Myeloablative or Reduced-Intensity Conditioning Regimen in Treating Patients with High-Risk, Relapsed, or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Donor Stem Cell Transplant
This phase II trial studies the side effects and how well a myeloablative or reduced-intensity conditioning regimen works in treating patients with acute myeloid leukemia or myelodysplastic syndrome that is high-risk, has come back, or does not respond to treatment. Giving chemotherapy (myeloablative or reduced-intensity conditioning regimen) before a donor peripheral blood stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When healthy stem cells from a donor that have been genetically modified are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Giving tacrolimus or cyclosporine after the transplant may stop this from happening. It is not yet known whether myeloablative or reduced-intensity conditioning regimens given before the transplant will work better in treating patients with acute myeloid leukemia or myelodysplastic syndrome.
Inclusion Criteria
- MYELOBLATIVE CONDITIONING TRANSPLANT: Diagnosis of acute myeloid leukemia or myelodysplastic syndrome, either high-risk, relapsed or primary refractory, minimal residual disease (MRD)-positive without circulating myeloblasts or active extramedullary disease at the time of transplant. Active marrow disease is permitted. (“High-risk” acute myeloid leukemia [AML] features are defined by the following: greater than 15% blasts in the bone marrow after the first course of induction chemotherapy; adverse cytogenetic abnormalities of monosomy 5, monosomy 7, or 5q deletion; presence of FLT3 positive internal tandem duplication (FLT3/internal tandem duplication [ITD] positive [+]), particularly high allelic ratio; or treatment-related AML.)
- MYELOBLATIVE CONDITIONING TRANSPLANT: Stem cell sources include bone marrow, peripheral blood stem cells, or umbilical cord blood
- MYELOBLATIVE CONDITIONING TRANSPLANT: Related bone marrow, peripheral blood stem cell, or cord blood unit: sibling should be human leukocyte antigen (HLA)-matched at A, B, and DR-B1 loci. Unrelated cord blood unit should be at a minimum of 4/6 matched at antigen level on HLA A and B, and allele level at HLA DR-B1 loci. Unrelated bone marrow or peripheral blood stem cell donor should be HLA allele level matched at A, B, C, and DR-B1
- MYELOBLATIVE CONDITIONING TRANSPLANT: Minimum prefreezing cell dose for cord blood units: 3 x 10^7 total nucleated cells/kg and 1.5 x 10^5 CD34+ cells/kg. If this is not attainable, then double cord blood transplant should be considered
- MYELOBLATIVE CONDITIONING TRANSPLANT: Patient, parent, or legal guardian must have given written informed consent and/or assent
- MYELOBLATIVE CONDITIONING TRANSPLANT: Patient must have adequate performance status (Lansky score >= 60% for patients < 16 years; Karnofsky score >= 60% for patients >= 16 years)
- MYELOBLATIVE CONDITIONING TRANSPLANT: Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2
- MYELOBLATIVE CONDITIONING TRANSPLANT: Total bilirubin =< 2.0 mg/dL unless the increase in bilirubin is attributable to Gilbert’s syndrome
- MYELOBLATIVE CONDITIONING TRANSPLANT: Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) < 4 x upper limit of normal (ULN) for age
- MYELOBLATIVE CONDITIONING TRANSPLANT: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 4 x upper limit of normal (ULN) for age
- MYELOBLATIVE CONDITIONING TRANSPLANT: Alkaline phosphatase < 4 x upper limit of normal (ULN) for age
- MYELOBLATIVE CONDITIONING TRANSPLANT: Normal cardiac function by echocardiogram or radionuclide scan, as defined by left ventricular ejection fraction at rest > 45%, or shortening fraction > 26%
- MYELOBLATIVE CONDITIONING TRANSPLANT: Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for hemoglobin) >= 50% of predicted; if unable to perform pulmonary function tests, then oxygen saturation >= 92% on room air
- REDUCED-INTENSITY CONDITIONING TRANSPLANT: Diagnosis of acute myeloid leukemia or myelodysplastic syndrome, either high-risk, relapsed or primary refractory, MRD-positive without circulating myeloblasts or active extramedullary disease at the time of transplant. Active marrow disease is permitted. (“High-risk” AML features are defined by the following: greater than 15% blasts in the bone marrow after the first course of Induction chemotherapy; adverse cytogenetic abnormalities of monosomy 5, monosomy 7, or 5q deletion; presence of FLT3 positive internal tandem duplication (FLT3/ITD+), particularly high allelic ratio; or treatment-related AML.)
