Back to resultsReduced-Intensity Regimen Before Donor Bone Marrow Transplant in Treating Patients With Myelodysplastic Syndromes
Primary Purpose
Leukemia, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Cyclosporine
Methotrexate
Photopheresis
Mycofenolate mofetil
Pentostatin
allogeneic bone marrow
peripheral blood stem cell
Total body irradiation
Sponsored by
About this trial
This is an interventional treatment trial for Leukemia focused on measuring chronic myelomonocytic leukemia, de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, refractory anemia, refractory anemia with excess blasts, refractory anemia with ringed sideroblasts, secondary myelodysplastic syndromes, atypical chronic myeloid leukemia, BCR-ABL1 negative, myelodysplastic/myeloproliferative neoplasm, unclassifiable
Eligibility Criteria
Inclusion Criteria: One of the following cytologically proven myelodysplastic syndromes Refractory anemia (RA) RA with ringed sideroblasts RA with excess blasts Chronic myelomonocytic leukemia International Prognosis Scoring System (IPSS) score of at least 0.5 OR red cell transfusion dependence for at least 6 months (2 units per month) Patients with an IPSS score less than 0.5 may be eligible provided they previously had a higher IPSS score and received chemotherapy at that time Suitable human leukocyte antigen (HLA)-matched donor (related or unrelated) available No cord blood donors Related donors must be genotypically matched (HLA A, B and DR) at 5/6 or 6/6 loci and may be a sibling, parent, or child Unrelated donors must have high resolution typing done at A, B, C and DR, and must be matched at all or may have a single antigen or allele mismatch at no more than one of these loci Patients must have < 20% blasts on bone marrow study within 1 month of study entry Age of 18 to 70 years Eastern Cooperative Oncology Group performance status 0-1 Life expectancy at least 6 months At least 90 days since prior autologous bone marrow transplantation Serum erythropoietin level greater than 100 for patients who have not received a prior course of epoetin alfa No iron deficiency Iron deficiency anemia treated with iron replacement therapy allowed Bilirubin less than 2.0 mg/dL Alkaline phosphatase less than 2 times upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 3 times ULN Creatinine less than 2.0 mg/dL OR creatinine clearance greater than 50 mL/min Left ventricular ejection fraction (LVEF) at least 45% by Multigated Acquisition scan (MUGA) or echocardiogram Carbon Monoxide Diffusing Capacity (DLCO) at least 50% of predicted (corrected for hemoglobin) Forced expiratory volume in 1 second (FEV_1) at least 50% of predicted Recovered from prior chemotherapy Physically and psychologically capable of undergoing study regimen Able to receive 600 cGy of total body irradiation HIV negative Negative pregnancy test Exclusion Criteria: Pregnant or nursing Having other medical condition that would reduce life expectancy Active ongoing infection Prior myeloablative or nonmyeloablative allogeneic transplantation for Myelodysplastic syndrome or acute myeloid leukemia
Sites / Locations
- Mayo Clinic Scottsdale
- Mayo Clinic - Jacksonville
- Tufts-NEMC Cancer Center
- Mayo Clinic Cancer Center
- Jewish Hospital Cancer Center
- Abramson Cancer Center of the University of Pennsylvania
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Arm I
Arm Description
Preparative Regimen: Patients underwent photopheresis on two consecutive days and received pentostatin 4 mg/m2/d (total dose = 8 mg/m2) by continuous IV infusion on two consecutive days following photopheresis. Total body irradiation was administered on two consecutive days following pentostatin for a total of 600 cGy given in three 200 cGy fractionated doses. Transplantation: Unmanipulated allogeneic bone marrow or G-CSF mobilized peripheral blood stem cells were infused on day 0 within 48 hours of completion of TBI. Minimum cell dose was 2 ×106 CD34 cells/kg recipient. Acute graft-vs-host-disease (GVHD) prophylaxis: Patients received Cyclosporine or Tacrolimus per institutional preference or protocol beginning no later than day -1. Methotrexate (MTX) was administered on day +1 and +3. Mycofenolate mofetil (MMF) was introduced on day 100 and could be tapered and discontinued after 12 months if no active cGVHD.
Outcomes
Primary Outcome Measures
Complete Response Rate
Completed response is defined as:
Bone marrow evaluation: Repeat bone marrow showing < 5% myeloblasts with normal maturation of all cell lines, with no evidence for dysplasia (see dysplasia qualifier under peripheral blood evaluation).
