Acute GVHD
Conditions
Keywords
Acute GVHD, Standard-Risk, Sirolimus, Refined Minnesota Risk Criteria, Ann Arbor, Biomarker, Steroid-Free
Brief summary
The study is a Phase II randomized, open label, multicenter trial designed to identify whether sirolimus is a potential alternative to prednisone as an up-front treatment for patients with standard-risk acute GVHD defined according to clinical and biomarker-based risk stratification. This trial incorporates both a novel up front GVHD therapy (sirolimus) as well as a novel BMT CTN developed acute GVHD biomarker test.
Detailed description
The study is a Phase II randomized, open label, multicenter trial designed to identify whether sirolimus is a potential alternative to prednisone as an up-front treatment for patients with standard-risk acute GVHD defined according to clinical and biomarker-based risk stratification. Patients with previously untreated, standard-risk acute GVHD, according to the refined Minnesota Criteria, who are in need of systemic therapy, will have a 5 mL blood sample collected prior to randomization to assess their biomarker Ann Arbor Risk status. Ann Arbor scoring results will be provided 48-72 hours after randomization. Patients will begin their study treatment assignments within 24 hours of randomization. Those with biomarker results of combined AA1/2 risk will continue on their randomized study treatment and will be included for primary endpoint analysis (Day 28 complete or partial response) and all planned study procedures and assessments. In contrast, patients with AA3 biomarker risk and those patients with missing biomarker results may continue on their randomized therapies or start another therapy at their physicians' discretion. In addition, AA3 risk patients and those with missing results will not be considered in primary endpoint analysis, but will be included in a subset analysis.
Interventions
DRUGSirolimus
Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.
DRUGPrednisone
Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Blood and Marrow Transplant Clinical Trials Network
National Marrow Donor Program
Medical College of Wisconsin
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. Patients with standard-risk acute GVHD, according to refined Minnesota Criteria. Refined Minnesota Criteria are available at https://redcap.ahc.umn.edu/surveys/?s=bNmFhseJIf. Standard-risk acute GVHD according to the refined Minnesota Risk Criteria requires meeting one of the criteria below: 1. Single organ involvement (Stage 1-3 skin, Stage 1 upper GI, or Stage 1-2 lower GI) 2. Multiple organ involvement (Stage 1-3 skin plus stage 1 upper GI, Stage 1-3 skin plus stage 1 lower GI, Stage 1-3 skin plus stage 1 lower GI plus stage 1 upper GI, Stage 1-3 skin plus stage 1-4 liver, or Stage 1 lower GI plus stage 1 upper GI) 2. Acute Minnesota Standard Risk GVHD requiring systemic immune suppressive therapy. 3. Acute GVHD developing after allogeneic hematopoietic cell transplantation using either bone marrow, peripheral blood, or umbilical cord blood. Recipients of non-myeloablative, reduced intensity conditioning and myeloablative transplants are eligible. All allogeneic donor sources are permitted, including siblings, unrelated donors, human leukocyte antigen (HLA)-haploidentical related donors and umbilical cord blood. 4. Patients NOT receiving systemic immune suppressive therapy for treatment of active GVHD (topical skin and GI corticosteroids are allowed). 5. Ability to tolerate oral or enterically-administered medications. 6. Patients of all ages. 7. Absolute neutrophil count (ANC) greater than 500/µL. 8. Biopsy confirmation of GVHD is not required. Enrollment should not be delayed for biopsy or pathology results unless local institutional practice mandates biopsy confirmation to make a GVHD treatment decision. 9. Written informed consent and/or assent from patient, parent or guardian. 10. Collection of a 5 ml blood sample (red top for serum) from the patient for Ann Arbor Scoring and ready to be shipped immediately after randomization.
