Follicular lymphoma

What every physician needs to know:

Follicular non-Hodgkin’s lymphoma is the most common indolent B cell lymphoproliferative disorder.

Follicular lymphoma (FL) is characterized by diffuse lymphadenopathy, bone marrow involvement, splenomegaly, and less commonly, other extranodal sites of disease, besides the bone marrow. Cytopenias can occur but B symptoms (fever, nightsweats, and weight loss) are uncommon.

Are you sure your patient has follicular lymphoma? What should you expect to find?

FL patients present with diffuse painless lymphadenopathy often present for years and often waxing and waning. Bone marrow involvement is present in over 70% of patients and splenomegaly in about 30%. Computed tomography (CT) scans will confirm the adenopathy and if present, splenomegaly. Less than 15% of patients have B symptoms (fever, nightsweats, or weight loss). The most common cytopenia is anemia, and elevated LDH is present in less than 20% of patients.

The diagnosis is optimally made from a lymph node biopsy, specifically a surgical biopsy. Less optimal is a core needle biopsy. A fine needle aspirate is usually inadequate to make a diagnosis. The characteristic histology with malignant follicles is seen histologically, and immunohistochemistry studies show CD20, CD10 monoclonal surface immunoglobulin staining, with overexpression of the bcl-2 protein. Molecular cytogenetics shows the t(14;18) translocation in greater than 85% of cases.

Beware of other conditions that can mimic follicular lymphoma:

The differential diagnosis of diffuse lymphadenopathy includes a large number of benign and malignant conditions. Reactive lymphadenopathy due to bacterial or viral infection, inflammatory or connective tissue disorders do not contain monoclonal B cells, do not have overexpression of bcl-2 protein, and lack the t(14;18) IgH/bcl-2 (the translocation involving the immunoglobulin heavy chain gene and the bcl-2 gene) translocation.

A variety of other lymphomas might be considered. These include nodal marginal zone lymphoma which is not CD10+ and lacks t(14;18), mantle cell lymphoma which is CD5+, CD10-, CD23- and expresses the t(11;14) translocation, and T cell rich large B cell lymphoma which contains large transformed neoplastic B cells in a background of normal T cells.

Which individuals are most at risk for developing follicular lymphoma:

Follicular lymphoma is the second most common lymphoma in the USA and Western Europe and the most common indolent NHL. Approximately 24,000 new cases are diagnosed annually in the USA.

A number of environmental exposures have been associated with follicular lymphoma including herbicides and pesticides, and increased risk has been seen in farmers in the Midwestern USA.

Approximately 9% of individuals with follicular lymphoma have a first degree relative also with a lymphoproliferative disorder, although the precise genetic risk factors are yet to be determined.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Once a histologic diagnosis of FL is made, based on an adequate tissue biopsy, patients should have baseline laboratory studies including complete blood count (CBC) and differential, liver, and renal function tests. The most common hematologic disorder in patients with lymphoma is anemia, followed by thrombocytopenia and leukopenia. Although liver function tests (LFTs) are usually normal, an abnormal result might indicate occult liver involvement, and since ureteral obstruction can occur in lymphoma, the measurement of the serum creatinine is important.

These baseline studies are also necessary for planning therapy in terms of drug choices and possible dose modifications. The calcium and uric acid can be checked, but unless there is histologic transformation, one would expect normal results. Serum LDH can be elevated as a marker of the disease in about 10% of patients.

In contrast, the serum beta-2 microglobulin can be a more useful marker of indolent B cell non-Hodgkin lymphomas (NHLs) than LDH. We also check serum immunoglobulin levels, for baseline and on the small possibility of making a diagnosis of an immunodeficiency disorder such as previously undiagnosed combined variable immunodeficiency. HIV testing should be done since indolent lymphomas can occur in HIV+ individuals. Finally, prior to any therapy, we check hepatitis B and C serologies, since anti-B cell monoclonal antibody based therapy can lead to reactivation of hepatitis B infection.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of follicular lymphoma?

CT scans of the chest, abdomen, and pelvis are helpful in staging the disease, determining sites of adenopathy, evaluating spleen size, and detecting the uncommon involvement of other extranodal sites. Neck CT scanning in general does not add significantly to the evaluation. Functional imaging with positron emission tomography-computed tomography (PET-CT) scans is controversial in the evaluation and management of patients with FL. However, if areas of intense uptake are seen this raises the possibility of histologic transformation to a more aggressive NHL.

If you decide the patient has follicular lymphoma, what therapies should you initiate immediately?