- REDUCED-INTENSITY CONDITIONING TRANSPLANT: Stem cell sources include bone marrow, peripheral blood stem cells, or umbilical cord blood
- REDUCED-INTENSITY CONDITIONING TRANSPLANT: Related bone marrow, peripheral blood stem cell, or cord blood unit: sibling should be HLA-matched at A, B, and DR-B1 loci. Unrelated cord blood unit should be at a minimum of 4/6 matched at antigen level on HLA A and B, and allele level at HLA DR-B1 loci. Unrelated bone marrow or peripheral blood stem cell donor should be HLA allele level matched at A, B, C, and DR-B1
- REDUCED-INTENSITY CONDITIONING TRANSPLANT: Minimum prefreezing cell dose for cord blood units: 3 x 10^7 total nucleated cells/kg and 1.5 x 10^5 CD34+ cells/kg. If this is not attainable, then double cord blood transplant should be considered
- REDUCED-INTENSITY CONDITIONING TRANSPLANT: Patient, parent, or legal guardian must have given written informed consent and/or assent
- REDUCED-INTENSITY CONDITIONING TRANSPLANT: Patient must have adequate performance status (Lansky score >= 60% for patients < 16 years; Karnofsky score >= 60% for patients >= 16 years
- REDUCED-INTENSITY CONDITIONING TRANSPLANT: Patient is excluded from myeloablative conditioning transplant due to failure to meet any of the criteria: * Creatinine clearance or radioisotope GFR >= 70 mL/min/1.73 m^2 * Total bilirubin =< 2.0 mg/dL unless the increase in bilirubin is attributable to Gilbert’s syndrome * SGOT (AST) < 4 x upper limit of normal (ULN) for age * SGPT (ALT) < 4 x upper limit of normal (ULN) for age * Alkaline phosphatase < 4 x upper limit of normal (ULN) for age * Normal cardiac function by echocardiogram or radionuclide scan, as defined by left ventricular ejection fraction at rest > 45%, or shortening fraction > 26% * FEV1, FVC, and DLCO (corrected for hemoglobin) >= 50% of predicted; if unable to perform pulmonary function tests, then oxygen saturation >= 92% on room air
- REDUCED-INTENSITY CONDITIONING TRANSPLANT: Creatinine clearance or radioisotope GFR >= 70 mL/min/1.73 m^2
- REDUCED-INTENSITY CONDITIONING TRANSPLANT: Total bilirubin =< 2.5 mg/dL unless the increase in bilirubin is attributable to Gilbert’s syndrome
- REDUCED-INTENSITY CONDITIONING TRANSPLANT: SGOT (AST) < 5 x upper limit of normal (ULN) for age
- REDUCED-INTENSITY CONDITIONING TRANSPLANT: SGPT (ALT) < 5 x upper limit of normal (ULN) for age
- REDUCED-INTENSITY CONDITIONING TRANSPLANT: Alkaline phosphatase < 5 x upper limit of normal (ULN) for age
- REDUCED-INTENSITY CONDITIONING TRANSPLANT: Normal cardiac function by echocardiogram or radionuclide scan, as defined by left ventricular ejection fraction at rest > 40%, or shortening fraction > 26%
- REDUCED-INTENSITY CONDITIONING TRANSPLANT: FEV1, FVC, and DLCO (corrected for hemoglobin) >= 40% of predicted; if unable to perform pulmonary function tests, then oxygen saturation >= 92% on room air
Exclusion Criteria
- MYELOBLATIVE CONDITIONING TRANSPLANT: Recipient of an autologous stem cell transplant
- MYELOBLATIVE CONDITIONING TRANSPLANT: Allogeneic hematopoietic stem cell transplant within the previous 3 months
- MYELOBLATIVE CONDITIONING TRANSPLANT: Uncontrolled bacterial, viral, fungal, or other infection at the time of cytoreduction. Uncontrolled infection defined by positive blood cultures and fevers > 38.0 within 24-48 hours of start of conditioning therapy
- MYELOBLATIVE CONDITIONING TRANSPLANT: Evidence of human immunodeficiency virus (HIV)/human T-lymphotropic virus (HTLV) infection or HIV/HTLV positive serology
- MYELOBLATIVE CONDITIONING TRANSPLANT: Pregnancy or lactating. All females of 11 years of age or older and/or who have begun menstruating will be screened for HCG by either urinalysis or a blood sample in order to screen for pregnancy status
- MYELOBLATIVE CONDITIONING TRANSPLANT: Patients with any inherited bone marrow failure syndrome (including, but not limited to, Fanconi anemia, Shwachman-Diamond syndrome, and dyskeratosis congenital) or Down syndrome (defined as either constitutional trisomy 21 or constitutional mosaicism of trisomy 21)
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02626715.