Exclusion criteria
1. Patients receiving sirolimus (for any indication including GVHD prophylaxis) within 14 days of screening for enrollment. 2. Relapsed, progressing or persistent malignancy requiring withdrawal of systemic immune suppression. 3. Patients with acute GVHD developing after a donor lymphocyte infusion. 4. Active or recent (within 7 days) episode of transplant associated microangiopathy. 5. Patients with uncontrolled infections will be excluded. Infections are considered controlled if appropriate therapy has been instituted and, at the time of enrollment, no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection. 6. Patients unlikely to be available for evaluation at the transplant center on Day 28 and 56 of therapy. 7. A clinical presentation resembling de novo chronic GVHD or overlap syndrome developing before or present at the time of enrollment. 8. Patients receiving corticosteroids for any indication within 7 days before the onset of acute GVHD, except the following: Stable replacement doses of corticosteroids for adrenal insufficiency are permitted (e.g. hydrocortisone total dose of 10-12 mg/m\^2/day or prednisone 5-7.5mg daily or equivalent). Corticosteroids administered as premedication before transfusion of blood products or before intravenous medications to prevent infusion reactions are allowed. 9. Patients who are pregnant or breastfeeding. 10. Females of childbearing potential (FCBP) or a man who has sexual contact with a FCBP and is unwilling to use effective birth control for the duration of the study. 11. Patients on dialysis. 12. Patients on mechanical ventilation. 13. Patients with severe hepatic sinusoidal obstruction syndrome who in the judgment of the treating physician are not expected to have normalized bilirubin by Day 56 after enrollment. 14. Patients with a history of hypersensitivity to sirolimus or any component of the formulation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment | Days 28 and 56 Post-randomization | Scoring of CR/PR is in comparison to the participant's acute GVHD status at randomization. Complete response (CR) is defined as staging of 0 for in all target organs for GVHD - skin, GI tract, and liver. Partial response (PR) is defined as improvement in some target organ(s) without worsening in others. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are considered failures for this endpoint. Organ staging is defined below: Skin stage: 0: No rash 1. Rash \<25% of body surface area (BSA) 2. Rash on 25-50% of BSA 3. Rash on \>50% of BSA 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level): 0: \<2 mg/dL 1. 2-3 mg/dL 2. 3.01-6 mg/dL 3. 6.01-15.0 mg/dL 4. \>15 mg/dL GI stage: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Acute GVHD Response | Days 28 and 56 Post-randomization | Acute GVHD response is classified as CR, PR, mixed response (MR), no response (NR), and progression and scored by comparison to acute GVHD status at randomization. MR is defined as improvement in some organ(s) with worsening in another, progression as worsening in some organ(s) without improvement in others, and NR as absence of any improvement or worsening. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are classified as NR. Organ staging is defined as: Skin stage: 0: No rash 1. Rash \<25% of body surface area (BSA) 2. Rash 25-50% of BSA 3. Rash \>50% of BSA 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level in mg/dL): 0: \<2 1. 2-3 2. 3.01-6 3. 6.01-15.0 4. \>15 GI stage: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus |
| Percentage of Participants With Treatment Failure | Days 28 and 56 Post-randomization | Treatment failure is defined as either no response (NR) or progression and scored by comparison to acute GVHD status at randomization. Progression is defined as worsening in some target organ(s) without improvement in others and NR is defined as absence of any improvement or worsening in target organs. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are classified as NR. Organ staging is defined as: Skin stage: 0: No rash 1. Rash \<25% of body surface area (BSA) 2. Rash 25-50% of BSA 3. Rash \>50% of BSA 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level in mg/dL): 0: \<2 1. 2-3 2. 3.01-6 3. 6.01-15.0 4. \>15 GI stage: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus |
| Percentage of Participants With Overall Survival | 6 and 12 Months Post-randomization | Overall survival is defined as survival of death from any cause. |
