Clonal Evolution in Follicular Lymphoma

Background:

- Follicular lymphoma (FL) is the second most common form of non-Hodgkin lymphoma and is
incurable with standard first-line systemic therapy

- The clinical course of FL varies from slowly progressive over many years to a more rapid
disease course that requires therapy shortly after diagnosis

- Early initiation of therapy does not improve survival, and asymptomatic patients are
often managed with an initial period of watchful waiting

- Clinical prognostic indices predict survival, but cannot predict outcome for individual
patients; biologic-based classifiers (gene-expression profiling and somatic mutational
analyses) are more robust than clinical indices, but require prospective clinical
validation from the time of diagnosis in the modern treatment era

- Paired samples linked to clinical information can lead to the discovery and/or
validation of therapeutic targets for FL patients at the highest risk of early disease
progression

Objective:

Characterize the molecular biology and clinical course of FL patients, and evaluate the time
to treatment initiation for those patients who require first-line systemic therapy

Eligibility:

- Follicular lymphoma (grade 1-2, 3a) with no evidence of histological transformation

- No previous cytotoxic, biologic or monoclonal antibody therapy for FL (previous
radiation therapy permitted)

- Age greater than or equal to 18 years

- ECOG performance status of 0-2

Design:

- Patients with FL who meet all eligibility criteria will enroll on the study for expert
monitoring of their disease, improved risk-stratification, and donation of tissue and
cellular products for research. Patients will be monitored prospectively until they
require second-line systemic treatment or the patient decides to withdraw from the
study; untreated patients will be followed with clinic visits every 4 months for the
first 2 years. After 2 years, protocol-specified visits will be increased to every 6
months until 5 years. After 5 years, protocol-specified visits will be annually until
disease progression requiring first-line therapy.

- Patients without an indication for first-line systemic therapy at 2 years from initial
study enrollment will be offered an optional biopsy of their lymph node and bone marrow.

- During first-line systemic therapy, patients can continue being monitored on this study
for post-therapy clonal evolution. Protocol-specified visits after therapy will be every
6 months until 3 years. After 3 years, protocol-specified visits will be annually until
disease progression requiring second-line therapy.

- Upon initiation of second-line therapy, if applicable, patients will move to survival
follow-up only.

- INCLUSION CRITERIA:

- Histologically or cytologically confirmed follicular lymphoma (FL), grades 1-2, or 3a
confirmed by the Laboratory of Pathology, NCI; patients who meet criteria for
immediate initiation of systemic therapy are eligible

- Adequate tissue available from original diagnostic biopsy.

NOTE: If biopsy was >12 months prior to enrollment OR adequate tissue is not available,
tissue biopsy may be optionally repeated at study enrollment unless such a biopsy is
considered unacceptable risk to the patient. Patients without adequate tissue are eligible
at the discretion of the PI.

- Must have disease that is measurable or evaluable on either computed tomography (CT)
scans or FDG-positron emission tomography (FDG-PET) scans

- Age greater than or equal to 18 years

NOTE: Patients with the pediatric-type follicular lymphoma are usually <18 years of age,
and often have a very different clinical course than patients with the adult-type of FL.
Due to this difference in biology, children are excluded from this study.

- ECOG performance status <2 (Karnofsky >60%

EXCLUSION CRITERIA:

- Previous history of diffuse large B-cell lymphoma or histologic transformation

- Any prior systemic treatment for lymphoma including cytotoxic chemotherapy, biologic
therapy, and monoclonal antibody therapy (radiotherapy permitted); patients who have
received chemotherapy, biologic therapy, hormonal therapy, or monoclonal antibody for
other malignancies are potentially eligible provided that all of the following are
true: a) that malignancy was not lymphoma, b) systemic therapy ended at least 3 years
prior to the diagnosis of FL, and c) there is no evidence of active malignancy other
than FL

NOTE: Initiation of first-line systemic therapy is allowed while on this trial; concurrent
participation in first-line treatment clinical trials will be permitted.

- Patients who are HIV-positive

- Any second malignancy that requires active systemic therapy

- Any other (non-lymphoma) life-threatening disease

- Patients unable to provide informed consent (surrogates will not be used)

- Pregnant women are excluded from enrollment onto this study because the invasive
procedures and/or sedation needed to perform these may cause unnecessary harm to the
unborn fetus. In the event a woman becomes pregnant while on study, she will not be
removed from the study; however, no follow-up invasive clinical or research procedures
will be done that include unacceptable to risk to the patient and/or to the unborn
fetus.