|Year : 2019 | Volume
| Issue : 3 | Page : 214-218
Follicular lymphoma: Saudi Lymphoma Group's clinical practice guidelines for diagnosis, management and follow-up
Reyad Dada1, Mubarak Al-Mansour2, Hani Alhashmi3, Magdy Kandil4, Ayman Alhejazi5, Ahmed Sagheir6, Musa Alzahrani7, Ibraheem Motabi8
1 Department of Oncology, King Faisal Specialist Hospital and Research Centre, Jeddah; College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia
2 College of Medicine, King Saud Bin Abdulaziz University for Health Sciences; Adult Medical Oncology, Princess Noorah Oncology Center, King Abdulaziz Medical City, Ministry of National Guard Health Affairs-Western Region, Jeddah, Saudi Arabia
3 Adult Hematology and Stem Cell Transplantation Department, King Fahad Specialist Hospital, Dammam, Saudi Arabia
4 Oncology Department, Prince Sultan Military Medical City, Riyadh, Saudi Arabia; Clinical Oncology Department, Cairo University, Giza, Egypt
5 Department of Oncology, King Abdulaziz Medical City, Ministry of National Guard Health Affairs-Central Region, Riyadh, Saudi Arabia
6 Oncology Institute, John Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
7 Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia
8 Department of Adult Hematology and BMT, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia
|Date of Submission||25-Mar-2019|
|Date of Decision||06-May-2019|
|Date of Acceptance||24-Jul-2019|
|Date of Web Publication||28-Aug-2019|
Dr. Mubarak Al-Mansour
Adult Medical Oncology, Princess Noorah Oncology Center, King Abdulaziz Medical City, Ministry of National Guard Health Affairs-Western Region, PO. Box 9515, Jeddah 21423
|How to cite this article:|
Dada R, Al-Mansour M, Alhashmi H, Kandil M, Alhejazi A, Sagheir A, Alzahrani M, Motabi I. Follicular lymphoma: Saudi Lymphoma Group's clinical practice guidelines for diagnosis, management and follow-up. Saudi J Med Med Sci 2019;7:214-8
|How to cite this URL:|
Dada R, Al-Mansour M, Alhashmi H, Kandil M, Alhejazi A, Sagheir A, Alzahrani M, Motabi I. Follicular lymphoma: Saudi Lymphoma Group's clinical practice guidelines for diagnosis, management and follow-up. Saudi J Med Med Sci [serial online] 2019 [cited 2021 Mar 7];7:214-8. Available from: https://www.sjmms.net/text.asp?2019/7/3/214/265636
| Introduction|| |
Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin's lymphoma (NHL) after diffuse large B-cell lymphoma (DLBCL). It accounts for approximately 20.3% of NHL cases among Saudi adults in 2011. It affected 42 (11.0%) males and 27 (9.3%) females out of 744 NHL cases. The annual number of cases of this disease has increased from 34 in 2001 to 69 in 2011.
| Methods|| |
A committee comprising experts in hematology and medical oncology was established under the supervision of the Saudi Lymphoma Group and in collaboration with the Saudi Oncology Society. For collecting evidence, a literature search was carried out with relevant keywords using online database search engines such as PubMed/Medline, Web of Science and Scopus. In addition, expert opinion was considered when necessary. The levels of evidence used in developing this guideline were as follows:
- Evidence level (EL)-1 (highest), evidence from Phase III randomized trials or meta-analyses
- EL-2 (intermediate), evidence from well-designed Phase II trials or Phase III trials with limitations
- EL-3 (low), evidence from retrospective or observational studies/reports and/or expert opinion.
This easy-to-follow grading system is convenient for readers to understand and allows an accurate assessment of the guideline's applicability in individual patients.
1.1. Excisional biopsy is the optimal approach for initial diagnosis of FL. Typically, it has a distinctly nodular growth pattern and is comprised of a mixture of centrocytes and centroblasts. Partially involved lymph nodes can also be seen (EL-1).
