Graft Versus Host Disease
Conditions
Keywords
Allogeneic stem cell grafts, Allogeneic bone marrow graft, Blood and Marrow Transplantation, Stem cell graft, Graft Versus Host Disease, GVHD, Extracorporeal Photopheresis, ECP, Photopheresis, Methylprednisolone, Medrol, Depo-Medrol, Solu-Medrol
Brief summary
The goal of this clinical research study is to find out whether adding extracorporeal photopheresis (ECP) to standard therapy for acute GVHD with corticosteroids improves response to treatment, length of treatment, and survival.
Detailed description
ECP uses ultraviolet A radiation to treat lymphocytes. Although the exact reason why ECP may be beneficial is not completely understood, researchers believe that the lymphocytes treated this way are less likely to continue causing GVHD. In this study, researchers want to evaluate whether adding another treatment to standard therapy with corticosteroids, in this case ECP, will improve the response to therapy, duration of therapy, and survival. After the diagnosis of acute GVHD, you will be randomly selected (at the toss of a coin) to be in one of 2 treatment groups. One group will receive treatment with corticosteroids (like methylprednisolone or prednisone) alone, and the other will receive ECP treatments in addition to the corticosteroids. ECP treatments are explained below. In order to have ECP, you will need a special central venous catheter similar to the one you have now. A central venous catheter is a sterile flexible tube that will be placed into a large vein while you are under local anesthesia. Your physician will explain this procedure to you in more detail, and you will be required to sign a separate consent form for this procedure. Blood is drawn by a machine called photopheresis machine. This blood goes into a bowl inside the machine, where it is spun and separated into white cells (called buffy coat), red cells, and platelets. The red cells and platelets are promptly returned to you, while the white cells in the buffy coat undergo the process of ECP. The buffy coat will come out of the bowl and will be mixed with a substance called methoxsalen, that will make lymphocytes more sensitive to the effects of light. After mixing with methoxsalen, the buffy coat goes in to chamber where it is exposed to ultraviolet A radiation, and from there back to you. This process is done gradually, in cycles, and takes about 3 hours. You will have up to 4 of these treatments weekly for the first 14 days of therapy, then 3 treatments weekly from Day 15-28, and after that 2 treatments weekly until Day 60, which is the end of the study. After Day 60, your doctor will decide whether ECP is worth continuing, and also the frequency of treatments. It is not necessary to be in the study to continue to receive ECP treatments. If you respond to the treatment, your corticosteroids will be reduced slowly to prevent the GVHD from coming back. The length of corticosteroid therapy will depend on how GVHD responds to the treatment. You will follow a corticosteroid therapy tapering schedule according to the suggested guidelines. You will continue to receive tacrolimus or cyclosporine, whichever you have been using as GVHD prevention, throughout the study independent of what treatment group you are assigned. While you are getting treatment in this study, every week you will have a physical exam and blood (about 1 tablespoon) will be drawn for routine tests. If your doctor thinks it is necessary, blood may be drawn more often. You will be considered off-study after 6 months of treatment completion. You will be taken off study if you are unable to comply with study requirements, you refuse to continue participation in the study, or intolerable side effects occur. This is an investigational study. ECP has been approved by the FDA for the treatment of a certain type of lymphomas of the skin and is commercially available. Its use in patients with GVHD is considered to be investigational. Up to 95 patients will take part in this study. All will be enrolled at MD Anderson.
Interventions
PROCEDUREPhotopheresis
8-9 photopheresis treatments weekly for days 1-14, 6 treatments weekly from days 15-28, and after that 2 treatments weekly until day 60. After day 60, your doctor will decide whether ECP is worth continuing, and the frequency of treatments.
DRUGMethylprednisolone
2 mg/kg daily with a taper to no less than 1 mg/kg/day by day 14, followed by a tapering schedule according to the suggested guidelines.
