Tandem Auto-Allo Transplant for Lymphoma
Condition: Diffuse, Large B-Cell, Lymphoma; Lymphoma, Low-Grade; T-Cell Lymphoma; Mantle-Cell Lymphoma; Hodgkin's Lymphoma; Chronic Lymphocytic Leukemia; Lymphoma, Small Lymphocytic
MeSH terms: Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Hodgkin Disease; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Lymphoma, Large B-Cell, Diffuse
Intervention: Busulfan (conditioning for AUTO transplant); Etoposide (conditioning for AUTO transplant); Cyclophosphamide (conditioning for AUTO transplant); Mesna (prior to AUTO transplant); autologous (auto) peripheral blood stem cell transplantation; Neupogen; Fludarabine (conditioning for ALLO Transplant); Busulfan (conditioning for ALLO Transplant); non-myeloablative allogeneic (allo) transplant; Tacrolimus; Sirolimus; Methotrexate
Intervention description: 0.8 mg/kg intravenous (IV) bolus every six hours (Q6H) on days -8,-7,-6,-5 (total of 14 doses). The total daily dose of busulfan will be 3.2 mg/kg on days -8,-7, and -6 and 1.6 mg/kg on day -5; Etoposide 30 mg/kg IV bolus every day (QD) on day -4. The total daily dose of etoposide will be 30 mg/kg.; Cyclophosphamide 60 mg/kg IV bolus QD on days -3 and -2. The total daily dose of cyclophosphamide will be 60 mg/kg.; Mesna 15 mg/kg IV bolus on days -3 and -2 infused over 15 minutes and given 15 minutes prior to cyclophosphamide administration. This is followed by Mesna given 15 mg/kg IV bolus three times daily (TID) on days -3 and -2 infused over 15 minutes at 3, 6, and 9 hours after completion of cyclophosphamide infusion. Total daily dose of Mesna should be equivalent to daily dose of cyclophosphamide. Lastly, Mesna will be given at 15 mg/kg IV bolus QD on day -1. This makes a total of 9 doses of Mesna; Infusion of autologous peripheral blood stem cells on Day 0.; Neupogen 5 mcg/kg subcutaneous (SQ) daily starting on day +1 until absolute neutrophil count (ANC) is greater than or equal to 1000 per micro liter on two separate occasions or greater than 5000 per micro liter once; Fludarabine 30 mg/m2/day will be administered as a bolus infusion over approximately 30 minutes for 4 days on days -5, -4, -3, -2.; Busulfan will be administered by IV infusion over approximately 3 hours on days -5, -4, -3, -2. The dose of busulfan will be 0.8 mg/kg/day; Donor peripheral blood stem cells (PBSC) will be infused intravenously beginning on Day 0. The minimum total CD34+ cell dose will be 2 x 10^6 CD34+cells/kg of recipient's actual body weight with a maximum dose of 8 x 10^6/kg of recipient's actual body weight; Tacrolimus (FK506) will be given orally at a dose of 0.05 mg/kg orally (PO) twice a day (BID) starting day -3.; Sirolimus (rapamycin) will be given orally at a dose of 12 mg times one on day -3 and then the dose shall be 4 mg by mouth daily starting on day -2. The dose may then be adjusted according to serum levels at the discretion of the treating physician; Methotrexate will be administered once daily on days 1, 3, and 6 as an IV bolus over 15 minutes at a dose of 5 mg/m2
Intervention MeSH terms: Sirolimus; Cyclophosphamide; Busulfan; Methotrexate; Fludarabine; Etoposide; Tacrolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 42.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Lymphoma; non-hodgkins lymphoma; Hodgkin's lymphoma; Hodgkin's disease; stem cell transplant; High-risk diffuse large B cell; Transformed low grade lymphoma; T-cell non-Hodgkin's lymphoma; Mantle cell lymphoma at any time in therapy; "Double-hit" lymphoma

Summary:

      Relapse remains a principle cause of treatment failure for patients with aggressive lymphoma
      after autologous transplantation. Non-myeloablative allogeneic transplantation allows
      patients to receive an infusion of donor cells in an attempt to induce a graft versus
      lymphoma effect. This study will assess the feasibility, safety and efficacy of the
      combination of autologous stem cell transplantation followed by non-myeloablative
      transplantation for patients with poor-risk aggressive lymphoma.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients with high-risk diffuse large B cell or transformed low grade lymphoma defined
             as:

               -  Residual disease after at least 6 cycles of anthracycline-based chemotherapy
                  (with residual disease defined as persistent bone marrow involvement and/or
                  persistent measurable lymph node or solid organ masses that are PET or gallium
                  avid)