1.2. Tumor grade [Table 1] and Follicular Lymphoma International Prognostic Index (FLIPI) are the best tools to predict the outcome of newly diagnosed patients (EL-1).,
|Table 1: Classification of follicular lymphoma into three histologic grades|
Click here to view
1.3. Almost all cases are positive for CD19, CD20, CD79a, CD21, and CD10 (60%), but lack expression of CD5, CD43, and CD11c. CD23 expression is variable but typically negative (EL-1).,,
1.4. BCL-2 protein is strongly positive in almost all Grades 1 and 2 subtypes. BCL-6 is expressed by at least some of the neoplastic cells in all FL tumors (EL-1).,
1.5. Fine needle aspiration should be avoided for diagnosing FL, as it does not allow to determine the typical growth pattern and grading of the disease (EL-3).
2. STAGING WORKUP
2.1. Pathology review is essential for all referral cases.
2.2. Evaluations should include complete history (i.e., age; gender; comorbidities; B-symptoms; Eastern Cooperative Oncology Group performance status; hepatitis or human immunodeficiency virus [HIV] risk factors; medications; allergy to contrast media or drugs as well as social and family history) and physical examination (i.e., of lymph nodes, Waldeyer's ring, spleen, liver, central nervous system, gastrointestinal tract, lung, bone and skin).
2.3. Laboratory evaluations of all patients should include complete blood count (CBC) with differential count, liver function test as well as routine blood chemistry including lactate dehydrogenase (LDH), electrolytes and calcium.
2.4. Hepatitis serology (hepatitis B surface antigen, core antibody and surface antibody as well as hepatitis C virus), and PCR for hepatitis B surface antigen-positive or core antibody-positive cases.
2.5. Screening test for HIV is required
2.6. Computed tomography (CT) scan of neck and chest, abdomen and pelvis (CAP) should be performed in all cases.
2.7. Bone marrow biopsy is recommended as standard for staging FL patients.
2.8. Cardiac function (i.e., left ventricular function) should be assessed by echocardiogram before treatment in all patients receiving anthracycline-based chemotherapy.
2.9. Pregnancy test should be done for women of childbearing age.
2.10. Infertility and fertility preservation should be discussed depending on the type of treatment.
3. STAGE CLASSIFICATION OF FOLLICULAR LYMPHOMA
Staging of FL is based on imaging results.
3.1. Stages: Stages I or II versus Stages III or IV according to Ann Arbor staging system [Table 2] (EL-1).,
3.2. B-symptoms is defined as recurrent unexplained fever of >38°C, recurrent night sweats or unexplained ≥10% loss of bodyweight in the past 6 months.
3.3. Bulky disease is defined as a tumor of diameter ≥10 cm on CT or a mass more than one-third the maximal transthoracic diameter on chest X-ray.
3.4. Limited stage is defined as Stages I or II and non-bulky disease, with no B-symptoms.
3.5. Advanced stage is defined as Stages III or IV, presence of B-symptoms or bulky disease regardless of the stage, except non-bulky Stage IB where B-symptoms are unlikely to be related to the disease and can be treated as limited stage.
4. MANAGEMENT OF FOLLICULAR LYMPHOMA
The limited stage (I/II) and advanced stage (III/IV) management have been distinguished as follows.
4.1. Limited stages
Only 15–30% of patients with FL have limited-stage disease at diagnosis.,
4.1.1. Stages I and II: Grades 1, 2 or 3a:
22.214.171.124 A potential curative radiation therapy to all involved tumor sites is the preferred option With this approach, the 10-year overall survival (OS) is the range of 60–80% (median, about 19 years) (EL-1).
126.96.36.199 Adding rituximab or chemotherapy to radiation improves progression-free survival (PFS) but not OS (EL-1).,
188.8.131.52 In patients with the non-bulky disease, if radiation is not feasible (in areas with expected significant radiation-induced morbidity), observation is a reasonable option (EL-3).,
184.108.40.206 In patients with the bulky (>5 cm) limited stage disease, there is need for systemic treatment with immunochemotherapy used in advanced stages, or immunotherapy with or without radiation (EL-2).
