lymphoma. Grade 3 follicular lymphoma often has a lower percentage of cells with a t(14;18) or may even lack it entirely; in these cases, Bcl-2 protein overexpression occurs through alternative mutations. Other chromosomal aberrations commonly associated with follicular lymphoma include gains of +7, +12q13-14, and +18q or deletion of 6q (6q–), 9p21–, or 17p13–, all of which correlate with unfavorable outcomes (Table 1).13,14
Genetic alterations associated with genomic instability and transformation to DLBCL include acquisition of MYC, loss of TP53, and translocation of BCL6. These karyotypic abnormalities are seen to a greater extent in grade 3 follicular lymphomas compared to the lower histologic grades.18 A proposed model of how these cytogenetic alterations relate to follicular lymphomagenesis and DLBCL transformation is depicted in Figure 1.3
Figure 1 Immortalization of a naïve B cell may result after primary VDJ recombination (via the RAG complex) through acquisition of a chromosomal translocation, t(14;18), with Bcl-2 protein overexpression. These cells can seed lymph nodes and reside within normal secondary follicles, proliferating at the low rate characteristic of follicular lymphoma among follicular dendritic cells (FDC) and reactive T cells. Secondary cytogenetic alterations may occur over time (chromosomal gains/losses, loss of tumor suppressor genes), resulting in secondary transformation to diffuse large B-cell lymphoma (DLBCL). If critical cytogenetic events occur early in the evolution of this process, the cells may lose the need for a germinal center (GC) microenvironment, and a de novo DLBCL may form. Cb = centroblast; Cc = centrocyte. Adapted, with permission, from Winter et al.3
Gene-expression profiling. A gene-array prediction model based on whole biopsy specimens from 191 untreated follicular lymphoma patients demonstrated two different tumor microenvironment signatures that correlated with survival independent of the IPI.19 An immune response (IR)-1 signature predicted a favorable outcome and included T-cell marker genes and other genes highly expressed in macrophages. An IR-2 signature included genes expressed in dendritic cells and/or macrophages and correlated with an unfavorable outcome. The median survival of patients grouped into quartiles based on these signatures ranged from 3.9 to 13.6 years.
Glas et al20 reported on the gene expression profiles of 80 follicular lymphoma patients and discovered 81 genes that predicted indolent versus aggressive behavior more accurately than did the histologic grade or IPI. However, these gene-expression profiles were not correlated with outcomes of survival, making this model system less useful in its predictive capacity.
Although clinical prognostic models, such as the FLIPI, and pathologic prognostic factors, such as those based on IHC, cytogenetics, or gene-expression profiling, are useful for elucidating disease biology and therapeutic outcomes, they currently cannot be used for treatment stratification of follicular lymphoma. The FLIPI lacks predictive capacity for OS when applied to patients treated with immunochemotherapy and fails to identify a poor-outcome group with low rates of OS.
IHC and molecular prognostic markers in follicular lymphoma lack clinical utility, as they have not yet been evaluated in patients receiving immunochemotherapy. However, the improved outcomes seen with immunochemotherapy demand that current clinical indices and pathologic prognostic markers in follicular lymphoma be re-evaluated and incorporated actively in prospective trials to assist in the development of risk-adapted treatment guidelines and novel targeted therapies.
Adapted from a presentation by Myron S. Czuczman, MD, Associate Professor of Medicine, Roswell Park Cancer Institute, Buffalo, New York.
Treatment often is deferred in patients with early (stage I/II) or advanced (stage III/IV) follicular lymphoma until they develop systemic disease or a high tumor burden and require a management strategy of “watchful waiting.” Stage I/II follicular lymphoma patients usually respond well to up-front involved-field radiation therapy (IFRT), whereas symptomatic, advanced-stage patients usually are treated up front with systemic chemotherapy.21
The most common subgroup of follicular lymphoma features asymptomatic, stage III/IV disease; individuals in this subgroup usually have been treated with a watchful waiting strategy to maintain a good quality of life. One institutional retrospective series reported a median survival of 8–10 years for follicular lymphoma patients followed over decades.5
Historically, early treatment using standard single or multiagent chemotherapy-based regimens without rituximab resulted in high relapse rates and showed no survival benefit. As such, no universally accepted first-line treatment exists for follicular lymphoma; alkylating agents (cyclophosphamide, chlorambucil), purine analogs (fludarabine), combination chemotherapy (cyclophosphamide, vincristine, prednisone [CVP]; CHOP; or fludarabine, mitoxantrone, dexamethasone [FND]), and intensive chemotherapy plus autologous/allogeneic bone marrow or peripheral blood stem-cell transplantation have been used historically.