               -  Progressive disease after at least 2 cycles of anthracycline-based chemotherapy

               -  Patients with an initial complete response but subsequent relapse within 6 months
                  after completion of anthracycline-based chemotherapy

          -  Patients with any T-cell non-Hodgkin's lymphoma as defined as:

               -  Peripheral T-cell lymphoma (ALK negative PTCL-U) including PTCL-NOS, HSGD
                  (hepato-splenic gamma-delta TCL), AITL (angioimmunoblastic T-cell lymphoma), EATL
                  (enteropathy associated T-cell lymphoma), ALK-negative anaplastic large cell
                  lymphoma

               -  Any T-cell histology (except LGL) with residual disease after at least 4 cycles
                  of anthracycline-based chemotherapy (with residual disease defined as persistent
                  bone marrow involvement and/or persistent measurable lymph node or solid organ
                  masses that are PET or gallium avid)

          -  Patients with mantle cell lymphoma at any time in therapy

          -  Patients with "double-hit" lymphoma as characterized by the presence of concurrent
             overexpression of Bcl-2 and c-myc

          -  Patients with Hodgkin's lymphoma that is

               -  Refractory to first-line therapy and at least one second line chemotherapy
                  regimen

               -  Relapsed Hodgkin's lymphoma which is refractory to at least one salvage
                  chemotherapy regimen.

          -  Patients with CLL/SLL with 17p- cytogenetic abnormality

          -  Age 18 years and greater

          -  ECOG performance status 0-2

          -  Ability to understand and the willingness to sign a written informed consent document.

          -  Responsive disease to last therapy as determined by at least one of the following:

               -  At least PR by Revised Response Criteria

               -  At least PR by traditional Cheson Criteria

               -  < 10% of overall cellularity involved with disease on bone marrow biopsy for
                  patients with involvement of the bone marrow

          -  Minimum of 2 x 106 CD34+ cells / kg already collected and frozen. These stem cells may
             have been collected from PBSC pheresis, bone marrow harvest, or the combination.

        Exclusion Criteria:

        Patients will be re-evaluated after autologous transplant prior to proceeding to
        non-myeloablative transplant

          -  Pregnancy

          -  Evidence of HIV infection

          -  Heart failure uncontrolled by medications or ejection fraction less than 45%

          -  Active involvement of the CNS by lymphoma

          -  Inability to provide informed consent

          -  Previous autologous or allogeneic stem cell transplant

          -  Creatinine greater than 2 gm/dL or 24 hour urine creatinine clearance < 50 cc/minute
             (does not have to satisfy both)

          -  Total bilirubin greater than 2 times the upper limit of normal except when due to
             Gilbert's syndrome or hemolysis.

          -  Transaminases greater than 3 times the upper limit of normal

          -  FVC or DLCO of less than 50% of predicted (DLCO corrected for hemoglobin level)

          -  Already known to not possess suitably HLA-matched related or unrelated donor

        Eligibility to proceed to allogeneic transplant Cannot be admitted for allogeneic
        transplant earlier than 40 days and no later than 180 days after autologous stem cell
        transplant.

          -  HLA identical (A, B, C and DR) related or unrelated donor available. HLA typing of
             class I loci (HLA- A, B, C) will be based on complement dependent cytotoxicity assay
             or PCR of sequence specific oligonucleotide primers (SSOP). Typing of HLA class II
             (DRB1) will be based on PCR of sequence specific oligonucleotide primers (SSOP).

          -  No need for intravenous hydration in the previous 2 weeks

          -  Resolved mucositis

          -  Renal, cardiac, pulmonary, and hepatic function meet standard criteria for
             nonmyeloablative SCT as listed below:

               -  Serum Cr < 2 gm/dL

               -  LV ejection fraction > 30% and no uncontrolled symptoms of congestive heart
                  failure

               -  DLCO > 50% of predicted value (corrected for hemoglobin)

               -  Transaminases < 5X the institution upper limit of normal

               -  Bilirubin < 3X the institution upper limit of normal except when Gilbert's
                  Syndrome or hemolysis is present

               -  ECOG PS ≤ 2

          -  No intravenous antimicrobials within 2 weeks

          -  No evidence of progressive disease, defined as a 25% increase from nadir in the sum of
             the product of the diameters (SPD) of any lymph node previously identified as abnormal
             prior to autologous transplant or the appearance of any new lymph node greater than
             1.5 cm in greatest diameter, new bone marrow involvement, or new solid organ nodule
             greater than 1 cm in diameter. This restaging study will be performed at least 28 days
             after the autologous transplant and within 60 days prior to admission for allogeneic
             transplant. Status of stable disease (SD) is acceptable to proceed to allogeneic
             transplant.