Reduced-Intensity Conditioning Before Donor Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies
Study Details
Study Description
Brief Summary
This clinical trial studies reduced-intensity conditioning before donor stem cell transplant in treating patients with high-risk hematologic malignancies. Giving low-doses of chemotherapy and total-body irradiation before a donor stem cell transplant helps stop the growth of cancer 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 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.
Detailed Description
PRIMARY OBJECTIVE:
- To compare the rate of disease-free survival (DFS) at 1 year post hematopoietic stem cell transplant (HSCT) in patients undergoing HSCT treated on this successor Thomas Jefferson University (TJU) 2 Step reduced intensity conditioning (RIC) haploidentical regimen and compare it with that of the initial 2 Step RIC regimen.
SECONDARY OBJECTIVES:
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To assess the 100 day regimen-related mortality (RRM) in patients undergoing HSCT on this treatment protocol.
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To determine the incidence and severity of graft-versus-host disease (GVHD) in patients undergoing treatment on this regimen.
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To evaluate engraftment rates and lymphoid reconstitution in patients treated on this trial.
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To assess overall survival at 1 and 3 years past HSCT in patients treated on this trial.
OUTLINE:
REDUCED INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 60 minutes on days -15 to -12, thiotepa IV over 2 hours on days -15 to -13, donor lymphocyte infusion (DLI) on day -6, and cyclophosphamide IV over 2 hours on days -3 and -2. Patients also undergo total-body irradiation (TBI) on day -10.
TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell transplant (PBSCT) on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV on days -1 to 42 followed by taper and mycophenolate mofetil IV twice daily (BID) on days -1 to 28.
After completion of study treatment, patients are followed up periodically.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (RIC and stem cell transplant) REDUCED INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV on days -15 to -12, thiotepa IV over 2 hours on days -15 to -13, donor lymphocyte infusion (DLI) on day -6, and cyclophosphamide IV on days -3 and -2. Patients also undergo TBI on day -10. TRANSPLANT: Patients undergo allogeneic PBSCT on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV on days -1 to 42 followed by taper and mycophenolate mofetil IV BID on days -1 to 28. |
Drug: Fludarabine phosphate
Given IV
Other Names:
Drug: Thiotepa
Given IV
Other Names:
Radiation: Total body irradiation
Undergo TBI
Other Names:
Biological: Therapeutic allogeneic lymphocytes
Undergo donor lymphocyte infusion
Other Names:
Drug: Cyclophosphamide
Given IV
Other Names:
Procedure: Allogeneic hematopoietic stem cell transplantation (HSCT)
Undergo allogeneic PBSCT
Procedure: Peripheral blood stem cell transplantation
Undergo allogeneic PBSCT
Other Names:
Drug: Tacrolimus
Given IV
Other Names:
Drug: Mycophenolate mofetil
Given IV
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Disease-free survival (DFS) [1 year]
The primary null hypothesis is that 1 year DFS rate is at most 35%. 35% is the rounded number (actual 36%) representing the DFS at 1 year of patients treated on the initial TJU 2 Step RIC HSCT trial and consistent with the outcome of patients treated on similar protocols outside of our institution.
Secondary Outcome Measures
- Overall survival [1 year and 3 years]
- Incidence of Regimen Related Toxicity [Up to 1 year]
Graded according to the National Cancer Institute (NCI) Common Toxicity Criteria version 4.0
- Immune reconstitution [Up to 1 year]
- Incidence and degree of GVHD [Up to 1 year]
- Engraftment rates [Up to 1 year]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Any patient with a high-risk hematologic or oncologic diagnosis in which allogeneic HSCT is thought to be beneficial, and in whom front-line therapy has already been applied. High risk is defined as:
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Acute myeloid leukemia with high risk features as defined by:
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Age greater than or equal to 60
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Secondary AML (prior therapy or hematologic malignancy)
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Normal cytogenetics but FLT3/ITD positive
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Any relapse or primary refractory disease
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Greater than 3 cytogenetic abnormalities or any one of the following cytogenetic abnormalities: -5/del(5q), -7/del(7q), Abn(9q),(11q),(3q),(21q),(17p),t(6;9), t(6;11), t(11;19), +8,del(12p),inv(3),t(10;11),-17, 11q 23
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Any single autosomal monosomy
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Acute lymphoid leukemia in 1st or 2nd morphological remission. ALL with any morphological evidence of disease will not be eligible.
