LIMITED STAGE I OR II FOLLICULAR LYMPHOMA
Patients with stage I or II FL represent only 10 to 30 percent of cases in most series.2,4 Standard management for stage I or limited contiguous stage II FL involves the administration of involved field radiotherapy (35 to 40 Gray [Gy]).7 Adjuvant chemotherapy does not appear to improve survival in this setting, although some studies suggest that combined chemoradiotherapy may improve PFS. A retrospective review of 177 patients with stage I or II and grade 1 or 2 FL reported a median survival of 14 years following radiation therapy as a single modality.27 Approximately 50 percent of the patients were relapse-free after 5 to 10 years.
Excellent survival has also been observed in highly selected patients with early stage FL who received no initial therapy.25 In a group of 43 patients, 56 percent were free from the requirement for treatment for at least 10 years and 86 percent were alive 10 years after diagnosis. Based on this study, many authorities have concluded that “watchful waiting” is an acceptable alternative to radiotherapy for stage I or II FL. A watchful waiting approach may be particularly appropriate for certain variants of FL, such as FL presenting in the small intestine, which pursues a remarkably indolent course, rarely exhibits progressive growth, very rarely disseminates (two of 63 patients) and does not transform to high-grade disease.26
A large observational study, the National LymphoCare Study, assessed the outcomes of 471 patients with stage I FL according to treatment administered, including rituximab plus chemotherapy (28 percent of patients), radiotherapy alone (27 percent), observation (17 percent), systemic therapy + radiotherapy (13 percent), rituximab monotherapy (12 percent), and other treatments (3 percent).28 This large, prospectively enrolled group of patients showed that national guidelines endorsing radiotherapy alone for stage I FL were not followed by practicing clinicians in the majority of cases. All treatment approaches resulted in excellent outcomes, though PFS was significantly better after a median followup of 57 months in patients treated with either rituximab plus chemotherapy (84 percent) or systemic therapy plus radiotherapy (96 percent) than in patients receiving radiotherapy alone (68 percent).28 This study challenges the paradigm that radiotherapy alone should be the standard of care for patients with early stage indolent lymphoma, although the observational nature of this study, without randomization to treatment arm and the absence of differences in OS, attenuates the impact of the study.
ADVANCED STAGE FOLLICULAR LYMPHOMA
Many patients with FL, particularly grades 1 or 2, will exhibit an indolent, asymptomatic course despite the absence of therapy. Because there is no conclusive evidence that survival of FL patients is improved by immediate institution of therapy, or that conventional management (other than allogeneic stem cell transplantation) can cure the disease, a “watch-and-wait” approach is often recommended for patients with extensive stage II or stage III or IV FL. In one study, survival was 82 percent at 5 years and 73 percent at 10 years after an initial strategy of observation alone, and the median time until therapy was required was 3 years.29 Spontaneous regressions occurred in 23 percent of untreated patients. No differences in survival were observed in a trial of 309 patients randomized to initial watchful waiting or to chlorambucil.30 In another trial, patients were randomized to either watchful waiting or to immediate aggressive combination chemotherapy with prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, procarbazine, prednisone (ProMACE/MOPP) chemotherapy followed by total nodal irradiation.31 The OS rates for the two groups were similar, although the disease-free survival rate was naturally higher in the patients treated with combined modality therapy. Criteria established by the Groupe d’Etudes des Lymphomes Folliculaires (GELF) are useful to identify patients who may benefit from intervention rather than “watchful waiting.” These criteria suggest that treatment is likely to be required for patients with a maximum diameter of any site of disease greater than 7 cm, more than three nodal sites greater than 3 cm in diameter, systemic B symptoms, a spleen size greater than 16 cm, pleural effusions, local compressive symptoms, circulating lymphoma cells, or cytopenias as a result of the lymphoma.32
FL patients can be palliated effectively with a variety of single chemotherapy agents (Table 99–1). Responses to single-agent therapy, such as chlorambucil, a nucleoside analogue, or bendamustine, range from 70 to 90 percent and may last for several years.30,33
Table 99–1.Therapeutic Regimens for Follicular Lymphoma
Monoclonal Antibody Therapy