The therapeutic value of immediate versus delayed treatment with conventional chemotherapy regimens in asymptomatic, advanced-stage follicular lymphoma patients has been the subject of a number of large prospective studies; however, most of these studies have failed to demonstrate a survival advantage to up-front treatment compared with watchful waiting. For example, Young et al22 reported a study wherein 104 patients with advanced follicular lymphoma were randomized to receive watchful waiting or up-front treatment with ProMACE-MOPP followed by total nodal irradiation. The watchful waiting arm was allowed to receive palliative radiation for local disease control. The 5-year OS rate in both arms of the study exceeded 75%, although the 4-year disease-free survival (DFS) rates favored immediate treatment over watchful waiting (51% vs 12%).
The GELF8 randomized follicular lymphoma patients with a low tumor burden to receive watchful waiting, prednimustine, or interferon alfa for 18 months, with the result that similar 5-year OS rates were found in all three arms.
In still another study with a long follow-up, the British National Lymphoma Investigation (BNLI) randomized 204 asymp-tomatic patients with advanced-stage follicular lymphoma to receive immediate or delayed treatment with chlorambucil; low-dose IFRT was permitted for symptomatic lymphadenopathy in both treatment arms.23 At a median follow-up of 16 years, similar OS rates were noted in both arms of the study, although the immediate-treatment arm had a higher complete response (CR) rate than did the delayed-treatment arm (63% vs 27%). This finding led to the question, is the sensitivity of follicular lymphoma to oral alkylating agents higher at an earlier stage in the disease process?
The sensitivity of asymptomatic follicular lymphoma to standard chemotherapy given up front compared with administration after disease progression is demonstrated by the prolonged DFS rate and higher CR rate achieved when chemotherapy is given early. Because chemotherapy alone is not curative in follicular lymphoma, OS may have been a misdirected outcome goal when the strategies of up-front treatment and watchful waiting were compared in the past. Given the improved survival outcomes now seen with immunochemotherapy in advanced-stage patients,24,25 however, the benefit of watchful waiting in asymptomatic stage III/IV patients may need to be revisited. A large, prospective, randomized controlled trial may clarify this matter and help to delineate specific risk groups that may benefit most from up-front immunochemotherapy.
Neither conventional chemotherapy nor high-dose chemotherapy with stem-cell transplantation is curative in follicular lymphoma. Further, the absence of a plateau in the survival curves of these therapies suggests that all patients will eventually experience relapse.26 It is possible that early treatment with immunochemotherapy in selected patients will allow a true cure, forcing a change in the goals of therapy from delaying disease progression to providing a cure.
Two large, prospective trials reported encouraging outcomes when rituximab-based immunochemotherapy regimens were compared with the same regimens without rituximab in previously untreated patients. Marcus et al24 randomized 321 stage III/IV, mostly symptomatic, patients with follicular lymphoma to receive 8 cycles of rituximab plus CVP (R-CVP) or CVP alone. The CR rates were 57% in the R-CVP arm and 10% in the CVP arm. At a median follow-up of 30 months, the median time to progression (TTP) was 32 months in the R-CVP group and 15 months in the CVP group. Kaplan-Meier estimates for OS at 30 months were not significantly different (89% vs 85%, respectively). However, when the GLSG25 randomized 428 untreated, advanced-stage patients requiring therapeutic intervention to receive R-CHOP or CHOP alone, investigators reported statistically higher overall response rates (96% vs 90%, respectively) and estimated 2-year OS rates (95% vs 90%) in the R-CHOP arm.
Any potential curative therapy would require that both a molecular CR of bcl-2-positive cells, as determined by polymerase chain reaction (PCR), and a nodal CR be attained. However, there are many limitations to molecular monitoring in follicular lymphoma that involve standardizing PCR methology, such as the techniques and sensitivity used, defining the optimal specimen location and frequency of testing for PCR positivity, and assigning quantitative cut-off values to limit false-positive results, as BCL2 gene rearrangements are present in a small percentage of the general population.26
To date, rituximab has been studied in the maintenance setting in numerous -trials of both untreated and relapsed follicular lymphoma. The Eastern Cooperative Oncology Group (ECOG)/Cancer and Leukemia Group B (CALGB) E1496 phase III trial27 studied the effect of maintenance rituximab therapy given to patients with advanced-stage disease after first-line CVP without up-front rituximab therapy. In all, 237 patients were randomized to receive either rituximab every 6 months for 4 courses or observation alone. The 4-year PFS rates of 56% and 33%, respectively, and 4-year OS rates of 88% and 72%, respectively, were significantly different in a subgroup analysis, suggesting that maintenance therapy with rituximab provides a survival benefit.
