Pocket Oncology (Pocket Notebook Series), 1st Ed.

FOLLICULAR LYMPHOMA

Zachary H. Word

Epidemiology

• Most common indolent lymphoma & 2nd most common lymphoma overall, representing ∼25% of NHLs

• More common in Caucasians than other races, incidence ↑ w/age. Equal incidence in men vs. women

Biology/Pathology

• Composed primarily of small cleaved lymphocytes that grow in a follicular pattern resembling that of nl 2° lymphoid tissue

• Variable numbers of larger centroblasts are typically present, w/↑ number indicating higher grade

• Grade I, II, & IIIA share the tx paradigm outlined below. Grade IIIB is treated as DLBCL

• Immunophenotypically, FL cells classically express the B-cell Ags CD-19 & CD-20, the follicular center Ag CD-10, & the anti-apoptotic protein BCL-2. They do not express T-cell Ags, including CD-3 or CD-5 (the latter is often aberrantly expressed in CLL/SLL or MCL)

• Overexpression of BCL-2, an anti-apoptotic protein, is mediated by the t(14:18) w/c juxtaposes the BCL-2 gene to the Ig heavy chain locus in a large majority of cases. Translocation not sufficient to diagnose FL

• As w/other lymphomas, incisional or excisional bx is preferred for initial dx

• The term “follicular center cell lymphoma” is nonspecific & may refer to FL or DLBCL

Staging and Workup

• Ann Arbor Staging w/Cotswolds modifications, as for HL (J Clin Oncol 1989;7:1630)

• Staging primarily consists of cross-sectional imaging w/either a CT scan of chest/abdomen/pelvis ± neck or a PET scan

• PET particularly useful if there is concern for transformed disease or to confirm limited distribution in early stage

• Peripheral nodal areas evaluated w/PEx

• BM bx needed to complete staging, but can be deferred if observation or standard Rx for adv disease is planned

• CBC, comprehensive profile, LDH, HIV & hepatitis B & C serologies should also be sent

Prognostic Models

• As w/other lymphomas, stage alone confers limited prognostic info

• 2 main prognostic models have been reported: The FLIPI(Blood 2004;104:1258) & the FLIPI2 (J Clin Oncol 2009;26:4555)

Management: Stages I–II

• ISRT alone results in 10-y RFS of ∼40% w/Stage I pts faring better than Stage II (J Clin Oncol 1996;14:1282). The current recommended dose is 2400 cGy

• Observation is also reasonable in selected cases w/systemic or local Rx being employed when indicated by NCCN/GELF criteria, as for Stages III–IV

Management: Asymptomatic Stages III–IV (or intra-abdominal Stage II)

• Generally considered incurable w/standard therapies, & no survival advantage has been demonstrated w/earlier initiation of Rx

• Observation alone is recommended for most asymptomatic pts

• Observed pts are usu followed w/serial clinical exams & periodic CT (not PET). Optimal timing of scans not determined, may vary according to individual pt characteristics

• Median time to initiation of Rx in observed pts is ∼3 y

• Rituximab monotherapy increases time to first chemotherapy, but not survival (ASH Annual Meeting 2010;116:Abstract 6)

Management: Symptomatic Stages III–IV (or bulky Stage II), Front-line

• Enrollment in clinical trial should be encouraged

• Commonly accepted indications for Rx include: Any node >7 cm, or 3 nodes >3 cm, sx, cytopenias, fluid collections (ascites, pleural effusions), organ impairment & leukemic phase of disease (J Clin Oncol1998;16:2332)

• Multiple front-line therapeutic options. Choice of Rx is based on pt & disease characteristics, including: Volume & distribution of disease, age, & functional status of the pt, potential need for rapid response, potential concern for transformed disease (see below)

• Rituximab is a monoclonal Ab directed at the B-cell Ag CD-20. Efficacy has been shown w/both single-agent & combination Rx

• Rituximab monotherapy (4 weekly doses) is used 1° in pts w/low volume disease. ORR ∼70–75%, CR ∼40–45% in untreated pts (J Clin Oncol 2005;23:1103)

• More often, rituximab is added to chemotherapy. Standard regimens include R-CHOP, R-CVP, R-Bendamustine, & R-Fludarabine. Addition of rituximab to chemotherapy improves RR, PFS, & OS over chemo alone. No single regimen is preferred; individual pt factors guide decision

Maintenance & Consolidation Therapy

• Maintenance dosing of rituximab after completing initial Rx improves PFS (J Natl Cancer Inst 2011;103:1799)

• Rituximab re-tx at the time of progression results in similar TTTF, but uses less rituximab than maintenance (ASH Annual Meeting 2011;118, Abstract 6)

• RIT also improves PFS but not OS. It converts some PRs to CRs (J Clin Oncol 2008;26:5156)

Relapsed or Refractory Disease

• Transformed disease should be excluded w/PET ± bx

• Asymptomatic relapsed pts can be observed, as w/untreated pts

• Choice of 2nd-line Rx influenced by degree & duration of response to initial Rx. Front-line regimen can be re-used if remission duration was long

• Rituximab remains effective in relapsed pts. The single agent ORR is ∼45%, but it’s more commonly combined w/chemotherapy

• Very low-dose RT (400 cGy) may provide excellent local control & palliation in 70% of relapsed refractory pts

• Radioimmunotherapy

• Pts w/a short duration of remission may be considered for consolidation w/stem cell transplant after the 2nd- or subsequent-line Rx

• Choice of autologous or allogeneic transplant is made individually; usu based on such factors as pt age & comorbidity, availability of a suitable donor, & the biology & behavior of the lymphoma

Histologic Transformation

• There is a ~3%/y risk of transformation from FL to DLBCL, usu characterized by rapid nodal enlargement & rising LDH, ± systemic sx

• Bx required to diagnose transformation. PET may be useful in determining a site for bx. SUV values >10–13 suggest transformation (Ann Oncol 2009;20:508)

• No intervention has been demonstrated to prevent transformation

• Transformed disease is treated similar to de novo DLBCL, except that ISRT alone may be considered in selected pts