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1642 Part XI: Malignant Lymphoid Diseases Chapter 99: Follicular Lymphoma 1643

losses of 1p36.33–p36.31,6q23.3–q24.1, and 10q23.1–q25.1 and gains of 1.00
2p16.1–p15,8q24.13–q24.3, and 12q12–q13.13. Copy-number abnor-
malities more commonly observed in transformed FL include gains of
3q27.3–q28 and chromosome 11 and losses of 9p21.3 and 15q. Impor- 0.75 ±R
10
tant candidate genes whose expression is affected by these copy-num-
ber abnormalities includeTNFRSF14, PRDM16, TP73, and ARIDIA 0.50 ±R
on chromosome 1p36; BCL10 on chromosome 1p; REL and BCL11A Cumulative progression 3-year PFS
on 2p16; BCL6 on chromosome 3q27; histocompatibility locus anti- –R +R ±R
gen (HLA)-B, HLA-C, CCND3, and PRDM1 on chromosome 6p21; 0.25 FLIPI 0–1 72% FLIPI 0–1 81%
TNFAIP3 or PERP on chromosome 6q23; CARD11 on chromosome FLIPI 2 50% FLIPI 2 65%
7p22; MYC on chromosome 8q24; CDKN2A or CDKN2B on chromo- FLIPI 3–5 40% FLIPI 3–5 54%
p < 0.001
p < 0.001
some 9p21; STAT6 on 12q13.3; and MDM2 on 12q15. 10 0
0 6 12 18 24 30 36 42 48
Months
STAGING THE DISEASE
Evaluation of FL involves performance of a medical history, physical Figure 99–3. Progression-free survival (PFS) of 827 patients with FL
stratified by the Follicular Lymphoma International Prognostic Index
examination (with attention to the lymph nodes in Waldeyer ring and (FLIPI) into low risk (0 to 1 risk factors, 40% of patients, black lines), inter-
size and involvement of liver and spleen), laboratory testing (including mediate risk (2 risk factors, 33% of patients, blue lines), or high risk (3 to
a complete blood count, examination of the blood film and a differen- 5 risk factors, 27% of patients, red lines). Of the 827 patients, 267 were
tial white cell count, lactic dehydrogenase [LDH], β -microglobulin, treated with chemotherapy regimens without rituximab (dotted lines)
2
comprehensive metabolic panel, serum uric acid level); lymph node and 560 were treated with rituximab-containing regimens (solid lines).
biopsy; marrow aspiration and biopsy; flow cytometric analysis of blood, (Data from Federico M, Bellei M, Pro B: Revalidation of FLIPI in patients with
marrow, and lymph node cells; and computed tomography (CT) of the follicular lymphoma registered in the F2 study and treated upfront with
chest, abdomen, and pelvis. Excisional lymph node biopsies are strongly immunochemotherapy. Proc Am Soc Clin Oncol 25:443s, 2007.)
7
preferred for the initial histologic diagnosis of FL, although in cases in
which nodal masses are inaccessible, generous needle-core biopsies may ≥120 g/L), number of nodal areas (>4 vs. ≤4), and serum LDH level
suffice. The diagnosis should not be established merely on the basis of (high vs. normal). Three risk groups were defined: low risk (zero to one
flow cytometry of the blood or marrow, or on cytologic examination of adverse factors, 36% of patients), intermediate risk (two adverse factors,
aspiration needle biopsies of lymph node or other tissue. Hepatitis B 37% of patients, hazard ratio [HR] = 2.3), and poor risk (three or more
11
serology should be assessed if rituximab therapy is contemplated, as hep- adverse factors, 27% of patients, HR = 4.3). The Follicular Lymphoma
atitis reactivation with rituximab may occasionally be life-threatening. In International Prognostic Index (FLIPI) discriminated outcomes for FL
selected circumstances, additional CT scans of the neck, measurement better than the IPI, both in the original cohort and in later studies evalu-
of the cardiac ejection fraction, serum protein electrophoresis, quantita- ating patients treated with modern combined rituximab-chemotherapy
tive immunoglobulins, and hepatitis C testing may be useful. Patients for regimens (Fig. 99–3). A revised version of the FLIPI index (FLIPI2)
15
whom chemotherapy is contemplated should receive counseling regard- was subsequently proposed to address perceived deficiencies in the
ing contraception, fertility issues, and sperm or egg banking. The role of original model. The FLIPI2 model is also based on assessment of five
16
fluoro-2-deoxyglucose (FDG)-positron emission tomography (PET)/ adverse risk factors, namely the presence or absence of an elevated β -
2
CT imaging in FL is rapidly evolving. Although PET/CT imaging was microglobulin level, the longest diameter of the largest involved lymph
previously considered optional in FL, recent studies suggest that PET- node (>6 cm), presence of marrow involvement, hemoglobin level less
negativity at the completion of induction chemotherapy is one of the most than 12 g/dL, and age older than 60 years. Although several studies have
powerful predictors of both progression-free survival (PFS) and overall demonstrated the superiority of the FLIPI2 model compared to the
survival (OS) in this disease. 12 original FLIPI model, it has not been widely adopted in North America.
A simpler prognostic model was developed based solely on the baseline
PROGNOSTIC FACTORS serum LDH and β -microglobulin level that has been shown to be supe-
2
rior to the original FLIPI model and equivalent to the FLIPI2 model in
prognostic power for predicting outcomes for FL patients. 17, 18
CLINICAL AND LABORATORY VARIABLES
An international working group developed an international prognostic
index (IPI) based on five independent variables (age, stage, LDH level, GENOMICS OF FOLLICULAR LYMPHOMA
performance status, and number of extranodal sites) that affected OS of New molecular approaches are revolutionizing our understanding of the
aggressive lymphoma patients treated with anthracycline-based com- pathogenesis of FL and providing insights into the pathways that might
13
bination chemotherapy. The IPI was subsequently applied retrospec- be targeted in the future by rationally designed therapies. Early gene-
tively to FL and found to be predictive of both OS and PFS for FL (as expression profiling studies of biopsy specimens from patients with
well as diffuse large B-cell lymphoma). Nevertheless, the IPI was con- untreated FL identified two gene-expression signatures that allowed
sidered to be suboptimal for segregating indolent lymphoma patients construction of a survival predictor enabling segregation of patients
into prognostic categories because only 10 to 15 percent of patients into four quartiles with disparate median lengths of survival (13.6, 11.1,
19
with FL fall into the poor risk category using this index. To redress this 10.8, and 3.9 years), independent of clinical prognostic variables. One
deficiency, a French cooperative group conducted a detailed prognostic signature (“immune response 1”) was associated with a good prognosis
factor analysis of 4167 patients with FL diagnosed between 1985 and and included genes encoding T-cell markers (e.g., CD7, CD8B1, ITK,
14
1992 for whom prolonged followup was available to assess OS. Five LEF1, and STAT4) as well as genes that are highly expressed in macro-
adverse prognostic factors were detected: age (>60 years vs. ≤60 years), phages (e.g., ACTN1 and TNFSF13B). The “immune response 2” signa-
Ann Arbor stage (III to IV vs. I to II), hemoglobin level (<120 g/L vs. ture was associated with a poor prognosis and included genes known

Kaushansky_chapter 99_p1641-1652.indd 1643 9/18/15 3:57 PM