Peripheral blood evaluation [absolute values must last at least 2 months] Hemoglobin >11 g/dl (untransfused, not on erythropoietin) Neutrophils (1500/mm3 (not on a myeloid growth factor)) Platelets (100,000/mm3 (not on a thrombopoetic agent)) Blasts - 0% No dysplasia. No detectable cytogenetic abnormality, if preexisting abnormality was present
Secondary Outcome Measures
Number of Patients Who Developed Disease Progression After Achieving Complete Response
Disease free survival (DFS) was listed as a secondary endpoint in the study protocol, which would be assessed in patients who achieved complete response (CR). It was defined to be time from CR to documented progression or to death without progression. Patients without documented progression or death reported were censored at the time of last disease evaluation. However, due to the small number of patients with CR, the number of patients who developed disease progression was reported here.
Overall Survival
Overall survival (OS) is defined to be the time from registration to death from any cause, with follow-up censored at the date of last contact. Kaplan-Meier method was used to estimate the distribution of OS.
Proportion of Graft Versus Host Disease
Proportion of Graft versus Host Disease is calculated as number of patients with Graft versus Host Disease divided by all eligible and treated patients
Time to Engraftment for Neutrophil
Time to neutrophil engraftment is defined from date of infusion to date of neutrophil engraftment. Neutrophil engraftment is defined as ANC > 500/mm3 on two consecutive measurements. The date of engraftment is the date of the first ANC > 500/mm3.
Time to Engraftment for Platelet
Time to platelet engraftment is defined from date of infusion to date of platelet engraftment. The platelet engraftment is defined as platelets > 20,000 on two consecutive measurements, at least seven days apart, without platelet transfusions in between and for at least three days before the first measurement that is over 20,000. The date of engraftment is the date of the first measurement that is over 20,000.
Full Information
NCT ID
NCT00045305
First Posted
September 6, 2002
Last Updated
June 13, 2023
Sponsor
Eastern Cooperative Oncology Group
Collaborators
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT00045305
Brief Title
Reduced-Intensity Regimen Before Donor Bone Marrow Transplant in Treating Patients With Myelodysplastic Syndromes
Official Title
A Phase II Study of Reduced Intensity Allogeneic Bone Marrow Transplant for the Treatment of Myelodysplastic Syndromes
Study Type
Interventional
2. Study Status
Record Verification Date
June 2023
Overall Recruitment Status
Completed
Study Start Date
October 24, 2006 (Actual)
Primary Completion Date
February 2014 (Actual)
Study Completion Date
September 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Eastern Cooperative Oncology Group
Collaborators
National Cancer Institute (NCI)
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
RATIONALE: Photopheresis treats the patient's blood with drugs and ultraviolet light outside the body and kills the white blood cells. Giving photopheresis, pentostatin, and radiation therapy before a donor bone marrow or stem cell transplant helps stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving pentostatin before transplant and cyclosporine or mycophenolate mofetil after transplant may stop this from happening.
PURPOSE: This phase II trial is studying how well giving pentostatin together with photopheresis and total-body irradiation work before donor bone marrow transplant in treating patients with myelodysplastic syndromes.
Detailed Description
OBJECTIVES:
Determine the complete response rate in patients with myelodysplastic syndromes treated with reduced-intensity allogeneic bone marrow transplantation, including photopheresis, total body irradiation, and pentostatin.
Determine the disease-free and overall survival of patients treated with this regimen.
Determine the engraftment rate of donor cells in patients treated with this regimen.
Determine the extent and duration of acute and chronic graft-versus-host disease in patients treated with this regimen.
Determine the toxicity of this regimen in these patients.
OUTLINE: This is a single-arm, two-stage, multicenter phase II study.
Preparative Regimen: Patients undergo photopheresis using methoxsalen on days -7 and -6 and receive pentostatin intravenously (IV )continuously on days -5 and -4. Total body irradiation is administered on days -3 and -2 for a total of 3 doses.
Transplantation: Allogeneic bone marrow or peripheral blood stem cells are infused on day 0.
Acute graft-vs-host-disease (GVHD) prophylaxis: Patients receive cyclosporine IV on days -1 to 30 and then orally every 12 hours. Cyclosporine dose is then tapered beginning after day 50 and continuing for 6 months in the absence of GVHD. Once cyclosporine dose is significantly decreased, oral mycophenolate mofetil (MMF) is then administered twice a day. MMF dose is then tapered for 12 months in the absence of GVHD. Patients also receive methotrexate IV on days 1 and 3.
Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
PROJECTED ACCRUAL: A total of 33 patients would be accrued for this study within 2.1 years.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms
Keywords
chronic myelomonocytic leukemia, de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, refractory anemia, refractory anemia with excess blasts, refractory anemia with ringed sideroblasts, secondary myelodysplastic syndromes, atypical chronic myeloid leukemia, BCR-ABL1 negative, myelodysplastic/myeloproliferative neoplasm, unclassifiable
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
17 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Arm I
Arm Type
Experimental
Arm Description
Preparative Regimen: Patients underwent photopheresis on two consecutive days and received pentostatin 4 mg/m2/d (total dose = 8 mg/m2) by continuous IV infusion on two consecutive days following photopheresis. Total body irradiation was administered on two consecutive days following pentostatin for a total of 600 cGy given in three 200 cGy fractionated doses.
Transplantation: Unmanipulated allogeneic bone marrow or G-CSF mobilized peripheral blood stem cells were infused on day 0 within 48 hours of completion of TBI. Minimum cell dose was 2 ×106 CD34 cells/kg recipient.
Acute graft-vs-host-disease (GVHD) prophylaxis: Patients received Cyclosporine or Tacrolimus per institutional preference or protocol beginning no later than day -1. Methotrexate (MTX) was administered on day +1 and +3. Mycofenolate mofetil (MMF) was introduced on day 100 and could be tapered and discontinued after 12 months if no active cGVHD.
Intervention Type
Drug
Intervention Name(s)
Cyclosporine
Other Intervention Name(s)
Sandimmune®, cyclosporin A, Neoral®Gengraf®, Gengraf®, CSA
Intervention Description
Immunosuppressant
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Other Intervention Name(s)
Methotrexate sodium, MTX, Mexate, Mexate-AQ, Folex, Folex PFS, Abitrexate, Rheumatrex, Amethopterin
Intervention Description
Antimetabolite
Intervention Type
Drug
Intervention Name(s)
Photopheresis
Other Intervention Name(s)
8-methoxypsoralen, Uvadex ®, Methoxsalen
Intervention Description
Psoralens
Intervention Type
Drug
Intervention Name(s)
Mycofenolate mofetil
Other Intervention Name(s)
Cellcept®, RS-61443, mycophenolic acid, Lilly-68618, MMF, Mycophenolate mofetil
Intervention Description
an antibiotic with immunosuppressamt properties isolated from Penicillium spp
Intervention Type
Drug
Intervention Name(s)
Pentostatin
Other Intervention Name(s)
DCF, 2-Deoxycoformycin, Nipent
Intervention Description
Purine analogue
Intervention Type
Procedure
Intervention Name(s)
allogeneic bone marrow
Intervention Description
Unmanipulated allogeneic bone marrow
Intervention Type
Procedure
Intervention Name(s)
peripheral blood stem cell
Intervention Description
G-CSF mobilized peripheral blood stem cell
Intervention Type
Radiation
Intervention Name(s)
Total body irradiation
Other Intervention Name(s)
radiation therapy
Intervention Description
a total of 600 cGy given in 3 200 cGy fractionated doses
Primary Outcome Measure Information:
Title
Complete Response Rate
Description
Completed response is defined as:
Bone marrow evaluation: Repeat bone marrow showing < 5% myeloblasts with normal maturation of all cell lines, with no evidence for dysplasia (see dysplasia qualifier under peripheral blood evaluation).
Peripheral blood evaluation [absolute values must last at least 2 months] Hemoglobin >11 g/dl (untransfused, not on erythropoietin) Neutrophils (1500/mm3 (not on a myeloid growth factor)) Platelets (100,000/mm3 (not on a thrombopoetic agent)) Blasts - 0% No dysplasia. No detectable cytogenetic abnormality, if preexisting abnormality was present
Time Frame
Monthly for the first 3 months from study entry, every 3 months for the first two years from study entry thereafter and then every 6 months for years 3-5.
Secondary Outcome Measure Information:
Title
Number of Patients Who Developed Disease Progression After Achieving Complete Response
Description
Disease free survival (DFS) was listed as a secondary endpoint in the study protocol, which would be assessed in patients who achieved complete response (CR). It was defined to be time from CR to documented progression or to death without progression. Patients without documented progression or death reported were censored at the time of last disease evaluation. However, due to the small number of patients with CR, the number of patients who developed disease progression was reported here.
Time Frame
Monthly for the first 3 months from study entry, every 3 months for the first two years from study entry thereafter and then every 6 months for years 3-5.
