to aggressive treatments. however, most cases of fl have a less favorable prognosis at some stage of their disease and will therefore require intervention. there is little consensus regarding the guidelines to be used to define the prognosis and treatment for fl at its presentation or during its course.. currently used indicators for this include the disease's: 1) histology; 2) subtype; 3) predicted indolence and potential for transformation; and 4) extent of disease as measured by clinical examinations, bone marrow biopsy to determine bone marrow involvement, and pet/ct imaging of the chest, abdomen, pelvis, and any areas outside of these regions if physical examination suggests involvement. some suggested guidelines using these parameters to indicate the prognosis and need for treatment in fl include: the who criteria using histological grade (see previous section): patients with grades 1, 2, and 3a disease are predicted to have the same low risk prognosis that is seen in cases of typical fl while patients with grade 3b disease are predicted to have the high risk prognosis typical of t-fl. the follicular lymphoma international prognostic index (flipi): flipi uses the following criteria: age ≥60 years; ann arbor disease stage iii (i.e. lesions located both above and below the thoracic diaphragm) or iv (i.e. disseminated lesions involving one or more non-lymphatic organs); blood hemoglobin <12 gram/deciliter; serum lactose dehydrogenase level above normal; and involvement of >4 lymph nodes. patients positive for 0–1, 2, or ≥3 of these factors are classified as in low, intermediate, and high risk group, respectively, and after treatment with regimens that include rituximab have 2 year predicted progression free survivals of 84, 72, and 65%, respectively, and overall survivals of 98, 94, and 87%, respectively. the flip2 index. this modification of flip1 uses age ≥60; blood hemoglobin <12 gram/deciliter; serum lactose dehydrogenase level above normal; serum beta-2 microglobulin level above normal; ≥1 lymph node with a diameter >6 centimeters; and bone marrow involvement. the predicted percentage of therapy-treated patients with progression free survival at 5 years for individuals positive for 0, 1–2, and ≥3 of these factors are 80, 51, and 19%, respectively. ct/pet imaging: this method measures total body tumor volume as detected by tissue uptake of radioactive fludeoxyglucose (f18). progression free and overall survival at 5 years for patients with estimated tumor volumes above versus below 510 cubic centimeters are reported to be 32.7 and 84.8% versus 65.1 and 94.7%, respectively. lugano staging: this method classifies stage i disease as involving a single lymphatic region or extra-lymphatic site; stage ii disease as involving ≥2 lymphatic sites or 1 lymphatic site plus 1 extralympatic site with all lesions being on the same side of the diaphragm; stage iii disease as involving ≥2 lymphatic regions that are on opposite sides of the diaphragm; and stage iv disease as disseminated lesions that are found to be in ≥1 non-lymphatic organs. response-based prognosis: fl patients whose disease progresses within 24 months of initiating treatment with chemotherapy and immunotherapy versus patients whose disease does not progress within 24 months are predicted to have 5 year survival rates of 50–74% versus ~90%, respectively. the prognosis and treatment for the specific presentations of typical fl cases (see above sections for the prognoses and treatment recommendations for primary gastrointestinal tract fl, predominantly diffuse fl with 1p36 deletion, pediatric-type fl, and primary fl of the testis) that are in common use are as follows: in situ follicular lymphoma isfl is a benign condition that may be reevaluated periodically to detect the rare cases of it which progress to fl; otherwise isfl is not treated. localized follicular lymphoma in 10–20% of cases, fl appears limited to single radiation field, does not involve the bone marrow, and is therefore regarded as localized early-stage fl. in these cases, which are sometimes classified as ann arbor stage i (i.e. disease limited to a single restricted region) or stage ii (i.e. disease restricted to two sites that are on the same side of the diaphragm), radiation therapy achieves 10 year overall survival rates of 60–80% and median overall survival times of 19 years. it seems likely that many of the relapses in these cases are due to undetected disease outside of the radiation field at the time of radiation treatment. the use of pet/ct imaging is strongly recommended to insure that the