Leukemia, Lymphocytic, Acute, Leukemia, Myelocytic, Acute, Leukemia, Myeloid, Chronic, Myelodysplastic Syndromes
Conditions
Keywords
Acute Myelogenous Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia
Brief summary
The study is designed as a phase III, randomized, open label, multicenter, prospective, comparative trial of sirolimus and tacrolimus versus tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis after human leukocyte antigen (HLA)-matched, related, peripheral blood stem cell transplantation in individuals with hematologic cancer. Participants will be stratified by transplant center and will be randomly assigned to the sirolimus/tacrolimus or tacrolimus/methotrexate arms at a 1:1 ratio.
Detailed description
BACKGROUND: Stem cell transplantation is a standard therapy for acute and chronic leukemias and myelodysplastic disorders. A common problem that may occur after a stem cell transplant is a condition known as GVHD. The purpose of this study is to compare two combinations of medications to see which is better at preventing GVHD. The combinations of medications in this study are: * Sirolimus and tacrolimus * Methotrexate and tacrolimus Doctors want to know if one combination is better than the other or if they both have the same result. DESIGN NARRATIVE: Participants will receive one of the two conditioning regimens described in the protocol, at the discretion of the transplant physician. The transplant physician must choose among these regimens prior to the participant's assignment to the GVHD prophylaxis treatment. Conditioning regimens will vary by center, but will be the same for all participants at each center. Stem cell donors will donate peripheral blood stem cells according to local institutional practices. Peripheral blood stem cells will not be manipulated or T-depleted prior to administration. Standard post-transplant care will be administered. Participants will be randomly assigned to one of two GVHD prophylaxis regimens and will be followed for the endpoints of interest. Participants will be followed for 114 days post-randomization for evaluation of the primary endpoint, with additional follow-up for 2 years after transplantation for evaluation of secondary endpoints.
Interventions
DRUGTacrolimus
Adults and Children: Tacrolimus will be given at a dose of 0.02 mg/kg every 24 hours as a continuous intravenous infusion beginning on Day -3. An effort will be made to convert the tacrolimus to oral dosing at 2-3 times the total 24-hour intravenous dose, split into 2 doses given every 12 hours as soon as clinically feasible. The target serum level for tacrolimus is 5-10 ng/mL.
DRUGMethotrexate
Methotrexate will be given at a dose of 15 mg/m2 on Day 1 after transplantation, and at a dose of 10 mg/m2 on Days 3, 6 and 11 after transplantation.
DRUGSirolimus
Adults: Sirolimus will be given in a loading dose of 12 mg on Day -3 followed by a daily oral dose of 4 mg per day. Doses may be repeated if the subject vomits within 15 minutes of an oral dose. Children: Children aged \< 12.0 years OR weighing \< 40.0 kg will be given an oral loading dose of sirolimus of 3 mg/m2 followed by a daily oral dose of 1 mg/m2, rounded to the nearest full milligram. The target serum level for sirolimus is 3-12 ng/mL.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
Medical College of Wisconsin
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* 6/6 HLA-matched sibling, defined by Class I (HLA-A and B) serologic typing (or higher resolution) and Class II (HLA-DRBI) molecular typing, who is willing to donate peripheral blood stem cells, and meets institutional criteria for stem cell donation. The donor must be medically eligible to donate stem cells, according to individual transplant center criteria. Pediatric patients for whom a pediatric sibling donor is not anticipated to be a suitable leukapheresis candidate are not eligible. * Karnofsky performance status of at least 70% or Lansky performance status of at least 70% for participants less than 16 years old * For participants less than 18 years old, willing and able to take oral medications, per the treating physician's recommendations
Exclusion criteria
