A Feasibility Study of "Early" Allogeneic Hematopoietic Cell Transplantation for Relapsed or Refractory High-Grade Myeloid Neoplasms
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Feasibility of Early Allogeneic Hematopoietic Cell Transplant Assessed by Relapsed-free Survival 6 Months After Transplant
研究概览
简要总结
This clinical trial studies how well early stem cell transplantation works in treating patients with high-grade myeloid neoplasms that has come back after a period of improvement or does not respond to treatment. Drugs used in chemotherapy, such as filgrastim, cladribine, cytarabine and mitoxantrone hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a donor peripheral blood cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The donated stem cells may also replace the patient's immune cells and help destroy any remaining cancer cells. Early stem cell transplantation may result in more successful treatment for patients with high-grade myeloid neoplasms.
详细描述
OUTLINE:
RE-INDUCTION CHEMOTHERAPY: Patients receive filgrastim subcutaneously (SC) on days 0-5, mitoxantrone hydrochloride intravenously (IV) over 60 minutes on days 1-3, cladribine IV over 2 hours on days 1-5, and cytarabine IV over 2 hours on days 1-5.
CONDITIONING REGIMEN: Beginning 14-60 days after re-induction chemotherapy, patients receive fludarabine phosphate IV over 30 minutes on days -6 to -2, melphalan IV on days -3 to -2, cyclosporine orally (PO) twice daily (BID) starting on day -3. Sirolimus PO BID starting on day -3 will be given to patients who have matched unrelated donors or mismatched unrelated donors. Patients >55 years or with significant co-morbidities will only receive melphalan IV on day -2 and will also receive total body irradiation (TBI) on day -1 or day 0.
EARLY TRANSPLANT: Patients undergo allogeneic HCT after conditioning regimen on day 0.
GVHD PROPHYLAXIS: Patients with matched donors will receive mycophenolate mofetil PO three times daily (TID) on days 0-30, then twice a day (BID) until day 40; and cyclosporine PO BID on days -3 to 96, with a taper until day 150. Patients with matched unrelated donors also receive sirolimus PO BID on days -3 to 150, with a taper until day 180. Patients with mismatched unrelated donors will receive mycophenolate mofetil PO TID on days 0-30, then BID until day 100, with a taper until day 150; cyclosporine PO BID on days -3 to 150, then taper until day 180; and sirolimus BID PO days -3 to 180, then a taper until day 365.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA (ENROLLMENT)
- •Relapsed or refractory high-grade myeloid neoplasms, defined as having a blast count of >= 10% blasts at initial diagnosis; examples include excess blasts (EB)-2, with >= 10% blasts at initial diagnosis, acute myeloid leukemia (AML) or chronic myelomonocytic leukemia (CMML-2); standard definitions of relapse will apply (i.e., characterized by >= 5% abnormal blasts or blast equivalents as assessed by multiparameter flow cytometry or morphologic examination; peripheral blood blasts or blast equivalents; or extramedullary granulocytic sarcoma, per European LeukemiaNet [ELN] 2017 guidelines); bone marrow aspirate/biopsy will be accepted if performed outside University of Washington/Fred Hutchinson Cancer Research Center (UW/FHCRC); determination of disease status should occur within 30 days of signing informed consent
- •R/R high-grade myeloid neoplasm following intensive induction chemotherapy; relapsed high-grade myeloid neoplasm: patients will be classified as relapsed if they have >= 5% blasts after being in a complete remission (CR) following treatment for high-grade myeloid neoplasm; refractory high-grade myeloid neoplasm: patients may be classified as refractory if they have received at least one prior cycle of induction chemotherapy, whether with cladribine cytarabine mitoxantrone (GCLAM) or another regimen
