Blood Stem Cell Transplant With Low Dose Chemotherapy for Relapsed Follicular Non-Hodgkin's Lymphoma (BMT CTN 0701)

Follicular NHL, a type of blood cancer, is the second most common type of non-Hodgkin's
lymphoma, with approximately 15,000 new cases being diagnosed each year in the United States.
Chemotherapy is a common treatment option for people with NHL, and at first most people
achieve cancer remission with initial chemotherapy. However, after the initial chemotherapy,
people with this disease typically experience a continuous pattern of relapse that results in
progressively shorter remission durations. A blood stem cell transplant is another treatment
option for people with follicular NHL. In a blood stem cell transplant procedure, healthy
blood stem cells are taken from a donor and transplanted into the patient. The cells can be
donated by a family member or an unrelated donor who has a similar tissue type. Typically,
people who are undergoing a blood stem cell transplant receive high doses of chemotherapy
before the transplant to prepare their bodies to accept the donor stem cells. In this study,
participants will undergo a type of stem cell transplant called a nonmyeloablative
transplant, which involves a reduced intensity method of transplantation that does not
require high doses of chemotherapy. The purpose of the study is to examine the effectiveness
of a nonmyeloablative allogeneic blood stem cell transplant at improving survival rates in
people with relapsed follicular NHL.

This study will enroll people with relapsed follicular NHL. At a baseline study visit,
participants will undergo a medical history review, physical examination, blood collection,
lung function testing, computed tomography (CT) scans, a bone marrow biopsy, and
questionnaires to assess quality of life. Participants will be admitted to the hospital and
on various days in the 2 weeks before the transplant, they will receive fludarabine,
cyclophosphamide, rituximab, which are cancer medications, and tacrolimus, a medication that
will help prevent graft-versus-host disease (GVHD), which is an attack by the donor cells on
the body's normal tissues. Participants will then undergo the blood stem cell transplant. At
various times during the 2 weeks after the transplant, participants will receive rituximab
and methotrexate, which is another medication to prevent GVHD. They will also receive
tacrolimus for at least 6 months to help prevent GVHD. Participants will remain in the
hospital for as long as necessary to recover from the transplant. Follow-up study visits will
occur weekly for Weeks 1 to 14, and then at Months 6, 12, 18, and 24. At each study visit,
select baseline procedures will be repeated.

Inclusion Criteria:

- Must have confirmed CD20+ follicle center lymphoma that meets one of the following:

1. Histologically confirmed recurrent Revised European American Lymphoma (REAL)
Classification CD20+ follicle center lymphoma, follicular grades I and II

2. Histologically confirmed World Health Organization (WHO) classification CD20+
follicular lymphoma grades 1, 2, or 3a.

For either classification, the diffuse component of large cleaved cells (if
present) cannot be greater than 50% of cellularity. Patients do not have to
express t(14;18) to be eligible.

- Any number of prior regimens (including autologous hematopoietic cell transplantation
[HCT]); the most recent prior regimen must have occurred more than 28 days before
study entry

- Must demonstrate chemosensitive or radiosensitive disease to most recent prior regimen
and meet one of the following criteria:

1. Patients in second or subsequent complete remission (CR)

2. Patients in first or subsequent partial remission (PR)

3. Patients experiencing a relapse that demonstrates a response, as defined as
largest nodal mass less than or equal to 3 cm or greater than or equal to 50%
reduction in estimated lymph node volume measured as a product of bi-dimensional
measurements (see protocol for detailed definition).

4. Patients with stable follicular lymphoma are eligible if all lymph node masses
are less than or equal to 3 cm and are smaller or unchanged in size to the most
recent salvage regimen.

- Patients with human leukocyte antigen (HLA)-matched donors that meet the following
criteria:

1. 6/6 HLA-matched related donor. HLA typing must be performed by DNA methods for
HLA-A and B at intermediate (or higher) resolution, and DRB1 at high resolution.
The donor must be willing to donate peripheral blood stem cells and meet
institutional criteria for stem cell donation. The donor must be medically
eligible to donate stem cells according to individual transplant center criteria;
or,

2. 8/8 HLA-matched unrelated donor. HLA typing must be performed by DNA methods for
HLA-A, B, C, and DRB1 at high resolution. The donor must be willing to donate
peripheral blood stem cells and meet National Marrow Donor Program (NMDP)
criteria for stem cell donation. The donor must be medically eligible to donate
stem cells according to NMDP criteria.

- Patients with adequate organ function, as measured by the following:

1. Heart: Left ventricular ejection fraction at rest greater than 45%

2. Lungs: Diffusing capacity of the lung for carbon monoxide (DLCO), forced
expiratory volume in one second (FEV1), or forced vital capacity (FVC) greater
than 50% of predicted (corrected for hemoglobin). For patients in whom pulse
oximetry is performed, baseline O2 saturation greater than 85% (when lung
function testing cannot be performed due to age restrictions)

3. Liver: Bilirubin less than two times the upper limit of normal for age as per
local laboratory; alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) less than three times the upper limit of normal as per local laboratory

4. Kidney: Calculated or measured creatinine clearance greater than or equal to 40
mL/min; if creatinine is greater than or equal to 1.5 mg/dL then 24-hour urine
for measured creatinine clearance should be performed.

Exclusion Criteria:

- Patients in first CR

- Karnofsky performance score less than 70%

- Patients with follicular lymphoma that demonstrates evidence of histologic
transformation. In the presence of B symptoms, rapid growth of a single dominant site,
or prolonged (> 2 yrs) interval since last tissue diagnosis, investigators are
encouraged to consider re-biopsy of nodes prior to enrollment.

- Uncontrolled hypertension

- Uncontrolled bacterial, viral, or fungal infection (i.e., currently taking medication
and progression of clinical symptoms)

- Prior cancer, other than resected basal cell carcinoma or treated cervical carcinoma
in situ. Cancer treated with curative intent less than 5 years will not be allowed
unless approved by the medical monitor or protocol chair. Cancer treated with curative
intent greater than 5 years will be allowed.

- Pregnant or breastfeeding

- Seropositive for human immunodeficiency virus (HIV)

- Fertile men or women unwilling to use contraception from the time of initiation of
conditioning until 6 months post-transplant

- Prior allogeneic HSCT

- Known anaphylactic reaction to rituximab

- Seropositive for any of the following: HIV ab, hepatitis B sAg or polymerase chain
reaction (PCR)+, or hepatitis C ab or PCR+