Lymphoma, Non-Hodgkin
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGEtoposide
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.
DRUGCyclophosphamide
4 gm /m² IV over 2 hours on day 8
DRUGBCNU
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)
DRUGFilgrastim
10µg/kg sc qd starting day following cyclosphamide (or VP-16) until last day of apheresis
DRUGAntithymocyte globulin
1.5 mg/kg/d, IV from day -11 to -7
DRUGCyclosporine
5mg/kgbid,variable, po or IV
DRUGMycophenolate mofetil
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.
DRUGRituximab
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)
PROCEDURETotal lymphoid irradiation
TLI is administered in 80cGy fractions on Days -11 to Day-7 relative to allo-HSCT
DRUGCD34+ Cells
2 x 10e6 CD34+ cells per kg actual body weight on Day 0
DRUGSolu-Medrol
1 mg/kg, Day-11 to Day-7
Sponsors
Stanford University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Age 18 to 70 years. * Histologically proven non-Hodgkin's lymphoma * Relapse after achieving initial remission or failure to achieve initial remission. * KPS \> 70% * Matched related or unrelated donor identified and available. Donor must be a complete match or have only a single allele mismatch. * Recent Bone marrow biopsy and cytogenetic analysis * Patients must have a pretreatment serum bilirubin \< 2 x the institutional ULN, a serum creatinine \< 2 x the institutional ULN and measured or estimated creatinine clearance \> 50 cc/min by the following formula (all tests must be performed within 28 days prior to mobilization ): Estimated Creatinine Clearance = (140 age) X WT(kg) X 0.85 if female 72 X serum creatinine(mg/dl). * Patients must have an EKG within 42 days prior to registration that shows no significant abnormalities that are suggestive of active cardiac disease. * Patients must have an echocardiogram or MUGA scan within 42 days of registration. If the ejection fraction is \< 40%, the patient will not be eligible. If the ejection fraction is 40-50%, patients must have an exercise echocardiogram or dobutamine-echo with a normal response to exercise. * Patients must have a corrected diffusion capacity \> 50% prior to the autologous transplant and \> 40% prior to the allogeneic transplant. * Patients with known allergy to etoposide or a history of Grade 3 hemorrhagic cystitis with cyclophosphamide are not eligible. * Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.
Exclusion criteria
* Pregnant or breast-feeding women are ineligible due to the known birth defects association with the treatments used in this study. * Patients known to be human immunodeficiency virus (HIV)-positive are ineligible because the concern for opportunistic infection and hematologic reserve are considered to be significantly greater in this population. * Patients with prior maligancies diagnosed \> 5 years ago without evidence of disease are eligible. Patients with a prior malignancy treated \< 5 years ago but have a life expectancy of \> 5 years for that malignancy are eligible. * Patients with uncontrolled infection. * No prior autologous or allogeneic hematopoietic cell transplantation. Donor Selection/Evaluation: * 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. * Virology testing including CMV, HIV, EBV, HTLV, RPR, Hepatitis A, B and C will be performed within 30 days of donation. * No prior malignancy is allowed except adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer or other cancer for which the donor has been disease-free for five years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival (EFS) | 3 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relapse Rate | 3 years | Relapse rate (disease recurrence) 3 years after transplant, for participants who received both transplants, as determined by Kaplan-Meier estimation. |
| Overall Survival (OS) | 3 years | Overall Survival (OS) 3 years after transplant, for participants who received both transplants, as determined by Kaplan-Meier estimation. |
| Incidence of Acute Graft Versus Host Disease (GvHD) | 6 Months | The development of GvHD in vaccinated patients of any grade and at 6 months. |
| Incidence of Chronic Graft Versus Host Disease (GvHD) | 3 years | The development of GvHD in vaccinated patients of any grade at 6 months. |
| Incidence of Chemotherapy-associated Pneumonitis | 3 years | 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. |
| Median Time to Neutrophile Engraftment | up to 45 days | 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. |
| Achieving Full Donor Chimerism | Up to 1 year | 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%. |
| Median Time to Platelet Engraftment | Up to 45 days | 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. |
| Overall Mortality Rate | 3 years | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| T & B Cell Mobilization Auto & Allo HCT A transplant regimen that conditions the subjects using total lymphoid irradiation (TLI) and anti-thymocyte globulin(ATG) which will reduce acute graft-vs-host disease to negligible rates while maintaining the anti-tumor graft vs lymphoma GvL benefit. Along with TLI/ATG regiment; Solumedrol will be used as pre-medication and anti-emetic for any side effects. For stem cell mobilization, participants will be given either B Cell NLH or T Cell NHL. Before the filgrastim (G-CSF) mobilized PBPC infusion: acetaminophen, diphenhydramine and hydrocortisone will also be given as another set of pre-medications. BCNU, Etoposide, and Cyclophosphamide will be used as a preparative regimen. Cyclosporine and mycophenolate mofetil will be administered as an immunosuppressant after transplantation. Lastly, rituximab will be infused at the end of the transplantation regimen. | 50 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Enrollment | Physician Decision | 8 |
| Enrollment | Unable to collect enough stem cells | 2 |
| Inter-transplant Period | Adverse Event | 4 |
| Inter-transplant Period | Death | 3 |
| Inter-transplant Period | Disease relapse | 11 |
| Inter-transplant Period | Lack of allogeneic donor | 5 |
| Inter-transplant Period | Physician Decision | 4 |
Baseline characteristics
| Characteristic | T & B Cell Mobilization Auto & Allo HCT |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 7 Participants |
| Age, Categorical Between 18 and 65 years | 43 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) White | 38 Participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 24 / 50 |
| other Total, other adverse events | 4 / 50 |
| serious Total, serious adverse events | 5 / 50 |
Outcome results
Primary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T & B Cell Mobilization Auto & Allo HCT | Event-free Survival (EFS) | 35 percentage of participants |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T & B Cell Mobilization Auto & Allo HCT | Achieving Full Donor Chimerism | 10 Participants |
Secondary
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
Population: Only 13 participants received both therapies and were evaluated for GVHD
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T & B Cell Mobilization Auto & Allo HCT | Incidence of Acute Graft Versus Host Disease (GvHD) | 3 Participants |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T & B Cell Mobilization Auto & Allo HCT | Incidence of Chemotherapy-associated Pneumonitis | 16 Participants |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T & B Cell Mobilization Auto & Allo HCT | Incidence of Chronic Graft Versus Host Disease (GvHD) | 3 Participants |
Secondary
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| T & B Cell Mobilization Auto & Allo HCT | Median Time to Neutrophile Engraftment | 17 Days |
Secondary
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| T & B Cell Mobilization Auto & Allo HCT | Median Time to Platelet Engraftment | 11 Days |
Secondary
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.
Time frame: 3 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T & B Cell Mobilization Auto & Allo HCT | Overall Mortality Rate | 56 percentage of participants |
Secondary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T & B Cell Mobilization Auto & Allo HCT | Overall Survival (OS) | 57 percentage of participants |
Secondary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T & B Cell Mobilization Auto & Allo HCT | Relapse Rate | 27 percentage of participants |