- •** Patients may have received up to two courses of intensive induction chemotherapy during initial treatment prior to enrollment on this protocol; for example, patients who have received two courses of granulocyte colony stimulating factor (G-CSF) GCLAM (or similar) chemotherapy, with most recent high-dose cytarabine-containing chemotherapy > 6 months ago and CR lasting > 6 months, will be eligible for this protocol; regimens "similar to GCLAM" would include cytarabine at doses of 1g/m^2 for at least 5 doses; examples of regimens "similar to GCLAM" would be GCLA, fludarabine cytarabine granulocyte (FLAG), and FLAG-idarubicin (ida); however, patients who received more than two courses of GCLAM (or similar) chemotherapy, or patients who received two courses of GCLAM and had CR lasting < 6 months, would not be eligible
- •R/R high-grade myeloid neoplasm following less intensive induction chemotherapy. Patients who have received at least three cycles of treatment with a hypomethylating agent (HMA; such as azacitidine or decitabine) and still have >= 10% blasts will be eligible for the study (they will be considered refractory); similarly, patients who have received three or more cycles of HMA therapy who have had a response (e.g., achieving CR with < 5% blasts), but who then progress using standard definitions of relapse, will also be eligible (they will be considered relapsed)
- •Potentially eligible for reduced intensity conditioning based on known organ function (formal organ function testing may occur after consent)
- •Caregiver capable of providing post-HCT care
- •Written informed consent
- •INCLUSION CRITERIA (TRANSPLANT)
- •Identified donor (see DONOR SELECTION below for further details)
- •Matched related or unrelated (one allele mismatch in HLA-A, B, or C OK) donor according to institutional standards
- •Unrelated volunteer donor who is mismatched with the recipient (i.e. 9/10 match)
- •Caregiver capable of providing post-HCT care, who will be present once induction therapy with filgrastim, cladribine, cytarabine, mitoxantrone hydrochloride (GCLAM) begins
- •Written informed consent for transplant
- •Either bone marrow or peripheral blood is allowed
排除标准
- •EXCLUSION CRITERIA (ENROLLMENT)
- •Prior allogeneic HCT
- •More than two prior courses of induction chemotherapy
- •Relapse after minimal residual disease (MRD)-negative CR within 3 months of most recent GCLAM chemotherapy
- •Low likelihood of being eligible for reduced intensity conditioning HCT based on known information
- •Cardiac ejection fraction < 40% or symptomatic coronary artery disease or uncontrolled arrhythmia, as assessed by multigated acquisition (MUGA) or transthoracic echocardiography (TTE) within previous 3 months and since the most recent anthracycline exposure
- •Corrected diffusing capacity of the lungs for carbon monoxide (DLCOc) < 40% or forced expiratory volume in 1 second (FEV1) < 50%
- •Estimated glomerular filtration rate (GFR) < 40 ml/min
- •Need for supplemental oxygen
- •Direct bilirubin or alanine aminotransferase (ALT) > 2 x upper limit of normal, unless these abnormalities are thought to be related to Gilbert's disease or leukemic infiltration of hepatic parenchyma
- •Known human immunodeficiency virus (HIV) positivity
- •Pregnant or nursing (to be confirmed with quantitative human chorionic gonadotropin [HCG] testing)
- •Invasive solid tumor within 5 years; non-melanoma skin cancer or in situ malignancies are allowed
- •Evidence of serious uncontrolled infection
- •Eastern Cooperative Oncology Group (ECOG) of 3 or 4
- •EXCLUSION CRITERIA (TRANSPLANT)
- •Donor specific antibodies against donor HLA-DQ or -DP
- •Active bacterial, fungal or viral infections unresponsive to medical therapy
- •Active leukemia in the central nervous system (CNS)
- •HIV positive
- •Cardiac ejection fraction < 40% or symptomatic coronary artery disease or uncontrolled arrhythmia
- •DLCOc < 40% or FEV1 < 50%
- •Estimated GFR < 40 ml/min
- •Need for supplemental oxygen
- •Direct bilirubin or ALT > 2 x upper limit of normal, unless these abnormalities are thought to be related to Gilbert's disease or leukemic infiltration of hepatic parenchyma
- •DONOR SELECTION:
- •Identification of an appropriate donor will follow the general guidelines listed below.