Rituximab is a human–mouse chimeric monoclonal antibody that binds to the CD20 antigen that is expressed on nearly all normal and malignant B cells but not on other human tissues. After binding to B cells, rituximab induces cell death via antibody-dependent cellular cytotoxicity (ADCC), complement-fixation (complement-dependent cytotoxicity [CDC]), induction of apoptosis, and by facilitating cross-presentation of lymphoma-associated antigens by dendritic cells. Rituximab was approved by the FDA for therapy of indolent lymphomas based on the results of a pivotal trial that evaluated treatment of 166 patients with relapsed or refractory indolent lymphoma with four weekly infusions of 375 mg/m2. The response rate was 48 percent, including a 6 percent complete response rate and a median time to progression of approximately 1 year.34 The response rate to first-line therapy with rituximab in newly diagnosed FL is approximately 70 to 75 percent with a complete remission rate of 18 to 27 percent.35,36 A second response to rituximab may be achieved in 40 percent of patients who relapse after an initial remission to rituximab.37 Extended courses of rituximab or “rituximab maintenance” therapy have become popular. Various schedules are employed, including administration of one dose of 375 mg/m2 every 2 months for 2 years (usually as part of frontline therapy), one dose every 3 months for 2 years (for relapsed patients), four doses every 6 months for 2 years, or one dose every 2 months for four doses.38,39,40,41,42 No comparative studies of these disparate “maintenance” rituximab regimens have been performed. Several newer, humanized or fully human anti-CD20 monoclonal antibodies (ofatumumab, veltuzumab, obinutuzumab) have been engineered to exhibit superior ADCC, CDC, or improved induction of cell death. All are undergoing clinical trials to determine if they are superior to rituximab and one of them, obinutuzumab, has recently been approved for therapy of chronic lymphocytic leukemia (CLL) (but not FL). “Biosimilar” CD20 antibodies will also soon be available as an alternative to rituximab.
The introduction of rituximab into treatment protocols for FL has revolutionized the management of this disease. Multiple randomized, controlled clinical trials have documented the superiority of combining rituximab with chemotherapy compared to the use of chemotherapy alone in terms of overall response rates (ORRs), complete response (CR) rates, event-free survival (EFS), PFS, and OS (Table 99–2).43,44,45,46,47 In one study, induction therapy consisting of eight cycles of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) was compared to eight cycles of CVP without rituximab in 321 patients with newly diagnosed FL (Fig. 99–4).48 R-CVP was superior to CVP alone in terms of ORR (81 percent vs. 57 percent), CR rate (41 percent vs. 10 percent), time to progression (34 months vs. 15 months), time to treatment failure (27 months vs. 7 months), and OS (83 percent vs. 77 percent at 4 years, p = 0.029).45 Similarly, R-CHOP was compared to CHOP for first-line treatment of 428 patients with advanced stage FL. R-CHOP exhibited a superior ORR (96 percent vs. 90 percent), time to treatment failure (p <0.001), duration of response (p = 0.001), and OS (p = 0.016) compared to CHOP alone.46 Similar benefits have also been reported for the addition of rituximab to other regimens for both frontline therapy and relapsed FL.41,47,49,50 The selection of the “optimal” chemotherapy regimen to combine with rituximab remains hotly contentious.51 Two recent large international phase III randomized studies compared the efficacy and toxicity of R-CVP, R-CHOP, and rituximab-fludarabine–based therapy, which until recently were the three most commonly employed regimens for frontline therapy of FL. Both trials demonstrated superior PFS for patients treated with R-CHOP or rituximab-fludarabine regimens than with R-CVP, although OS did not differ. Both studies also concluded that regimens with fludarabine and rituximab had significantly more hematologic toxicity and a higher risk of secondary malignancies than either R-CVP or R-CHOP, making fludarabine-based regimens less desirable. The investigators conducting these trials concluded that R-CHOP was the preferred regimen for FL, although some oncologists are hesitant to routinely employ R-CHOP in patients with indolent lymphomas because of its greater toxicity, including a 1 to 2 percent risk of cardiomyopathy, and the absence of a demonstrated OS advantage. These risks may be particularly justifiable, however, for patients with grade 3 FL, as many authorities believe anthracycline-based regimens may be curable for high-grade FL, which National Comprehensive Cancer Network (NCCN) guidelines advise treated identically to diffuse large B-cell lymphoma.7 To further amplify the controversy, two recent randomized trials comparing bendamustine plus rituximab (BR) with R-CHOP show similar efficacy for the two regimens, and less toxicity for BR.52,53 Although these studies have been criticized for methodologic flaws, they have been highly influential and have catapulted BR to prominence as the most popular frontline induction regimen for FL, with approximately 65 to 70 percent of FL patients in the United States and Europe currently receiving this regimen for frontline therapy.