Although nearly 90% of patients have advanced stage disease, most do not require immediate treatment. Many patients will have waxing and waning disease and 20% may have a spontaneous remission at some time. There is no evidence from randomized trials of immediate chemotherapy versus observation or even rituximab versus observation, that there is a survival advantage to early treatment in asymptomatic patients. If patients have cytopenias, B symptoms, compromised end organ function, symptomatic extranodal disease, effusions, bulky symptomatic nodal disease, or splenomegaly, then treatment is indicated. The median time for needing treatment is at least 3 years.

When patients need their initial treatment, multiple randomized trials have shown improved response rates, duration of remission, and overall survival with the addition rituximab (R) to conventional chemotherapy. The most commonly used chemotherapy regimens were cyclophosphamide, vincristine, prednisone (CVP), and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). However, bendamustine plus R has been shown to be superior to CHOP-R, in terms of progression-free survival, and with less toxicity, but no difference in overall survival, but now is a very commonly used upfront regimen. For patients who have non-bulky disease another option is R alone, which has a 70% response rate, with a median time to progression of 2 to 3 years. The use of R plus lenalidomide has a high response rate and durable responses at 5 years. This regimen is being compared in a randomized trial to conventional therapy for treatment naive patients.

More definitive therapies?

N/A

What other therapies are helpful for reducing relapse?

Approaches to prolonging remission have included some form of maintenance or consolidation therapy. These include maintenance R and autologous stem cell transplantation. Maintenance R has been given following induction therapy with R alone, as well as after chemotherapy. A recent update of a randomized trial of the initial treatment with R alone for 4 weekly doses followed by four maintenance doses (or observation) has reported that the maintenance R improved remission duration by more than two fold, and 45% of previously untreated patients are in remission at 8 years who receive the maintenance R. The event free survival was not improved when maintenance was extended to 5 years.

Maintenance R has also been shown to benefit patients who receive chemotherapy (CVP or CHOP but not bendamustine) and R for their initial treatment. A recent randomized trial using 2 years of maintenance R or observation, found significant improvement in progression free survival following chemoimmunotherapy, but to date there is no improvement in overall survival.

High dose therapy and autologous stem cell transplantation (ASCT) has been examined in several large randomized trials for consolidating first remission following conventional chemotherapy for FL. Although most studies demonstrate a significant improvement in PFS, there has been no impact on overall survival with first remission ASCT.

What should you tell the patient and the family about prognosis?

The prognosis of patients with FL is dependent on stage and other clinical/laboratory prognostic factors. Less than 10% of patient with FL present with early stage I or II disease. For these patients, involved field radiation therapy (largely for stage I) leads to a median survival of 19 years.

The majority of patients with FL have advanced disease, and a large proportion of patients do not require immediate treatment. Probably the best clinical prognostic model used presently is the Follicular Lymphoma International Prognostic index or FLIPI score. The overall survival data is based on a multivariable analysis of over 4,000 patients treated in the pre-rituximab era from 1985 to 1992. Five adverse parameters were identified: age greater than 60, LDH above normal, hemoglobin less than 12 g/dl, stage III/IV, and greater than 4 nodal sites. The median progression-free survival was 84, 70, and 42 months for low (0-1), intermediate (2), and poor risk (3 or more) disease

“What if” scenarios.

The overwhelming majority of patients with advanced stage FL will relapse following conventional therapy. At relapse, the first question is whether the patient can be observed again. When the patient needs treatment, however there are a vast number of options. These range from low dose local radiation for solitary sites of disease, to combination chemotherapy, usually with single agent rituximab (R), clinical trials with novel agents, as well as stem cell transplantation (autologous and allogeneic) for patients with multiple relapses or refractory disease. Low dose radiation 200cGy has response rates of 90% with excellent durable control for localized progressive symptomatic sites of disease. Although single agent R has been reported to be quite effective for relapsed FL, with response rates of 50 to 65%, these studies were largely done in patients who were R naive.

In the current paradigm of chemoimmunotherapy for FL, it remains uncertain how effective single agent R is in relapsed patients. However, single agent R should still be considered for relapsed patients who had at least 6 months of benefit from an R-containing regimen, with low volume disease. If the patient responds to weekly doses (for 4 weeks) of R, we generally recommend the Swiss Group for Clinical Cancer Research (SAKK) regimen of one dose q 2 months for four additional doses of maintenance.

The addition of R to conventional chemotherapy followed by maintenance R for 2 years has enhanced the efficacy of treatment of relapsed FL by 24 months in a large international randomized study of CHOP or CHOP-R for relapsed patients. Unfortunately the relevance of this study to the current paradigm of treatment is not clear, since these were rituximab and CHOP naive patients. Other regimens that are effective include bendamustine and rituximab.

