Donor Atorvastatin Treatment in Preventing Severe Acute GVHD After Nonmyeloablative Peripheral Blood Stem Cell Transplant in Patients With Hematological Malignancies
Study Details
Study Description
Brief Summary
This phase II trial studies how well donor atorvastatin treatment works in preventing severe graft-versus-host disease (GVHD) after nonmyeloablative peripheral blood stem cell (PBSC) transplant in patients with hematological malignancies. Giving low doses of chemotherapy, such as fludarabine phosphate, before a donor PBSC transplantation slows the growth of cancer cells and may also prevent the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also cause an immune response against the body's normal cells (GVHD). Giving atorvastatin to the donor before transplant may prevent severe GVHD.
Detailed Description
PRIMARY OBJECTIVES:
- To assess whether 2 weeks of donor statin treatment reduces the risk of severe acute GVHD.
SECONDARY OBJECTIVES:
- To assess whether 2 weeks of statin treatment of normal PBSC donors is feasible, tolerable and safe.
OUTLINE:
DONOR: Donors receive atorvastatin orally (PO) once daily (QD) beginning on day -14 and continuing until the last day of stem cell collection.
NONMYELOABLATIVE PREPARATIVE REGIMEN: If the patient is enrolled on an investigational nonmyeloablative hematopoietic cell transplant (HCT) protocol or a treatment plan that uses a nonmyeloablative preparative regimen with postgrafting cyclosporine (CSP) that does not use acute GVHD as its primary endpoint, the preparative regimen and immunosuppression after transplant will be according to respective protocol or treatment plan (Protocol 2546 serves as adjunct protocol).
If the patient is not enrolled on an investigational nonmyeloablative HCT protocol or a treatment plan that uses a nonmyeloablative preparative regimen, Protocol 2546 serves as an independent primary treatment protocol. The preparative regimen and immunosuppression after transplant is as follows:
Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 (except for patients who had prior autologous HCT or equivalent high-dose therapy without HCT) and undergo low-dose total body irradiation (TBI) on day 0.
TRANSPLANT: Patients undergo donor PBSC transplant on day 0.
POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27.
After completion of study treatment, patients are followed up at 1 year and then annually thereafter.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Prevention (donor statin treatment) See Detailed Description |
Drug: Atorvastatin Calcium
Given PO
Other Names:
Drug: Cyclosporine
Given PO
Other Names:
Drug: Fludarabine Phosphate
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mycophenolate Mofetil
Given PO or IV
Other Names:
Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Undergo nonmyeloablative allogeneic PBSC transplant
Other Names:
Procedure: Peripheral Blood Stem Cell Transplantation
Undergo nonmyeloablative allogeneic PBSC transplant
Other Names:
Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Number of Patients With Grade III-IV Acute Graft-versus-host Disease (GVHD) Post-transplant [100 days post-transplant]
Number of patients who developed acute GVHD post allogeneic transplant. aGVHD Stages Skin: a maculopapular eruption involving < 25% BSA a maculopapular eruption involving 25 - 50% BSA generalized erythroderma generalized erythroderma w/ bullous formation and often w/ desquamation Liver: bilirubin 2.0 - 3.0 mg/100 mL bilirubin 3 - 5.9 mg/100 mL bilirubin 6 - 14.9 mg/100 mL bilirubin > 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade II: Stage 1 - 2 skin w/ no gut/liver involvement Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 w/ extreme constitutional symptoms or death
Secondary Outcome Measures
- Number of Patients With Grades II-IV Acute Graft-versus-host-disease (GVHD) [100 days post-transplant]
Number of patients who developed acute GVHD post allogeneic transplant. aGVHD Stages Skin: a maculopapular eruption involving < 25% BSA a maculopapular eruption involving 25 - 50% BSA generalized erythroderma generalized erythroderma w/ bullous formation and often w/ desquamation Liver: bilirubin 2.0 - 3.0 mg/100 mL bilirubin 3 - 5.9 mg/100 mL bilirubin 6 - 14.9 mg/100 mL bilirubin > 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade II: Stage 1 - 2 skin w/ no gut/liver involvement Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 w/ extreme constitutional symptoms or death
- Number of Patients Requiring Secondary Systemic Immunosuppressive Therapy [1 Year post-transplant]
Number of patients requiring systemic immunosuppressive therapy other than those used for prophylaxis and initial therapy.