| Percentage of Participants With Disease-free Survival | 6 and 12 Months Post-randomization | Disease-free survival is defined as freedom from death and relapse of the underlying malignancy. |
| Proportion of Participants With Event-free Survival | 6 and 12 Months Post-randomization | Event-free survival is defined as freedom from acute GVHD progression, chronic GVHD, malignancy relapse, and death. |
| Percentage of Participants With Complete or Partial Response (CR/PR) and Steroid Dose Less Than 0.25 mg/kg Per Day | Day 28 Post-randomization | The proportion of patients with CR/PR and on a prednisone-equivalent steroid dose of 0.25 mg/kg/day or less is evaluated. CR/PR scoring is in comparison to acute GVHD status at randomization. CR is defined as staging of 0 in all target organs. PR is defined as improvement in some organ(s) without worsening in others. Death and initiation of steroid-free, systemic acute GVHD treatment beyond randomized therapy are considered failures for this endpoint. Organ staging is defined as: Skin stage: 0: No rash 1. Rash \<25% of body surface area (BSA) 2. Rash 25-50% of BSA 3. Rash \>50% of BSA 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level in mg/dL): 0: \<2 1. 2-3 2. 3.01-6 3. 6.01-15.0 4. \>15 mg/dL GI stage: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus |
| Percentage of Participants With Malignancy Relapse | 6 and 12 Months Post-randomization | The cumulative incidence of relapse of the primary malignancy is described, with death treated as a competing risk. |
| Percentage of Participants With Chronic GVHD | 6 and 12 Months Post-randomization | Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification. The cumulative incidence of chronic GVHD is described, with death and malignancy relapse treated as competing risks. |
| Percentage of Participants With GVHD-free Survival | 6 and 12 Months Post-randomization | GVHD-free survival is defined as freedom from acute GVHD, chronic GVHD, and death. The proportion of participants alive and free of both acute and chronic GVHD are described at 6 and 12 months post-randomization. |
| Percentage of Participants With Serious Infections | 6 and 12 Months Post-randomization | The cumulative incidence of serious infections (Grade 2 or 3 per BMT CTN MOP) is described, with death treated as a competing risk. |
| Percentage of Participants With Non-relapse Mortality | 6 and 12 Months Post-randomization | Non-relapse mortality is defined as death due to any cause other than relapse of the underlying malignancy. The cumulative incidence of non-relapse mortality is described, with malignancy relapse treated as a competing risk. |
Countries
United States
Participant flow
Pre-assignment details
The primary analysis population includes only participants with an AA score of 1 or 2 (n=64 on the prednisone arm, n=58 on the sirolimus arm). Three participants on the prednisone arm and two on the sirolimus arm were excluded because they had an AA score of 3 or missing.
Participants by arm
| Arm | Count |
|---|---|
| Sirolimus Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established.
Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization. | 58 |
| Prednisone Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established.
Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment. | 64 |
| Total | 122 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 5 | 1 |
Baseline characteristics
| Characteristic | Sirolimus | Total | Prednisone |
|---|---|---|---|
| Age, Continuous | 58.0 years | 54.6 years | 52.4 years |
| Ann Arbor Biomarker Risk Score 1 | 38 Participants | 83 Participants | 45 Participants |
| Ann Arbor Biomarker Risk Score 2 | 20 Participants | 39 Participants | 19 Participants |
| Liver Abnormalities at Enrollment Bilirubin 2.0-3.0mg/dL | 0 Participants | 1 Participants | 1 Participants |
| Liver Abnormalities at Enrollment Bilirubin <2.0mg/dL | 58 Participants | 121 Participants | 63 Participants |
| Lower GI Abnormalities at Enrollment Adult: 1000-1500mL/day, Child: 20-30mL/kg/day | 0 Participants | 1 Participants | 1 Participants |
| Lower GI Abnormalities at Enrollment Adult: 500-999mL/day, Child: 10-19.9mL/kg/day | 2 Participants | 9 Participants | 7 Participants |
| Lower GI Abnormalities at Enrollment Adult: <500 mL/day, Child: <10mL/kg/day | 3 Participants | 13 Participants | 10 Participants |
