Blood Cancer, Leukemia
Conditions
Brief summary
To measure how frequently and to what degree a complication of transplant cell acute graft versus host disease (GvHD) occurs.
Detailed description
This study evaluated whether TLI-ATG conditioning followed by allogeneic hematpoietic cell transplant (HCT), which has provided excellent overall survival for patients with relapsed lymphoma after failed autologous HCT, provides a similar benefit in the setting of elderly patients with hematologic malignancies.
Interventions
DRUGCyclosporine
Starting day -3 at a dose of 5 mg/kg orally twice daily with a target trough level of 350 to 450 ng/mL
1.5 mg/kg for total dose of 7.5mg/kg, IV starting on day -11 to day -7 before HCT
DRUGMycophenolate mofetil (MMF)
Begins on day 0 after HCT at a dose of 15 mg/kg. Transplant recipients who received related donor grafts received MMF twice daily and those who received unrelated donor grafts received MMF 3 times daily.
DRUGFilgrastim
* Donors mobilized with 16 µg/kg/day filgrastim. * As needed, myelosuppression in transplant recipients will be managed with subcutaneous filgrastim 5 µg/kg/day
RADIATIONTotal Lymphoid Irradiation (TLI)
0.8 Gy/day from day -11 to day -7 (inclusive) from day -4 to day -2 (inclusive) with 2 additional fractions of 0.8 Gy delivered on day -1 for total dose of 8 Gy.
Sponsors
Stanford University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Any patient with one of the following hematolymphoid malignancies or syndromes in whom allogeneic hematopoietic stem cell transplant (HST) is warranted. Specific disease categories include: * Indolent advanced stage non-Hodgkin lymphomas * Mantle cell lymphoma * Chronic lymphocytic leukemia * Hodgkin disease (Hodgkin's lymphoma) * Acute leukemias in complete remission * Aplastic anemia * Paroxysmal nocturnal hemoglobinuria * Myelodysplastic or myeloproliferative syndromes. * Other selected malignancies/disorders may also be considered but must be approved by the transplant team and the Principal Investigator. * Age \> 50 years, or if \< 50 years of age, considered to be at high risk for regimen-related toxicity associated with conventional myeloablative transplants due to pre-existing medical conditions or prior therapy. * A fully human leukocyte antigen (HLA)-identical sibling or matched unrelated donor is available. Potential participants with one antigen mismatched donors can be considered but only after discussion with the transplant team and the Principal Investigator. * Participant must be competent to give consent.
Exclusion criteria
* Progressive hematolymphoid malignancies despite conventional therapies, or acute leukemias not in complete remission. * Uncontrolled central nervous system (CNS) involvement with disease * Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment * Pregnant * Cardiac ejection fraction \< 30% * Uncontrolled cardiac failure * Pulmonary diffusing capacity (DLCO) \< 40% predicted * Elevation of bilirubin to \> 3 mg/dL * Transaminases \> 4 x the upper limit of normal * Creatinine clearance \< 50 cc/min (24-hour urine collection) * Karnofsky performance score \< 60% * Poorly controlled hypertension on multiple antihypertensives * Documented fungal disease that is progressive despite treatment * HIV-positive. Other viral infections, ie, Hepatitis B- and C- positive, evaluated on a case-by-case basis * Psychiatric disorders or psychosocial problems which in the opinion of the primary physician or Principal Investigator would place the patient at unacceptable risk from this regimen.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Acute Graft vs Host Disease (GvHD) | 100 days post-transplant | The incidence of acute GvHD after transplantation was assessed per Glucksberg GvHD grade, a compound scale based on the following combinations of disease stages. Skin Stages * 0: No rash * 1: Maculopapular (MP) rash \<25% of body surface area * 2: MP rash on 25-50% of body surface area * 3: Generalized erythroderma (ED) * 4: Generalized ED with bullous formation and desquamation Liver Stages (Bilirubin in mg/dL) * 0: \<2 * 1: 2-3 * 2: 3.01-6 * 3: 6.01-15.0 * 4: \>15 Gastrointestinal (GI) Stages (diarrhea) * 0: None or \< 500 mL/day * 1: 500-999 mL/day * 2: 1000-1499 mL/day * 3: \>1500 mL/day * 4: Severe abdominal pain, with