- Number of Patients With Chronic Extensive GVHD [1 Year post-transplant]
Number of patients who developed chronic extensive GVHD post-transplant. The diagnosis of chronic GVHD requires at least one manifestation that is distinctive for chronic GVHD as opposed to acute GVHD. In all cases, infection and others causes must be ruled out in the differential diagnosis of chronic GVHD. Patients were evaluated as described in the National Institutes of Health (NIH) consensus project guidelines.
- Number of Patients With Recurrent or Progressive Malignancy [1 Year post-transplant]
CML New cytogenetic abnormality and/or development of accelerated phase or blast crisis. The criteria for accelerated phase will be defined as unexplained fever greater than 38.3°C, new clonal cytogenetic abnormalities in addition to a single Ph-positive chromosome, marrow blasts and promyelocytes >20%. AML, ALL, MDS >5% marrow blasts by morphologic or flow cytometric, or appearance of extramedullary disease. CLL ≥1 of: Physical exam/Imaging studies (nodes, liver, and/or spleen) ≥50% increase or new, circulating lymphocytes by morphology and/or flow cytometry ≥50% increase, and lymph node biopsy w/ Richter's transformation. NHL >25% increase in the sum of the products of the perpendicular diameters of marker lesions, or the appearance of new lesions. MM ≥100% increase of the serum myeloma protein from its lowest level, or reappearance of myeloma peaks that had disappeared w/ treatment; or definite increase in the size or number of plasmacytomas or lytic bone lesions.
- Number of Non-relapse Mortalities [1 Year post-transplant]
Number of patients who died without relapsed/progressive disease.
- Number of Patients Surviving Overall [1 Year post-transplant]
Number of patients surviving overall post-transplant
- Number of Donors Discontinuing Atorvastatin Due to Toxicity [Prior to stem cell collection]
The number of donors who prematurely discontinue atorvastatin therapy due to toxicity. Donors will be assessed for the following events: Musculoskeletal and connective tissue disorders: grade 2-5 Hepatobiliary disorders: grade 2-5 Other unexpected events thought related to the use of atorvastatin; grade 2-5 In cases where the NCI criteria do not apply, intensity will be defined as: Mild: awareness of symptom or sign, but easily tolerated Moderate: discomfort is enough to cause interference with normal activities Severe: inability to perform normal daily activities Life threatening: immediate risk of death from the reaction as it occurred
Eligibility Criteria
Criteria
Inclusion Criteria:
IF PROTOCOL 2546 SERVES AS AN ADJUNCT PROTOCOL, THE PATIENTS ONLY NEEDS TO MEET INCLUSION CRITERIA 1 THROUGH 5A
-
Availability of human leukocyte antigen (HLA)-identical sibling donor
-
Transplantation with PBSC
-
CSP-based postgrafting immunosuppression
-
Willingness to give informed consent
-
Patient is enrolled on an investigational nonmyeloablative HCT protocol or a nonmyeloablative treatment plan with postgrafting CSP that does not use acute GVHD as its primary endpoint (protocol 2546 serves as adjunct protocol); OR
-
Patient is not enrolled on an investigational nonmyeloablative HCT protocol, in which case protocol 2546 serves as an independent primary treatment protocol and the patient must meet the following inclusion and exclusion criteria:
-
Patients must have a hematologic malignancy treatable by nonmyeloablative HCT; the following diseases will be permitted although other diagnoses can be considered if approved by Patient Care Conference (PCC) and the principal investigator:
-
Aggressive non-Hodgkin lymphomas (NHL) and other histologies such as diffuse large B-cell NHL - not eligible for autologous HCT, not eligible for high-dose allogeneic HCT, or after failed autologous HCT
-
Mantle-cell NHL - may be treated in first complete remission (CR); (diagnostic lumbar puncture [LP] required pre-transplant)
-
Low grade NHL - with < 6 month duration of CR between courses of conventional therapy
-
Chronic lymphocytic leukemia (CLL) - must have either:
-