Time to disease progression, relapse, or death after a median followup of 30 months among 321 patients with grade 1 or 2 follicular lymphoma assigned to chemotherapy with CVP (cyclophosphamide, vincristine, prednisone) or with R-CVP (rituximab plus cyclophosphamide, vincristine, prednisone). Solid line represents CVP; dotted line, R-CVP. (Reproduced with permission from Marcus R, Imrie K, Belch A, et al: CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105(4):1417–1423, 2005.)
Table 99–2.Selected Randomized Studies of Chemotherapy Alone Versus Rituximab Plus Chemotherapy for First-Line Therapy of Follicular Lymphoma ||Download (.pdf) Table 99–2. Selected Randomized Studies of Chemotherapy Alone Versus Rituximab Plus Chemotherapy for First-Line Therapy of Follicular Lymphoma
|Study ||Treatment, No. of Patients ||Median Followup (Months) ||ORR (%) ||CR (%) ||Median TTP/TTF/EFS (Months) ||OS (%) |
|Marcus45 || |
|53 || |
p = 0.0290
|Hiddemann46 || |
|18 || |
p = 0.016
|Herold47 || |
|47 || |
p = 0.0096
|Bachy43 || |
|100 || |
p = 0.0004
78 at 8 years
p = 0.076
|Hochster44 || |
CVP + rituximab maintenance, 153
|36 || |
P = 4.4 × 10−10
86 at 3 years
p = 0.05 one sided
Despite the ability to induce long-lasting remissions in the majority of FL patients treated with chemoimmunotherapy regimens as outlined above, most patients will eventually relapse. Several strategies have emerged to prolong the remission durations and to delay lymphoma recurrence. The most popular approach is to administer extended courses of rituximab, also known as rituximab “maintenance” to forestall reappearance of FL. The PRIMA trial randomized 1217 patients with FL to either maintenance rituximab (375 mg/m2 every 2 months for 2 years) or no maintenance therapy, following frontline induction therapy with R-CVP, R-CHOP, or rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM).42 This study convincingly demonstrated the superiority of 2 years of maintenance rituximab (PFS 74.9 percent) compared to observation alone after induction (PFS, 57.6 percent, p <0.0001), regardless of which induction chemotherapy regimen is used. Despite the marked improvement in PFS afforded by maintenance rituximab in PRIMA, however, there was no significant difference in OS between the rituximab maintenance and observation arms. Similar improvements in PFS but not OS have also been demonstrated for maintenance rituximab given for 2 years following rituximab monotherapy in the frontline setting30 and following CHOP or R-CHOP induction in the relapsed setting.54
Radiolabeled monoclonal antibodies targeting lymphoma-associated cell surface antigens, including idiotypic immunoglobulin, CD20, CD22, and HLA-DR, have emerged as effective and safe therapeutic agents for patients with FL.55,56 Two radioimmunoconjugates targeting the CD20 antigen, 131iodine-tositumomab (Bexxar) and 90yttrium-ibritumomab tiuxetan (Zevalin), have been extensively tested in indolent lymphomas.57,58,59 Radioimmunotherapy (RIT) is an attractive therapeutic option for lymphomas because (1) many high-quality antibodies are available targeting pan–B-cell antigens expressed at high levels on lymphoma cells, (2) lymphomas are exquisitely sensitive to radiotherapy, and (3) cross-fire radiotherapy from β particles emitted by decaying radionuclides on targeted lymphoma cells can kill neighboring antigen-negative tumor cells (or inaccessible cells deep in tumor clumps), which would escape killing by nonradioactive antibodies. Several trials have demonstrated ORRs of 50 to 80 percent and CR rates of 15 to 40 percent in patients with relapsed or refractory indolent lymphoma treated with either 131iodine-tositumomab or 90yttrium-ibritumomab tiuxetan.57,59,60 In a randomized study comparing treatment of patients with relapsed FL with either90 Y-ibritumomab tiuxetan or rituximab, the ORR (86 percent vs. 55 percent) and the CR rate (30 percent vs. 15 percent) were both statistically superior in the group treated with the radioimmunoconjugate.59 Similarly, 131I-tositumomab was compared with unlabeled tositumomab in a randomized trial of relapsed indolent lymphoma and both the ORR (55 percent vs. 19 percent) and the CR rate (33 percent vs. 8 percent) were higher in patients receiving the radiolabeled antibody.61
