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

Eastern Cooperative Oncology Group

Status and phase

Completed

Phase 2

Conditions

Leukemia

Myelodysplastic Syndromes

Myelodysplastic/Myeloproliferative Neoplasms

Treatments

Drug: Mycofenolate mofetil

Radiation: Total body irradiation

Procedure: peripheral blood stem cell

Procedure: allogeneic bone marrow

Drug: Methotrexate

Drug: Pentostatin

Drug: Photopheresis

Drug: Cyclosporine

Study type

Interventional

Funder types

NETWORK

NIH

Identifiers

NCT00045305

CDR0000256928

E1902 (Other Identifier)

U10CA021115 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment

17 patients

Sex

All

Ages

18 to 70 years old

Volunteers

No Healthy Volunteers

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

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

17 participants in 1 patient group

Arm I

Experimental group

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.

Treatment: