Tandem Stem Cell Transplantation for Non-Hodgkin's Lymphoma

The approach to recurrent or primary refractory non-Hodgkin's lymphoma has been to treat
patients with second-line chemotherapy (usually 2-3 courses) for the purposes of
cytoreduction and to establish sensitivity to chemotherapy. Thereafter, peripheral blood
progenitor cells have been mobilized with cyclophosphamide and granulocyte colony stimulating
factor, apheresed and cryopreserved. 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.

In a group of 17 patients with transformed lymphoma who received autologous transplants at
Stanford University, the median EFS and OS were 1.48 and 2.7 years respectively with a 7-year
survival of only 20%. In comparison, patients with chemosensitive follicular lymphoma who
received the same regimen also had a poor median EFS of 1.3 years, but the median survival
was 6.7 years. The outcomes for patients with chemotherapy-resistant relapsed NHL is also
poor with EFS in the range of 20% in many studies of autologous transplantation.

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 we have 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. In addition, there are limited reports of using an autologous/allogeneic
approach for lymphoma patients using non-myeloablative allogeneic transplants. Eligible
patients will be treated with high-dose chemotherapy using BCNU, etoposide, cytarabine and
melphalan 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

- High risk disease including at least one of the following:

- Relapsed or refractory disease

- Transformed lymphoma

- Aggressive T-cell lymphoma

- Failure to achieve completed remission (CR) following Auto SCT

- Less than a 20% chance of event-free survival from autologous transplant
determined by the treating physician and the Principal Investigator

- ECOG performance status < or = 2

- Underwent Autologous SCT 60-120 days prior to registration including:

- BEAM conditioning (BCNU: 300 mg/m2 IV day -7, Etoposide: 100 mg/m2 IV BID days
-6,-5,-4,-3, Cytarabine: 100 mg/m2 IV BID days -6,-5,-4,-3, Melphalan: 140 mg/m2
IV day -2)

- Minimum of 2 x 106 CD34+ cells/kg infused

- Full hematologic recovery following Auto HCT including:

- Absolute neutrophil count (ANC) >1000 µl

- Platelet count of ≥50,000 µl independent of transfusion for >7 days

- Available matched related or unrelated donor. Selected donor must be a complete match
or have only a single antigen mismatch.

- Women of child-bearing potential and sexually active males must use an accepted and
effective method of birth control.

- Bone marrow comprising of < 10% lymphoma on most recent biopsy/aspiration (within 9
months of Allo transplant; may have been performed prior to autologous transplant).

- Serum bilirubin < or = 2 x the institutional ULN

- Serum creatinine < or = 2 x the institutional ULN and measured or estimated creatinine
clearance > 60 cc/min by the following formula

- Estimated Creatinine Clearance = (140 age)X WT(kg) X 0.85 if female 72X serum
creatinine(mg/dl).

- 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

- Prior autologous or allogeneic hematopoietic cell transplantation (other than
autologous SCT 60-120 days prior to registration)

- Prior radioimmunotherapy

- Known or suspected progressive disease following autologous SCT

- Additional treatment for NHL administered from time of autologous SCT through
registration

- Pregnant or breast-feeding women (due to the known birth defects association with the
treatments used in this study)

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

- Any prior malignancy is allowed except adequately treated basal cell or squamous cell
skin cancer, in situ cervical cancer or other cancer for which the patients has been
disease-free for five years.

- Active infection requiring oral or intravenous antibiotics.

Inclusion of Women and Minorities

-Both men and women and members of all races and ethnic groups are eligible for this trial.