Six phase II studies have studied frontline RIT for patients with newly diagnosed FL, either as a single agent or in combination with various chemotherapy regimens, including CVP, CHOP, and fludarabine. In all six studies, outstanding ORR rates (90 to 100 percent) and CR rates (50 to 96 percent) were observed with first-line RIT, with median PFSs in excess of 5 years in several of the studies.62,63,64 A phase III randomized study evaluated the utility of consolidation therapy with 90Y-ibritumomab tiuxetan for patients with FL in remission after frontline chemotherapy.65 In this trial, 414 patients in either partial or complete remission after a variety of chemotherapy induction regimens (chlorambucil, CVP, CHOP, fludarabine or rituximab combinations) were randomized to either consolidation with RIT or to no consolidation. RIT dramatically improved the median PFS in the total patient population (36.5 months vs. 13.3 months, p <0.0001), and this advantage was observed regardless of whether patients were in partial remission (PR; 29.3 months vs. 6.2 months, p <0.0001) or CR (53.9 months vs. 29.5 months, p = 0.015) at the time of consolidation. Furthermore, RIT consolidation converted 77 percent of patients who were in PR after induction chemotherapy to CR following RIT. However, a recent study comparing six cycles of R-CHOP with six cycles of CHOP (without rituximab) followed by a single dose of 131I-tositumomab (CHOP-RIT) demonstrated similar outcomes in both treatment arms.17
The major toxicity of RIT is myelosuppression, with cytopenic nadirs occurring 4 to 7 weeks after treatment and requiring 2 to 4 weeks for recovery. Growth factor administration and transfusions are required in approximately 20 percent of patients. Human antimouse antibodies (HAMA) may develop in the serum of approximately 1 percent of patients treated with 90Y-labeled ibritumomab and in 10 percent of patients treated with 131I-labeled tositumomab. A potential long-term concern with both radiolabeled antibody formulations is the potential development of myelodysplasia and acute leukemia as late complications. Hypothyroidism may also occur as a delayed toxicity of 131I-labeled tositumomab in approximately 10 percent of patients.
Interferon (IFN)-α2 has been studied in 10 large phase III studies evaluating its utility in both the induction phase of treatment and for maintenance therapy. A meta-analysis of 1922 newly diagnosed patients with FL treated in these trials concluded that the addition of IFN-α2 to induction chemotherapy did not significantly influence response rates, but did show a significant difference in favor of IFN-α2 with regard to survival.66 Results differed greatly from trial to trial and further analyses were carried out to define the circumstances in which IFN-α2 prolonged OS. The survival advantage was seen when IFN-α2 was given (1) in conjunction with relatively intensive initial chemotherapy (p = 0.00005), (2) at a dose of 5 million units or greater (p = 0.000002), (3) at a cumulative dose of 36 million units or greater per month (p = 0.000008), and (4) when given with induction chemotherapy rather than as maintenance therapy (p = 0.004).66 With regard to remission duration, there was also a significant difference in favor of IFN-α2, irrespective of the intensity of chemotherapy used, IFN dose, or whether IFN was given as a maintenance strategy or with chemotherapy. Despite these salutary findings, IFN is rarely employed to treat FL in the United States because of its unfavorable toxicity profile (asthenia, fatigue, flu-like symptoms, cytopenias) and because of the perception that rituximab confers similar or superior advantages with much less toxicity.
