Graft Versus Host Disease, Recurrent Adult Acute Lymphoblastic Leukemia
Conditions
Brief summary
This randomized phase III trial is studying low-dose prednisone or methylprednisolone to see how well they work compared with standard-dose prednisone or methylprednisolone in treating patients with newly diagnosed acute graft-versus-host disease (GVHD). Glucocorticoids, such as prednisone or methylprednisolone at a starting dose of 2 mg/kg/day are standard treatment for acute graft-versus-host disease caused by a donor stem cell transplant. It is not yet known whether low-dose glucocorticoids are more effective than standard-dose glucocorticoids in treating acute graft-versus-host-disease
Detailed description
OBJECTIVES: I. To determine whether a lower starting dose of prednisone for treatment of newly diagnosed acute GVHD results in decreased prednisone exposure without compromising overall survival. II. To estimate the magnitude of clinical benefit associated with the reduction in prednisone exposure. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I (Low-dose; prednisone-equivalent dose at initiation of treatment of 0.5 mg/kg/day or 1.0 mg/kg/day; stratified according to initial symptom severity): Patients receive low-dose prednisone or methylprednisolone once or twice daily in the absence of disease progression or unacceptable toxicity. ARM II (Standard-dose; prednisone-equivalent dose at initiation of treatment of 1.0 mg/kg/day or 2.0 mg/kg/day; stratified according to initial symptom severity): Patients receive standard-dose prednisone or methylprednisolone once or twice daily in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 1 year and then annually thereafter.
Interventions
DRUGprednisone
immunosuppressive drug
DRUGmethylprednisolone
immunosuppressive drug
OTHERquestionnaire administration
Ancillary studies
Sponsors
National Cancer Institute (NCI)
Fred Hutchinson Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Patients with newly diagnosed acute GVHD (\>= grade IIa) for whom, in the judgment of the attending physician, initial treatment with systemic glucocorticoids is indicated * Patient or guardian able and willing to provide informed consent
Exclusion criteria
* Hallmarks of chronic GVHD * GVHD after donor lymphocyte infusion (DLI) * Patient unwilling to remain in Seattle under the care of the Fred Hutchinson Cancer Research Center (FHCRC)/Seattle Cancer Care Alliance (SCCA) through day 42 after the start of treatment for GVHD * Uncontrolled infection or other underlying comorbidity (i.e. severe psychiatric illness) that precludes the use of standard-dose prednisone * Recent diagnosis of recurrent or progressive malignancy that precludes the use of standard-dose prednisone * Any prior systemic therapy for acute GVHD (Patients may receive up to 2 doses of low-dose prednisone prior to randomization; low-dose prednisone is defined as 0.5 mg/kg/dose for patients who present with grade IIa GVHD and 1 mg/kg/dose for those who present with grade IIb-IV GVHD) * Enrollment on Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) trial 0802
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Cumulative Prednisone Dose (mg/kg) Over 42 Days From the Start of Treatment | At day 42 after initiation of treatment | The total cumulative dose of prednisone (milligrams/kilogram) was calculated starting from the start of therapy through study day 42. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Prednisone-associated Toxicity as Assessed by Hyperglycemia | Baseline and then through 42 days after starting treatment | Impact on blood glucose (BG) control will be assessed by comparing average BG and BG-variability between patients given standard-dose and low-dose prednisone. |
| Prednisone-associated Toxicity as Assessed by Invasive Infections (Bacterial, Fungal and Viral) | Baseline and through 100 days of treatment | The total number of invasive infections (bacterial, fungal and viral) occurring in patients in each group were collected. |
| Prednisone-associated Toxicity as Assessed by Myopathy | Baseline and then weekly until 42 days after starting treatment | Assessed by mean change from baseline to day 42 using Manual Muscle Testing measure. The degree of resistance against pressure applied by tester was measured on a 5-point scale. A score of 5 indicates the patient can hold the position against maximum to strong resistance. A score of 0 indicates the patient has no resistance against pressure. Testing included upper and lower extremities: shoulder (deltoid at 90 degrees), and hip and knee in a sitting position. |