* Prior allogeneic or autologous transplant using any hematopoietic stem cell source * Seropositive for the human immunodeficiency virus (HIV) * Uncontrolled bacterial, viral, or fungal infection (currently taking medication and progression of clinical symptoms) * Pregnant (positive serum human chorionic gonadotropin \[β-HCG\] test) or breastfeeding within 4 weeks of study entry * Kidney function: serum creatinine outside the normal range for age, or measured creatinine clearance less than 50 mL/min/1.72m\^2 within 4 weeks of study entry * Liver function: most recent direct bilirubin, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) greater than two times the upper limit of normal within 4 weeks of study entry * Lung disease: in adults, forced vital capacity (FVC) or forced expiratory volume in one second (FEV1) less than 60% of predicted value (corrected for hemoglobin); in children, overt hypoxemia, as measured by an oxygen saturation of less than 92% within 4 weeks of study entry * Cardiac ejection fraction of less than 45% in adults and children, or less than 26% shortening fraction in children within 4 weeks of study entry * Cholesterol level greater than 500 mg/dL or triglyceride level greater than 500 mg/dL while being treated, or not on appropriate lipid-lowering therapy within 4 weeks of study entry * Prior history of allergy to sirolimus * Requires voriconazole at time of study entry * Currently receiving another investigational drug unless cleared by the protocol officer or protocol chair * Participants with a history of cancer, other than resected basal cell carcinoma or treated carcinoma in-situ. Cancer treated with curative intent for more than 5 years previously will be allowed. Cancer treated with curative intent for less than 5 years previously will not be allowed unless approved by the protocol officer or protocol chair.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Grades II-IV Acute GVHD-free Survival | Day 114 | The primary objective is to compare rates of 114-day Grades II-IV acute GVHD-free survival post randomization for HLA-matched, related donor allogeneic peripheral blood stem cell transplantation using two different GVHD prophylaxis regimens. Participants are graded on a scale of 1 to 4 according to their symptoms and organs involved, where 4 represents a worse grade. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Neutrophil and Platelet Engraftment | Measured through Day 100 | Neutrophil engraftment is defined as achieving an Absolute Neutrophil Count (ANC) \> 500/mcL for three consecutive measurements on different days. Platelet engraftment is defined as a platelet count \> 20,000/mcL for three consecutive measurements over three or more days. |
| Mucositis Severity | Measured at Day 21 | Mucositis severity will be scored per the modified Oral Mucositis Assessment Scale (OMAS) scoring system on a scale of 0 - 4, where 0 equals normal mucosa and 4 represents severe mucosa. |
| Rate of Veno-occlusive Disease (VOD) | Measured through Day 100 | VOD will be defined as the occurrence of VOD (based on the Baltimore Criteria for the diagnosis of VOD) in conjunction with other end-organ dysfunction. |
| Thrombotic Microangiopathy (TMA) Infection | Measured through Day 100 | The occurrence of TMA within the first 100 days after stem cell transplantation will be recorded. The first day of onset will be used for reporting purposes. |
| Reactivation of Cytomegalovirus (CMV) Infection | Measured at Year 2 | — |
| Incidence of Acute GVHD | Measured at Day 100 | Cumulative incidence of acute GVHD (grade II-IV) occurring 100 days from transplantation. |
| Malignant Disease Relapse | Measured at Year 2 | Testing for recurrent malignancy in the blood, marrow or other sites will be used to assess relapse after transplantation. For the purpose of this study, relapse is defined by either morphological or cytogenetic evidence of AML, ALL, CML, MDS or CMML consistent with pre-transplant features. |
| Overall Survival | Measured at Year 2 | — |
| Infections | Measured at Year 2 | — |
| Time to Discharge After Transplant | Measured at Year 2 | — |
| Treatment-related Mortality | Measured at Day 100 and Year 2 | — |
Countries
France, United States
Participant flow
Recruitment details
Participants were enrolled from 2006 to 2011 from 24 different transplant centers.