The idiotypic immunoglobulin protein expressed on the surface of B lymphoma cells represents a true tumor-specific antigen and is an ideal target for immunotherapeutic strategies. Several groups have reported favorable phase II trials using idiotypic vaccines produced either by rescue hybridoma fusions or recombinant DNA approaches. The idiotypic immunoglobulin in most of the vaccines is coupled to keyhole limpet hemocyanin (KLH) and administered with sargramostim (granulocyte-macrophage colony-stimulating factor) to enhance immunogenicity. Specific immune responses are generated in approximately 50 percent of immunized FL patients who are in complete remission at the time of vaccination. Patients exhibiting immune responses to the vaccine experience longer remission durations and superior survival compared to patients failing to mount immune responses to the vaccine. Three phase III randomized trials have been conducted using idiotypic vaccination following induction therapy. Two of these studies found no statistical differences in PFS between an idiotypic KLH vaccine and a control vaccine.67,68 The third study reported an improved disease-free survival for specifically vaccinated patients,69 although the study has been criticized for a variety of methodologic imperfections.68
Hematopoietic Stem Cell Transplantation
The role of high-dose chemoradiotherapy and hematopoietic stem cell transplantation in the management of patients with FL remains highly controversial. Proponents of autologous stem cell transplantation for indolent NHL note the favorable outcome of a collaborative study of 121 adult patients conducted by St. Bartholomew’s Hospital and the Dana-Farber Cancer Institute, where an apparent plateau in the remission duration curve was observed in 48 percent of patients with a median followup of 13.5 years.70 Survival was longer in patients transplanted in second remission compared to those transplanted later in their disease course. The value of autologous stem cell transplantation was also tested in a randomized trial of 89 patients with relapsed FL (Fig. 99–5). Transplanted patients experienced a marked advantage in PFS and a marginal OS advantage compared to patients randomized to continued conventional salvage chemotherapy without transplantation.71 When used as part of initial therapy for high-risk patients, randomized studies demonstrate a prolongation of PFS, but no improvement in OS.72,73 Adverse outcomes associated with autologous stem cell transplantation include treatment-related mortality (3 to 5 percent) and a substantial increase in the incidence of secondary myelodysplasia and acute myelogenous leukemia, occurring in 7 to 19 percent of patients, particularly if total-body irradiation is employed in the conditioning regimen.
Progression-free survival of 70 patients with relapsed follicular lymphoma randomized to either conventional chemotherapy (solid line), or to high-dose chemoradiotherapy with autologous marrow transplantation using either marrow purged to remove tumor cells (long dashes) or unpurged marrow (short dashes). ABMT, autologous bone marrow transplantation. (Reproduced with permission from 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 21(21):3918–3927, 2003.)