or without ileus Glucksberg Overall grade * Grade 1: Skin 1/2; GI 0; Liver 0; Karnofsky performance scale (KPS) 90-100% * Grade 2: Skin 1-3; GI 1; Liver 1; KPS 70-80 * Grade 2: Skin 2/3; GI 2/3; Liver 2-4; KPS 50-60 * Grade 4: Skin 2-4; GI 2-4; Liver 2-4; KPS 30-40 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Acute Graft vs Host Disease (GvHD), All Evaluable | 100 days post-transplant | The incidence of acute GvHD after transplantation was assessed per Glucksberg GvHD grade, a compound scale based on the following combinations of disease stages. Skin Stages * 0: No rash * 1: Maculopapular (MP) rash \<25% of body surface area * 2: MP rash on 25-50% of body surface area * 3: Generalized erythroderma (ED) * 4: Generalized ED with bullous formation and desquamation Liver Stages (Bilirubin in mg/dL) * 0: \<2 * 1: 2-3 * 2: 3.01-6 * 3: 6.01-15.0 * 4: \>15 Gastrointestinal (GI) Stages (diarrhea) * 0: None or \< 500 mL/day * 1: 500-999 mL/day * 2: 1000-1499 mL/day * 3: \>1500 mL/day * 4: Severe abdominal pain, with or without ileus Glucksberg Overall grade * Grade 1: Skin 1/2; GI 0; Liver 0; Karnofsky performance scale (KPS) 90-100% * Grade 2: Skin 1-3; GI 1; Liver 1; KPS 70-80 * Grade 2: Skin 2/3; GI 2/3; Liver 2-4; KPS 50-60 * Grade 4: Skin 2-4; GI 2-4; Liver 2-4; KPS 30-40 |
| Incidence of Relapse | 3 years | Reports the overall rate of disease relapse, occurring any time within 3 years after transplant |
| Overall Survival (OS) | 3 and 5 years | — |
| Event-free Survival (EFS) | 3 and 5 years | Reports the number and proportion of participants who neither died due to any cause nor experienced relapse. |
| Transplant-related Mortality | 1 year | Reports the proportion of participants who expired within 1 year due to any complication or failure of the transplant. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Non-myeloablative Transplantation Pre-transplant total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) infusion with Day 0 allogeneic hematopoietic cell transplant (HCT), followed by post-transplant immunosuppression by cyclosporine and mycophenolate mofetil | 303 |
| Total | 303 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 138 |
| Overall Study | Not Eligible | 4 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Non-myeloablative Transplantation |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 43 Participants |
| Age, Categorical Between 18 and 65 years | 260 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 276 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants |
| Histology Acute Biphenotypic Leukemia | 1 participants |
| Histology Acute Leukemia, Nos | 1 participants |
| Histology Acute Monocytic Leukemia | 2 participants |
| Histology Acute Myeloid Leukemia | 84 participants |
| Histology Acute Promyelocytic Leukemia | 4 participants |
| Histology Angioimmunoblastic T-Cell Lymphoma | 1 participants |
| Histology B-Cell Chr. Lymph. Leuk./Small Lymph. Lymphoma | 45 participants |
| Histology B lymphoblastic leukemia/lymphoma, NOS | 1 participants |
| Histology Chronic Myelogenous Leukemia, Bcr/Abl Positive | 1 participants |
| Histology Chronic Myeloid Leukemia, Nos | 8 participants |
| Histology Chronic Myeloproliferative Disease, Nos | 2 participants |
| Histology Cutaneous T-Cell Lymphoma, Nos | 1 participants |
| Histology Follicular Lymphoma, Grade 1-3 | 4 participants |
| Histology Hodgkin Lymphoma, Nodular Sclerosis, Nos | 4 participants |
| Histology Hodgkin Lymphoma, Nos | 20 participants |
| Histology Malignant Lymphoma, Non-Hodgkin | 86 participants |
| Histology Mantle Cell Lymphoma | 10 participants |
| Histology Marginal Zone B-Cell Lymphoma, Nos | 2 participants |
| Histology Mature T-Cell Lymphoma, Nos | 1 participants |
| Histology Ml, Large B-Cell, Diffuse | 2 participants |
| Histology Ml, Small B Lymphocytic, Nos | 1 participants |
| Histology Myelodysplastic Syndrome, Nos | 3 participants |
| Histology Precursor Cell Lymphoblastic Leukemia, Nos | 15 participants |
| Histology Prolymphocytic Leukemia, Nos | 1 participants |
| Histology Prolymphocytic Leukemia, T-Cell Type | 1 participants |
| Histology Subcutaneous Panniculitis-Like T-Cell Lymphoma | 1 participants |