Again however, the treatment paradigm has shifted to bendamustine plus rituximab as upfront therapy, making the utility of this regimen for salvage much less clear. CVP-R or CHOP-R may turn out to be used more for second or greater lines of conventional therapy. Unfortunately, the duration of subsequent remissions for patients with relapsed FL become progressively shorter.

Of the number of new agents being evaluated in follicular NHL, an oral kinase inhibitor, idelalisb, was recently FDA approved. Idelalisib has a 57% response rate with a median duration of 12 months. This agent targets the PI3 kinase delta isoform. Other new monoclonal antibodies, antibody-drug conjugates, and small molecules are being investigated in follicular NHL.

Both autologous and allogeneic stem cell transplantation have been used in patients with relapsed FL. The only randomized trial of autologous transplant (ASCT) versus chemotherapy predated the use of rituximab. In the CUP trial, the only randomized trial of ASCT, there was a significant improvement in PFS and OS for patients undergoing ASCT as compared to the control arm of no transplant. Although the treatment related mortality is low, at least 50% of patients relapse following ASCT. Concerns of late toxicities of ASCT include second malignancies such as myelodysplasia, secondary acute myeloblastic leukemia, as well as other solid tumors.

Myeloablative and reduced intensity non myeloablative allogeneic stem cell transplants have also been performed in patients with relapsed FL. The relapse rates are generally less than 20%, however higher treatment related mortality, ranging from 15 to 40%, has made the widespread applicability of this approach controversial in patients with relapsed FL.

Part of the natural history of indolent lymphomas is transformation to a higher grade histology, usually diffuse large B cell lymphoma (DLBCL). The risk over time is about 3% per year for patients with FL. Generally these patients are treated with CHOP-R or other regimens for DLBCL, and consideration is given to consolidating the remission with ASCT following remission induction. Although historically the prognosis for patients with histologic transformation has been poor, patients who are previously untreated for FL may have a similar prognosis as patients with de novo DLBCL.

Pathophysiology

FLs are neoplastic transformations of normal germinal center B cells that reside in secondary lymphoid follicles. The pathobiology of this disease is not completely understood.

The overwhelming majority of cases express the t(14;18) translocation. This translocation involves the immunoglobulin heavy chain (IgH) on chromosome 14 and the Bcl-2 gene on chromosome 18. The Bcl-2 gene comes under the control of the IgH promoter, which leads to the overexpression of Bcl-2 mRNA and protein. This protein which is a mitochondrial membrane protein, prevents programmed cell death or apoptosis, leading to prolonged cell survival. However, additional genetic lesions are necessary for the development of FL since t(14;18) is seen in a subset of diffuse large B cell lymphomas, and small numbers of normal B cells bearing t(14;18) have been detected in the peripheral blood and lymphoid tissues of normal individuals.

Further evidence for the need for additional genetic lesions is that mice engineered to overexpression the IgH- Bcl-2 translocation, develop follicular hyperplasia and not follicular lymphoma. Additional genetic lesions in these mice are needed before seeing lymphomas develop.

In addition to the genetic aberrancies of the neoplastic cells, more recent evidence suggests that the normal cells in the malignant microenvironment contribute to the behavior of FL. Specifically, using gene expression profiling, the presence of a T cell infiltrate may confer a more favorable prognosis, whereas an infiltrate rich in macrophages/monocytes may confer a disease with a more aggressive course and less favorable prognosis.

What other clinical manifestations may help me to diagnose follicular lymphoma?

N/A

What other additional laboratory studies may be ordered?

Infrequently the pathologic diagnosis for FL cannot be made by conventional histology and immunohistochemistry, so fluorescent in situ hybridization (FISH) for t(14;18) may be helpful.

What’s the Evidence?

Solal-Celigny, P, Roy, P, Colombat, P. “Follicular lymphoma international prognostic index”. Blood.. vol. 104. 2004. pp. 1258-1265. (The clinical international prognostic model for follicular lymphoma based on a large data set of patients treated from 1985 to 1992.)

Nooka, AK, Nabhan, C, Zhou, X, Taylor, MD. “Examination of the follicular lymphoma international prognostic index (FLIPI) in the National LymphoCare study (NLCS): a prospective US patient cohort treated predominantly in community practices”. Ann Oncol.. vol. 24. 2013. pp. 441(Improvement in outcomes by FLIPI score in the rituixmab era.)

Ardeshna, KM, Smith, P, Norton, A. “Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial”. Lancet. vol. 362. 2003. pp. 516-522. (This paper demonstrates that early chemotherapy of asymptomatic patients does not lead to a survival advantage in FL.)