4.1.2. Grade 3b:
220.127.116.11 The consensus is to treat this group of patients as those with DLBCL; i.e. combined immunochemotherapy with rituximab plus cyclophosphamide, vincristine, doxorubicin and prednisone (R-CHOP) for six cycles followed by two additional rituximab applications (EL-3).
18.104.22.168 Another option is three to four cycles of R-CHOP followed by radiation (EL-3).
4.2. Advanced stages
4.2.1 In patients with low tumor burden and advanced stages, it is not necessary to initiate chemotherapy. However, these patients need to be followed-up regularly, as some may experience spontaneous remission (EL-1).
4.2.2 In patients with high tumor burden and those fulfilling the GELF (Groupe d-Etude des Lymphomes Folliculaires) and/or BNLI criteria (British National Lymphoma Investigation), treatment should be initiated [Table 3] (EL-1).
|Table 3: Indication for treatment in follicular lymphoma (any one parameter indicates need for treatment)|
Click here to view
4.2.3 The preferred regimen for advanced stages is combined immunochemotherapy with rituximab and bendamustine (RB) (EL-1)., Obinutuzumab-based chemotherapy is another option (EL-1).
4.2.4 R-CHOP is also a viable first-line treatment option (EL-1).
4.2.5 Despite the high efficacy of the above-mentioned conventional first-line regimens, none are curative given that the 10-year OS of FL patients is about 70%.
4.2.6 In patients with significant comorbidities and those who are not candidates for such combination regimens but have slow tumor dynamic, a single agent rituximab is an acceptable option (EL-3). In has been found that patients receiving once-weekly rituximab for four consequent weeks had improved quality of life in asymptomatic, advanced-stage and low-tumor-burden FL patients compared with the observation only group (EL-1).
4.2.7 Similar results were observed when high-dose chemotherapy and autologous stem cell transplantation was performed in the management of newly diagnosed patients with high-risk FL. Prospective randomized and retrospective studies have found that these treatment options do improve the PFS but not OS (EL-1).,,,
4.3. Maintenance with rituximab after first-line treatment
4.3.1 In the PRIMA trial, as compared with placebo, patients on maintenance with rituximab (375 mg/m 2 every 2 months for 2 years) after RCHOP and RCVP improved PFS (75% and 58%, respectively) (EL-1).
4.3.2 There are no supportive data from randomized trials to advocate the use of rituximab after RB (EL-3).
4.4. Management of relapsed and refractory disease
4.4.1 The tools to assess indication for initiating first-line treatment are generally also applicable in relapsed patients (EL-1).,
4.4.2 Therefore, treatment would not immediately begin for all relapse cases, unless there is an indication [Table 3] (EL-1).,
4.4.3 Lymph node biopsy should be performed if transformation is suspected. The positron emission tomography-CT may be useful in determining lymph node for biopsy (EL-3).
4.4.4 The most widely used regimens are single-agent rituximab, RCHOP, RCVP, rituximab, fludarabine and mitoxantrone (RFM), rituximab and bendamustine (RB) or obinutuzumab plus RB, depending on the first-line therapy and duration of response after the initial treatment (EL-1).,,,,,
4.4.5 A few studies have found encouraging results with when novel agents such as lenalidomide or bortezomib have been used in combination with rituximab or immunochemotherapy (EL-2).,
4.4.6 Radiation is also an option in selected patients with localized relapse (EL-3).
4.4.7 The role of maintenance therapy with rituximab in relapsed patients who had received rituximab as first-line therapy is unclear.
4.4.8. The role of autologous stem cell transplantation in relapsed patient is unclear.
4.4.9. Allogeneic transplantation should be limited to selected young patients. Non-myeloablative approach is preferred over myeloablative regimens, which should be limited to highly selected young patients with relapsed FL.,
4.6.1. Every 3 months for 2 years, then every 6 months for 3 years, and then annually.
4.6.2. History and physical examination should be documented in each visit.
4.6.3. CBC with differential count and LDH evaluations should be requested in each visit.
4.6.4. Thyroid-stimulating hormone (TSH) test should be carried out at least once annually if the patient had received radiotherapy to the neck.