| Prednisone-associated Toxicity as Assessed by Hypertension | Baseline and then through 42 days after starting treatment | The number of different anti-hypertensive medications administered to control hypertension were collected. The mean change in the number of medications from baseline to day 42 was measured. |
| Prednisone-associated Toxicity as Assessed by Quality of Life | Baseline and then every other week until 42 days after starting treatment | Patients completed the MD Anderson Symptom Inventory (MDASI), which is a quality of life questionnaire validated for oncology/transplant patients. On a 1-10 point scale, patients scored the degree of severity of symptoms or the degree of interference in feelings or function due to symptoms at baseline or in the previous week. A score of 1 indicates symptom is not present or does not interfere with feelings or function. A score of 10 indicates the symptom is as bad as you can imagine or interferes completely with feelings or function. The mean change in score from baseline to day 42 was measured. |
| Non-relapse Mortality | At 12 months after the start of prednisone therapy | Non-relapse mortality (NRM) is defined as death due to any cause in the absence of documented relapse/progression. |
| Recurrent or Progressive Malignancy | At 12 months after the start of prednisone therapy | Percentage of relapse estimated by cumulative incidence methods |
| Progression to Grade III-IV Acute GVHD | At approximately 100 days after transplant | Diagnosed and graded according to standard established criteria. Measure is percent of patients with baseline scores of IIa (Group A) or IIb (Group B) who progressed to more severe GVHD (Grade III/IV). Percentage estimated by cumulative incidence methods. |
| Secondary Therapy for Acute GVHD Beyond Prednisone | At approximately 100 days after transplant | This includes any intervention intended to control acute GVHD through an immunosuppressive effect from oral or parenteral administration of any systemic medication not given previously. This does not include topical therapy, an increase in the dose of glucocorticoids or the resumption of treatment after previous discontinuation or any increase in the dose of immunosuppressive medication previously administered for GVHD prophylaxis, or reinstatement of GVHD prophylaxis previously discontinued. A change in treatment from cyclosporine to tacrolimus or vice versa because of drug toxicity is not considered secondary therapy, but any change made because of uncontrolled GVHD is considered secondary therapy. Percentage is estimated by cumulative incidence methods. |
| Chronic Extensive GVHD | At 12 months after the start of prednisone therapy | Percentage of patients with chronic extensive GVHD, estimated by cumulative incidence methods |
| Overall Survival | At 12 months after the start of prednisone therapy | Percentage of patients surviving as estimated by Kaplan-Meier. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A (Low-dose) Patients received prednisone-equivalent low doses of prednisone depending on presenting grade of acute GVHD (0.5 mg/kg/day for mild GVHD or 1.0 mg/kg/day for moderate/severe GVHD). Patients could receive prednisone or methylprednisolone. | 73 |
| Group B (Standard-dose) Patients received prednisone-equivalent standard doses of prednisone depending on presenting grade of acute GVHD (1.0 mg/kg/day for mild GVHD or 2.0 mg/kg/day for moderate/severe GVHD). Patients could receive prednisone or methylprednisolone. | 77 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 1 |
| Overall Study | discharge home | 4 | 3 |
| Overall Study | incorrect stratification | 2 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Group A (Low-dose) | Group B (Standard-dose) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 8 Participants | 14 Participants | 22 Participants |
| Age, Categorical >=65 years | 6 Participants | 7 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 59 Participants | 56 Participants | 115 Participants |
| Sex: Female, Male Female | 31 Participants | 26 Participants | 57 Participants |
| Sex: Female, Male Male | 42 Participants | 51 Participants | 93 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 38 / 81 | 30 / 83 |
Outcome results
Primary
Mean Cumulative Prednisone Dose (mg/kg) Over 42 Days From the Start of Treatment
The total cumulative dose of prednisone (milligrams/kilogram) was calculated starting from the start of therapy through study day 42.