Failed to meet National Cancer Institute (NCI) Working Group criteria for complete or partial response after therapy with a regimen containing fludarabine phosphate (FLU) (or another nucleoside analog) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog)
-
Failed FLU-cyclophosphamide (CY)-Rituximab (FCR) combination chemotherapy at any time point; or
-
Have "17p deletion" cytogenetic abnormality; patients should have received induction chemotherapy but could be transplanted in 1st CR
-
Patients with a diagnosis of CLL (or small lymphocytic lymphoma) that progresses to prolymphocytic leukemia (PLL); or
-
Patients with T-cell CLL or PLL
-
Hodgkin lymphoma - must have received and failed frontline therapy
-
Multiple myeloma - must have received prior chemotherapy; consolidation of chemotherapy by autografting prior to nonmyeloablative HCT is permitted
-
Acute myeloid leukemia (AML) - must have < 5% marrow blasts at the time of transplant
-
Acute lymphocytic leukemia (ALL) - must have < 5% marrow blasts at the time of transplant
-
Chronic myeloid leukemia (CML) - Patients will be accepted if they have shown intolerance to tyrosine kinase inhibitors or are beyond first chronic phase (CP1) and if they have received previous myelosuppressive chemotherapy or HCT, and have < 5% marrow blasts at time of transplant
-
Myelodysplasia (MDS)/myeloproliferative syndrome (MPS) - Patients must have < 5% marrow blasts at time of transplant
-
Waldenstrom's macroglobulinemia - must have failed 2 courses of therapy
-
Patients < 12 years of age must be approved by the principal investigator and by a relevant patient review committee, such as the Fred Hutchinson Cancer Research Center (FHCRC) Patient Care Conference (PCC)
-
Patients must have either relapsed after previous high-dose chemotherapy and autologous or allogeneic HCT, or else be ineligible for such an approach due to age, failure to mobilize sufficient hematopoietic stem cells, medical comorbidities, or patient refusal
-
Patients who refuse to be treated on a conventional autologous or allogeneic HCT protocol
-
DONOR: Age >= 18 years
-
DONOR: HLA genotypically identical sibling
-
DONOR: Willingness to give informed consent
Exclusion Criteria:
IF PROTOCOL 2546 SERVES AS AN ADJUNCT PROTOCOL, THE PATIENT ONLY NEEDS TO MEET EXCLUSION CRITERIA 1 THROUGH 3
-
Myeloablative preparative regimen
-
Participation in an investigational study that has acute GVHD as the primary endpoint
-
The allogeneic PBSC donor has a contraindication to statin treatment
-
Patients eligible for and willing to receive potentially curative high-dose chemotherapy and autologous HCT
-
Cardiac ejection fraction < 30% on multi gated acquisition scan (MUGA) scan or cardiac echocardiogram (echo) or active symptomatic coronary artery disease; patients with cardiac disease should be evaluated with appropriate cardiac studies and/or cardiology consultation as clinically indicated
-
Corrected diffusion capacity of the lung for carbon monoxide (DLCO) < 40% of predicted, total lung capacity (TLC) < 30% of predicted, forced expiratory volume in one second (FEV1) < 30% of predicted, or receiving continuous supplementary oxygen
-
Patients with clinical or laboratory evidence of liver disease should be evaluated in conjunction with the gastrointestinal (GI) consult service for the cause of the liver disease, its clinical severity, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, refractory ascites related to portal hypertension, bacterial or fungal liver abscess, chronic viral hepatitis with total serum bilirubin > 3mg/dl, or actively symptomatic biliary disease
-
Patients with renal failure are eligible; however, patients with pre-existing renal insufficiency will likely have further compromise in renal function and may require dialysis
-
Patients who are seropositive for human immunodeficiency virus (HIV)
-
Women who are pregnant or breast-feeding
-
Fertile men or women unwilling to use contraception during HCT and for 12 months afterward
-