fl is localized. in any case, the excellent results achieved with radiation therapy strongly support its use in localized disease. the use of an immunotherapeutic agent such as rituximab alone or in combination with a chemotherapeutic regimen such as cvp (i.e. cyclophosphamide, vincristine, prednisone and rituximab) in cases of localized, early-stage disease may be appropriate choices for some of these early-stage patients. however, the latter approach is recommended for cases of localized disease in which the disease extends beyond a single field: 56% of patients treated in this manner had progression-free survival at 10 years while patients treated with other regimens had progression free survivals of 41%. nonetheless, overall survival did not differ between the two groups. asymptomatic follicular lymphoma patients with asymptomatic but not localized low grade fl, gastrointestinal tract fl, and pediatric-type follicular lymphoma have been served by careful follow-up without therapeutic intervention. even high grade, aggressive, relapsed, or transformed fl may also be served with observation in patients who are asymptomatic. findings in asymptomatic patients who have been recommended as triggers for starting treatment include one or more of the following: tumor size ≥7 cm in diameter; involvement of ≥3 nodes in 3 distinct areas, each of which is ≥3 cm in diameter; organ compression; presence of ascites or pleural effusion (i.e. build-up of fluid in the abdominal or pleural cavities); poor performance status due to the disease; elevated levels of serum lactose dehydrogenase or beta-2 microglobulin; presence of localized bone lesions; kidney involvement; reduced levels of circulating blood platelets or any of the various types of white blood cells; onset of significant pruritus (i.e. itching sensation) or other b symptoms; and enlargement (i.e. ≥50% increase in size over a period of at least 6 months) of lymph nodes, spleen, or other follicular lymphoma-infiltrated organs or tissues. symptomatic follicular lymphoma symptomatic fl requires treatments directed at relieving symptoms by reducing the load of tumor cells. various chemotherapeutic regimens have been used for this including combinations of alkylating antineoplastic agents, nucleoside analogues, and/or anthracyclines. two commonly used chemotherapeutic regimens are cvp (see localized fl section) and chop (i.e. cvp plus the anthracycline adriamycin). newer agents used to treat fl include monoclonal antibodies such as rituximab, obinutuzumab, galiximab, inotuzumab ozogamicin, or epratuzumab and immunomodulators such as lenalidomide and interferon. the latter medications have been used in combination or alone to treat symptomatic fl. most such regimens add rituximab (a monoclonal antibody which binds and thereby kills the cd20 cell surface protein on b cells) with cvp or chop regimens (termed r-cvp and r-chop regimens). the r-chop regimen appears superior to the r-cvp regimen with, for example, one study finding 8-year progression-free survival rates of 57% versus 46% for the two respective regimens. more recently, fl patients have been treated with other regimens including: 1) rituximab combined with the chemotherapeutic alkylating agent bendamustine; 2) rituximab combined with the chemotherapeutic agent fludarabine and the inhibitor of type ii topoisomerase, mitoxantrone; and 3) rituximab combined with another immunotherapeutic agent such as galiximab, epratuzumab (monoclonal antibodies directed respectively against the cd80 or cd22 cell surface proteins on immune cells including b cells), or the immunomodulating medication, lenalidomide. while it is too soon to judge the long-term results of the latter regimens, the regimens have shown similar results when analyzed based on poor treatment responses (~10–20% poor responses). bendamustine with rituximab may be preferable to r-chop or r-cvp for treating low-grade (i.e. grades 1, 2, and possibly 3a) fl; r-chop may be preferred in fl that has high-risk characteristics (e.g. high levels of beta-2 macroglobulin or bone marrow involvement). the combination of lenalidomide with rituximab has shown good potential in treating indolent cases of fl. studies indicate that maintenance therapy with rituximab following successful induction therapy prolongs progression-free survival; for example one study found progression-free survival after 6 years of treatment was 59.2% in patients treated with rituximab maintenance and 42.7% without this maintenance; however, overall survival at 6 years was similar in the two groups, 87.4% and 