| Lower GI Abnormalities at Enrollment No Diarrhea | 53 Participants | 99 Participants | 46 Participants |
| Race/Ethnicity, Customized American Indian / Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Hawaiian/Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Multiracial | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 55 Participants | 114 Participants | 59 Participants |
| Sex: Female, Male Female | 21 Participants | 52 Participants | 31 Participants |
| Sex: Female, Male Male | 37 Participants | 70 Participants | 33 Participants |
| Skin Abnormalities at Enrollment Maculopapular Rash 25-50% body surface area | 14 Participants | 27 Participants | 13 Participants |
| Skin Abnormalities at Enrollment Maculopapular Rash <25% body surface area | 8 Participants | 19 Participants | 11 Participants |
| Skin Abnormalities at Enrollment Maculopapular Rash >50% body surface area | 16 Participants | 37 Participants | 21 Participants |
| Skin Abnormalities at Enrollment No active GVHD rash | 20 Participants | 39 Participants | 19 Participants |
| Upper GI Abnormalities at Enrollment No or Intermittent Nausea, Vomiting, or Anorexia | 32 Participants | 68 Participants | 36 Participants |
| Upper GI Abnormalities at Enrollment Persistent Nausea, Vomiting, or Anorexia | 26 Participants | 54 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 12 / 58 | 17 / 64 |
| other Total, other adverse events | 0 / 58 | 0 / 64 |
| serious Total, serious adverse events | 8 / 58 | 3 / 64 |
Outcome results
Primary
Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment
Scoring of CR/PR is in comparison to the participant's acute GVHD status at randomization. Complete response (CR) is defined as staging of 0 for in all target organs for GVHD - skin, GI tract, and liver. Partial response (PR) is defined as improvement in some target organ(s) without worsening in others. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are considered failures for this endpoint. Organ staging is defined below: Skin stage: 0: No rash 1. Rash \<25% of body surface area (BSA) 2. Rash on 25-50% of BSA 3. Rash on \>50% of BSA 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level): 0: \<2 mg/dL 1. 2-3 mg/dL 2. 3.01-6 mg/dL 3. 6.01-15.0 mg/dL 4. \>15 mg/dL GI stage: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus
Time frame: Days 28 and 56 Post-randomization
Population: CR/PR was evaluated in participants remaining on study until the assessment time point. At Day 28, one prednisone and four sirolimus arm participants were excluded from the analysis due to prior study withdrawal. At Day 56, one prednisone and five sirolimus arm participants were excluded from the analysis due to prior study withdrawal.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Sirolimus | Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment | CR/PR at Day 28 | Yes | 35 Participants |
| Sirolimus | Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment | CR/PR at Day 28 | No | 19 Participants |
| Sirolimus | Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment | CR/PR at Day 56 | Yes | 34 Participants |
| Sirolimus | Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment | CR/PR at Day 56 | No | 19 Participants |
| Prednisone | Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment | CR/PR at Day 56 | No | 13 Participants |
| Prednisone | Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment | CR/PR at Day 28 | Yes | 46 Participants |
| Prednisone | Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment | CR/PR at Day 56 | Yes | 50 Participants |
| Prednisone | Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment | CR/PR at Day 28 | No | 17 Participants |
Comparison: The primary objective of this Phase II trial was to describe the proportion of patients with Day 28 CR/PR in each treatment arm and to estimate the risk difference of these rates using a point estimate and 90% confidence interval. These estimates are used to inform about the efficacy of sirolimus in contrast to prednisone for potential future research.90% CI: [-0.223, 0.059]
Comparison: A secondary objective of this Phase II trial was to describe the proportion of patients with Day 56 CR/PR in each treatment arm and to estimate the risk difference of these rates using a point estimate and 95% confidence interval. These estimates are used to inform about the efficacy of sirolimus in contrast to prednisone for potential future research.95% CI: [-0.315, 0.011]