Sponsors
Mallinckrodt
M.D. Anderson Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. Patients must be recipients of allogeneic bone marrow or stem cell grafts. 2. Patient must weigh above 40 kg 3. Patients must have new onset, clinical grade II-III acute or late-acute GVHD of the GI tract or liver, or the skin that developed post transplantation. The diagnosis of GVHD must be pathologically confirmed in at least one organ or highly suspected clinically. Pathological confirmation may occur after registration and after the start of therapy. Definition of Late Acute GVHD vs Acute GVHD: The diagnosis of Late Acute GVHD includes clinical features that are identical to Acute GVHD, however, Late Acute GVHD is diagnosed on or after day 100 post transplantation. 4. Continued from #3: These manifestations include a maculopapular rash, abnormal liver studies (cholestatic jaundice) and/or nausea/vomiting / diarrhea. Patients must not have any concurrent classical features of chronic GVHD in addition to the above manifestations. Features of chronic GVHD include dry eyes and mouth, contractures, and/ or sclerodermal, lichenoid skin changes. 5. In the clinical judgment of the PI, patients must be able to sustain a platelet count and a hematocrit \>/= 20,000/mL and \>/= 27% respectively, with or without transfusions. 6. The absolute white blood cell count (WBC) must be \>1500/mL 7. Patient must be willing to comply with all study procedures. 8. All patients with childbearing potential, including males and females, must commit to using adequate contraceptive precautions throughout their participation in the study and for 3 months following the last ECP treatment.
Exclusion criteria
1. Patients developing chronic GVHD following immune modulation with immunosuppression withdrawal or donor lymphocyte infusion (DLI). 2. Any clinical Manifestation consistent with de novo chronic GVHD or overlapped syndrome of acute and chronic GVHD. 3. Patients who are unable to tolerate the volume shifts associated with ECP treatment due to the presence of any of the following conditions: uncompensated congestive heart failure, pulmonary edema, severe asthma or chronic obstructive pulmonary disease, hepatorenal syndrome. 4. Active bleeding 5. International normalized ration (INR) \>2 6. Patients cannot have received methylprednisolone \> 2mg/kg/day for more than 72 hours prior to registration. 7. Patients cannot have received any other immunosuppression for treatment of GVHD but calcineurin inhibitors and corticosteroids. Patients are allowed to have had any GVHD prophylaxis with the exception of ECP 8. Patients with known hypersensitivity or allergy to psoralen 9. Patients with known hypersensitivity or allergy to both citrate and heparin 10. Patients with co-existing photosensitive disease (e.g. porphyria, systemic lupus erythematosus, albinism) or coagulation disorders. 11. Uncontrolled, persistent hypertriglyceridemia, with levels \> 800 mg%
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Day 56 Treatment Success | Day 1 to Day 63 (approximately 9 weeks), Acute GVHD scored weekly. | Definition of Treatment Failure: No Response according to the following: A) Skin: 1) No change in GVHD stage by day 14; 2) Gut: No change in GVHD stage by Day 7; 3) Liver: No change in GVHD stage by Day 21. B) Progressive Disease (PD): 1) Skin/Gut: Increase in Stage by 72 hours from the start of therapy; 2) Liver: Increase in Stage by Day 14; 3) Initiation of 2nd line treatment at any time for acute GVHD: 4) Any new organ involvement by acute GVHD. C) Inability to Taper: 1) Patient still on \>1 mg/kg/d of methylprednisolone equivalent at 1 month. 2) Patient still on \> 0.5 mg/kg/d of methylprednisolone equivalent at 2 months; 3) Death from GVHD. Definition of Treatment Success: Participants not defined above in Treatment Failure definition. Baseline biopsy with Acute GVHD assessed weekly until last ECP procedure (anticipated Day 63). At 6 months follow up with a phone call for survival and GVHD status. |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: January 23, 2008 to November 19, 2014. All recruitment done at The University of Texas (UT) MD Anderson Cancer Center.
