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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
50
4 gm /m² IV over 2 hours on day 8
The dose of BCNU will be based on actual body weight unless the actual body weight is more than 15 kg greater than the ideal body weight in which case the adjusted ideal body weight will be used: 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)
60mg/kg, IV over 4 hours on day -4 pre-transplant and for preparative regimen. The dose of etoposide for mobilization is 2 gm/ m².
Stanford University School of Medicine
Stanford, California, United States
Event-free Survival (EFS)
Event-free survival (EFS) as determined for participants who receive both planned transplants, for a minimum of 3 years. Events are defined as "disease progression/relapse" and "death of all causes".
Time frame: 3 years
Incidence of Chemotherapy-associated Pneumonitis
Interstitial pneumonitis (IP) is a risk associated with high-dose carmustine (BCNU) or other chemotherapy drugs used for transplantation. IP is diagnosed by 1) a decrease of \>25% in DLCO compared with pre-transplant PFT DLCO values or 2) a drop of 7% or more in oxygen saturation after exertion.
Time frame: 3 years
Relapse Rate
Relapse rate (disease recurrence) 3 years after transplant, for participants who received both transplants, as determined by Kaplan-Meier estimation.
Time frame: 3 years
Overall Survival (OS)
Overall Survival (OS) 3 years after transplant, for participants who received both transplants, as determined by Kaplan-Meier estimation.
Time frame: 3 years
Incidence of Acute Graft Versus Host Disease (GvHD)
The development of GvHD in vaccinated patients of any grade and at 6 months.
Time frame: 6 Months
Incidence of Chronic Graft Versus Host Disease (GvHD)
The development of GvHD in vaccinated patients of any grade at 6 months.
Time frame: 3 years
Overall Mortality Rate
Overall mortality is determined by Kaplan-Meier estimation. The overall morality rate is expressed as the percentage of patients who died for any reason, including disease-related death.
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10µg/kg sc qd starting day following cyclosphamide (or VP-16) until last day of apheresis
1.5 mg/kg/d, IV from day -11 to -7
5mg/kgbid,variable, po or IV
15 mg/kg po on day 0, at 5-10 hours after mobilized PBPC infusion is complete. Thereafter, beginning 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. Doses will be rounded up to the nearest 250 mg (capsules are 250 mg). MMF will be stopped on day +28 for matched related donors. For one antigen mismatched related or unrelated donors, the taper will begin on day +40. MMF will be tapered by 10% weekly till off, typically by day +96. If there is nausea and vomiting at any time preventing the oral administration of MMF, MMF should be administered intravenously at an equal dose. MMF dosing is based on actual body weight.
375 mg/m2 IV (calculated based on actual body weight) on day 1 and day 7. Administered per current standard of care..
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
2 x 10e6 CD34+ cells per kg actual body weight on Day 0
1 mg/kg, Day-11 to Day-7
Time frame: 3 years
Median Time to Neutrophile Engraftment
Complete blood counts were measured daily after allogeneic transplant. Time to neutrophil engraftment is defined as the number of days it takes to reach an absolute neutrophils count (ANC) \>500, counting from the day of transplant.
Time frame: up to 45 days
Achieving Full Donor Chimerism
Achieving full donor chimerism (donor T cells \>95%): Blood was sent for donor cell percentage measured by short tandem repeat (STR) at post-transplant Day 30; Day 60; Day 90; Day 120; Day 180; Day 270; and Day 360. Full donor chimerism is defined as donor CD3+ cells \> 95%.
Time frame: Up to 1 year
Median Time to Platelet Engraftment
Complete blood counts were measured daily after allogeneic transplant. Time to platelet engraftment is defined as the number of days it takes to reach platelet count \>20,000, counting from the day of transplant.
Time frame: Up to 45 days