Participants by arm
| Arm | Count |
|---|---|
| Tacrolimus/Sirolimus Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis. | 151 |
| Tacrolimus/Methotrexate Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis. | 153 |
| Total | 304 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did not undergo transplantation | 2 | 1 |
Baseline characteristics
| Characteristic | Tacrolimus/Sirolimus | Total | Tacrolimus/Methotrexate |
|---|---|---|---|
| Age, Continuous | 45 years | 44 years | 43 years |
| Conditioning Regimen Cyclophosphamide/Total Body Irradiation | 124 participants | 246 participants | 122 participants |
| Conditioning Regimen Etoposide/Total Body Irradiation | 27 participants | 58 participants | 31 participants |
| Disease Status at Transplantation ABL 1st Complete Remission | 1 participants | 2 participants | 1 participants |
| Disease Status at Transplantation ALL 1st Complete Remission | 41 participants | 96 participants | 55 participants |
| Disease Status at Transplantation ALL 2nd Complete Remission | 10 participants | 23 participants | 13 participants |
| Disease Status at Transplantation AML 1st Complete Remission | 60 participants | 116 participants | 56 participants |
| Disease Status at Transplantation AML 2nd Complete Remission | 11 participants | 18 participants | 7 participants |
| Disease Status at Transplantation CML 1st Complete Remission | 7 participants | 17 participants | 10 participants |
| Disease Status at Transplantation CML 2nd Complete Remission | 2 participants | 6 participants | 4 participants |
| Disease Status at Transplantation MDS | 19 participants | 26 participants | 7 participants |
| Karnofsky Score Scores < 90 | 50 participants | 87 participants | 37 participants |
| Karnofsky Score Scores 90 - 100 | 101 participants | 217 participants | 116 participants |
| Primary Disease Acute Biphenotypic Leukemia (ABL) | 1 participants | 2 participants | 1 participants |
| Primary Disease Acute Lymphoblastic Leukemia (ALL) | 51 participants | 119 participants | 68 participants |
| Primary Disease Acute Myelogenous Leukemia (AML) | 71 participants | 134 participants | 63 participants |
| Primary Disease Chronic Myelogenous Leukemia (CML) | 9 participants | 23 participants | 14 participants |
| Primary Disease Myelodysplastic Syndrome (MDS) | 19 participants | 26 participants | 7 participants |
| Recipient-Donor Cytomegalovirus Status -/- | 38 participants | 68 participants | 30 participants |
| Recipient-Donor Cytomegalovirus Status -/+ | 30 participants | 74 participants | 44 participants |
| Recipient-Donor Cytomegalovirus Status +/- | 14 participants | 38 participants | 24 participants |
| Recipient-Donor Cytomegalovirus Status +/+ | 59 participants | 106 participants | 47 participants |
| Recipient-Donor Cytomegalovirus Status Missing | 10 participants | 18 participants | 8 participants |
| Sex: Female, Male Female | 74 Participants | 142 Participants | 68 Participants |
| Sex: Female, Male Male | 77 Participants | 162 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 149 | 0 / 152 |
| serious Total, serious adverse events | 9 / 149 | 12 / 152 |
Outcome results
Primary
Rate of Grades II-IV Acute GVHD-free Survival
The primary objective is to compare rates of 114-day Grades II-IV acute GVHD-free survival post randomization for HLA-matched, related donor allogeneic peripheral blood stem cell transplantation using two different GVHD prophylaxis regimens. Participants are graded on a scale of 1 to 4 according to their symptoms and organs involved, where 4 represents a worse grade.
Time frame: Day 114
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus/Sirolimus | Rate of Grades II-IV Acute GVHD-free Survival | 67 percentage of participants |
| Tacrolimus/Methotrexate | Rate of Grades II-IV Acute GVHD-free Survival | 62 percentage of participants |
Secondary
Incidence of Acute GVHD
Cumulative incidence of acute GVHD (grade II-IV) occurring 100 days from transplantation.
Time frame: Measured at Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus/Sirolimus | Incidence of Acute GVHD | 26 percentage of participants |
| Tacrolimus/Methotrexate | Incidence of Acute GVHD | 34 percentage of participants |
Secondary
Infections
Time frame: Measured at Year 2
Population: Insufficient data to report on this outcome measure
Secondary
Malignant Disease Relapse
Testing for recurrent malignancy in the blood, marrow or other sites will be used to assess relapse after transplantation. For the purpose of this study, relapse is defined by either morphological or cytogenetic evidence of AML, ALL, CML, MDS or CMML consistent with pre-transplant features.
