A Pilot Trial Of Reduced Intensity Allogeneic Stem Cell Transplantation With Fludarabine, Melphalan, And Low Dose Total Body Irradiation
Overview
- Phase
- Not Applicable
- Intervention
- fludarabine phosphate
- Conditions
- Accelerated Phase Chronic Myelogenous Leukemia
- Sponsor
- Roswell Park Cancer Institute
- Enrollment
- 62
- Locations
- 1
- Primary Endpoint
- Day 100 TRM
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
This clinical trial is studying how well giving fludarabine phosphate and melphalan together with total-body irradiation followed by donor stem cell transplant works in treating patients with hematologic cancer or bone marrow failure disorders. Giving low doses of chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells or abnormal cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer or abnormal cells (graft-versus-tumor effect)
Detailed Description
PRIMARY OBJECTIVES: I. To determine the transplant related mortality (TRM) of this reduced intensity transplantation (RIT) combination in a patient population that is usually not eligible for a full myeloablative allogeneic transplant. SECONDARY OBJECTIVES: I. To evaluate engraftment, safety, clinical response, evidence of graft-versus-malignancy effect/graft-versus-host disease (GVHD) and overall outcomes of treatment with our RIT regimen across a variety of hematological conditions. OUTLINE: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -5 to -2 and melphalan\* IV over 30 minutes on day -2. Patients then undergo total-body irradiation on day -1 and allogeneic stem cell transplantation on day 0. Note: \*Patients with chromosomal breakage syndromes, such as Fanconi anemia or dyskeratosis congenita, receive anti-thymocyte globulin IV over 4 hours on day -4 to -2 instead of melphalan. After completion of study treatment, patients are followed up periodically.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Diagnosis of a histology documented hematologic malignancy or marrow disorder
- •Bone marrow failure disorders and other non-malignant hematologic or immunologic disorders:
- •Acquired bone marrow failure disorders include aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH):
- •Primary allogeneic hematopoietic stem cell transplantation (HSCT) is appropriate for selected patients with severe aplastic anemia; however, patients with aplastic anemia must have failed at least one cycle of standard immunosuppressive therapy with calcineurin inhibitor plus anti-thymocyte globulin (ATG) if a fully-matched donor is not available
- •Patients with PNH must have a history of thrombosis related to PNH
- •Hereditary bone marrow failure disorders include Fanconi anemia or related chromosomal breakage syndrome dyskeratosis congenita, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, Kostmann syndrome, congenital amegakaryocytic thrombocytopenia:
- •Fanconi anemia or related chromosomal breakage syndrome: positive chromosome breakage analysis using diepoxybutane (DEB) or mitomycin C if applicable
- •Dyskeratosis: diagnosis is supported by using either telomerase reverse transcriptase (TERC) gene mutation in autosomal dominant Dyskeratosis Congenita or Xlinked DKC1 gene mutation
- •Other non-malignant hematologic or immunologic disorders that require transplantation
- •Quantitative or qualitative congenital platelet disorders (including but not limited to congenital amegakaryocytopenia, absent-radii syndrome, Glanzmann's thrombasthenia)
Exclusion Criteria
- •Uncontrolled central nervous system (CNS) disease (for hematologic malignancies)
- •Karnofsky (adult) or Lansky (for =\< 16 years) performance status =\< 50%
- •Diffusing capacity of the lung for carbon monoxide (DLCO) less than 40% predicted, corrected for hemoglobin (Hb) and/or alveolar ventilation
- •Cardiac: left ventricular ejection fraction less than 40%
- •Bilirubin \>= 3 x upper limit of normal
- •Liver alkaline phosphatase \>= 3 x upper limit of normal
- •Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvate transaminase (SGPT) \>= 3 x upper limit of normal
- •Child's class B and C liver failure
- •Calculated creatinine clearance \< 40 cc/min by the modified Cockcroft-Gault formula for adults or the Schwartz formula for pediatrics
- •Patients who have received maximally allowed doses (given in 2 Gy fractions, or equivalent) of previous radiation therapy to various organs as follows:
Arms & Interventions
Treatment (Reduced intensity allogeneic stem cell transplant)
Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -2 and melphalan\* IV over 30 minutes on day -2. Patients then undergo total-body irradiation on day -1 and allogeneic stem cell transplantation on day 0. Note: \*Patients with chromosomal breakage syndromes, such as Fanconi anemia or dyskeratosis congenita, receive anti-thymocyte globulin IV over 4 hours on day -4 to -2 instead of melphalan.
Intervention: fludarabine phosphate
Treatment (Reduced intensity allogeneic stem cell transplant)
Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -2 and melphalan\* IV over 30 minutes on day -2. Patients then undergo total-body irradiation on day -1 and allogeneic stem cell transplantation on day 0. Note: \*Patients with chromosomal breakage syndromes, such as Fanconi anemia or dyskeratosis congenita, receive anti-thymocyte globulin IV over 4 hours on day -4 to -2 instead of melphalan.
Intervention: melphalan
Treatment (Reduced intensity allogeneic stem cell transplant)
Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -2 and melphalan\* IV over 30 minutes on day -2. Patients then undergo total-body irradiation on day -1 and allogeneic stem cell transplantation on day 0. Note: \*Patients with chromosomal breakage syndromes, such as Fanconi anemia or dyskeratosis congenita, receive anti-thymocyte globulin IV over 4 hours on day -4 to -2 instead of melphalan.
Intervention: total-body irradiation
Treatment (Reduced intensity allogeneic stem cell transplant)
Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -2 and melphalan\* IV over 30 minutes on day -2. Patients then undergo total-body irradiation on day -1 and allogeneic stem cell transplantation on day 0. Note: \*Patients with chromosomal breakage syndromes, such as Fanconi anemia or dyskeratosis congenita, receive anti-thymocyte globulin IV over 4 hours on day -4 to -2 instead of melphalan.
Intervention: allogeneic hematopoietic stem cell transplantation
Treatment (Reduced intensity allogeneic stem cell transplant)
Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -2 and melphalan\* IV over 30 minutes on day -2. Patients then undergo total-body irradiation on day -1 and allogeneic stem cell transplantation on day 0. Note: \*Patients with chromosomal breakage syndromes, such as Fanconi anemia or dyskeratosis congenita, receive anti-thymocyte globulin IV over 4 hours on day -4 to -2 instead of melphalan.
Intervention: anti-thymocyte globulin
Outcomes
Primary Outcomes
Day 100 TRM
Time Frame: First 100 days
Day 100 Treatment Related Mortality An exact 95% confidence interval will be provided.
Secondary Outcomes
- Median Time to Platelet Engraftment(Day 100)
- 3 yr Overall Survival(Up to 4.5 years)
- Rate of Complete Donor Chimerism - Blood(Day 100)
- Median Time to ANC Engraftment(Days 30)
- Acute GVHD Grade III-IV(Up to day 100)
- 1 yr Extenstive Chronic GVHD(Up to 4.5 years)