Patients with active non-hematological malignancies (except non-melanoma skin cancers) or those with non-hematological malignancies (except non-melanoma skin cancers) who have been rendered with no evidence of disease, but have a greater than 20% chance of having disease recurrence within 5 years; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
-
Karnofsky score < 60 for adult patients
-
Lansky-play performance score < 50 for pediatric patients
-
Patients with fungal pneumonia with radiological progression after receipt of amphotericin formulation or mold-active azoles for greater than 1 month
-
DONOR: Age < 18 years
-
DONOR: History of liver disease; a donor with a history of liver disease would be eligible if the serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) are < 2 times upper limit of normal (ULN)
-
DONOR: History of myopathy
-
DONOR: Hypersensitivity to atorvastatin
-
DONOR: Pregnancy
-
DONOR: Nursing mother
-
DONOR: Current serious systemic illness
-
DONOR: Concurrent treatment with strong inhibitors of hepatic CYP 3A4 (i.e. clarithromycin, erythromycin, protease inhibitors, azole antifungals)
-
DONOR: Failure to meet local criteria for stem cell donation
-
DONOR: Total creatinine kinase > 2 times the ULN
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Presbyterian - Saint Lukes Medical Center - Health One | Denver | Colorado | United States | 80218 |
| 2 | Fred Hutch/University of Washington Cancer Consortium | Seattle | Washington | United States | 98109 |
Sponsors and Collaborators
- Fred Hutchinson Cancer Center
- National Cancer Institute (NCI)
- National Heart, Lung, and Blood Institute (NHLBI)
Investigators
- Principal Investigator: Marco Mielcarek, Fred Hutch/University of Washington Cancer Consortium
Study Documents (Full-Text)
More Information
Publications
None provided.- 2546.00
- NCI-2011-03828
- 2546.00
- P01CA018029
- P30CA015704
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Primary - Reg A (Flu/TBI) | Primary - Reg B (TBI Alone) | Adjunct |
|---|---|---|---|
| Arm/Group Description | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 (except for patients who had prior autologous HCT or equivalent high-dose therapy without HCT) and undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients will undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: The preparative regimen and immunosuppression after transplant will be according to respective protocol or treatment plan. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. |
| Period Title: Overall Study | |||
| STARTED | 30 | 5 | 12 |
| COMPLETED | 29 | 5 | 12 |
| NOT COMPLETED | 1 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Primary - Reg A (Flu/TBI) | Primary - Reg B (TBI Alone) | Adjunct | Total |
|---|---|---|---|---|
| Arm/Group Description | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 (except for patients who had prior autologous HCT or equivalent high-dose therapy without HCT) and undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients will undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: The preparative regimen and immunosuppression after transplant will be according to respective protocol or treatment plan. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | Total of all reporting groups |
| Overall Participants | 30 | 5 | 12 | 47 |
| Age (Count of Participants) | ||||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
13
43.3%
|
4
80%
|
9
75%
|
26
55.3%
|
| >=65 years |
17
56.7%
|
1
20%
|
3
25%
|
21
44.7%
|
| Age (years) [Median (Full Range) ] | ||||
| Median (Full Range) [years] |
65.4
|
54
|
62.35
|
64.1
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
10
33.3%
|
3
60%
|
3
25%
|
16
34%
|
| Male |
20
66.7%
|
2
40%
|
9
75%
|
31
66%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||
| Hispanic or Latino |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Not Hispanic or Latino |
29
96.7%
|
5
100%
|
12
100%
|
46
97.9%
|
| Unknown or Not Reported |
1
3.3%
|
0
0%
|
0
0%
|
1
2.1%
|
| Race (NIH/OMB) (Count of Participants) | ||||
| American Indian or Alaska Native |
1
3.3%
|
0
0%
|
0
0%
|
1
2.1%
|
| Asian |
3