| Histology Unknown | 1 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 37 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 7 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 20 Participants |
| Race (NIH/OMB) White | 233 Participants |
| Sex: Female, Male Female | 128 Participants |
| Sex: Female, Male Male | 175 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 138 / 303 |
| other Total, other adverse events | 55 / 303 |
| serious Total, serious adverse events | 138 / 303 |
Outcome results
Primary
Acute Graft vs Host Disease (GvHD)
The incidence of acute GvHD after transplantation was assessed per Glucksberg GvHD grade, a compound scale based on the following combinations of disease stages. Skin Stages * 0: No rash * 1: Maculopapular (MP) rash \<25% of body surface area * 2: MP rash on 25-50% of body surface area * 3: Generalized erythroderma (ED) * 4: Generalized ED with bullous formation and desquamation Liver Stages (Bilirubin in mg/dL) * 0: \<2 * 1: 2-3 * 2: 3.01-6 * 3: 6.01-15.0 * 4: \>15 Gastrointestinal (GI) Stages (diarrhea) * 0: None or \< 500 mL/day * 1: 500-999 mL/day * 2: 1000-1499 mL/day * 3: \>1500 mL/day * 4: Severe abdominal pain, with or without ileus Glucksberg Overall grade * Grade 1: Skin 1/2; GI 0; Liver 0; Karnofsky performance scale (KPS) 90-100% * Grade 2: Skin 1-3; GI 1; Liver 1; KPS 70-80 * Grade 2: Skin 2/3; GI 2/3; Liver 2-4; KPS 50-60 * Grade 4: Skin 2-4; GI 2-4; Liver 2-4; KPS 30-40
Time frame: 100 days post-transplant
Population: Reports the incidence of Grades 2 to 4 acute GvHD, as observed for the initial 37 participants treated on this study, who constitute the Primary Analysis for the study. See linked citation Lowsky, et al. NEJM. 29Sep2005;353(13)1321-1331.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-myeloablative Transplantation | Acute Graft vs Host Disease (GvHD) | 2.7 percentage of participants |
Secondary
Acute Graft vs Host Disease (GvHD), All Evaluable
The incidence of acute GvHD after transplantation was assessed per Glucksberg GvHD grade, a compound scale based on the following combinations of disease stages. Skin Stages * 0: No rash * 1: Maculopapular (MP) rash \<25% of body surface area * 2: MP rash on 25-50% of body surface area * 3: Generalized erythroderma (ED) * 4: Generalized ED with bullous formation and desquamation Liver Stages (Bilirubin in mg/dL) * 0: \<2 * 1: 2-3 * 2: 3.01-6 * 3: 6.01-15.0 * 4: \>15 Gastrointestinal (GI) Stages (diarrhea) * 0: None or \< 500 mL/day * 1: 500-999 mL/day * 2: 1000-1499 mL/day * 3: \>1500 mL/day * 4: Severe abdominal pain, with or without ileus Glucksberg Overall grade * Grade 1: Skin 1/2; GI 0; Liver 0; Karnofsky performance scale (KPS) 90-100% * Grade 2: Skin 1-3; GI 1; Liver 1; KPS 70-80 * Grade 2: Skin 2/3; GI 2/3; Liver 2-4; KPS 50-60 * Grade 4: Skin 2-4; GI 2-4; Liver 2-4; KPS 30-40
Time frame: 100 days post-transplant
Population: Reports data for all evaluable participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-myeloablative Transplantation | Acute Graft vs Host Disease (GvHD), All Evaluable | 11 percentage of participants |
Secondary
Event-free Survival (EFS)
Reports the number and proportion of participants who neither died due to any cause nor experienced relapse.
Time frame: 3 and 5 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Non-myeloablative Transplantation | Event-free Survival (EFS) | 3 years | 44 Participants |
| Non-myeloablative Transplantation | Event-free Survival (EFS) | 5 years | 38 Participants |
Secondary
Incidence of Relapse
Reports the overall rate of disease relapse, occurring any time within 3 years after transplant
Time frame: 3 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-myeloablative Transplantation | Incidence of Relapse | 53 percentage of participants |
Secondary
Overall Survival (OS)
Time frame: 3 and 5 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Non-myeloablative Transplantation | Overall Survival (OS) | 3 years | 70 percentage of participants |
| Non-myeloablative Transplantation | Overall Survival (OS) | 5 years | 64 percentage of participants |
Secondary
Transplant-related Mortality
Reports the proportion of participants who expired within 1 year due to any complication or failure of the transplant.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-myeloablative Transplantation | Transplant-related Mortality | 6 percentage of participants |