Phase 2 Poor Risk DLBCL of TLI and ATG Followed by Matched Allogeneic HT as Consolidation to Autologous HCT

The purpose of this study is to determine if double autologous then allogeneic hematopoietic cell transplant may offer an improved treatment option for patients with relapsed diffuse large B-cell lymphoma (DLBCL) who are not likely to be cured by the conventional transplantation regimen.

This study tests a tandem transplant approach that starts with transplantation of the participant's own hematopoietic (blood) cells, eg, autologous hematopoietic cell transplant (auto-HCT) as preparation for an subsequent matched-donor allogeneic HCT (allo-HCT).

Participants will be have progenitor cells (stem cells) mobilized into the peripheral blood with rituximab, chemotherapy (cyclophosphamide or etoposide), and filgrastim (G-CSF); undergo apheresis to collect autologous peripheral blood stem cells (PBSC, aka hematopoietic cells); and be re-infused with ≥ 3 x 10e6 CD34+ cells/kg (auto-HCT). Subsequently, participants will receive therapeutic, non-myeloablative chemotherapy (carmustine + cyclophosphamide + etoposide), then transplant conditioning \[total lymphoid irradiation (TLI) + anti-thymocyte globulin (ATG)\] followed by ≥ 2 x 10e6 CD34+ cells/kg allogeneic PBSC obtained from a human leukocyte antigen (HLA)-matched or HLA single allele / antigen-mismatched donor (allo-HCT). Donors will be mobilized with 16 µg/kg filgrastim. Participant allo-HCT transplant is to occur within 150 days of auto-HCT. Post-allo-HCT infusion treatment includes cyclosporine and mycophenolate mofetil (MMF)

Subject's participation ends if a suitable matched donor is not identified within the 150 days.

Pre-medication treatments administered during this study may include acetaminophen; diphenhydramine; hydrocortisone; and methylprednisolone.

Eligibility Criteria:
INCLUSION CRITERIA

* Age 18 to 70 years.
* Histologically-proven diffuse large B-cell lymphoma (DLBCL) by the World Health Organization (WHO) classification.
* Relapse after achieving initial remission or failure to achieve initial remission. Patients with residual radiographic abnormalities after primary therapy are eligible if abnormalities are postive by fluorodeoxyglucose (FDG)-positron emission tomography (PET) (FDG-PET).
* Receipt of 2 cycles of second-line therapy and FDG-PET positive per Stanford (central) review. FDG-PET to be done 2 weeks after cycle 2 of second line chemotherapy.
* Eastern Cooperative Oncology Group (ECOG) performance status \< 2
* Matched related or unrelated donor identified and available
* Bone marrow biopsy and cytogenetic analysis within 8 weeks of registration
* Pretreatment serum bilirubin \< 2 x the institutional upper limit of normal (ULN)
* Serum creatinine \< 2 x the institutional ULN and measured or estimated creatinine clearance \> 60 mL/min by the following formula (all tests must be performed within 28 days prior to registration):

  * Estimated Creatinine Clearance = (140 age) x weight (kg) x 0.85 if female 72 x serum creatinine (mg/dL).
* EKG within 42 days prior to registration with no significant abnormalities suggestive of active cardiac disease
* Patients must have a radionuclide ejection fraction within 42 days of registration. If the ejection fraction is \< 40%, the patient will not be eligible. If the ejection fraction is 40-50%, the patient will have a cardiology consult.
* Corrected diffusion capacity \> 55%.
* Sexually active males are advised to use an accepted and effective method of birth control
* Women of child-bearing potential are advised to use an accepted and effective method of birth control
* Patients must sign and give written informed consent in accordance with institutional and federal guidelines. Patients must be informed of the investigational nature of this study.

EXCLUSION CRITERIA

* Known allergy to etoposide or a history of Grade 3 hemorrhagic cystitis with cyclophosphamide
* Greater than Grade 2 sensory or motor peripheral neuropathy from prior vinca alkaloid use
* Requiring therapy for coronary artery disease, cardiomyopathy, dysrhythmia, or congestive heart failure
* Known to be human immunodeficiency virus (HIV)-positive. The antibody test for HIV must be performed within 42 days of registration.
* Prior chemotherapy other than corticosteroids administered within 2 weeks of the initiation of protocol therapy.
* Prior malignancy, 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.
* Prior diagnosis of non-Hodgkin's lymphoma
* Active infection requiring oral or intravenous antibiotics
* Prior autologous or allogeneic hematopoietic cell transplantation
* Prior radioimmunotherapy
* Pregnant
* Lactating

DONOR ELIGIBILITY

* 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.
* Donors will be evaluated with a full history and physical examination.
* Virology testing including HIV; cytomegalovirus (CMV); Epstein-Barr virus (EBV); human T-lymphotropic virus (HTLV); rapid plasma reagin (RPR); Hepatitis A, B and C be performed within 30 days of donation.
* Prospective donors will be screened for CMV seroreactivity and seronegative donors will be utilized if available.
* If more than one human leukocyte antigen (HLA)-matched related donor exists, then the donor will be selected on the basis of CD31 allotype.