10%
|
1
20%
|
1
8.3%
|
5
10.6%
|
| Native Hawaiian or Other Pacific Islander |
1
3.3%
|
0
0%
|
0
0%
|
1
2.1%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| White |
25
83.3%
|
4
80%
|
10
83.3%
|
39
83%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
1
8.3%
|
1
2.1%
|
| Region of Enrollment (participants) [Number] | ||||
| United States |
30
100%
|
5
100%
|
12
100%
|
47
100%
|
Outcome Measures
| Title | Number of Patients With Grade III-IV Acute Graft-versus-host Disease (GVHD) Post-transplant |
|---|---|
| Description | Number of patients who developed acute GVHD post allogeneic transplant. aGVHD Stages Skin: a maculopapular eruption involving < 25% BSA a maculopapular eruption involving 25 - 50% BSA generalized erythroderma generalized erythroderma w/ bullous formation and often w/ desquamation Liver: bilirubin 2.0 - 3.0 mg/100 mL bilirubin 3 - 5.9 mg/100 mL bilirubin 6 - 14.9 mg/100 mL bilirubin > 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade II: Stage 1 - 2 skin w/ no gut/liver involvement Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 w/ extreme constitutional symptoms or death |
| Time Frame | 100 days post-transplant |
Outcome Measure Data
| Analysis Population Description |
|---|
| One subject on Reg A aborted transplant during conditioning due to donor related medical issue and subsequently went on to transplant on a different study. This subject was counted towards accrual but not evaluated with respect to outcome measures. |
| Arm/Group Title | Primary - Reg A (Flu/TBI) | Primary - Reg B (TBI Alone) | Adjunct |
|---|---|---|---|
| Arm/Group Description | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 (except for patients who had prior autologous HCT or equivalent high-dose therapy without HCT) and undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients will undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: The preparative regimen and immunosuppression after transplant will be according to respective protocol or treatment plan. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. |
| Measure Participants | 29 | 5 | 12 |
| Count of Participants [Participants] |
2
6.7%
|
0
0%
|
0
0%
|
| Title | Number of Patients With Grades II-IV Acute Graft-versus-host-disease (GVHD) |
|---|---|
| Description | Number of patients who developed acute GVHD post allogeneic transplant. aGVHD Stages Skin: a maculopapular eruption involving < 25% BSA a maculopapular eruption involving 25 - 50% BSA generalized erythroderma generalized erythroderma w/ bullous formation and often w/ desquamation Liver: bilirubin 2.0 - 3.0 mg/100 mL bilirubin 3 - 5.9 mg/100 mL bilirubin 6 - 14.9 mg/100 mL bilirubin > 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade II: Stage 1 - 2 skin w/ no gut/liver involvement Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 w/ extreme constitutional symptoms or death |
| Time Frame | 100 days post-transplant |
Outcome Measure Data
| Analysis Population Description |
|---|
| One subject on Reg A aborted transplant during conditioning due to donor related medical issue and subsequently went on to transplant on a different study. This subject was counted towards accrual but not evaluated with respect to outcome measures. |
| Arm/Group Title | Primary - Reg A (Flu/TBI) | Primary - Reg B (TBI Alone) | Adjunct |
|---|---|---|---|
| Arm/Group Description | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 (except for patients who had prior autologous HCT or equivalent high-dose therapy without HCT) and undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients will undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: The preparative regimen and immunosuppression after transplant will be according to respective protocol or treatment plan. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. |
| Measure Participants | 29 | 5 | 12 |
| Count of Participants [Participants] |
15
50%
|
2
40%
|
6
50%
|
| Title | Number of Patients Requiring Secondary Systemic Immunosuppressive Therapy |
|---|---|
