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Follicular lymphomas grades 1, 2, and 3A

Photomicrograph of follicular lymphoma grade I. Click to enlarge. Photomicrograph of follicular lymphoma grade 2. Click to enlarge. Photomicrograph of HE-stained follicular lymphoma grade 3a. Click to enlarge.

Follicular lymphomas grade 1, 2, and 3A are considered mildly aggressive and constitute about 60% of indolent lymphomas and about 25% of all non-Hodgkin lymphomas. Cytogenetic changes are observed in most cases. The most common is the t(14;18)(q32;q21) translocation leading to rearrangement of the BCL2 gene and an overexpression of the Bcl-2-protein (anti-apoptotic). The cells are normally positive for immunoglobulin, CD10 and B-cell markers (CD19, CD20, CD22 and CD79a). Grading of follicular lymphomas is based on the number of centroblasts per vision field using light microscopy. 

The disease affects both peripheral and central lymph nodes (mediastinal and abdominal), and in 40% of patients, also bone marrow. Less than 1/3 of patients are in stage I or II at the time of diagnosis. It is usually a biopsy from enlarged lymph nodes that leads to the diagnosis. Patients are otherwise asymptomatic. A minority of patients have B symptoms.  

Median survival for patients treated without rituximab is 9 years, for patients less than 60 years 12 years. For patients treated in the rituximab era median survival has not been reached, but is expected to be much longer. 

Treatment of localized disease (stage I and stage II where only two neighboring lymph node regions are involved)

Treatment is based on the recommendations by the Nordic Lymphoma Group consisting of local curative radiotherapy (2 Gy x 15) to the involved field including the macrotumor (GTV) with a 2–3 cm margin (ITV). The field border is then 3-4 cm from GTV. In the transversal plane, the margin from GTV to ITV should be 1–2 cm and to the field border 2–3 cm. It is normal to include the entire involved node station in the transversal plane within ITV. Some university hospitals in Norway irradiate ITV defined as the entire involved lymph node station with a 2-3 cm margin to the tumor (GTV) and one draining lymph node station, which is considered an acceptable alternative. Less than half of patients will have recurrence outside the radiation field, and chemotherapy is appropriate when the patient requires treatment.

Treatment of advanced disease (stage II-IV) with chemotherapy

First line treatment

As for all indolent lymphomas, "watching and waiting" is a good alternative for patients with asymptomatic disease. When treatment is indicated, treatment of follicular lymphomas has been standardized with chlorambucil as the dominating drug of use. There is much evidence suggesting that a more differentiated strategy where the treatment plan is customized to the age of the patient, extent of the tumor, and other factors may be a better approach. The FLIPI-score makes it possible to group patients into three categories (low, intermediary, and high risk) with different prognoses. Chlorambucil is still given when the disease is indolent, and maybe in elderly patients where toxicity of more intensive therapy is expected to be a greater problem. In younger patients and especially more aggressive disease, treatment with CHOP/COP combined with rituximab is expected to give a quicker response and more complete remissions.  

These regimens are also considered more appropriate in situations where tumor masses threaten organ function, such as kidneys. Rituximab monotherapy may be a good alternative when preservation of fertility is especially important, or where toxicity from chemotherapy is an expected problem or unwanted by the patient. However, this drug is not approved for use alone as first-line treatment in Norway. A study is underway in Norway which patients are encouraged to be part of. This is a Nordic phase III study protocol where patients are randomized between 8 courses of rituximab with or without addition of IFN. 

Chlorambucil gives objective remission in about 70% of patients with this type of lymphoma. It is known that for chronic lymphatic leukemia, prednisone in addition to chlorambucil does not improve survival. There is reason to believe that the same applies for follicular lymphomas. It is therefore recommended that standard treatment should be chlorambucil given alone. Indications for prednisone given with chlorambucil are autoimmune hemolytic anemia and autoimmune thrombocytopenia. Patients with prominent B symptoms at the start of treatment may benefit from a short period (2-4 weeks) of prednisone treatment having a palliative effect. Chlorambucil is toxic for the hematopoietic stem cell, and for younger patients where high-dose treatment with autologous stem cell support is appropriate, a less stem cell-toxic treatment may be considered initially. Younger patients wanting to conceive must be informed of the possibility of sterility and be offered another form of treatment, including experimental immunotherapy.   