Secondary
Acute GVHD Response
Acute GVHD response is classified as CR, PR, mixed response (MR), no response (NR), and progression and scored by comparison to acute GVHD status at randomization. MR is defined as improvement in some organ(s) with worsening in another, progression as worsening in some organ(s) without improvement in others, and NR as absence of any improvement or worsening. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are classified as NR. Organ staging is defined as: Skin stage: 0: No rash 1. Rash \<25% of body surface area (BSA) 2. Rash 25-50% of BSA 3. Rash \>50% of BSA 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level in mg/dL): 0: \<2 1. 2-3 2. 3.01-6 3. 6.01-15.0 4. \>15 GI stage: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus
Time frame: Days 28 and 56 Post-randomization
Population: Acute GVHD response was evaluated in participants remaining on study until the assessment day. At Day 28, one prednisone and four sirolimus arm participants were excluded from the analysis due to prior study withdrawal. At Day 56, one prednisone and five sirolimus arm participants were excluded from the analysis due to prior study withdrawal.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Sirolimus | Acute GVHD Response | Acute GVHD Response at Day 28 | Complete Response (CR) | 30 Participants |
| Sirolimus | Acute GVHD Response | Acute GVHD Response at Day 28 | Partial Response (PR) | 5 Participants |
| Sirolimus | Acute GVHD Response | Acute GVHD Response at Day 28 | Mixed Response (MR) | 1 Participants |
| Sirolimus | Acute GVHD Response | Acute GVHD Response at Day 28 | No Response (NR) | 16 Participants |
| Sirolimus | Acute GVHD Response | Acute GVHD Response at Day 28 | Progression | 2 Participants |
| Sirolimus | Acute GVHD Response | Acute GVHD Response at Day 56 | Complete Response (CR) | 30 Participants |
| Sirolimus | Acute GVHD Response | Acute GVHD Response at Day 56 | Partial Response (PR) | 4 Participants |
| Sirolimus | Acute GVHD Response | Acute GVHD Response at Day 56 | Mixed Response (MR) | 0 Participants |
| Sirolimus | Acute GVHD Response | Acute GVHD Response at Day 56 | No Response (NR) | 19 Participants |
| Sirolimus | Acute GVHD Response | Acute GVHD Response at Day 56 | Progression | 0 Participants |
| Prednisone | Acute GVHD Response | Acute GVHD Response at Day 56 | Mixed Response (MR) | 0 Participants |
| Prednisone | Acute GVHD Response | Acute GVHD Response at Day 28 | Complete Response (CR) | 39 Participants |
| Prednisone | Acute GVHD Response | Acute GVHD Response at Day 56 | Complete Response (CR) | 48 Participants |
| Prednisone | Acute GVHD Response | Acute GVHD Response at Day 28 | Partial Response (PR) | 7 Participants |
| Prednisone | Acute GVHD Response | Acute GVHD Response at Day 56 | Progression | 3 Participants |
| Prednisone | Acute GVHD Response | Acute GVHD Response at Day 28 | Mixed Response (MR) | 5 Participants |
| Prednisone | Acute GVHD Response | Acute GVHD Response at Day 56 | Partial Response (PR) | 2 Participants |
| Prednisone | Acute GVHD Response | Acute GVHD Response at Day 28 | No Response (NR) | 11 Participants |
| Prednisone | Acute GVHD Response | Acute GVHD Response at Day 56 | No Response (NR) | 10 Participants |
| Prednisone | Acute GVHD Response | Acute GVHD Response at Day 28 | Progression | 1 Participants |
Comparison: The null hypothesis is that there is no difference in classification of acute GVHD response at Day 28 post-randomization between participants on the sirolimus and prednisone arms. These classifications were compared between treatment arms using Fisher's exact test, due to the presence of small numbers of participants in some categories.p-value: 0.32Fisher Exact
Comparison: The null hypothesis is that there is no difference in classification of acute GVHD response at Day 56 post-randomization between participants on the sirolimus and prednisone arms. These classifications were compared between treatment arms using Fisher's exact test, due to the presence of small numbers of participants in some categories.p-value: 0.014Fisher Exact
Secondary
Percentage of Participants With Chronic GVHD
Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification. The cumulative incidence of chronic GVHD is described, with death and malignancy relapse treated as competing risks.
