Tandem Auto-Allo Transplant for Lymphoma

Phase 2

Completed

Conditions: Lymphoma, Low-Grade
T-Cell Lymphoma
Diffuse, Large B-Cell, Lymphoma
Mantle-Cell Lymphoma
Chronic Lymphocytic Leukemia
Lymphoma, Small Lymphocytic
Hodgkin's Lymphoma

Interventions: Drug: Busulfan (conditioning for AUTO transplant)
Drug: Etoposide (conditioning for AUTO transplant)
Drug: Cyclophosphamide (conditioning for AUTO transplant)
Drug: Mesna (prior to AUTO transplant)
Other: autologous (auto) peripheral blood stem cell transplantation
Drug: Neupogen
Drug: Fludarabine (conditioning for ALLO Transplant)
Drug: Busulfan (conditioning for ALLO Transplant)
Other: non-myeloablative allogeneic (allo) transplant
Drug: Tacrolimus
Drug: Sirolimus
Drug: Methotrexate

Registration Number: NCT01181271

Lead Sponsor: Massachusetts General Hospital

Brief 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.

Detailed Description: This is a phase II clinical trial investigating the feasibility, and efficacy of sequential autologous stem cell transplant followed by non-myeloablative allogeneic transplant for patients with poor risk lymphoma. Patients will be enrolled onto the trial when eligible and undergo standard high-dose chemotherapy with the combination with busulfan, cyclophosphamide, and etoposide followed by autologous stem cell transplant. After recovery of counts and clinical status, patients will then proceed to non-myeloablative allogeneic stem cell transplant using a fully matched related or unrelated donor.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 42

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Autologous then Allogeneic transplant	autologous (auto) peripheral blood stem cell transplantation	All patients will receive conditioning with busulfan, etoposide, and cyclophosphamide (with mesna) and then will undergo autologous (auto) peripheral blood stem cell transplantation. Patients will be re-evaluated after autologous transplant prior to proceeding to non-myeloablative allogeneic (allo) transplant. If eligible to proceed, allogenic transplantation will take place no earlier than 40 days and no later than 180 days after autologous stem cell transplantation. Conditioning for the allogeneic transplant will consist of fludarabine and busulfan. Participants will receive tacrolimus and sirolimus as prophylaxis against graft versus host disease (GVHD).
Autologous then Allogeneic transplant	non-myeloablative allogeneic (allo) transplant	All patients will receive conditioning with busulfan, etoposide, and cyclophosphamide (with mesna) and then will undergo autologous (auto) peripheral blood stem cell transplantation. Patients will be re-evaluated after autologous transplant prior to proceeding to non-myeloablative allogeneic (allo) transplant. If eligible to proceed, allogenic transplantation will take place no earlier than 40 days and no later than 180 days after autologous stem cell transplantation. Conditioning for the allogeneic transplant will consist of fludarabine and busulfan. Participants will receive tacrolimus and sirolimus as prophylaxis against graft versus host disease (GVHD).
Autologous then Allogeneic transplant	Tacrolimus	All patients will receive conditioning with busulfan, etoposide, and cyclophosphamide (with mesna) and then will undergo autologous (auto) peripheral blood stem cell transplantation. Patients will be re-evaluated after autologous transplant prior to proceeding to non-myeloablative allogeneic (allo) transplant. If eligible to proceed, allogenic transplantation will take place no earlier than 40 days and no later than 180 days after autologous stem cell transplantation. Conditioning for the allogeneic transplant will consist of fludarabine and busulfan. Participants will receive tacrolimus and sirolimus as prophylaxis against graft versus host disease (GVHD).
Autologous then Allogeneic transplant	Methotrexate	All patients will receive conditioning with busulfan, etoposide, and cyclophosphamide (with mesna) and then will undergo autologous (auto) peripheral blood stem cell transplantation. Patients will be re-evaluated after autologous transplant prior to proceeding to non-myeloablative allogeneic (allo) transplant. If eligible to proceed, allogenic transplantation will take place no earlier than 40 days and no later than 180 days after autologous stem cell transplantation. Conditioning for the allogeneic transplant will consist of fludarabine and busulfan. Participants will receive tacrolimus and sirolimus as prophylaxis against graft versus host disease (GVHD).
Autologous then Allogeneic transplant	Mesna (prior to AUTO transplant)	All patients will receive conditioning with busulfan, etoposide, and cyclophosphamide (with mesna) and then will undergo autologous (auto) peripheral blood stem cell transplantation. Patients will be re-evaluated after autologous transplant prior to proceeding to non-myeloablative allogeneic (allo) transplant. If eligible to proceed, allogenic transplantation will take place no earlier than 40 days and no later than 180 days after autologous stem cell transplantation. Conditioning for the allogeneic transplant will consist of fludarabine and busulfan. Participants will receive tacrolimus and sirolimus as prophylaxis against graft versus host disease (GVHD).
Autologous then Allogeneic transplant	Etoposide (conditioning for AUTO transplant)	All patients will receive conditioning with busulfan, etoposide, and cyclophosphamide (with mesna) and then will undergo autologous (auto) peripheral blood stem cell transplantation. Patients will be re-evaluated after autologous transplant prior to proceeding to non-myeloablative allogeneic (allo) transplant. If eligible to proceed, allogenic transplantation will take place no earlier than 40 days and no later than 180 days after autologous stem cell transplantation. Conditioning for the allogeneic transplant will consist of fludarabine and busulfan. Participants will receive tacrolimus and sirolimus as prophylaxis against graft versus host disease (GVHD).
Autologous then Allogeneic transplant	Busulfan (conditioning for ALLO Transplant)	All patients will receive conditioning with busulfan, etoposide, and cyclophosphamide (with mesna) and then will undergo autologous (auto) peripheral blood stem cell transplantation. Patients will be re-evaluated after autologous transplant prior to proceeding to non-myeloablative allogeneic (allo) transplant. If eligible to proceed, allogenic transplantation will take place no earlier than 40 days and no later than 180 days after autologous stem cell transplantation. Conditioning for the allogeneic transplant will consist of fludarabine and busulfan. Participants will receive tacrolimus and sirolimus as prophylaxis against graft versus host disease (GVHD).
Autologous then Allogeneic transplant	Busulfan (conditioning for AUTO transplant)	All patients will receive conditioning with busulfan, etoposide, and cyclophosphamide (with mesna) and then will undergo autologous (auto) peripheral blood stem cell transplantation. Patients will be re-evaluated after autologous transplant prior to proceeding to non-myeloablative allogeneic (allo) transplant. If eligible to proceed, allogenic transplantation will take place no earlier than 40 days and no later than 180 days after autologous stem cell transplantation. Conditioning for the allogeneic transplant will consist of fludarabine and busulfan. Participants will receive tacrolimus and sirolimus as prophylaxis against graft versus host disease (GVHD).
Autologous then Allogeneic transplant	Cyclophosphamide (conditioning for AUTO transplant)	All patients will receive conditioning with busulfan, etoposide, and cyclophosphamide (with mesna) and then will undergo autologous (auto) peripheral blood stem cell transplantation. Patients will be re-evaluated after autologous transplant prior to proceeding to non-myeloablative allogeneic (allo) transplant. If eligible to proceed, allogenic transplantation will take place no earlier than 40 days and no later than 180 days after autologous stem cell transplantation. Conditioning for the allogeneic transplant will consist of fludarabine and busulfan. Participants will receive tacrolimus and sirolimus as prophylaxis against graft versus host disease (GVHD).
Autologous then Allogeneic transplant	Fludarabine (conditioning for ALLO Transplant)	All patients will receive conditioning with busulfan, etoposide, and cyclophosphamide (with mesna) and then will undergo autologous (auto) peripheral blood stem cell transplantation. Patients will be re-evaluated after autologous transplant prior to proceeding to non-myeloablative allogeneic (allo) transplant. If eligible to proceed, allogenic transplantation will take place no earlier than 40 days and no later than 180 days after autologous stem cell transplantation. Conditioning for the allogeneic transplant will consist of fludarabine and busulfan. Participants will receive tacrolimus and sirolimus as prophylaxis against graft versus host disease (GVHD).
Autologous then Allogeneic transplant	Neupogen	All patients will receive conditioning with busulfan, etoposide, and cyclophosphamide (with mesna) and then will undergo autologous (auto) peripheral blood stem cell transplantation. Patients will be re-evaluated after autologous transplant prior to proceeding to non-myeloablative allogeneic (allo) transplant. If eligible to proceed, allogenic transplantation will take place no earlier than 40 days and no later than 180 days after autologous stem cell transplantation. Conditioning for the allogeneic transplant will consist of fludarabine and busulfan. Participants will receive tacrolimus and sirolimus as prophylaxis against graft versus host disease (GVHD).
Autologous then Allogeneic transplant	Sirolimus	All patients will receive conditioning with busulfan, etoposide, and cyclophosphamide (with mesna) and then will undergo autologous (auto) peripheral blood stem cell transplantation. Patients will be re-evaluated after autologous transplant prior to proceeding to non-myeloablative allogeneic (allo) transplant. If eligible to proceed, allogenic transplantation will take place no earlier than 40 days and no later than 180 days after autologous stem cell transplantation. Conditioning for the allogeneic transplant will consist of fludarabine and busulfan. Participants will receive tacrolimus and sirolimus as prophylaxis against graft versus host disease (GVHD).