Participants by arm
| Arm | Count |
|---|---|
| Corticosteroids Methylprednisolone at a dose of 2 mg/kg/day with a taper to no less than 1 mg/kg/day by day 14, and no less than 0.4 mg/kg/day by day 28. | 30 |
| ECP + Corticosteroids Extracorporeal Photopheresis (ECP) 8-9 treatments weekly for days 1-14, 6 treatments weekly from days 15-28, and after that 2 treatments weekly until day 60 + Methylprednisolone at a dose of 2 mg/kg/day with a taper to no less than 1 mg/kg/day by day 14, and no less than 0.4 mg/kg/day by day 28. | 51 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Progression | 4 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Corticosteroids | Total | ECP + Corticosteroids |
|---|---|---|---|
| Ablative Conditioned | 23 Participants | 56 Participants | 33 Participants |
| Age, Continuous | 53 years | 54 years | 54 years |
| Donor Match Matched | 24 Participants | 65 Participants | 41 Participants |
| Donor Match Mismatched/Haploidentical | 6 Participants | 16 Participants | 10 Participants |
| Donor Relation Related | 12 Participants | 30 Participants | 18 Participants |
| Donor Relation Unrelated | 18 Participants | 51 Participants | 33 Participants |
| Graft Source Bone Marrow | 5 Participants | 15 Participants | 10 Participants |
| Graft Source Peripheral Blood | 25 Participants | 61 Participants | 36 Participants |
| Graft Source Umbilical Cord | 0 Participants | 5 Participants | 5 Participants |
| GVHD Prophylaxis Other | 2 Participants | 4 Participants | 2 Participants |
| GVHD Prophylaxis Tacrolimus/MTX | 28 Participants | 72 Participants | 44 Participants |
| GVHD Prophylaxis Tacrolimus/Mycophenolate | 0 Participants | 5 Participants | 5 Participants |
| Region of Enrollment United States | 30 participants | 81 participants | 51 participants |
| Sex: Female, Male Female | 11 Participants | 31 Participants | 20 Participants |
| Sex: Female, Male Male | 19 Participants | 50 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 30 / 30 | 51 / 51 |
| serious Total, serious adverse events | 4 / 30 | 4 / 51 |
Outcome results
Primary
Day 56 Treatment Success
Definition of Treatment Failure: No Response according to the following: A) Skin: 1) No change in GVHD stage by day 14; 2) Gut: No change in GVHD stage by Day 7; 3) Liver: No change in GVHD stage by Day 21. B) Progressive Disease (PD): 1) Skin/Gut: Increase in Stage by 72 hours from the start of therapy; 2) Liver: Increase in Stage by Day 14; 3) Initiation of 2nd line treatment at any time for acute GVHD: 4) Any new organ involvement by acute GVHD. C) Inability to Taper: 1) Patient still on \>1 mg/kg/d of methylprednisolone equivalent at 1 month. 2) Patient still on \> 0.5 mg/kg/d of methylprednisolone equivalent at 2 months; 3) Death from GVHD. Definition of Treatment Success: Participants not defined above in Treatment Failure definition. Baseline biopsy with Acute GVHD assessed weekly until last ECP procedure (anticipated Day 63). At 6 months follow up with a phone call for survival and GVHD status.
Time frame: Day 1 to Day 63 (approximately 9 weeks), Acute GVHD scored weekly.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Corticosteroids | Day 56 Treatment Success | Skin-only | 57 percentage of participants |
| Corticosteroids | Day 56 Treatment Success | Visceral Involvement | 43 percentage of participants |
| Corticosteroids | Day 56 Treatment Success | Total | 53 percentage of participants |
| ECP + Corticosteroids | Day 56 Treatment Success | Skin-only | 72 percentage of participants |
| ECP + Corticosteroids | Day 56 Treatment Success | Visceral Involvement | 47 percentage of participants |
| ECP + Corticosteroids | Day 56 Treatment Success | Total | 65 percentage of participants |
Post Hoc
Non-relapse Mortality (NRM) at 6 Months
Percentage of participants at 6 months whose deaths were without relapse/recurrence.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Corticosteroids | Non-relapse Mortality (NRM) at 6 Months | 19.6 percentage of participants |
| ECP + Corticosteroids | Non-relapse Mortality (NRM) at 6 Months | 20.0 percentage of participants |
Post Hoc
Percentage of Participants Alive, In Remission & Without GVHD Progression Day 28 & Day 56
Percentage meeting steroid milestone who were alive, in remission and did not have GVHD progression before Day 28 or Day 56.
Time frame: Up to day 56
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Corticosteroids | Percentage of Participants Alive, In Remission & Without GVHD Progression Day 28 & Day 56 | Day 28 Steroid dose </= 0.25mg/kg | 10 percentage of participants |
| Corticosteroids | Percentage of Participants Alive, In Remission & Without GVHD Progression Day 28 & Day 56 | Day 56 steroid dose < 0.1mg/kg | 30 percentage of participants |
| ECP + Corticosteroids | Percentage of Participants Alive, In Remission & Without GVHD Progression Day 28 & Day 56 | Day 28 Steroid dose </= 0.25mg/kg | 23.5 percentage of participants |
| ECP + Corticosteroids | Percentage of Participants Alive, In Remission & Without GVHD Progression Day 28 & Day 56 | Day 56 steroid dose < 0.1mg/kg | 43 percentage of participants |