| Description | Number of patients requiring systemic immunosuppressive therapy other than those used for prophylaxis and initial therapy. |
| Time Frame | 1 Year post-transplant |
Outcome Measure Data
| Analysis Population Description |
|---|
| One subject on Reg A aborted transplant during conditioning due to donor related medical issue and subsequently went on to transplant on a different study. This subject was counted towards accrual but not evaluated with respect to outcome measures. |
| Arm/Group Title | Primary - Reg A (Flu/TBI) | Primary - Reg B (TBI Alone) | Adjunct |
|---|---|---|---|
| Arm/Group Description | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 (except for patients who had prior autologous HCT or equivalent high-dose therapy without HCT) and undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients will undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: The preparative regimen and immunosuppression after transplant will be according to respective protocol or treatment plan. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. |
| Measure Participants | 29 | 5 | 12 |
| Count of Participants [Participants] |
23
76.7%
|
3
60%
|
4
33.3%
|
| Title | Number of Patients With Chronic Extensive GVHD |
|---|---|
| Description | Number of patients who developed chronic extensive GVHD post-transplant. The diagnosis of chronic GVHD requires at least one manifestation that is distinctive for chronic GVHD as opposed to acute GVHD. In all cases, infection and others causes must be ruled out in the differential diagnosis of chronic GVHD. Patients were evaluated as described in the National Institutes of Health (NIH) consensus project guidelines. |
| Time Frame | 1 Year post-transplant |
Outcome Measure Data
| Analysis Population Description |
|---|
| One subject on Reg A aborted transplant during conditioning due to donor related medical issue and subsequently went on to transplant on a different study. This subject was counted towards accrual but not evaluated with respect to outcome measures. |
| Arm/Group Title | Primary - Reg A (Flu/TBI) | Primary - Reg B (TBI Alone) | Adjunct |
|---|---|---|---|
| Arm/Group Description | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 (except for patients who had prior autologous HCT or equivalent high-dose therapy without HCT) and undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients will undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: The preparative regimen and immunosuppression after transplant will be according to respective protocol or treatment plan. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. |
| Measure Participants | 29 | 5 | 12 |
| Count of Participants [Participants] |
8
26.7%
|
1
20%
|
5
41.7%
|
| Title | Number of Patients With Recurrent or Progressive Malignancy |
|---|---|
| Description | CML New cytogenetic abnormality and/or development of accelerated phase or blast crisis. The criteria for accelerated phase will be defined as unexplained fever greater than 38.3°C, new clonal cytogenetic abnormalities in addition to a single Ph-positive chromosome, marrow blasts and promyelocytes >20%. AML, ALL, MDS >5% marrow blasts by morphologic or flow cytometric, or appearance of extramedullary disease. CLL ≥1 of: Physical exam/Imaging studies (nodes, liver, and/or spleen) ≥50% increase or new, circulating lymphocytes by morphology and/or flow cytometry ≥50% increase, and lymph node biopsy w/ Richter's transformation. NHL >25% increase in the sum of the products of the perpendicular diameters of marker lesions, or the appearance of new lesions. MM ≥100% increase of the serum myeloma protein from its lowest level, or reappearance of myeloma peaks that had disappeared w/ treatment; or definite increase in the size or number of plasmacytomas or lytic bone lesions. |
| Time Frame | 1 Year post-transplant |
Outcome Measure Data
| Analysis Population Description |
|---|
| One subject on Reg A aborted transplant during conditioning due to donor related medical issue and subsequently went on to transplant on a different study. This subject was counted towards accrual but not evaluated with respect to outcome measures. |
