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

The purpose of this trial is to develop an alternative treatment for patients with poor risk non-Hodgkin's lymphoma. This trial uses a combination of high dose chemotherapy with stem cell transplant using the patient's own cells. This is followed with non-myeloablative transplant using stem cells from a related or unrelated donor to try and generate an anti-lymphoma response from the new immune system.

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.

Eligibility Criteria:
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