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1644 Part XI: Malignant Lymphoid Diseases Chapter 99: Follicular Lymphoma 1645

to be preferentially expressed in macrophages, dendritic cells, or both A watchful waiting approach may be particularly appropriate for certain
(e.g., TLR5, FCGR1A, SEPT10, LGMN, and C3AR1). Flow cytometry variants of FL, such as FL presenting in the small intestine, which pur-
and cell sorting confirmed that these signatures reflected gene expres- sues a remarkably indolent course, rarely exhibits progressive growth,
sion by nonmalignant tumor-infiltrating immune cells (CD19-negative very rarely disseminates (two of 63 patients) and does not transform to
cells) and not by the FL cells themselves (CD19-positive cells). The high-grade disease. 26
length of survival correlated with the molecular features of the nonma-
lignant immune cells present in the tumor at diagnosis and presumably Chemoimmunotherapy
reflected the robustness of the immune response mounted against the A large observational study, the National LymphoCare Study, assessed
tumor. the outcomes of 471 patients with stage I FL according to treatment
“Next-generation sequencing” studies employing whole-genome administered, including rituximab plus chemotherapy (28 percent of
or whole-exome sequencing and targeted mutational analyses have patients), radiotherapy alone (27 percent), observation (17 percent),
demonstrated that somatic mutations in epigenetic regulators are pres- systemic therapy + radiotherapy (13 percent), rituximab monotherapy
28
ent in almost all cases of FL, including MLL2 (also known as KMT2D), a (12 percent), and other treatments (3 percent). This large, prospectively
histone methyltransferase that is mutated in 89 percent of FL; CREBBP enrolled group of patients showed that national guidelines endorsing
and EP300, two highly related histone and nonhistone acetyltransfer- radiotherapy alone for stage I FL were not followed by practicing cli-
ases that act as transcriptional coactivators in multiple signaling path- nicians in the majority of cases. All treatment approaches resulted in
ways that are mutated in 30 percent and 11 percent of FL, respectively; excellent outcomes, though PFS was significantly better after a median
EZH2, the catalytic subunit of PRC2 that catalyzes trimethylation of followup of 57 months in patients treated with either rituximab plus
lysine 27 on histone H3, a repressive chromatin mark that is mutated in chemotherapy (84 percent) or systemic therapy plus radiotherapy (96
28
27 percent of FL; and MEF2B, a calcium-regulated gene that cooperates percent) than in patients receiving radiotherapy alone (68 percent).
with CREBBP and EP300 in acetylating histones that is mutated in 15 This study challenges the paradigm that radiotherapy alone should be
percent of FL. 20–24 Other mutational targets include genes involved in the standard of care for patients with early stage indolent lymphoma,
immune modulation (β -microglobulin, CD58, and TNFRSF14), Janus although the observational nature of this study, without randomization
2
kinase (JAK)-signal transducer and activator of transcription (STAT) to treatment arm and the absence of differences in OS, attenuates the
signaling (SOCS1 and STAT6) and B-cell receptor–nuclear factor (NF)- impact of the study.
22
κB signaling (BCL10, CARD11 and CD79B). Mutations in CREBBP
and EP300 lesions are usually heterozygous, suggesting a haploinsuf- ADVANCED STAGE FOLLICULAR LYMPHOMA
ficient role in tumor suppression, apparently by impairing acetylation-
mediated inactivation of the BCL6 oncoprotein and activation of the Observation Alone
21
p53 tumor suppressor. A unifying model of the genetic evolution of FL Many patients with FL, particularly grades 1 or 2, will exhibit an indo-
postulates that the t(14;18) translocation serves as a “founder mutation” lent, asymptomatic course despite the absence of therapy. Because there
that is succeeded by development of additional “driver mutations” (e.g., is no conclusive evidence that survival of FL patients is improved by
CREBBP), irrelevant “passenger” mutations, and accelerator mutations immediate institution of therapy, or that conventional management
(TNFRSF14). 22,23 Disagreement exists over whether MLL2/KMT2D (other than allogeneic stem cell transplantation) can cure the disease,
mutations are “driver” or “accelerator” mutations. 22,23 Mutations in EBF1 a “watch-and-wait” approach is often recommended for patients with
and in regulators of NF-κB signaling (e.g., MYD88, TNFAIP3) appear extensive stage II or stage III or IV FL. In one study, survival was 82
to be acquired at the time of histologic transformation to diffuse large percent at 5 years and 73 percent at 10 years after an initial strategy of
B-cell lymphoma. 22 observation alone, and the median time until therapy was required was
3 years. Spontaneous regressions occurred in 23 percent of untreated
29
patients. No differences in survival were observed in a trial of 309
THERAPY patients randomized to initial watchful waiting or to chlorambucil. In
30
another trial, patients were randomized to either watchful waiting or
LIMITED STAGE I OR II FOLLICULAR to immediate aggressive combination chemotherapy with prednisone,
LYMPHOMA methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlo-
Radiotherapy rethamine, vincristine, procarbazine, prednisone (ProMACE/MOPP)
31
Patients with stage I or II FL represent only 10 to 30 percent of cases in chemotherapy followed by total nodal irradiation. The OS rates for
most series. Standard management for stage I or limited contiguous the two groups were similar, although the disease-free survival rate
2,4
stage II FL involves the administration of involved field radiotherapy (35 was naturally higher in the patients treated with combined modality
to 40 Gray [Gy]). Adjuvant chemotherapy does not appear to improve therapy. Criteria established by the Groupe d’Etudes des Lymphomes
7
survival in this setting, although some studies suggest that combined Folliculaires (GELF) are useful to identify patients who may benefit
chemoradiotherapy may improve PFS. A retrospective review of 177 from intervention rather than “watchful waiting.” These criteria sug-
patients with stage I or II and grade 1 or 2 FL reported a median survival gest that treatment is likely to be required for patients with a maximum
27
of 14 years following radiation therapy as a single modality. Approx- diameter of any site of disease greater than 7 cm, more than three nodal
imately 50 percent of the patients were relapse-free after 5 to 10 years. sites greater than 3 cm in diameter, systemic B symptoms, a spleen size
greater than 16 cm, pleural effusions, local compressive symptoms, cir-
Observation culating lymphoma cells, or cytopenias as a result of the lymphoma. 32
Excellent survival has also been observed in highly selected patients
25
with early stage FL who received no initial therapy. In a group of Single-Agent Chemotherapy
43 patients, 56 percent were free from the requirement for treatment FL patients can be palliated effectively with a variety of single chemo-
for at least 10 years and 86 percent were alive 10 years after diagnosis. therapy agents (Table 99–1). Responses to single-agent therapy, such as
Based on this study, many authorities have concluded that “watchful chlorambucil, a nucleoside analogue, or bendamustine, range from 70
waiting” is an acceptable alternative to radiotherapy for stage I or II FL. to 90 percent and may last for several years. 30,33

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