Autologous Followed by Non-myeloablative Allogeneic Transplantation for Non-Hodgkin's Lymphoma

Currently, patients with recurrent or primary refractory non-Hodgkin's lymphoma are treated
with second-line chemotherapy (usually 2-3 courses) for the purpose of cytoreduction and to
establish sensitivity to chemotherapy. Thereafter, peripheral blood progenitor cells are
mobilized with cyclophosphamide and granulocyte colony stimulating factor, apheresed and
cryopreserved. The standard high dose regimen consists of augmented carmustine, etoposide and
cyclophosphamide. Unfortunately, there are subgroups of patients with poor outcomes using
autologous transplantation including those with transformed lymphoma as well as patients who
do not attain a minimal disease state due to chemoresistant disease.

These groups of patients have limited disease control and survival with standard chemotherapy
regimens, and although they often have excellent cytoreduction with the high-dose
chemotherapy regimen, relapse remains the primary cause of treatment failure. The current
trial utilizes a similar approach that has been taken with patients with multiple myeloma,
who appear to benefit from an allogeneic graft-versus-tumor effect, using a combined
autologous and non-myeloablative allogeneic transplant regimen to reduce transplant-related
complications. Eligible patients will be treated with high-dose chemotherapy using BCNU,
etoposide and cyclophosphamide with autologous hematopoietic cell support as a method of
cytoreduction. Approximately 60-120 days after the autologous transplant, patients will
receive an allogeneic transplant using a preparative regimen of total lymphoid irradiation
and anti-thymocyte globulin in an attempt to develop a graft-versus-lymphoma effect.

Inclusion Criteria:

- Age 18 to 70 years.

- Histologically proven non-Hodgkin's lymphoma

- Relapse after achieving initial remission or failure to achieve initial remission.

- KPS > 70%

- Matched related or unrelated donor identified and available. Donor must be a complete
match or have only a single allele mismatch.

- Recent Bone marrow biopsy and cytogenetic analysis

- Patients must have a pretreatment serum bilirubin < 2 x the institutional ULN, a serum
creatinine < 2 x the institutional ULN and measured or estimated creatinine clearance
> 50 cc/min by the following formula (all tests must be performed within 28 days prior
to mobilization ): Estimated Creatinine Clearance = (140 age) X WT(kg) X 0.85 if
female 72 X serum creatinine(mg/dl).

- Patients must have an EKG within 42 days prior to registration that shows no
significant abnormalities that are suggestive of active cardiac disease.

- Patients must have an echocardiogram or MUGA scan within 42 days of registration. If
the ejection fraction is < 40%, the patient will not be eligible. If the ejection
fraction is 40-50%, patients must have an exercise echocardiogram or dobutamine-echo
with a normal response to exercise.

- Patients must have a corrected diffusion capacity > 50% prior to the autologous
transplant and > 40% prior to the allogeneic transplant.

- Patients with known allergy to etoposide or a history of Grade 3 hemorrhagic cystitis
with cyclophosphamide are not eligible.

- Patients must be informed of the investigational nature of this study and must sign
and give written informed consent in accordance with institutional and federal
guidelines.

Exclusion Criteria:

- Pregnant or breast-feeding women are ineligible due to the known birth defects
association with the treatments used in this study.

- Patients known to be human immunodeficiency virus (HIV)-positive are ineligible
because the concern for opportunistic infection and hematologic reserve are considered
to be significantly greater in this population.

- Patients with prior maligancies diagnosed > 5 years ago without evidence of disease
are eligible. Patients with a prior malignancy treated < 5 years ago but have a life
expectancy of > 5 years for that malignancy are eligible.

- Patients with uncontrolled infection.

- No prior autologous or allogeneic hematopoietic cell transplantation.

Donor Selection/Evaluation:

- Related or unrelated HLA identical donors who are in good health and have no
contra-indication to donation.

- No contra-indication for the donor to collection by apheresis of mononuclear cells
mobilized by G-CSF at a dose of 16 µg/kg of body weight.

- Virology testing including CMV, HIV, EBV, HTLV, RPR, Hepatitis A, B and C will be
performed within 30 days of donation.

- No prior malignancy is allowed except adequately treated basal cell or squamous cell
skin cancer, in situ cervical cancer or other cancer for which the donor has been
disease-free for five years