Busulfan, Fludarabine, and Total-Body Irradiation in Treating Patients Who Are Undergoing a Donor Stem Cell Transplant for Hematologic Cancer

Phase 1

Completed

Conditions: Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Precancerous Condition
Myelodysplastic/Myeloproliferative Neoplasms

Interventions: Biological: therapeutic allogeneic lymphocytes
Drug: busulfan
Drug: cyclosporine
Drug: fludarabine phosphate
Drug: mycophenolate mofetil
Procedure: peripheral blood stem cell transplantation
Radiation: Total Body Irradiation (TBI)
Drug: Granulocyte colony-stimulating factor (G-CSF)
Drug: Phenytoin
Drug: Methotrexate

Registration Number: NCT00245037

Lead Sponsor: OHSU Knight Cancer Institute

Brief Summary: RATIONALE: Giving low doses of chemotherapy, such as fludarabine and busulfan, before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops 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). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.

PURPOSE: This phase I/II trial is studying the side effects of giving busulfan and fludarabine together with total-body irradiation and to see how well they work in treating patients who are undergoing a donor stem cell transplant for hematologic cancer.

Detailed Description: OBJECTIVES:

Primary

* To assess safety and toxicity of the addition of busulfan added to an established fludarabine and low-dose total-body irradiation (TBI) conditioning regimen for non-myeloablative allogeneic transplantation in patients with hematologic malignancies. (Phase I)

* To assess the non-relapse mortality 1-year after conditioning with busulfan and fludarabine/TBI in patients with hematologic malignancies at moderate to high risk for graft rejection and/or relapse of underlying disease. (Phase II)

Secondary

* To assess overall survival 1-year survival. (Phase II)

* To assess the incidence of graft rejection. (Phase II)

* To assess the incidence of grade II-IV acute graft-vs-host disease (GVHD) and chronic extensive GVHD. (Phase II)

* To assess rates of disease progression and/or relapse-related mortality. (Phase II)

* To determine non-hematologic grade III-IV organ specific toxicity. (Phase II)

OUTLINE:

* Nonmyeloablative-conditioning regimen: Patients receive busulfan IV on day -5 and fludarabine IV over 30 minutes on days -4 to -2. Patients undergo total body irradiation on day 0.

* Allogeneic peripheral blood stem cell transplantation (PBSC): Patients undergo donor PBSC infusion on day 0.

* Graft-versus-host disease prophylaxis: Patients receive oral cyclosporine twice daily on days -3 to 56 followed by a taper to day 180. Patients with a related stem cell donor receive oral mycophenolate mofetil twice daily on days 0-28. Patients with an unrelated stem cell donor receive oral mycophenolate mofetil 3 times daily on days 0-28 followed by a taper twice daily to day 56. Patients with evidence of relapse or persistent disease may also receive up to 3 donor lymphocyte infusions.

PROJECTED ACCRUAL: A total of 225 patients will be accrued for this study; 25 patients accrued into the Phase I and 200 patients into Phase II.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 147

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)	therapeutic allogeneic lymphocytes	Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)	Granulocyte colony-stimulating factor (G-CSF)	Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)	peripheral blood stem cell transplantation	Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)	Total Body Irradiation (TBI)	Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)	busulfan	Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)	cyclosporine	Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)	fludarabine phosphate	Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)	mycophenolate mofetil	Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)	Phenytoin	Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)	Methotrexate	Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0

Primary Outcome Measures

Name	Time	Method
Regimen-Related Toxicities	5 years post-transplant	Non-hematologic toxicities and adverse experiences ≥ Grade 3 occurrences measured up to day +100 using the NCI Common Toxicity Criteria for Adverse Events v3.0 (CTCAE). Infections and GVHD will be assessed up to 5 years post transplant. The following data represents the number of regimen-related, grade 3 and 4 toxicities that occurred in each category.
Non-relapse Mortality	Two years post-transplant	Percent of subjects with non-relapse mortality two years after conditioning with busulfan with fludarabine/200 cGy TBI in patients with hematologic malignancies at moderate to high risk for graft rejection and/or relapse of underlying disease.

Secondary Outcome Measures

Name	Time	Method
Overall Survival	Years 1, 2, 3 and 5	The percentage of overall patient survival (out of 147 participants) for Years 1, 2, 3 and 5.
Progression-Free Survival	Years 1, 2, 3, and 5	The percentage of progression-free patients (out of 147 participants) at Years 1, 2, 3, and 5. Definition of Disease Progression: MM/Plasma Cell: Increasing bone pain or increase in serum/urine monoclonal protein by 25%. CLL/NHL/HD: New sites of lymphadenopathy; ≥ 25% increase in lymph node size; Blood or bone marrow involvement with clonal B-cells; Increase of ≥ 25% bone marrow involvement; ≥ 25% increase in blood involvement with clonal B-cells. AML/ALL: Any incidence of relapse (\>5% blasts) by evaluation of the bone marrow aspirate. CML: Inability to control platelet or granulocyte counts; Increase in baseline number of metaphases demonstrating the Ph+ chromosome by \>25%; Any other new cytogenetic abnormality; Transformation to accelerated phase or blast crisis. MDS/MPD: Any evidence by morphologic or flow cytometric evaluation of the bone marrow aspirate of new blasts (\>5%) or worsening cytopenia or cytogenetic evidence of recurrence.
Relapse Mortality	Years 1 and 2	The percentage of patients (out of 147 participants) who relapsed at Years 1 and 2. Relapse is defined as the presence of \>5% blasts by morphology on a post-transplant bone marrow aspirate.
Acute Graft-Versus-Host Disease (aGVHD) Outcome	Day 100, Month 6	Grading of Acute GVHD: Severity of Individual Organ Involvement: Skin * 1 a maculopapular eruption involving less than 25% of the body surface * 2 a maculopapular eruption involving 25-50% of the body surface * 3 generalized erythroderma * 4 generalized erythroderma with bullous formation and/or with desquamation Liver * 1 bilirubin 2.0-3.0mg/100mL * 2 bilirubin 3-5.9mg/100mL * 3 bilirubin 6-14.9mg/100mL * 4 bilirubin \>15mg/100mL Gut Diarrhea is graded +1 to +4 in severity. Nausea/vomiting and/or anorexia caused by GVHD is assigned as +1 in severity Diarrhea * 1 \<1000mL of liquid stool/day * 2 \>1,000mL of stool/day * 3 \>1,500mL of stool/day * 4 2,000mL of stool/day, severe abdominal pain, with or without ileus Severity of GVHD: Grade 1 +1 to +2 skin rash; No gut or liver involvement Grade 2 +1 to +3 skin rash;+1 GI involvement and/or +1 liver
Chronic Graft-Versus-Host Disease (cGVHD) Outcome	Years 1, 2 and 3	Grading of Chronic GVHD: Limited: Localized skin involvement and/or hepatic dysfunction due to chronic GVHD Extensive: One or more of the following: Generalized skin involvement Liver histology showing chronic aggressive hepatitis, bridging necrosis or cirrhosis Involvement of the eye: Schirmer's test with \<5 mm wetting Involvement of minor salivary glands or oral mucosa demonstrated on labial biopsy Involvement of any other target organ Chronic GVHD Severity: Mild: Signs and symptoms of cGVHD do not interfere substantially with function and do not progress once appropriately treated with local therapy or standard systemic therapy. Moderate: Signs and symptoms of cGVHD interfere somewhat with function despite appropriate therapy or are progressive through first line systemic therapy. Severe: Signs and symptoms of cGVHD limit function substantially despite appropriate therapy or are progressive through second line systemic therapy