Time frame: 6 and 12 Months Post-randomization
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With Chronic GVHD | Chronic GVHD at 6 Months | 25.7 percentage of participants |
| Sirolimus | Percentage of Participants With Chronic GVHD | Chronic GVHD at 12 Months | 31.4 percentage of participants |
| Prednisone | Percentage of Participants With Chronic GVHD | Chronic GVHD at 6 Months | 31.2 percentage of participants |
| Prednisone | Percentage of Participants With Chronic GVHD | Chronic GVHD at 12 Months | 40.6 percentage of participants |
Comparison: The null hypothesis is that there is no difference in the proportions of participants with chronic GVHD between the sirolimus and prednisone arms during the 12 month period post-randomization, with death and malignancy relapse treated as competing risks for chronic GVHD. These proportions were compared between treatment arms using Gray's test.p-value: 0.296Gray's test
Secondary
Percentage of Participants With Complete or Partial Response (CR/PR) and Steroid Dose Less Than 0.25 mg/kg Per Day
The proportion of patients with CR/PR and on a prednisone-equivalent steroid dose of 0.25 mg/kg/day or less is evaluated. CR/PR scoring is in comparison to acute GVHD status at randomization. CR is defined as staging of 0 in all target organs. PR is defined as improvement in some organ(s) without worsening in others. Death and initiation of steroid-free, systemic acute GVHD treatment beyond randomized therapy are considered failures for this endpoint. Organ staging is defined as: Skin stage: 0: No rash 1. Rash \<25% of body surface area (BSA) 2. Rash 25-50% of BSA 3. Rash \>50% of BSA 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level in mg/dL): 0: \<2 1. 2-3 2. 3.01-6 3. 6.01-15.0 4. \>15 mg/dL GI stage: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus
Time frame: Day 28 Post-randomization
Population: The endpoint was evaluated only in participants that remained on study until Day 28. One participant on the prednisone arm and four on the sirolimus arm were deemed unevaluable at Day 28 due to prior study withdrawal.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With Complete or Partial Response (CR/PR) and Steroid Dose Less Than 0.25 mg/kg Per Day | Yes | 36 Participants |
| Sirolimus | Percentage of Participants With Complete or Partial Response (CR/PR) and Steroid Dose Less Than 0.25 mg/kg Per Day | No | 18 Participants |
| Prednisone | Percentage of Participants With Complete or Partial Response (CR/PR) and Steroid Dose Less Than 0.25 mg/kg Per Day | Yes | 20 Participants |
| Prednisone | Percentage of Participants With Complete or Partial Response (CR/PR) and Steroid Dose Less Than 0.25 mg/kg Per Day | No | 43 Participants |
Comparison: The null hypothesis is that there is no difference in the proportions of participants with CR/PR and steroid dose of 0.25mg/kg/day or less at Day 28 post-randomization between the sirolimus and prednisone arms. These proportions were compared between treatment arms using a Z test of the difference of binomial proportions.p-value: <0.001Z test comparing binomial proportions
Secondary
Percentage of Participants With Disease-free Survival
Disease-free survival is defined as freedom from death and relapse of the underlying malignancy.
Time frame: 6 and 12 Months Post-randomization
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With Disease-free Survival | Disease-free Survival at 6 Months | 72.8 percentage of participants |
| Sirolimus | Percentage of Participants With Disease-free Survival | Disease-free Survival at 12 Months | 61.6 percentage of participants |
| Prednisone | Percentage of Participants With Disease-free Survival | Disease-free Survival at 6 Months | 78.1 percentage of participants |
| Prednisone | Percentage of Participants With Disease-free Survival | Disease-free Survival at 12 Months | 70.2 percentage of participants |
Comparison: The null hypothesis is that there is no difference in the proportions of participants with disease-free survival between the sirolimus and prednisone arms during the 12 month period post-randomization. These proportions were compared between treatment arms using a log rank test.p-value: 0.34Log Rank
Secondary
Percentage of Participants With GVHD-free Survival
GVHD-free survival is defined as freedom from acute GVHD, chronic GVHD, and death. The proportion of participants alive and free of both acute and chronic GVHD are described at 6 and 12 months post-randomization.