| Arm/Group Title | Primary - Reg A (Flu/TBI) | Primary - Reg B (TBI Alone) | Adjunct |
|---|---|---|---|
| Arm/Group Description | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 (except for patients who had prior autologous HCT or equivalent high-dose therapy without HCT) and undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients will undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: The preparative regimen and immunosuppression after transplant will be according to respective protocol or treatment plan. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. |
| Measure Participants | 29 | 5 | 12 |
| Count of Participants [Participants] |
7
23.3%
|
4
80%
|
3
25%
|
| Title | Number of Non-relapse Mortalities |
|---|---|
| Description | Number of patients who died without relapsed/progressive disease. |
| Time Frame | 1 Year post-transplant |
Outcome Measure Data
| Analysis Population Description |
|---|
| One subject on Reg A aborted transplant during conditioning due to donor related medical issue and subsequently went on to transplant on a different study. This subject was counted towards accrual but not evaluated with respect to outcome measures. |
| Arm/Group Title | Primary - Reg A (Flu/TBI) | Primary - Reg B (TBI Alone) | Adjunct |
|---|---|---|---|
| Arm/Group Description | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 (except for patients who had prior autologous HCT or equivalent high-dose therapy without HCT) and undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients will undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: The preparative regimen and immunosuppression after transplant will be according to respective protocol or treatment plan. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. |
| Measure Participants | 29 | 5 | 12 |
| Count of Participants [Participants] |
4
13.3%
|
1
20%
|
0
0%
|
| Title | Number of Patients Surviving Overall |
|---|---|
| Description | Number of patients surviving overall post-transplant |
| Time Frame | 1 Year post-transplant |
Outcome Measure Data
| Analysis Population Description |
|---|
| One subject on Reg A aborted transplant during conditioning due to donor related medical issue and subsequently went on to transplant on a different study. This subject was counted towards accrual but not evaluated with respect to outcome measures. |
| Arm/Group Title | Primary - Reg A (Flu/TBI) | Primary - Reg B (TBI Alone) | Adjunct |
|---|---|---|---|
| Arm/Group Description | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 (except for patients who had prior autologous HCT or equivalent high-dose therapy without HCT) and undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients will undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: The preparative regimen and immunosuppression after transplant will be according to respective protocol or treatment plan. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. |
| Measure Participants | 29 | 5 | 12 |
| Count of Participants [Participants] |
21
70%
|
3
60%
|
9
75%
|
| Title | Number of Donors Discontinuing Atorvastatin Due to Toxicity |
|---|---|
| Description | The number of donors who prematurely discontinue atorvastatin therapy due to toxicity. Donors will be assessed for the following events: Musculoskeletal and connective tissue disorders: grade 2-5 Hepatobiliary disorders: grade 2-5 Other unexpected events thought related to the use of atorvastatin; grade 2-5 In cases where the NCI criteria do not apply, intensity will be defined as: Mild: awareness of symptom or sign, but easily tolerated Moderate: discomfort is enough to cause interference with normal activities Severe: inability to perform normal daily activities Life threatening: immediate risk of death from the reaction as it occurred |
| Time Frame | Prior to stem cell collection |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Primary - Reg A (Flu/TBI) | Primary - Reg B (TBI Alone) | Adjunct |
|---|---|---|---|