Time frame: Measured at Year 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus/Sirolimus | Malignant Disease Relapse | 28 percentage of participants |
| Tacrolimus/Methotrexate | Malignant Disease Relapse | 29 percentage of participants |
Secondary
Mucositis Severity
Mucositis severity will be scored per the modified Oral Mucositis Assessment Scale (OMAS) scoring system on a scale of 0 - 4, where 0 equals normal mucosa and 4 represents severe mucosa.
Time frame: Measured at Day 21
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tacrolimus/Sirolimus | Mucositis Severity | 0.31 units on a scale | Standard Deviation 0.28 |
| Tacrolimus/Methotrexate | Mucositis Severity | 0.47 units on a scale | Standard Deviation 0.4 |
Secondary
Overall Survival
Time frame: Measured at Year 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus/Sirolimus | Overall Survival | 59 percentage of participants |
| Tacrolimus/Methotrexate | Overall Survival | 63 percentage of participants |
Secondary
Rate of Veno-occlusive Disease (VOD)
VOD will be defined as the occurrence of VOD (based on the Baltimore Criteria for the diagnosis of VOD) in conjunction with other end-organ dysfunction.
Time frame: Measured through Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus/Sirolimus | Rate of Veno-occlusive Disease (VOD) | 11 percentage of participants |
| Tacrolimus/Methotrexate | Rate of Veno-occlusive Disease (VOD) | 5 percentage of participants |
Secondary
Reactivation of Cytomegalovirus (CMV) Infection
Time frame: Measured at Year 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus/Sirolimus | Reactivation of Cytomegalovirus (CMV) Infection | 13 percentage of participants |
| Tacrolimus/Methotrexate | Reactivation of Cytomegalovirus (CMV) Infection | 15 percentage of participants |
Secondary
Thrombotic Microangiopathy (TMA) Infection
The occurrence of TMA within the first 100 days after stem cell transplantation will be recorded. The first day of onset will be used for reporting purposes.
Time frame: Measured through Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus/Sirolimus | Thrombotic Microangiopathy (TMA) Infection | 5 percentage of participants |
| Tacrolimus/Methotrexate | Thrombotic Microangiopathy (TMA) Infection | 1 percentage of participants |
Secondary
Time to Discharge After Transplant
Time frame: Measured at Year 2
Population: Insufficient data to report on this outcome measure
Secondary
Time to Neutrophil and Platelet Engraftment
Neutrophil engraftment is defined as achieving an Absolute Neutrophil Count (ANC) \> 500/mcL for three consecutive measurements on different days. Platelet engraftment is defined as a platelet count \> 20,000/mcL for three consecutive measurements over three or more days.
Time frame: Measured through Day 100
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tacrolimus/Sirolimus | Time to Neutrophil and Platelet Engraftment | Neutrophil Engraftment | 14 days |
| Tacrolimus/Sirolimus | Time to Neutrophil and Platelet Engraftment | Platelet Engraftment | 16 days |
| Tacrolimus/Methotrexate | Time to Neutrophil and Platelet Engraftment | Neutrophil Engraftment | 16 days |
| Tacrolimus/Methotrexate | Time to Neutrophil and Platelet Engraftment | Platelet Engraftment | 19 days |
Secondary
Treatment-related Mortality
Time frame: Measured at Day 100 and Year 2
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tacrolimus/Sirolimus | Treatment-related Mortality | Day 100 | 7 percentage of participants |
| Tacrolimus/Sirolimus | Treatment-related Mortality | Year 2 | 20 percentage of participants |
| Tacrolimus/Methotrexate | Treatment-related Mortality | Day 100 | 7 percentage of participants |
| Tacrolimus/Methotrexate | Treatment-related Mortality | Year 2 | 16 percentage of participants |