88.7%, respectively. another study found that prolonged maintenance with rituximab did not have any benefits over an eight-month maintenance period. finally, surgery and radiation are additional therapies that can be used to relieve symptoms caused by bulky t-fl disease or to treat lesions in patients who cannot withstand other types of treatment. transformed follicular lymphoma early studies on treating t-fl with various purely chemotherapy regimens gave poor results with median overall survival times of 1–2 years. however, the addition of rituximab to the regimens such as cvp and chop as part of induction and maintenance therapies (i.e. r-cvp and r-chop) greatly improved overall 5 year survival to rates of 73%. the r-chop regimen is a good option for treating such cases. however, these regimens need not be started in people with fl who are asymptomatic and have low tumor burdens: the outcomes in such patients show no difference between early versus delayed treatment. some recent studies found that the use of rituximab in combination with bendamustine (i.e. the rb regimen) provided better results than r-chop: progression-free survival times in one study were 69.5 months for rb and 31.2 months for r-chop. similar results were obtained when rb was compared to r-cvp. these studies also found no overall survival time benefit between the rb and r-chop regimens. other recently examined regimens include 1) the use of obinutuzumab instead of rituximab in the r-chop and r-cvp regiments to attain progression-free survival rates at 3 years of 80% for the obinutuzumab-chemotherapy regimen versus 73% for the rituximab-chemotherapy regimen and 2) the combination of rituximab with lenalidomide (no chemotherapy agent) versus various chemotherapy plus immunotherapy (principally rituximab) to achieve similar complete remission and 3 year progression-free survival rates but with rituximab plus lenalidomide causing less toxicity (i.e. severe neutropenia). many of these studies did use rituximab maintenance therapy after induction therapy. prevention several studies, while not conclusive, suggest that the early treatment of low risk fl reduces the incidence of the disease progressing to t-fl. the treatments used in these studies include chemotherapy, radiation therapy, and immunotherapy combinations plus rituximab maintenance therapy. relapsed follicular lymphoma patients who relapse after initial therapy for fl may be followed closely without therapy if asymptomatic. when treatment is required, patients may be treated with the initial treatment regimen when such treatment led to a remission that lasted for at least one year; otherwise an alternative regimen is used. the regimens commonly used in relapsed lymphoma include r-chop, r-cvp, rfm (i.e. rituximab, fludarabine, and mitoxantrone), and rb (bendamustine plus rituximab). patients who have early treatment failure (e.g. within 1–2 years of initial treatment) or multiple relapses have also been treated with either autologous (i.e. stem cells taken from patient) or allogeneic (i.e. stem cells taken from a donor) stem cell bone marrow transplantation. while studies are inconclusive, autologous stem cell bone marrow transplantation appears to prolong survival in early treatment failure patients who are healthy enough to withstand this therapy. unfit patients may benefit from initial treatment with obinutuzumab plus bendamustine followed by maintenance treatment with obinutuzumab (if they have not been treated previously with obinutuzumab). other mostly experimental treatments currently under study in patients with multiple treatment failures include: 1) phosphoinositide 3-kinase inhibitors such as copanlisib, duvelisib, and idelalisib which block the phosphoinositide 3-kinase signaling pathway that promotes the survival, proliferation, and other potentially malignant behaviors of cells; 2) infusion of tisagenlecleucel chimeric antigen receptor t cells (i.e. car t cells) (i.e. t cells that have been isolated from patients, engineered to express a receptor for the cd19 protein on, and thereby kill, t cells, and then infused back into the donor patient); 3) bruon's tyrosine kinase inhibitor, ibrutinib, to block the b-cell maturating actions of this kianase; 4) bcl inhibitor venetoclax to block bcl2's action in promoting b-cell survival and proliferation; 5) histone deacetylase inhibitors abexinostat and tazemetostat to modify the expression of various genes; and 6) checkpoint inhibitors nivolumab, pidilizumab, and pembrolizumab to promote the immune system's ability to suppress cancer cell growth.