| Arm/Group Description | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 (except for patients who had prior autologous HCT or equivalent high-dose therapy without HCT) and undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients will undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: The preparative regimen and immunosuppression after transplant will be according to respective protocol or treatment plan. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. |
| Measure Participants | 30 | 5 | 12 |
| Count of Participants [Participants] |
2
6.7%
|
0
0%
|
1
8.3%
|
Adverse Events
| Time Frame | AEs: Conditioning through Day 100; SAEs: Conditioning through Day 200; All-Cause Mortality: Conditioning through 1 Year. | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | Primary - Reg A (Flu/TBI) | Primary - Reg B (TBI Alone) | Adjunct | |||
| Arm/Group Description | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 (except for patients who had prior autologous HCT or equivalent high-dose therapy without HCT) and undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: Patients will undergo low-dose total body irradiation (TBI) on day 0. TRANSPLANT: Patients undergo donor PBSC transplant on day 0. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | NONMYELOABLATIVE PREPARATIVE REGIMEN: The preparative regimen and immunosuppression after transplant will be according to respective protocol or treatment plan. POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27. | |||
All Cause Mortality |
||||||
| Primary - Reg A (Flu/TBI) | Primary - Reg B (TBI Alone) | Adjunct | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 8/29 (27.6%) | 2/5 (40%) | 3/12 (25%) | |||
Serious Adverse Events |
||||||
| Primary - Reg A (Flu/TBI) | Primary - Reg B (TBI Alone) | Adjunct | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/29 (3.4%) | 0/5 (0%) | 0/12 (0%) | |||
| Gastrointestinal disorders | ||||||
| Duodenal ulcer | 1/29 (3.4%) | 1 | 0/5 (0%) | 0 | 0/12 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||
| Primary - Reg A (Flu/TBI) | Primary - Reg B (TBI Alone) | Adjunct | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/29 (20.7%) | 1/5 (20%) | 2/12 (16.7%) | |||
| Blood and lymphatic system disorders | ||||||
| Febrile neutropenia | 1/29 (3.4%) | 1 | 0/5 (0%) | 0 | 0/12 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| Nausea | 0/29 (0%) | 0 | 0/5 (0%) | 0 | 1/12 (8.3%) | 1 |
| Vomiting | 0/29 (0%) | 0 | 0/5 (0%) | 0 | 1/12 (8.3%) | 1 |
| General disorders | ||||||
| Non-cardiac chest pain | 0/29 (0%) | 0 | 0/5 (0%) | 0 | 1/12 (8.3%) | 1 |
| Immune system disorders | ||||||
| Allergic reaction | 1/29 (3.4%) | 1 | 0/5 (0%) | 0 | 0/12 (0%) | 0 |
| Infections and infestations | ||||||
| Lung infection | 1/29 (3.4%) | 1 | 0/5 (0%) | 0 | 0/12 (0%) | 0 |
| Investigations | ||||||
| Blood bilirubin increased | 0/29 (0%) | 0 | 1/5 (20%) | 1 | 0/12 (0%) | 0 |
| Creatinine increased | 1/29 (3.4%) | 1 | 0/5 (0%) | 0 | 0/12 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||
| Hypertriglyceridemia | 1/29 (3.4%) | 1 | 0/5 (0%) | 0 | 0/12 (0%) | 0 |
| Hypophosphatemia | 0/29 (0%) | 0 | 0/5 (0%) | 0 | 1/12 (8.3%) | 1 |
| Nervous system disorders | ||||||
| Leukoencephalopathy | 1/29 (3.4%) | 1 | 0/5 (0%) | 0 | 0/12 (0%) | 0 |
| Psychiatric disorders | ||||||
| Delirium | 1/29 (3.4%) | 1 | 0/5 (0%) | 0 | 0/12 (0%) | 0 |
| Renal and urinary disorders | ||||||
| Acute kidney injury | 1/29 (3.4%) | 1 | 0/5 (0%) | 0 | 0/12 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Pleural effusion | 1/29 (3.4%) | 1 | 0/5 (0%) | 0 | 0/12 (0%) | 0 |
| Pneumothorax | 1/29 (3.4%) | 1 | 0/5 (0%) | 0 | 0/12 (0%) | 0 |
| Vascular disorders | ||||||
| Hypertension | 1/29 (3.4%) | 1 | 0/5 (0%) | 0 | 0/12 (0%) | 0 |
| Thromboembolic event | 1/29 (3.4%) | 1 | 0/5 (0%) | 0 | 0/12 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. Marco Mielcarek |
|---|---|
| Organization | Fred Hutchinson Cancer Research Center |
| Phone | (206) 667-2827 |
| mmielcar@fredhutch.org |
- 2546.00
- NCI-2011-03828
- 2546.00
- P01CA018029
- P30CA015704