Primary Outcome Measures

Name	Time	Method
Peripheral Blood All-cell Donor Chimerism	100 days post allogeneic transplant	Successful donor stem cell engraftment is defined as when ≥ 80% of hematopoietic elements are donor-derived as determined by chimerism assays from peripheral blood at day 100 after non-myeloablative allogeneic stem cell transplantation.

Secondary Outcome Measures

Name	Time	Method
Number of Days After Allogeneic Transplant Until Absolute Neutrophil Count Was Equal to or Greater Than 500/uL	within 28 days after allogeneic transplant
Cumulative Incidence of Grades II to IV Acute Graft Versus Host Disease (GVHD)	within 200 days after allogeneic transplant	Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening.
Cumulative Incidence of Extensive Chronic Graft-versus-host-disease	1-year after allogeneic transplant	Extensive chronic graft versus-host-disease (GVHD) was defined as GVHD that required systemic immunosuppression.
Estimated Two Year Progression Free Survival Rate for Participants Undergoing Both Autologous and Allogeneic Transplants	2 years after allogeneic transplant
Estimated Two Year Overall Survival Rate for Participants Undergoing Both Autologous and Allogeneic Transplants	Two-years after Allogeneic Transplant
Estimated Two Year Progression Free Survival Rate for All Participants	2 years
Cumulative Incidence of Non-relapse Mortality	2-years after allogeneic transplant	Non-relapse mortality is defined as participants who die from causes other than their underlying disease relapse, such as infection or graft versus host disease
Cumulative Incidence of Disease Relapse	2-years after allogeneic transplant
Estimated Two Year Overall Survival Rate for All Participants	2 years
Estimated Two Year Progression Free Survival Rate for Participants Undergoing Only Autologous Transplant	Two Years
Estimated Two Year Overall Survival Rate for Participants Undergoing Only Autologous Transplant	two years

Trial Locations

Locations (2): Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, United States
Dana Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States