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Myelodysplasia (MDS) other than refractory anemia (RA), refractory anemia with rare sideroblasts (RARS), or isolated 5q- syndrome subtypes.
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Hodgkin's or Non-Hodgkin's lymphoma in 2nd or greater remission or with persistent disease.
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Myeloma with evidence of persistent disease after front-line therapy.
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Chronic myeloid leukemia (CML) resistant to signal transducer inhibitor (STI) therapy
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Myelofibrosis and CMML
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Essential Thrombocytopenia or Polycythemia Vera with current or past evidence of evolution to acute leukemia
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Any hematological malignancy not cited above which is thought to be high-risk with increased chance of post HSCT relapse. Patients in this category require specific approval of the PI and the TJU BMT attending physician group for entrance.
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Any hematological malignancy or dyscrasia not cited above which is thought to be high-risk with increased chance of post HSCT relapse.
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Any patient who has an aggressive disease that would normally be treated on a myeloablative study, but is prevented from doing so by factors in their past medical history. Examples are patients with previous treatment with radiation therapy precluding TBI, or a past history of myeloablative therapy, precluding a 2nd myeloablative regimen.
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Patients with aplastic anemia may be treated on this protocol, with outcomes reported descriptively.
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Patients must have a related donor who is at least a 4 antigen match at the Human Leukocyte Antigen (HLA)-A; B; C; DR loci. Patients with only a 1 out of 8 mismatch in the GVH direction will be classified in the matched related category
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Patients must adequate organ function:
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Left ventricular end diastolic function (LVEF) of >50%
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Diffusion Lung Capacity of Oxygen (DLCO) >50% of predicted corrected for hemoglobin
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Adequate liver function as defined by a serum bilirubin <1.8, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5X upper limit of normal
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Creatinine Clearance of ≥ 60 mL/min 4) Patients must have adequate KPS and HCT-CI scores:
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Patients < age 60 years must have a KPS of ≥80% and an HCT-CI score of 5 or less
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Patients aged 60 to 65 years must have a KPS of ≥80% and an HCT-CI score of 4 or less
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Patients aged 66 to 69 years must have a KPS of 90% and an HCT-CI score of 3 or less
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Patients aged 70 years or more must have a KPS of 90% and an HCT-CI score of 2 or less (Patients with greater than the allowable HCT-CI points for age can be enrolled for trial with approval of the PI and at least 1 Co-I not on the primary care team of the patient). This is an adjustment to account for healthy patients who meet the spirit of the protocol but have histories that result in higher than guideline HCT-CI points. An examples is a patient with a solid tumor malignancy in their remote history (adds 3 points to HCT-CI total) where the treatment for the malignancy occurred years to decades before and there has been complete recovery of toxicities 5) Patients must be willing to use contraception if they have childbearing potential 6) Patient or patient's guardian is able to give informed consent
Exclusion Criteria:
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HIV positive
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Active involvement of the central nervous system with malignancy
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Pregnancy
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Patients with life expectancy of < 6 months for reasons other than their underlying hematologic/oncologic disorder
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Patients who have received alemtuzumab or ATG within 8 weeks of the transplant admission.
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Patients with evidence of another malignancy, exclusive of a skin cancer that requires only local treatment, should not be enrolled on this protocol
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Thomas Jefferson University | Philadelphia | Pennsylvania | United States | 19107 |
Sponsors and Collaborators
- Sidney Kimmel Cancer Center at Thomas Jefferson University
Investigators
- Principal Investigator: Dolores Grosso, RN, CRNP, DNP, Thomas Jefferson University
- Principal Investigator: Neal Flomenberg, MD, Thomas Jefferson University
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 12D.501
- 2012-67