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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase II Study of Reduced Intensity Allogeneic Bone Marrow Transplant for the Treatment of Myelodysplastic Syndromes

Conditions
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Leukemia, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms

Intervention / Treatment
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* Drug: Cyclosporine
* Drug: Methotrexate
* Drug: Photopheresis
* Drug: Mycofenolate mofetil
* Drug: Pentostatin
* Procedure: allogeneic bone marrow
* Procedure: peripheral blood stem cell
* Radiation: Total body irradiation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>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<br>* Immunosuppressant<br>* Other names: CSA;Drug: Methotrexate<br>* Antimetabolite<br>* Other names: Amethopterin;Drug: Photopheresis<br>* Psoralens<br>* Other names: Methoxsalen;Drug: Mycofenolate mofetil<br>* an antibiotic with immunosuppressamt properties isolated from Penicillium spp<br>* Other names: Mycophenolate mofetil;Drug: Pentostatin<br>* Purine analogue<br>* Other names: Nipent;Procedure: allogeneic bone marrow<br>* Unmanipulated allogeneic bone marrow<br>Procedure: peripheral blood stem cell<br>* G-CSF mobilized peripheral blood stem cell<br>Radiation: Total body irradiation<br>* a total of 600 cGy given in 3 200 cGy fractionated doses<br>* Other names: radiation therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| 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. | 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. | 
| 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 | 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. | 
| 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. | Daily while hospitalized and then at least 1x/week for the first 50 days and then at least every other week until day 100. | 
| 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. | Daily while hospitalized and then at least 1x/week for the first 50 days and then at least every other week until day 100. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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