For Physicians
Improvement in the Natural History of Follicular Lymphoma
Follicular lymphoma (FL) generally is a low grade malignancy with an indolent course, but it also has the potential to transform into an aggressive large cell lymphoma. FL is the second most common non-Hodgkin’s lymphoma (NHL), comprising 22% of all lymphoma types, but it constitutes 70% of “low grade” lymphomas. About a third of patients present with disease localized to one or two nodal groups on the same side of the diaphragm, one of six present with disease confined to nodes but present on both sides of the diaphragm, and half already have organ involvement at diagnosis (especially bone marrow, in 42%)1. Thus, about two-thirds of cases are widespread and apparently incurable on presentation.
PathogenesisFL arises from nodal B germinal center lymphocytes, both small cleaved and large non-cleaved follicular center cells. About 85%-90% of cases have a chromosomal translocation t(14;18). This causes overexpression of the BCL-2 oncogene that functions to block programmed cell death (apoptosis), resulting in prolonged survival of malignant lymphocytes2. However, this translocation, although very common, also can be found in some normal individuals as well as other lymphomas, indicating that additional ill-defined genetic events are required to explain the complete pathogenesis of this malignancy. Pathology
Neoplastic nodular follicles may be present throughout each involved node, or may occupy part of the node with the remainder comprised of a diffuse component. The dominant cell in the majority of cases is a small cleaved follicle center cell (centrocyte), but non-cleaved large follicle center cells (centroblasts) are always present. A grading system is based on the number of centroblasts per high powered field: grade I: 0 to 5, grade II: 6-15, and grade III: >15 (IIIa: a mixture of small and large cells, IIIb: solid sheets of large cells). Grade IIIb definitely is much more aggressive and often is categorized and treated as a large cell lymphoma. Whether grade IIIa also should be classified aggressive is somewhat controversial3.
Immunophenotyping is very important to confirm the diagnosis of FL. The malignant lymphocytes have clonal immunoglobulin on their surfaces, and also express CD20, CD19 and CD21, CD10 (in 60%), and are negative for CD5 and CD23 (variable). This pattern distinguishes them from other lymphoma types and from CLL. Also, the vast majority of grade I/II cases (85-90%) demonstrate cytoplasmic staining for the BCL-2 protein. Molecular genetic techniques can confirm immunoglobulin gene rearrangements and the t(14;18) translocation.
Natural HistoryThe course of FL is quite variable. Some patients with disseminated disease have no symptoms or signs of progression for years and do not require immediate therapy, while others cases demonstrate rapid tumor growth and need early treatment. After the standard staging evaluation, mainly by CT, bone marrow, and sometimes PET scan, to determine the extent and bulk of disease, the best predictors of outcome are the tumor grade (described above) and the Follicular Lymphoma International Prognostic Index (FLIPI). One point is assigned to each of the following clinical factors: age >60, elevated LDH, hemoglobin 4 involved nodal areas. Risk stratification is based on the FLIPI score; 0-1 points: low risk-71% 10 year survival, 2 points: intermediate risk-51% 10 year survival, 3 or more points: high risk-36% 10 year survival4. The accuracy of these survival figures is questionable now, because they are based on data collected prior to the present much more effective era of contemporary chemotherapy.
Curability Of Localized DiseaseUntil recently many treating hematologists and oncologists assumed that localized cases of FL were incurable because despite long survivals, a survival “plateau” could not be demonstrated and late recurrences seemed to occur steadily even during the second decade after diagnosis5. This belief led to a treatment bias as demonstrated by data collected between 2004 and 2007 from The National LymphoCare Study indicating that only 23.4% of patients with localized FL had radiation (RT) with curative intent, contrary to European and American guidelines. Although there is no published proof that Rituxan alone or with CT is curative for FL, 44% of localized cases were treated with chemotherapy (CT) with or without Rituxan® , or Rituxan® alone, and 29% had observation only5.
In fact, there have been a number of reports indicating that Stage I/II FL may be curable with involved field RT (IFRT) alone. One of the largest studies followed 177 patients and noted a median survival of 13.8 years, with 35% still surviving 20 years after treatment6. In the most recent report, 237 stage I/II FL patients were treated only with IFRT and at 10 years 49% were free of disease with an overall survival of 66%7. A plateau in progression-free survival after ten years was suggested by the data, indicating that cure was a possibility7.
The Best Initial TherapyFollicular lymphoma is considered incurable if it has spread above and below the diaphragm or involves organs or marrow. However, if patients are asymptomatic and have low risk disease, therapy can be delayed, as it has been demonstrated that a “watch and wait” policy of observation until symptoms occur does not have a detrimental effect on overall or disease-specific survival8. Treatment should be initiated when patients develop systemic symptoms and disease is bulky or progresses rapidly. Regimens, ranging from single agents (alkylating agents, Rituxan®) to complex chemotherapy have proved very effective, producing partial remissions in the majority as well as complete remissions in a significant percentage of patients. The monoclonal anti-CD20 antibody Rituxan® (R) is the best single agent for patients with a low tumor burden, since after weekly administration for only one month it produced responses in 73% and complete remissions in 20-24%. More than half of the responding patients still showed no sign of progression at 12 months9. Furthermore, when maintenance R was administered after induction therapy, the time to progression at least doubled10.
Combining Rituxan® with nearly any chemotherapy regimen is superior to the same regimen administered alone. In fact, the addition of R to chemotherapy (chemoimmunotherapy) has changed the natural history of follicular lymphoma. These regimens have been demonstrated to produce higher response rates and longer continuous initial complete remissions, and for the first time, unequivocal improvement in overall survival11. The most utilized regimens for first-line treatment of FL and their respective response and survival rates are13
Bendamustine (B) is an important new drug for the treatment of FL. A head-to-head comparison of B-R to R-CHOP found that B-R produced significantly longer progression-free survival and was much more tolerable and less toxic for FL patients in all risk groups12. Another recent advance demonstrated that after induction chemoimmunotherapy, maintenance Rituxan® produces a highly significant improvement in PFS (82% vs. 66% for placebo) at 2 years, although data are not available yet for OS14.
Radioimmunotherapy (RIT)Bexxar® and Zevalin® are two radioimmunoconjugates that target CD 20 and have been proved effective as alternate treatment for relapsed/refractory FL. RIT also has been studied in previously untreated FL patients. Bexxar produced an initial response rate of 97% with 75% CR and a median duration of response of six years; 40% remain progression-free at ten years 15.
Currently trials in the U.S. and Europe are enrolling previously untreated FL patients, who after responding to initial chemo-or chemoimmunotherapy, enter into treatment programs with adjuvant RIT. A U.S study of CHOP followed by Bexxar® reported OR 91%, CR 69%, with five year PFS 67% and OS 87%. A European trial of post-induction therapy Zevalin® vs. no further therapy also reported prolongation of PFS and a CR rate of 87% at 3.5 years. RIT clearly is an effective modality, but its utility in practice has been impaired by having to deal with the complexities of administration of a radiotherapeutic agent.
Conclusion
The introduction of Rituxan® has in a sense changed the natural history of FL. Not only is the antibody very effective as a single agent for fragile patients, but it has significantly improved outcomes if given in combination with chemotherapy, and also when used for maintenance. Furthermore, R seems to retain its usefulness in combination with alternative chemotherapy regimens for treating refractory/resistant disease a in a salvage situation. Although it is still much too early to assess the full impact of chemoimmunotherapy, so many options are now available that it is logical to consider not only prolonged survival as a goal for the future, but perhaps a possible chemoimmunotherapy cure.
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