Chlorambucil tablets of 15 mg/m2 for 5 days are given every 4th week for a total of 4-6 cycles until the patient is in good partial or complete remission. Continuous treatment is not recommended due to the serious risk of bone marrow toxicity and myelodysplastic syndrome. The exception may be elderly and debilitated patients where intermittent therapy gives unacceptable side effects. If there is no response after 3 weeks, chlorambucil is discontinued and second line treatment is considered. In patients with especially threatening organ complications (spinal cord compression, hydrophrenosis) and where a rapid treatment response is essential, a more aggressive chemotherapy is chosen (such as C(H)OP + Rituximab).

Prednisone

Prednisone treatment for autoimmune hemolytic anemia and autoimmune thrombocytopenia starts at 1 mg/kg daily orally and is reduced slowly over time, depending on treatment response. 

If a good and long-term response is reached with chlorambucil as first line treatment, the regimen can be repeated for recurrence requiring treatment. In the event of chlorambucil resistance or early aggressive recurrence, a new biopsy should be considered to exclude transformation to follicular lymphoma grade 3 or diffuse large B-cell lymphoma. 

CHOP or COP are more intensive therapies giving higher response rates, but little improvement of long-term prognosis (Nickenig C et al., Cancer 2006). Newer studies show that a combination with rituximab will further  improve the effect and is now used as standard treatment (see above). The toxicity is not significantly greater than for CHOP/COP alone. The regimen is well suited if there is more aggressive disease and poor response according to the FLIPI score and in younger patients who will most likely tolerate treatment well.

Bendamustine-rituximab

Bendamustine in a prospective phase III study has been shown to be more effective than CHOP-rituximab for the first remission. The study is currently only published in abstract form, but is an attractive regimen especially in elderly with comorbidity. Toxicity appears to be low.

Rituximab

Use of the chimeric anti-CD20 antibody is an established indication for recurrence of follicular lymphomas. The surface antigen CD20 is expressed in high concentration on the majority of cells of follicular lymphoma. Responses of median duration of around one year is observed in about 50% of patients in a recurrence situation, but are lower with larger tumor masses. Side effects such as chills, fever, and muscle pain during the infusion are frequent during the first treatment. Dosing of rituximab is 375 mg/m2 i.v. once per week for 4 weeks. Retreatment may be attempted in patients who responded with the first attempt with a remission duration of at least 6 months. Studies have shown that at least half of these patients will be able to reach new remission, and the median duration is longer than for initial therapy with rituximab. The effect of using rituximab as first line treatment is most likely somewhat better than for recurrence.

Maintenance treatment with rituximab in first remission

In a randomized prospective phase III study, two year maintenance treatment with rituximab after chemoimmunotherapy gave improved progression-free survival compared to no maintenance treatment. There is so far no difference in overall survival. Maintenance treatment with rituximab in first remission may be offered to selected patients for whom it is especially important to defer start of chemotherapy (women in reproductive age, patients with comorbidities).

Later treatment

Later treatment will to a great extent depend on which treatment the patient received initially. All the alternatives mentioned above are also appropriate for recurrence. The recently concluded EORTC study shows that patients with recurrence of follicular lymphoma achieve a better effect of the combination of CHOP + rituximab compared to CHOP alone. The combination does not give a significant increase in toxicity and is recommended for those who have not been given rituximab previously, or where previous therapy with rituximab has given good responses and long term remission.

Maintenance treatment with rituximab in later remissions

Multiple studies have shown that rituximab maintenance therapy for patients in remission prolongs recurrence-free survival. It has been an open question as to whether this provides a better result than observing the patient untreated until the next recurrence and then starting with rituximab. There are, however, results from the EORTC study indicating improvement of recurrence-free survival and total survival with maintenance treatment in the form of rituximab given every 3 months for 2 years after treatment with either CHOP or CHOP + rituximab. This applies for patients with recurrence of follicular lymphoma. Maintenance treatment given for this indication is now approved. Use of rituximab maintenance therapy should be considered for recurrence of follicular lymphoma, especially in patients at high risk of rapid recurrence.  