Title
Overall Survival
Description
Overall survival (OS) is defined to be the time from registration to death from any cause, with follow-up censored at the date of last contact. Kaplan-Meier method was used to estimate the distribution of OS.
Time Frame
Monthly for the first 3 months from study entry, every 3 months for the first two years from study entry thereafter and then every 6 months for years 3-5.
Title
Proportion of Graft Versus Host Disease
Description
Proportion of Graft versus Host Disease is calculated as number of patients with Graft versus Host Disease divided by all eligible and treated patients
Time Frame
Monthly for the first 3 months from study entry, every 3 months for the first two years from study entry thereafter and then every 6 months for years 3-5.
Title
Time to Engraftment for Neutrophil
Description
Time to neutrophil engraftment is defined from date of infusion to date of neutrophil engraftment. Neutrophil engraftment is defined as ANC > 500/mm3 on two consecutive measurements. The date of engraftment is the date of the first ANC > 500/mm3.
Time Frame
Daily while hospitalized and then at least 1x/week for the first 50 days and then at least every other week until day 100.
Title
Time to Engraftment for Platelet
Description
Time to platelet engraftment is defined from date of infusion to date of platelet engraftment. The platelet engraftment is defined as platelets > 20,000 on two consecutive measurements, at least seven days apart, without platelet transfusions in between and for at least three days before the first measurement that is over 20,000. The date of engraftment is the date of the first measurement that is over 20,000.
Time Frame
Daily while hospitalized and then at least 1x/week for the first 50 days and then at least every other week until day 100.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
One of the following cytologically proven myelodysplastic syndromes
Refractory anemia (RA)
RA with ringed sideroblasts
RA with excess blasts
Chronic myelomonocytic leukemia
International Prognosis Scoring System (IPSS) score of at least 0.5 OR red cell transfusion dependence for at least 6 months (2 units per month)
Patients with an IPSS score less than 0.5 may be eligible provided they previously had a higher IPSS score and received chemotherapy at that time
Suitable human leukocyte antigen (HLA)-matched donor (related or unrelated) available
No cord blood donors
Related donors must be genotypically matched (HLA A, B and DR) at 5/6 or 6/6 loci and may be a sibling, parent, or child
Unrelated donors must have high resolution typing done at A, B, C and DR, and must be matched at all or may have a single antigen or allele mismatch at no more than one of these loci
Patients must have < 20% blasts on bone marrow study within 1 month of study entry
Age of 18 to 70 years
Eastern Cooperative Oncology Group performance status 0-1
Life expectancy at least 6 months
At least 90 days since prior autologous bone marrow transplantation
Serum erythropoietin level greater than 100 for patients who have not received a prior course of epoetin alfa
No iron deficiency
Iron deficiency anemia treated with iron replacement therapy allowed
Bilirubin less than 2.0 mg/dL
Alkaline phosphatase less than 2 times upper limit of normal (ULN)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 3 times ULN
Creatinine less than 2.0 mg/dL OR creatinine clearance greater than 50 mL/min
Left ventricular ejection fraction (LVEF) at least 45% by Multigated Acquisition scan (MUGA) or echocardiogram
Carbon Monoxide Diffusing Capacity (DLCO) at least 50% of predicted (corrected for hemoglobin)
Forced expiratory volume in 1 second (FEV_1) at least 50% of predicted
Recovered from prior chemotherapy
Physically and psychologically capable of undergoing study regimen
Able to receive 600 cGy of total body irradiation
HIV negative
Negative pregnancy test
Exclusion Criteria:
Pregnant or nursing
Having other medical condition that would reduce life expectancy
Active ongoing infection
Prior myeloablative or nonmyeloablative allogeneic transplantation for Myelodysplastic syndrome or acute myeloid leukemia
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Selina M. Luger, MD
Organizational Affiliation
Abramson Cancer Center at Penn Medicine
Official's Role
Study Chair
Facility Information:
Facility Name
Mayo Clinic Scottsdale
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85259-5499
Country
United States
Facility Name
Mayo Clinic - Jacksonville
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224
Country
United States
Facility Name
Tufts-NEMC Cancer Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02111
Country
United States
Facility Name
Mayo Clinic Cancer Center
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Jewish Hospital Cancer Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45236
Country
United States
Facility Name
Abramson Cancer Center of the University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104-4283
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Reduced-Intensity Regimen Before Donor Bone Marrow Transplant in Treating Patients With Myelodysplastic Syndromes
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