4.6.5. CT of neck and CAP is required after completion of therapy, and if the findings are normal, no further routine imaging is required.
4.6.6. Mammogram should be done for women who received chest radiotherapy, beginning 10 years after the diagnosis of FL or at the age of 40 years, whichever comes first.
4.6.7. Annual influenza immunization is recommended (EL-3).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Jazieh AR, Saudi Lung Cancer Guidelines Committee. The lung cancer management guidelines 2012. J Infect Public Health 2012;5 Suppl 1:S4-10.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al
. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (IARC WHO Classification of Tumours). Revised 4th
ed. Lyon: International Agency for Research on Cancer; 2017.
Relander T, Johnson NA, Farinha P, Connors JM, Sehn LH, Gascoyne RD. Prognostic factors in follicular lymphoma. J Clin Oncol 2010;28:2902-13.
Freedman A. Follicular lymphoma: 2014 update on diagnosis and management. Am J Hematol 2014;89:429-36.
Barry TS, Jaffe ES, Kingma DW, Martin AW, Sorbara L, Raffeld M, et al.
CD5+ follicular lymphoma: A clinicopathologic study of three cases. Am J Clin Pathol 2002;118:589-98.
Karube K, Guo Y, Suzumiya J, Sugita Y, Nomura Y, Yamamoto K, et al.
CD10-MUM1+ follicular lymphoma lacks BCL2 gene translocation and shows characteristic biologic and clinical features. Blood 2007;109:3076-9.
Flenghi L, Bigerna B, Fizzotti M, Venturi S, Pasqualucci L, Pileri S, et al.
Monoclonal antibodies PG-B6a and PG-B6p recognize, respectively, a highly conserved and a formol-resistant epitope on the human BCL-6 protein amino-terminal region. Am J Pathol 1996;148:1543-55.
Pittaluga S, Ayoubi TA, Wlodarska I, Stul M, Cassiman JJ, Mecucci C, et al.
BCL-6 expression in reactive lymphoid tissue and in B-cell non-Hodgkin's lymphomas. J Pathol 1996;179:145-50.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al.
Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano classification. J Clin Oncol 2014;32:3059-68.
Anderson T, Chabner BA, Young RC, Berard CW, Garvin AJ, Simon RM, et al.
Malignant lymphoma 1. The histology and staging of 473 patients at the National Cancer Institute. Cancer 1982;50:2699-707.
Friedberg JW, Taylor MD, Cerhan JR, Flowers CR, Dillon H, Farber CM, et al.
Follicular Lymphoma in the United States:First report of the National LymphoCare study. J Clin Oncol 2009;27:1202-8.
Guadagnolo BA, Li S, Neuberg D, Ng A, Hua L, Silver B, et al.
Long-term outcome and mortality trends in early-stage, grade 1-2 follicular lymphoma treated with radiation therapy. Int J Radiat Oncol Biol Phys 2006;64:928-34.
Janikova A, Bortlicek Z, Campr V, Kopalova N, Benesova K, Belada D, et al.
Radiotherapy with rituximab may be better than radiotherapy alone in first-line treatment of early-stage follicular lymphoma: Is it time to change the standard strategy? Leuk Lymphoma 2015;56:2350-6.
Macmanus MP, Fisher R, Roos D, O'Brien P, Macann A, Tsang R, et al.
CVP or R-CVP given after involved-field radiotherapy improves progression free survival in stage I-II follicular lymphoma: Results of an international randomized trial. Hematol Oncol 2017;35:31.
Solal-Céligny P, Bellei M, Marcheselli L, Pesce EA, Pileri S, McLaughlin P, et al.
Watchful waiting in low-tumor burden follicular lymphoma in the rituximab era: Results of an F2-study database. J Clin Oncol 2012;30:3848-53.
Friedberg JW, Byrtek M, Link BK, Flowers C, Taylor M, Hainsworth J, et al.
