Phase 2 Poor Risk DLBCL of TLI and ATG Followed by Matched Allogeneic HT as Consolidation to Autologous HCT
Condition: Lymphoma, B-cell; Lymphoma, Non-Hodgkin; Diffuse Large B-cell Lymphoma (DLBCL); Malignant Lymphoma, Non-Hodgkin
MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin
Intervention: Autologous hematopoietic stem cell transplantation (auto-HSCT); Allogeneic hematopoietic stem cell transplantation (allo-HSCT); Total lymphoid irradiation (TLI); Rituximab; Carmustine; Etoposide; Filgrastim; Anti-thymocyte globulin (ATG); Cyclosporine; Mycophenolate mofetil (MMF); Cyclophosphamide; Acetaminophen; Diphenhydramine; Hydrocortisone; Methylprednisolone
Intervention description: Auto-HCT involves an intravenous infusion of a participant's previously collected and frozen white blood cells collected after treatment with mobilizing agents; Allo-HCT involves an intravenous infusion of a donor's white blood cells collected after treatment with mobilization with filgrastim (G-CSF); TLI is administered in 80cGy fractions on Days -11 to Day-7 relative to allo-HSCT; 375 mg/m2 IV days 1 and 7 over 4 to 8 hours; Based on body weight, unless its more than 15 kg greater than the idal body 15mg/kg (max dose 550 mg/m2) day -6 over 2 hours.
Males IBW = 50 kg + 2.3 kg/inch over 5 feet Females IBW = 45.5 kg + 2.3 kg/inch over 5 feet Adjusted IBW = IBW + 50% (actual weight - IBW); 60 mg/kg over 4 hours day -4 and alternatively VP-16 2 Gm/m² may be used (for mobilization); 10 µg/kg/day subcutaneous starting Day 9 until last day of apheresis. 5 ug/kg actual body weight per day will be started at Day +6 after allo-HCT until hematologic recovery; 1.5 mg/kg/day for 5 days; 5.0 mg/kg twice daily from day -3 until after day +56; 250 mg (total) twice daily, oral
15 mg/kg po on day 0, at 5-10 hours after mobilized PBPC infusion is complete. On day +1 MMF is taken at 15 mg/kg po b.i.d. (30 mg/kg/day) if transplantation was using a matched related donor and 15 mg/kg po t.i.d if from a matched unrelated donor or a one antigen mismatched donor.; 100 mg/kg will be administered over 2 hours on day -2; Pre-medication for rituximab and PBPC infusion. Administered at 650 mg by mouth 1 hour prior to infusion; Pre-medication for rituximab and PBPC infusion. Administered at 50 mg intravenous 1 hour prior to infusion; Pre-medication for the PBPC infusion. Administered at 100 mg intravenous 1 hour prior to infusion; Anti-reaction medication for the ATG infusion. Administered at 1 mg/kg, Day-11 to Day-7
Intervention MeSH terms: Acetaminophen; Diphenhydramine; Promethazine; Cyclosporine; Mycophenolic Acid; Methylprednisolone; Methylprednisolone Hemisuccinate; Hydrocortisone; Cyclophosphamide; Carmustine; Rituximab; Etoposide; Cyclosporins; Antilymphocyte Serum; Lenograstim
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      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.
    

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.