Reduced-Intensity Regimen Before Donor Bone Marrow Transplant in Treating Patients With Myelodysplastic Syndromes

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Eastern Cooperative Oncology Group
ClinicalTrials.gov Identifier:
NCT00045305
First received: September 6, 2002
Last updated: January 15, 2015
Last verified: January 2015
  Purpose

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.


Condition Intervention Phase
Leukemia
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasms
Drug: Cyclosporine
Drug: Methotrexate
Drug: Photopheresis
Drug: Mycofenolate mofetil
Drug: Pentostatin
Procedure: allogeneic bone marrow
Procedure: peripheral blood stem cell
Radiation: Total body irradiation
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Reduced Intensity Allogeneic Bone Marrow Transplant for the Treatment of Myelodysplastic Syndromes

Resource links provided by NLM:


Further study details as provided by Eastern Cooperative Oncology Group:

Primary Outcome Measures:
  • Complete Response Rate [ 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. ] [ Designated as safety issue: No ]

    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 [ 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. ] [ Designated as safety issue: No ]
    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 [ 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. ] [ Designated as safety issue: No ]
    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 [ 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. ] [ Designated as safety issue: No ]
    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 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. ] [ Designated as safety issue: No ]
    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 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. ] [ Designated as safety issue: No ]
    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.


Enrollment: 17
Study Start Date: May 2005
Study Completion Date: September 2014
Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I

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.

Drug: Cyclosporine
Immunosuppressant
Other Names:
  • Sandimmune®
  • cyclosporin A
  • Neoral®Gengraf®
  • Gengraf®
  • CSA
Drug: Methotrexate
Antimetabolite
Other Names:
  • Methotrexate sodium
  • MTX
  • Mexate
  • Mexate-AQ
  • Folex
  • Folex PFS
  • Abitrexate
  • Rheumatrex
  • Amethopterin
Drug: Photopheresis
Psoralens
Other Names:
  • 8-methoxypsoralen
  • Uvadex ®
  • Methoxsalen
Drug: Mycofenolate mofetil
an antibiotic with immunosuppressamt properties isolated from Penicillium spp
Other Names:
  • Cellcept®
  • RS-61443
  • mycophenolic acid
  • Lilly-68618
  • MMF
  • Mycophenolate mofetil
Drug: Pentostatin
Purine analogue
Other Names:
  • DCF
  • 2-Deoxycoformycin
  • Nipent
Procedure: allogeneic bone marrow
Unmanipulated allogeneic bone marrow
Procedure: peripheral blood stem cell
G-CSF mobilized peripheral blood stem cell
Radiation: Total body irradiation
a total of 600 cGy given in 3 200 cGy fractionated doses
Other Name: radiation therapy

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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00045305

Locations
United States, Arizona
Mayo Clinic Scottsdale
Scottsdale, Arizona, United States, 85259-5499
United States, Florida
Mayo Clinic - Jacksonville
Jacksonville, Florida, United States, 32224
United States, Massachusetts
Tufts-NEMC Cancer Center
Boston, Massachusetts, United States, 02111
United States, Minnesota
Mayo Clinic Cancer Center
Rochester, Minnesota, United States, 55905
United States, Ohio
Jewish Hospital Cancer Center
Cincinnati, Ohio, United States, 45236
United States, Pennsylvania
Abramson Cancer Center of the University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104-4283
Sponsors and Collaborators
Eastern Cooperative Oncology Group
Investigators
Study Chair: Selina M. Luger, MD Abramson Cancer Center of the University of Pennsylvania
  More Information

Additional Information:
No publications provided

Responsible Party: Eastern Cooperative Oncology Group
ClinicalTrials.gov Identifier: NCT00045305     History of Changes
Other Study ID Numbers: CDR0000256928, E1902, U10CA021115
Study First Received: September 6, 2002
Results First Received: January 9, 2015
Last Updated: January 15, 2015
Health Authority: United States: Federal Government

Keywords provided by Eastern Cooperative Oncology Group:
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

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Myelodysplastic-Myeloproliferative Diseases
Myeloproliferative Disorders
Preleukemia
Bone Marrow Diseases
Hematologic Diseases
Neoplasms
Precancerous Conditions
Cyclosporine
Cyclosporins
Methotrexate
Mycophenolate mofetil
Mycophenolic Acid
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions

ClinicalTrials.gov processed this record on March 26, 2015