Zevalin® radioimmunotherapy

90Y-ibritumomab tiuxetan (Zevalin®) has in multiple studies shown a positive effect on follicular lymphomas. The isotope yttrium-90 attaches to a monoclonal antibody against CD20. This treatment is administered by specific centers only. Results are similar to those achieved with chemotherapy, and side effects are less.

The entire treatment is completed in one week and can be done on an outpatient basis. The main problem is bone marrow suppression occurring 4-8 weeks after treatment, which is temporary. It is therefore important that the patient is monitored with weekly blood testing until this period is over. A small number of patients will require platelet transfusions and febrile neutropenia may occur. Radioimmunotherapy with Zevalin® can now be carried out at larger oncology centers. Treatment is approved for patients with recurrence after or lack of response to rituximab. This treatment is very costly, however, and there is currently no reimbursement program. 

Bendamustine

Bendamustine, possibly combined with rituximab, is also a possible treatment regimen for a recurrence situation. 

Fludarabine

Fludarabine, possibly in combination with cyclophosphamide (FC) and/or mitoxantrone are rarely used in Norway, but newer studies have shown that this combination may be very effective also for follicular lymphomas. An additional effect is also observed with the combination of rituximab (FC-R, FCM-R), similary to that observed with CHOP/CVP + rituximab. When this regimen is used on treated patients, it is recommended to measure the CD4 count in peripheral blood beforehand. Values < 200 are not recommended for flubarabine-based therapy due to the danger of serious suppression of cellular immunity and opportunistic infections.

Trofosfamide

Trosfosfamide tablets 50 mg x 2–3 are used for patients where side effects associated with combination chemotherapy are not expected to outweigh the benefit of therapy. Trofosfamide is an alkylating chemotherapy drug that does not show a particular degree of cross-resistance with chlorambucil. Except for bone marrow toxicity, trofosfamide has little side effects.

Interferon

Interferon-alpha-2-beta is now registered as treatment for follicular lymphoma with large tumor masses as combination and maintenance treatment after a combination regimen such as CHOP, based on a French randomized study. The recommended dose is relatively high (5 mill. I.E. s.c. 3 x per week). Many patients have unacceptable side effects such as cytopenias (in combination with chemotherapy) and subjective discomfort (influenza symptoms). Interferon monotherapy has not received great support in Norway for follicular lymphomas. The combination with rituximab in randomized Nordic phase II and phase III studies have shown high remission rates and progression free survival comparable to combined chemo-immunotherapy with rituximab.

High-dose treatment with autologous stem cell support (HDT with SCS)

High-dose treatment with autologous stem cell support (HDT with SCS) now has an established indication for recurrence of follicular lymphomas based on results from a European phase III study showing benefit for total survival compared to CHOP alone. Patients < 65 years in good general health may be possible candidates for this treatment. 

Allogeneic stem cell transplantation with reduced conditioning

This is a new treatment form winning attention internationally. Promising results are available for indolent lymphomas. A requirement is the presence of an HLA-compatible sibling donor. This treatment is accompanied by a series of serious side effects, but treatment is curative. Patients are now being included in a new study at Oslo University Hospital in cooperation with the NIH where patients with recurrence of indolent lymphomas may participate. New Norwegian guidelines are also allowed for allogeneic stem cell transplantation with unrelated donors in certain patients, usually with recurrence after HDT with SCS.

Palliative radiation therapy

Palliative radiation therapy may be a good treatment alternative for tumor masses threatening organ function (obstruction of bronchial tree, ureters, or spinal compression) or those causing pain. It is important to consider radiation therapy also in patients with advanced, chemo-resistant disease. Effects can be achieved even with far lower doses than those normally given for follicular lymphomas (24 Gy).

Transformation of indolent lymphomas

Transformation from indolent lymphoma to more aggressive histology is not an uncommon occurrence and generally leads to more severe prognosis. A Norwegian phase II study with HDT with SCS at remission after recurrence was recently concluded . The Norwegian Lymphoma Group recommends that HDT with SCS is used in selected patients with recurrence of transformed lymphoma. 

Experimental treatment for follicular lymphomas:

  • Randomized first line phase II study (SAKK / NLG: rituximab +/- lenalidomide)

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