Time frame: At day 42 after initiation of treatment
Population: From a total enrollment of 164 patients, the cumulative dose of prednisone at day 42 of treatment was available in 152 patients. The primary outcome was not measured in 12 patients due to withdrawal from study (2), discharge from Center before day 42 of treatment (10). Analysis was not completed in two patients due to an error in stratification.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Grade IIa GVHD; 0.5 mg/kg/d Prednisone | Mean Cumulative Prednisone Dose (mg/kg) Over 42 Days From the Start of Treatment | 22.2 milligrams per kilogram | Standard Deviation 13.7 |
| Grade IIa GVHD; 1.0 mg/kg/d Prednisone | Mean Cumulative Prednisone Dose (mg/kg) Over 42 Days From the Start of Treatment | 27.1 milligrams per kilogram | Standard Deviation 12.7 |
| Grade IIb-IV GVHD; 1.0 mg/kg/d Prednisone | Mean Cumulative Prednisone Dose (mg/kg) Over 42 Days From the Start of Treatment | 38.4 milligrams per kilogram | Standard Deviation 14.1 |
| Grade IIb-IV GVHD; 2.0 mg/kg/d Prednisone | Mean Cumulative Prednisone Dose (mg/kg) Over 42 Days From the Start of Treatment | 41.3 milligrams per kilogram | Standard Deviation 12.1 |
p-value: 0.08t-test, 2 sided
p-value: 0.4t-test, 2 sided
Secondary
Chronic Extensive GVHD
Percentage of patients with chronic extensive GVHD, estimated by cumulative incidence methods
Time frame: At 12 months after the start of prednisone therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grade IIa GVHD; 0.5 mg/kg/d Prednisone | Chronic Extensive GVHD | 47 percentage of participants |
| Grade IIa GVHD; 1.0 mg/kg/d Prednisone | Chronic Extensive GVHD | 54 percentage of participants |
Secondary
Non-relapse Mortality
Non-relapse mortality (NRM) is defined as death due to any cause in the absence of documented relapse/progression.
Time frame: At 12 months after the start of prednisone therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grade IIa GVHD; 0.5 mg/kg/d Prednisone | Non-relapse Mortality | 15 percentage of participants |
| Grade IIa GVHD; 1.0 mg/kg/d Prednisone | Non-relapse Mortality | 16 percentage of participants |
Secondary
Overall Survival
Percentage of patients surviving as estimated by Kaplan-Meier.
Time frame: At 12 months after the start of prednisone therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grade IIa GVHD; 0.5 mg/kg/d Prednisone | Overall Survival | 77 percentage of participants |
| Grade IIa GVHD; 1.0 mg/kg/d Prednisone | Overall Survival | 77 percentage of participants |
p-value: 0.9595% CI: [0.6, 1.74]Regression, Cox
Secondary
Prednisone-associated Toxicity as Assessed by Hyperglycemia
Impact on blood glucose (BG) control will be assessed by comparing average BG and BG-variability between patients given standard-dose and low-dose prednisone.
Time frame: Baseline and then through 42 days after starting treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Grade IIa GVHD; 0.5 mg/kg/d Prednisone | Prednisone-associated Toxicity as Assessed by Hyperglycemia | 140 mg/dL | Standard Error 7.4 |
| Grade IIa GVHD; 1.0 mg/kg/d Prednisone | Prednisone-associated Toxicity as Assessed by Hyperglycemia | 142 mg/dL | Standard Error 12.9 |
Secondary
Prednisone-associated Toxicity as Assessed by Hypertension
The number of different anti-hypertensive medications administered to control hypertension were collected. The mean change in the number of medications from baseline to day 42 was measured.
Time frame: Baseline and then through 42 days after starting treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Grade IIa GVHD; 0.5 mg/kg/d Prednisone | Prednisone-associated Toxicity as Assessed by Hypertension | -0.29 medications |
| Grade IIa GVHD; 1.0 mg/kg/d Prednisone | Prednisone-associated Toxicity as Assessed by Hypertension | -0.24 medications |
Secondary
Prednisone-associated Toxicity as Assessed by Invasive Infections (Bacterial, Fungal and Viral)
The total number of invasive infections (bacterial, fungal and viral) occurring in patients in each group were collected.