Allogeneic transplantation affords long-term PFS for approximately 40 to 50 percent of patients with relapsed FL, but widespread adoption of this approach has been hampered by transplant-related mortality ranging from 20 to 40 percent. Consequently, careful patient selection and informed consent are essential. When allogeneic and autologous stem cell transplantation are compared for patients with relapsed FL, the long-term survival rates are comparable.74,75 Autologous stem cell transplantation is associated with a greater likelihood of dying from recurrent disease, and allogeneic stem cell transplantation results in a higher frequency of death from graft-versus-host disease, infection, and venoocclusive disease. Nonmyeloablative and reduced-intensity allogeneic transplantation conditioning regimens have been developed to exploit the benefit of a graft-versus-lymphoma effect while minimizing transplant-related morbidity and mortality. Preliminary results of this approach are encouraging, with 52 to 85 percent OS and 43 to 83 percent PFS after 3 to 11 years with 8 to 43 percent nonrelapse mortality.76,77
TRANSFORMED FOLLICULAR LYMPHOMA
Approximately 30 to 40 percent of patients with FL undergo documented transformation to a more aggressive histology, usually diffuse large B-cell lymphoma, with an annual rate of transformation of approximately 3 percent (Fig. 99–6A). Clinically, histologic transformation is characterized by the sudden explosive growth of a single lymph node site (or extranodal mass). Anthracycline-based chemotherapy (e.g., R-CHOP) is the most appropriate therapy for patients experiencing transformation, however, most studies indicate that the prognosis is poor despite aggressive management. Whereas 50 to 65 percent of patients presenting with de novo diffuse large B-cell lymphoma are cured with R-CHOP chemotherapy, less than 10 percent of patients with diffuse large B-cell lymphoma arising by transformation from FL will be cured by this regimen (Fig. 99–6B). Most series report median survivals of 6 to 20 months for patients undergoing transformation,29,78,79,80 although one recent study reports a 50-month median survival, with particularly good survival in patients experiencing transformation more than 18 months after initial diagnosis of FL.81 Because of the historically poor outcome of chemotherapy alone, some authorities advise either autologous or allogeneic stem cell transplantation following induction of remission with R-CHOP. A recent multicenter cohort study of 172 patients with transformed FL concluded that patients undergoing autologous stem cell transplantation had better outcomes than those treated with rituximab-containing chemotherapy alone. However, allogeneic transplantation did not improve outcomes compared with rituximab-containing chemotherapy because of high rates of transplant-related mortality.82
A. Transformation of follicular lymphoma (FL) to an histologic pattern compatible with rapid progression of disease. The line depicts the cumulative incidence of histologic transformation to a histologic pattern compatible with more rapid progression (e.g., diffuse large B-cell lymphoma) in 325 patients followed from the date of diagnosis of FL. B. The proportion of patients with FL surviving after transformation to a less-favorable histologic pattern. The graph shows the survival of the 88 patients from the date of their transformation to aggressive lymphoma. (Reproduced with permission from Montoto S, Davies AJ, Matthews J, et al.: Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 25(17):2426–2433, 2007.)
A PRAGMATIC APPROACH TO THERAPY OF FOLLICULAR LYMPHOMA
There is currently little consensus among lymphoma experts with regard to the optimal management of patients with either frontline or relapsed FL.51 Therefore, at this time all patients with FL should be considered for entry into clinical trials to define the best regimens and to allow evaluation of the multitude of promising new drugs and antibodies that are now available. Patients who are ineligible for trials or who decline enrollment should receive individualized treatment. Patients with localized stage I or II disease may be offered local radiotherapy, observation or chemoimmunotherapy. Elderly patients with asymptomatic, stage III or IV disease are best monitored with observation alone, particularly if their disease is of low volume and if they have multiple coexistent medical illnesses. Patients who are symptomatic, have cytopenias, massive splenomegaly, effusions, or bulky adenopathy should be treated with rituximab plus chemotherapy. Several regimens are acceptable including BR, R-CVP, and R-CHOP, with the latter regimen being most appropriate for young patients with aggressive presentations and rapidly growing bulky adenopathy, B symptoms or for patients with grade 3 FL. The roles of maintenance rituximab and consolidative RIT following initial induction chemoimmunotherapy of newly diagnosed patients are contentious. It appears that either rituximab maintenance for 2 years or a single dose of consolidative RIT with 90Y-ibritumomab tiuxetan can prolong initial remission duration and PFS, but neither improves OS. Management of FL following relapse depends on the patient’s initial treatment and the resultant remission duration. If the first remission lasts many years, the initial treatment regimen may again be used (except for anthracycline-containing regimens). If the initial remission is short, an alternative second-line regimen should be selected from among the many available options, including BR, R-CVP, R-CHOP, R-FND (rituximab, fludarabine, mitoxantrone [Novantrone], and dexamethasone), and RIT. In the near future, many additional attractive options will be available, including ibrutinib,83,84 idelalisib,85,86 ABT-199,87,88 antibody–drug conjugates,89 and adoptive immunotherapy with chimeric antigen receptor modified T lymphocytes.90,91 Patients with a good performance status, who experience very short response durations, should be considered for autologous or allogeneic stem cell transplantation. Patients who undergo histologic transformation should receive R-CHOP and be offered the option of stem cell transplantation.