Time frame: 6 and 12 Months Post-randomization
Population: GVHD-free survival was evaluated only in participants that remained on study until the assessment time point. One participant on the prednisone arm and five on the sirolimus arm were excluded from the analysis at 6 and 12 months due to prior study withdrawal.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With GVHD-free Survival | GVHD-free Survival at 6 Months | 45.3 percentage of participants |
| Sirolimus | Percentage of Participants With GVHD-free Survival | GVHD-free Survival at 12 Months | 50.9 percentage of participants |
| Prednisone | Percentage of Participants With GVHD-free Survival | GVHD-free Survival at 6 Months | 46.0 percentage of participants |
| Prednisone | Percentage of Participants With GVHD-free Survival | GVHD-free Survival at 12 Months | 46.0 percentage of participants |
Comparison: The null hypothesis is that there is no difference in the proportions of participants with GVHD-free survival at 6 months post-randomization between the sirolimus and prednisone arms. These proportions were compared between treatment arms using a Z test of the difference of binomial proportions.p-value: 0.936Z test comparing binomial proportions
Comparison: The null hypothesis is that there is no difference in the proportions of participants with GVHD-free survival at 6 months post-randomization between the sirolimus and prednisone arms. These proportions were compared between treatment arms using a Z test of the difference of binomial proportions.p-value: 0.598Z test comparing binomial proportions
Secondary
Percentage of Participants With Malignancy Relapse
The cumulative incidence of relapse of the primary malignancy is described, with death treated as a competing risk.
Time frame: 6 and 12 Months Post-randomization
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With Malignancy Relapse | Malignancy Relapse at 6 Months | 14.5 percentage of participants |
| Sirolimus | Percentage of Participants With Malignancy Relapse | Malignancy Relapse at 12 Months | 21.9 percentage of participants |
| Prednisone | Percentage of Participants With Malignancy Relapse | Malignancy Relapse at 6 Months | 12.5 percentage of participants |
| Prednisone | Percentage of Participants With Malignancy Relapse | Malignancy Relapse at 12 Months | 15.7 percentage of participants |
Comparison: The null hypothesis is that there is no difference in the proportions of participants with malignancy relapse between the sirolimus and prednisone arms during the 12 month period post-randomization, with death treated as a competing risk for malignancy relapse. These proportions were compared between treatment arms using Gray's test.p-value: 0.402Gray's test
Secondary
Percentage of Participants With Non-relapse Mortality
Non-relapse mortality is defined as death due to any cause other than relapse of the underlying malignancy. The cumulative incidence of non-relapse mortality is described, with malignancy relapse treated as a competing risk.
Time frame: 6 and 12 Months Post-randomization
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With Non-relapse Mortality | Non-relapse Mortality at 6 Months | 12.7 percentage of participants |
| Sirolimus | Percentage of Participants With Non-relapse Mortality | Non-relapse Mortality at 12 Months | 16.5 percentage of participants |
| Prednisone | Percentage of Participants With Non-relapse Mortality | Non-relapse Mortality at 6 Months | 9.4 percentage of participants |
| Prednisone | Percentage of Participants With Non-relapse Mortality | Non-relapse Mortality at 12 Months | 14.2 percentage of participants |
Comparison: The null hypothesis is that there is no difference in the proportions of participants with non-relapse mortality between the sirolimus and prednisone arms during the 12 month period post-randomization, with malignancy relapse treated as a competing risk for non-relapse mortality. These proportions were compared between treatment arms using Gray's test.p-value: 0.726Gray's test
Secondary
Percentage of Participants With Overall Survival
Overall survival is defined as survival of death from any cause.
Time frame: 6 and 12 Months Post-randomization
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With Overall Survival | Overall Survival at 6 Months | 81.9 percentage of participants |
| Sirolimus | Percentage of Participants With Overall Survival | Overall Survival at 12 Months | 76.3 percentage of participants |
| Prednisone | Percentage of Participants With Overall Survival | Overall Survival at 6 Months | 82.7 percentage of participants |
| Prednisone | Percentage of Participants With Overall Survival | Overall Survival at 12 Months | 73.2 percentage of participants |
Comparison: The null hypothesis is that there is no difference in the proportions of participants with overall survival between the sirolimus and prednisone arms during the 12 month period post-randomization. These proportions were compared between treatment arms using a log rank test.p-value: 0.785Log Rank
Secondary
Percentage of Participants With Serious Infections
The cumulative incidence of serious infections (Grade 2 or 3 per BMT CTN MOP) is described, with death treated as a competing risk.