Time frame: Baseline and through 100 days of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grade IIa GVHD; 0.5 mg/kg/d Prednisone | Prednisone-associated Toxicity as Assessed by Invasive Infections (Bacterial, Fungal and Viral) | 52 percentage of participants |
| Grade IIa GVHD; 1.0 mg/kg/d Prednisone | Prednisone-associated Toxicity as Assessed by Invasive Infections (Bacterial, Fungal and Viral) | 53 percentage of participants |
Secondary
Prednisone-associated Toxicity as Assessed by Myopathy
Assessed by mean change from baseline to day 42 using Manual Muscle Testing measure. The degree of resistance against pressure applied by tester was measured on a 5-point scale. A score of 5 indicates the patient can hold the position against maximum to strong resistance. A score of 0 indicates the patient has no resistance against pressure. Testing included upper and lower extremities: shoulder (deltoid at 90 degrees), and hip and knee in a sitting position.
Time frame: Baseline and then weekly until 42 days after starting treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Grade IIa GVHD; 0.5 mg/kg/d Prednisone | Prednisone-associated Toxicity as Assessed by Myopathy | -0.18 units on a scale |
| Grade IIa GVHD; 1.0 mg/kg/d Prednisone | Prednisone-associated Toxicity as Assessed by Myopathy | -0.18 units on a scale |
Secondary
Prednisone-associated Toxicity as Assessed by Quality of Life
Patients completed the MD Anderson Symptom Inventory (MDASI), which is a quality of life questionnaire validated for oncology/transplant patients. On a 1-10 point scale, patients scored the degree of severity of symptoms or the degree of interference in feelings or function due to symptoms at baseline or in the previous week. A score of 1 indicates symptom is not present or does not interfere with feelings or function. A score of 10 indicates the symptom is as bad as you can imagine or interferes completely with feelings or function. The mean change in score from baseline to day 42 was measured.
Time frame: Baseline and then every other week until 42 days after starting treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Grade IIa GVHD; 0.5 mg/kg/d Prednisone | Prednisone-associated Toxicity as Assessed by Quality of Life | -2.3 units on a scale |
| Grade IIa GVHD; 1.0 mg/kg/d Prednisone | Prednisone-associated Toxicity as Assessed by Quality of Life | -1.9 units on a scale |
Secondary
Progression to Grade III-IV Acute GVHD
Diagnosed and graded according to standard established criteria. Measure is percent of patients with baseline scores of IIa (Group A) or IIb (Group B) who progressed to more severe GVHD (Grade III/IV). Percentage estimated by cumulative incidence methods.
Time frame: At approximately 100 days after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grade IIa GVHD; 0.5 mg/kg/d Prednisone | Progression to Grade III-IV Acute GVHD | 6 percentage of participants |
| Grade IIa GVHD; 1.0 mg/kg/d Prednisone | Progression to Grade III-IV Acute GVHD | 13 percentage of participants |
95% CI: [0.14, 1.33]
Secondary
Recurrent or Progressive Malignancy
Percentage of relapse estimated by cumulative incidence methods
Time frame: At 12 months after the start of prednisone therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grade IIa GVHD; 0.5 mg/kg/d Prednisone | Recurrent or Progressive Malignancy | 21 percentage of participants |
| Grade IIa GVHD; 1.0 mg/kg/d Prednisone | Recurrent or Progressive Malignancy | 21 percentage of participants |
Secondary
Secondary Therapy for Acute GVHD Beyond Prednisone
This includes any intervention intended to control acute GVHD through an immunosuppressive effect from oral or parenteral administration of any systemic medication not given previously. This does not include topical therapy, an increase in the dose of glucocorticoids or the resumption of treatment after previous discontinuation or any increase in the dose of immunosuppressive medication previously administered for GVHD prophylaxis, or reinstatement of GVHD prophylaxis previously discontinued. A change in treatment from cyclosporine to tacrolimus or vice versa because of drug toxicity is not considered secondary therapy, but any change made because of uncontrolled GVHD is considered secondary therapy. Percentage is estimated by cumulative incidence methods.
Time frame: At approximately 100 days after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grade IIa GVHD; 0.5 mg/kg/d Prednisone | Secondary Therapy for Acute GVHD Beyond Prednisone | 23 percentage of participants |
| Grade IIa GVHD; 1.0 mg/kg/d Prednisone | Secondary Therapy for Acute GVHD Beyond Prednisone | 7 percentage of participants |
p-value: 0.00995% CI: [0.12, 0.74]Regression, Cox