Ardeshna, KM, Qian, W, Smith, P, Braganca, N. “Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial”. Lancet Oncol.. vol. 15. 2014 Apr. pp. 424-35. (This paper demonstrates that early rituximab treatment of asymptomatic patients does not lead to a survival advantage in FL.)

Marcus, R, Imrie, K, Solal-Celigny, P. “Phase III Study of R-CVP Compared With Cyclophosphamide, Vincristine, and Prednisone Alone in Patients With Previously Untreated Advanced Follicular Lymphoma”. J Clin Oncol.. vol. 26. 2008. pp. 4579-4586. (This paper demonstrates the improvement in treatment outcome and survival for patients treated with rituximab plus chemotherapy, as compared to chemotherapy alone for previously untreated patients with FL.)

Rummel, MJ, Niederle, N, Maschmeyer, G, Banat, GA. “Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial”. Lancet. vol. 381. 2013. pp. 1203(This paper demonstrates the improvement in treatment outcome for patients treated with bendamustine plus rituximab as compared to CHOP plus rituximab for previously untreated patients with FL.)

Martinelli, G, Schmitz, SF, Utiger, U. “Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98”. J Clin Oncol.. vol. 28. 2010. pp. 4480-4484. (This paper demonstrates that rituximab alone is a safe and effective initial therapy for patients with FL. The Martinelli paper (also known as the SAKK study) further demonstrates that the addition of four maintenance doses of rituximab increases remission duration, especially for previously untreated patients.)

Taverna, C, Martinelli, G, Hitz, F. “Rituximab Maintenance for a Maximum of 5 Years After Single-Agent Rituximab Induction in Follicular Lymphoma: Results of the Randomized Controlled Phase III Trial SAKK 35/03”. J Clin Oncol.. vol. 34. 2016 Feb. pp. 495-500. (5 years of maintenance rituximab did not lead to improved event free survival when compared to 8 months).

Fowler, NH, Davis, RE, Rawal, S. “Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial”. Lancet Oncol.. vol. 15. November 2014. pp. 1311-1318. (Excellent response rates and durablity of the combination of rituixmab and lenalidomide in treatment naive patients with indolent lymphoma)

Salles, G, Seymour, JF, Offner, F. “Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial”. Lancet. vol. 377. 2011. pp. 42-51. (Maintenance rituximab has been shown to benefit previously untreated patients who receive chemoimmunotherapy.)

Robinson, KS, Williams, ME, van der Jagt, RH, Cohen, P. “Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin’s lymphoma”. J Clin Oncol.. vol. 26. 2008. pp. 4473(Use of bendamustine plus rituximab for previously treated patients.)

Press, OW, Unger, JM, Rimsza, LM, Friedberg, JW. “Phase III randomized intergroup trial of CHOP plus rituximab compared with CHOP chemotherapy plus (131)iodine-tositumomab for previously untreated follicular non-Hodgkin lymphoma: SWOG S0016”. J Clin Oncol.. vol. 31. 2013. pp. 314(Radioimmunotherapy did not prolong remissions as consolidation after chemotherapy.)

Schouten, HC, Qian, W, Kvaloy, S. “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.. vol. 21. 2003. pp. 3918-3927. (Autologous and allogeneic stem cell transplantation (SCT) are options for patients with relapsed FL. The only randomized study by Schouten et al. shows a progression free and overall survival benefit for autoSCT, but this is in the pre-rituximab era. Allogeneic SCT is an option but the higher treatment related mortality needs to be considered.)

Al Khabori, M, de Almeida, JR, Guyatt, GH, Kuruvilla, J, Crump, M.. “Autologous stem cell transplantation in follicular lymphoma: a systematic review and meta-analysis”. J Natl Cancer Inst.. vol. 104. 2012. pp. 18(Several randomized trials demonstrate that although high-dose therapy and autologous stem cell transplantion improves progression free survival when consolidating first remission, no survival advantage was seen.)

Khouri, IF, McLaughlin, P, Saliba, RM. “Eight year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab”. Blood.. vol. 111. 2008. pp. 5530-5536. (This paper summarized one of the largest single institution experiences of reduced intensity allogeneic stem cell transplantation for follicular lymphoma.)

Friedberg, JW.. “Treatment of follicular non-Hodgkin’s lymphoma: the old and the new”. Semin Hematol.. vol. 45. 2008. pp. S2-6. (A number of new agents, including kinase inhibitor and new monoclonal antibodies are changing the paradigm of treating follicular NHL.)

Gopal, AK, Kahl, BS, de Vos, S, Wagner-Johnston, ND. “PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma”. N Engl J Med.. vol. 370. 2014. pp. 1008(The oral PI3 kinase inhibitor idelalisib is active in patients with relapsed follicular NHL.)

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