- •HLA-matched related or unrelated donor. Donors must be:
- •Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing
- •Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing
- •HLA-mismatched unrelated donor. Unrelated volunteer donors who are mismatched with the recipient within one of the following limitations will be permitted:
- •Mismatch for one HLA class I antigen with or without an additional mismatch for one HLA-class I allele, but matched for HLA-DRB1 and HLA-DQ, OR
- •Mismatched for two HLA class I alleles, but matched for HLA-DRB1 and HLA-DQ
- •HLA class I HLA-A, -B, -C allele matched donors allowing for any one or two DRB1 and/or DQB1 antigen/allele mismatch
- •HLA-matching must be based on results of high resolution typing at HLA-A, -B, -C, -DRB1, and -DQ. If the patient is homozygous at the mismatch HLA class I locus or II locus, the donor must be heterozygous at that locus and one allele must match the patient (i.e., patient is homozygous A*01:01 and donor is heterozygous A*01:01, A*02:01)
研究组 & 干预措施
Treatment (chemotherapy, HCT)
See Detailed Description
干预措施: Cladribine (Drug)
Treatment (chemotherapy, HCT)
See Detailed Description
干预措施: Melphalan Hydrochloride (Drug)
Treatment (chemotherapy, HCT)
See Detailed Description
干预措施: Cyclosporine (Drug)
Treatment (chemotherapy, HCT)
See Detailed Description
干预措施: Cytarabine (Drug)
Treatment (chemotherapy, HCT)
See Detailed Description
干预措施: Filgrastim (Biological)
Treatment (chemotherapy, HCT)
See Detailed Description
干预措施: Fludarabine Phosphate (Drug)
Treatment (chemotherapy, HCT)
See Detailed Description
干预措施: Allogeneic Hematopoietic Stem Cell Transplantation (Procedure)
Treatment (chemotherapy, HCT)
See Detailed Description
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (chemotherapy, HCT)
See Detailed Description
干预措施: Melphalan (Drug)
Treatment (chemotherapy, HCT)
See Detailed Description
干预措施: Mitoxantrone Hydrochloride (Drug)
Treatment (chemotherapy, HCT)
See Detailed Description
干预措施: Mycophenolate Mofetil (Drug)
Treatment (chemotherapy, HCT)
See Detailed Description
干预措施: Questionnaire Administration (Other)
Treatment (chemotherapy, HCT)
See Detailed Description
干预措施: Sirolimus (Drug)
Treatment (chemotherapy, HCT)
See Detailed Description
干预措施: Total-Body Irradiation (Radiation)
结局指标
主要结局
Feasibility of Early Allogeneic Hematopoietic Cell Transplant Assessed by Relapsed-free Survival 6 Months After Transplant
时间窗: 6 months after early allogeneic HCT on study
Success will be defined as observing a 40% of higher 6-month relapse-free survival among patients who received early transplant on study.
Feasibility of Early Allogeneic Hematopoietic Cell Transplant Assessed by Enrollment and Incidence of Early Transplant
时间窗: Up to 60 days after start of chemotherapy
Success will be defined as enrollment of at least 30 patients with transplants occurring in 15 of these 30 (50%) within 60 days of enrollment or start of induction chemotherapy with G-CLAM, whichever is earlier.
次要结局
- Overall Survival (OS) Among Patients Who Did Not Receive Early Transplant(Up to 6 months after induction day 1)
- Relapse-free Survival (RFS) Among Patients Who Received Early Transplant(Up to 6 months post-transplant)
- Factors That Distinguish Patients Who Received Early Transplant From Those Who Did Not - GENDER(From time of subject's study enrollment to time of subject's feasibility success assessment (i.e. when subject received transplant within 60 days or when it was determined subject would not proceed with transplant on study))
- Demonstrate the Feasibility of Collecting Patient-reported Outcomes for Trial Participants(Up to 12 months post-HCT)
- Demonstrate the Feasibility of Collecting Resource Utilization Data for Trial Participants(Within the first year of induction chemotherapy on study)
- Response Assessments After Early Allogeneic Hematopoietic Cell Transplant, Day 28(Approximately 28 days after early allogeneic HCT)
- Acute Graft Versus Host Disease Among Patients Who Received Early Transplant(At day 100)
- Response Assessments After Early Allogeneic Hematopoietic Cell Transplant, Day 84(Approximately 84 days after early allogeneic HCT)
- Event-free Survival (EFS) Among Patients Who Received Early Transplant(Up to 6 months post-transplant)
- Overall Survival (OS) Among Patients Who Received Early Transplant.(Up to 6 months post-transplant)
- Treatment Related Mortality Among Patients Who Received Early Transplant vs Patients Who Did Not Receive Early Transplant(At day 100)
- Factors That Distinguish Patients Who Received Early Transplant From Those Who Did Not - TREATMENT RELATED MORTALITY(From time of subject's study enrollment to time of subject's feasibility success assessment (i.e. when subject received transplant within 60 days or when it was determined subject would not proceed with transplant on study))
- Factors That Distinguish Patients Who Received Early Transplant From Those Who Did Not - AGE(From time of subject's study enrollment to time of subject's feasibility success assessment (i.e. when subject received transplant within 60 days or when it was determined subject would not proceed with transplant on study))
研究者
Mary-Beth Percival
Assistant Professor, Division of Hematology
University of Washington