PRIMARY OBJECTIVES:
I. To determine the safety and preliminary efficacy of achieving acceptable rates of event-free survival at 6 months in pediatric patients receiving a fludarabine/busulfan/thiotepa (FLU/BU/THIO) (myeloablative) or alemtuzumab/hydroxyurea/fludarabine/melphalan/thiotepa (reduced-intensity) preparative regimen prior to hematopoietic stem cell transplantation for high-risk acute myeloid leukemia and myelodysplastic syndrome.
SECONDARY OBJECTIVES:
I. To describe the pace of neutrophil and platelet recovery.
II. To describe the incidence of acute graft versus host disease (GVHD) (II-IV, III-IV) and chronic GVHD.
III. To determine the treatment-related mortality (TRM), overall survival (OS), and disease-free survival (DFS) by days 100 and 180 post-transplant.
IV. To evaluate the pace of immune reconstitution.
V. To measure day 0 alemtuzumab levels and correlate with rate of relapse, rate of viral infections, and pace of immune reconstitution.
VI. To compare outcomes with historically-used “standard” conditioning regimen of busulfan and cyclophosphamide in terms of above objectives as well as short- and long-term complications.
OUTLINE: Patients are assigned to 1 of 2 arms.
ARM I (MYELOABLATIVE CONDITIONING REGIMEN): Patients undergoing serotherapy for CD52 positive malignancies receive alemtuzumab intravenously (IV) over 3 hours on day -12. All patients receive thiotepa IV over 2 hours on days -11 and -10, fludarabine IV over 1 hour on days -9 through -5, filgrastim IV on days -5 through -3, and busulfan IV over 2 hours every 6 hours on days -4 through -2 in the absence of disease progression or unacceptable toxicity.
ARM II (REDUCED-INTENSITY CONDITIONING REGIMEN): Patients receive alemtuzumab IV over 3 hours on day -14, hydroxyurea orally (PO) once daily on days -14 through -6, fludarabine IV over 1 hour on days -10 through -6, filgrastim IV on days -6 through -4, melphalan IV over 45 minutes on days -5 and -4, and thiotepa IV over 2 hours on days -3 and -2 in the absence of disease progression or unacceptable toxicity.
STEM CELL TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation (HSCT) on day 0.
PROPHYLAXIS FOR GVHD: Patients with sibling donor transplants receive cyclosporine IV continuously over 24 hours beginning on day -3. Patients with matched unrelated-donor transplants receive tacrolimus IV continuously over 24 hours beginning on day -3.
After completion of study treatment, patients are followed up for 30, 60, 100, 180, and 365 days.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationChildren's Hospital of Pittsburgh of UPMC
Principal InvestigatorRandy Marc Windreich
- Primary IDPRO14100126
- Secondary IDsNCI-2018-02832
- ClinicalTrials.gov IDNCT02626715