The value of rituximab maintenance in first-line therapy following rituximab-based immunochemotherapy has not been studied prospectively, but two randomized controlled trials have investigated this treatment strategy among relapsed patients. Forstpointner et al28 randomized 195 patients, including 113 with follicular lymphoma and 82 with mantle-cell lymphoma, to receive either rituximab maintenance or observation alone following induction therapy with fludarabine, cyclophosphamide, and mitoxantrone plus rituximab (R-FCM). The researchers found that maintenance rituximab therapy prolonged the response of follicular lymphoma patients to the initial regimen. Neither arm reached a median OS, although the entire population of patients who received rituximab maintenance therapy showed a trend toward improved survival.
Van Oers et al29 evaluated relapsed follicular lymphoma patients treated with R-CHOP or CHOP, finding that R-CHOP yielded a higher induction CR rate than did CHOP. A subgroup analysis of 189 patients on the R-CHOP arm showed that patients given maintenance rituximab therapy every 3 months for 2 years experienced a longer median response duration than did those in the observation-only arm (51 months vs 15 months, respectively).
In early 2004, the Primary Rituximab and Maintenance (PRIMA) trial began to prospectively examine outcome differences between various up-front rituximab-based immunochemotherapy regimens. Investigators hope to determine the value of rituximab maintenance therapy given after first-line rituximab-based immunochemotherapy. The trial was expected to end in March 2007.
Historically, it was believed that anthracycline-based therapy in follicular lymphoma should be saved for treating transformed disease and that its use should be delayed to limit the occurrence of side effects early in the course of treatment. Another common belief was that transformation to large-cell lymphoma is independent of the type of therapy received.
Contrary to these beliefs, one large prospective study and one recent retrospective review showed that up-front anthracycline-based chemotherapy for follicular lymphoma actually decreases the risk of transformation, possibly through early elimination of small subsets of transformed lymphoma cells or a decrease in the up-front tumor burden at risk of transformation over time.22,30
According to Young et al,22 up-front, combined, anthracycline-based chemotherapy for indolent lymphoma using ProMACE-MOPP showed no survival benefit when compared with watchful waiting; however, the anthracycline-treated arm showed a significantly decreased rate of histologic progression when compared with the observation arm (4 years, 0% vs 15%, respectively; 13 years, 15% vs 49%). Al-Tourah et al30 retrospectively reported on 260 patients given up-front anthracycline-based therapy who experienced a marked reduction in risk of transformation when compared with patients given a non–anthracycline-containing regimen; over a median follow-up of 90 months, transformation occurred in 18% of those given a doxorubicin-based regimen and 27% of patients given cyclophosphamide combined with cladribine.
Rituximab-based immunochemotherapy may be as effective as anthracycline-based chemotherapy in eradicating transformed subsets of lymphoma cells and in decreasing the tumor burden to lower the overall transformation risk. However, anthracycline-based therapies have shown additional clinical benefits apart from decreasing the risk of transformation in untreated, advanced-stage follicular lymphoma patients when compared with non–anthracycline-containing therapies. These benefits include increasing rates of overall response, CR, and TTP.
The two previously described, large, phase III studies that compared R-CVP with CVP and R-CHOP with CHOP both reported improved outcomes with rituximab-based immunochemotherapy regimens.24,25 In addition, Czuczman et al31 reported that in a phase II trial of R-CHOP in follicular lymphoma patients, most of whom were previously untreated, an overall response rate of 100% and a CR rate of 87% were observed.
No prospective, randomized controlled trial has compared CHOP with CVP in follicular lymphoma patients, although between-trial comparisons of the R-CHOP phase II/III data with the R-CVP phase III outcomes demonstrated that use of an anthracycline-based regimen produced higher overall response rates and a longer median TTP (Table 2).31 A higher CR rate was seen in the phase II R-CHOP trial than in the phase III R-CVP trial, although the phase III R-CHOP trial revealed a much lower (20%) CR rate. This difference in CR rates between the phase II and III R-CHOP trials may be explained by patient selection (a greater percentage of high-risk patients were included in the phase III study) and the initiation of treatment later in the disease process (need for therapeutic intervention was a criterion for enrollment in the phase III trial).
In this era of immunochemotherapy, the curative potential of new targeted therapies may supplant watchful waiting when treating asymptomatic, advanced-stage patients. Maintenance rituximab immunotherapy prolongs response duration in relapsed patients; in addition, it may improve the OS of this population. A large, prospective, intergroup study of maintenance rituximab therapy in the first-line setting is currently under way, and its results are awaited eagerly. Further, comparative data from randomized controlled trials suggest that anthracycline-based immunochemotherapy regimens improve outcomes when compared with non–anthracycline-based immunochemotherapy regimens.
Although up-front anthracycline-based chemotherapy may decrease the risk of transformation, its possible superiority over immunotherapy-based regimens in this regard must be validated in prospective, randomized clinical trials. Above all, development of any treatment plan for follicular lymphoma must consider each patient’s tumor characteristics and microenvironment together with prognostic information culled from clinical, genetic, and biologic factors.
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