Effectiveness of first-line management strategies for stage I follicular lymphoma: Analysis of the National LymphoCare study. J Clin Oncol 2012;30:3368-75.
Seymour JF, Pro B, Fuller LM, Manning JT, Hagemeister FB, Romaguera J, et al.
Long-term follow-up of a prospective study of combined modality therapy for stage I-II indolent non-Hodgkin's lymphoma. J Clin Oncol 2003;21:2115-22.
Ardeshna KM, Qian W, Smith P, Braganca N, Lowry L, Patrick P, et al.
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 2014;15:424-35.
Brice P, Bastion Y, Lepage E, Brousse N, Haïoun C, Moreau P, et al.
Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon Alfa: A randomized study from the groupe d'etude des lymphomes folliculaires. Groupe d'etude des lymphomes de l'adulte. J Clin Oncol 1997;15:1110-7.
Ardeshna KM, Smith P, Norton A, Hancock BW, Hoskin PJ, MacLennan KA, et al.
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 2003;362:516-22.
Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, et al.
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 2013;381:1203-10.
Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, et al.
Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: The BRIGHT study. Blood 2014;123:2944-52.
Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, et al.
Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 2017;377:1331-44.
Federico M, Luminari S, Dondi A, Tucci A, Vitolo U, Rigacci L, et al.
R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: Results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol 2013;31:1506-13.
Solal-Celigny P. Follicular lymphoma international prognostic index. Curr Treat Options Oncol 2006;7:270-5.
Lenz G, Dreyling M, Schiegnitz E, Forstpointner R, Wandt H, Freund M, et al.
Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: Results of a prospective, randomized trial of the German low-grade lymphoma study group. Blood 2004;104:2667-74.
Gyan E, Foussard C, Bertrand P, Michenet P, Le Gouill S, Berthou C, et al.
High-dose therapy followed by autologous purged stem cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: A randomized multicenter study by the GOELAMS with final results after a median follow-up of 9 years. Blood 2009;113:995-1001.
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 2012;104:18-28.
Schaaf M, Reiser M, Borchmann P, Engert A, Skoetz N. High-dose therapy with autologous stem cell transplantation versus chemotherapy or immuno-chemotherapy for follicular lymphoma in adults. Cochrane Database Syst Rev 2012;1:CD007678.
Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, et al.
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 2011;377:42-51.
Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R, et al.
Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: Results of a prospective randomized study of the German low-grade lymphoma study group. Blood 2005;106:3725-32.
Marcus R, Imrie K, Solal-Celigny P, Catalano JV, Dmoszynska A, Raposo JC, et al.
Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol 2008;26:4579-86.
Sehn LH, Chua N, Mayer J, Dueck G, Trněný M, Bouabdallah K, et al.
Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): A randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol 2016;17:1081-93.
Leonard JP, Jung SH, Johnson J, Pitcher BN, Bartlett NL, Blum KA, et al.
Randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (Alliance). J Clin Oncol 2015;33:3635-40.
Fowler N, Kahl BS, Lee P, Matous JV, Cashen AF, Jacobs SA, et al.
Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: The phase II VERTICAL study. J Clin Oncol 2011;29:3389-95.
Forstpointner R, Unterhalt M, Dreyling M, Böck HP, Repp R, Wandt H, et al.
Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German low grade lymphoma study group (GLSG). Blood 2006;108:4003-8.
Casulo C, Byrtek M, Dawson KL, Zhou X, Farber CM, Flowers CR, et al.
Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: An analysis from the National LymphoCare study. J Clin Oncol 2015;33:2516-22.
van Besien K, Loberiza FR Jr., Bajorunaite R, Armitage JO, Bashey A, Burns LJ, et al.
Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood 2003;102:3521-9.
Evens AM, Vanderplas A, Lacasce AS, Crosby AL, Nademanee AP, Kaminski MS, et al.
Stem cell transplantation for follicular lymphoma relapsed/refractory after prior rituximab: A comprehensive analysis from the NCCN lymphoma outcomes project. Cancer 2013;119:3662-71.
[Table 1], [Table 2], [Table 3]