Time frame: 6 and 12 Months Post-randomization
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With Serious Infections | Seirious Infections at 6 Months | 30.4 percentage of participants |
| Sirolimus | Percentage of Participants With Serious Infections | Seirious Infections at 12 Months | 39.6 percentage of participants |
| Prednisone | Percentage of Participants With Serious Infections | Seirious Infections at 6 Months | 43.8 percentage of participants |
| Prednisone | Percentage of Participants With Serious Infections | Seirious Infections at 12 Months | 51.8 percentage of participants |
Comparison: The null hypothesis is that there is no difference in the proportions of participants with serious infections between the sirolimus and prednisone arms during the 12 month period post-randomization, with death treated as a competing risk for serious infection. These proportions were compared between treatment arms using Gray's test.p-value: 0.221Gray's test
Secondary
Percentage of Participants With Treatment Failure
Treatment failure is defined as either no response (NR) or progression and scored by comparison to acute GVHD status at randomization. Progression is defined as worsening in some target organ(s) without improvement in others and NR is defined as absence of any improvement or worsening in target organs. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are classified as NR. Organ staging is defined as: Skin stage: 0: No rash 1. Rash \<25% of body surface area (BSA) 2. Rash 25-50% of BSA 3. Rash \>50% of BSA 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level in mg/dL): 0: \<2 1. 2-3 2. 3.01-6 3. 6.01-15.0 4. \>15 GI stage: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus
Time frame: Days 28 and 56 Post-randomization
Population: Treatment failure was evaluated in participants remaining on study until the assessment day. At Day 28, one prednisone and four sirolimus arm participants were excluded from the analysis due to prior study withdrawal. At Day 56, one prednisone and five sirolimus arm participants were excluded from the analysis due to prior study withdrawal.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Sirolimus | Percentage of Participants With Treatment Failure | Treatment Failure at Day 28 | Yes | 18 Participants |
| Sirolimus | Percentage of Participants With Treatment Failure | Treatment Failure at Day 28 | No | 36 Participants |
| Sirolimus | Percentage of Participants With Treatment Failure | Treatment Failure at Day 56 | Yes | 19 Participants |
| Sirolimus | Percentage of Participants With Treatment Failure | Treatment Failure at Day 56 | No | 34 Participants |
| Prednisone | Percentage of Participants With Treatment Failure | Treatment Failure at Day 56 | No | 50 Participants |
| Prednisone | Percentage of Participants With Treatment Failure | Treatment Failure at Day 28 | Yes | 12 Participants |
| Prednisone | Percentage of Participants With Treatment Failure | Treatment Failure at Day 56 | Yes | 13 Participants |
| Prednisone | Percentage of Participants With Treatment Failure | Treatment Failure at Day 28 | No | 51 Participants |
Comparison: The null hypothesis is that there is no difference in the proportions of participants with treatment failure at Day 28 post-randomization between the sirolimus and prednisone arms. These proportions were compared between treatment arms using a Z test of the difference of binomial proportions.p-value: 0.078Z test comparing binomial proportions
Comparison: The null hypothesis is that there is no difference in the proportions of participants with treatment failure at Day 56 post-randomization between the sirolimus and prednisone arms. These proportions were compared between treatment arms using a Z test of the difference of binomial proportions.p-value: 0.068Z test comparing binomial proportions
Secondary
Proportion of Participants With Event-free Survival
Event-free survival is defined as freedom from acute GVHD progression, chronic GVHD, malignancy relapse, and death.
Time frame: 6 and 12 Months Post-randomization
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Proportion of Participants With Event-free Survival | Event-free Survival at 6 Months | 47.3 percentage of participants |
| Sirolimus | Proportion of Participants With Event-free Survival | Event-free Survival at 12 Months | 35.9 percentage of participants |
| Prednisone | Proportion of Participants With Event-free Survival | Event-free Survival at 6 Months | 43.7 percentage of participants |
| Prednisone | Proportion of Participants With Event-free Survival | Event-free Survival at 12 Months | 31.2 percentage of participants |
Comparison: The null hypothesis is that there is no difference in the proportions of participants with event-free survival between the sirolimus and prednisone arms during the 12 month period post-randomization. These proportions were compared between treatment arms using a log rank test.p-value: 0.713Log Rank