Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

MRD Testing Before and After Hematopoietic Cell Transplantation for Pediatric Acute Myeloid Leukemia

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Resource for Clinical Investigations in Blood and Marrow Transplantation (RCI-BMT)
Pediatric Blood and Marrow Transplant Consortium
St. Baldrick's Foundation
Otsuka Pharmaceutical Development & Commercialization, Inc.
Information provided by (Responsible Party):
Center for International Blood and Marrow Transplant Research
ClinicalTrials.gov Identifier:
NCT01385787
First received: June 28, 2011
Last updated: October 31, 2014
Last verified: October 2014
  Purpose

This is a non-therapeutic study. Pediatric AML patients undergoing HCT with a myeloablative preparative regimen may be enrolled. Subjects can be enrolled 10-40 days prior to HCT. Three samples for MRD (measured by WT1 PCR and flow cytometry) will be collected from peripheral blood and bone marrow: 1) pre-HCT (<3 weeks prior to starting the preparative regimen), 2) day 42 +/- 14 days post HCT (early post-engraftment), and 3) day 100 (+/-20 days) post HCT. For two years after transplant, the subject's follow-up data will be collected using the Research Level Forms in the CIBMTR Forms Net internet data entry system. The main objective is to determine whether there is any association between level of pre-transplant and post-transplant bone marrow MRD using WT1 and flow cytometry with 2-year event-free-survival, and to estimate the strength of that association in terms of the predictive accuracy of MRD. The investigators hypothesize that measurable MRD at either time point will be associated with decreased 2-year event-free survival.


Condition
Acute Myeloid Leukemia

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: The Role of Minimal Residual Disease Testing Before and After Hematopoietic Cell Transplantation for Pediatric Acute Myeloid Leukemia

Resource links provided by NLM:


Further study details as provided by Center for International Blood and Marrow Transplant Research:

Primary Outcome Measures:
  • Two-year Event Free Survival (EFS) [ Time Frame: 2 years post-HCT ] [ Designated as safety issue: Yes ]
    Event-free survival is defined as the time from HCT to relapse, death, initiation of post-HCT therapy to treat AML relapse, loss to follow up or end of study whichever comes first.


Secondary Outcome Measures:
  • Two-year overall survival (OS) [ Time Frame: 2 years post-HCT ] [ Designated as safety issue: No ]
    Overall survival is the time from HCT to death from any cause, loss to follow up or end of study, whichever comes first.

  • Disease relapse at 2 years [ Time Frame: 2 years post-HCT ] [ Designated as safety issue: No ]
    Relapse includes morphologic reappearance of leukemia or treatment for impending relapse. Death in remission is a competing risk. Relapse is defined as in 3.1. Cytogenetic or molecular relapse with <5% leukemic blasts in the bone marrow does not constitute a relapse unless unplanned AML-directed therapy is administered.

  • Occurrence of acute grade II-IV and grade III-IV GVHD by 200 days post-HCT [ Time Frame: 200 days post-HCT ] [ Designated as safety issue: No ]
    Any skin, gastrointestinal or liver abnormalities fulfilling the consensus criteria [36] of grades II-IV or grades III-IV acute GVHD are considered events. Death and second transplants are competing risks, and patients alive without acute GVHD will be censored at the time of last follow-up.

  • Occurrence of chronic GVHD at 2 years post-HCT [ Time Frame: 2 years post-HCT ] [ Designated as safety issue: No ]
    Occurrence of any symptoms in any organ system fulfilling the CIBMTR criteria of limited or extensive chronic GVHD. Death and the second transplant are competing risks, and patients alive without chronic GVHD will be censored at time of last follow-up.

  • Time to neutrophil engraftment [ Time Frame: 42 days post-HCT ] [ Designated as safety issue: No ]
    1st consecutive day of a sustained ANC ≥ 500/ μL for 3 consecutive days. Death without engraftment and second transplants are considered competing risks.

  • Time to platelet engraftment [ Time Frame: 42 days post-HCT ] [ Designated as safety issue: No ]
    1st day of platelet count ≥20,000/μL that persists ≥7 days, without transfusion. Death without engraftment and second transplants are considered competing risks.

  • Veno-occlusive Disease [ Time Frame: 2 years post-HCT ] [ Designated as safety issue: No ]
    Cumulative incidence of veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS), with median maximum bilirubin for subjects diagnosed with VOD/SOS. Subjects classified as having had VOD/SOS must meet the Jones Criteria, defined as: bilirubin>2mg/dL and at least 2 of the following signs: a) hepatomegaly and/or right upper quadrant pain, and b) >5% weight gain.

  • Chimerism [ Time Frame: 100 days post-HCT ] [ Designated as safety issue: No ]
    Whole blood chimerism and T-cell chimerism will be classified according to full (>95%), mixed (5-95%), or none (<5%) at 100 days.


Estimated Enrollment: 150
Study Start Date: October 2011
Estimated Study Completion Date: March 2016
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Detailed Description:

This is a prospective, non-therapeutic study, assessing the significance of minimal residual disease (MRD) at three different time points in relation to allogeneic HCT for pediatric AML. The study is a collaboration between the Pediatric Blood and Marrow Transplant Consortium (PBMTC) and the Resource for Clinical Investigations in Blood and Marrow Transplantation (RCI-BMT) of the Center for International Blood and Marrow Transplant Research (CIBMTR). The study will enroll pediatric AML patients who undergo myeloablative HCT at PBMTC sites. The eligibility criteria for this non-therapeutic study mirror widely accepted criteria for allogeneic HCT in pediatric AML.

The study tests the hypothesis that assessment of pre-transplant and post-transplant MRD predicts 2-year outcomes following transplant. Two MRD methodologies are being studied: flow cytometry and WT1 PCR. The secondary hypothesis is that combining these 2 methodologies will improve the accuracy in predicting 2-year outcomes following transplant.

It is well established that the level of minimal residual disease (MRD) during chemotherapy is a strong predictor of relapse in children with acute lymphoblastic leukemia (ALL) [33, 34]. Within this population, MRD levels have the potential to predict those patients who will respond well to standard therapy, thus allowing clinicians to tailor therapy and minimize toxicity while ensuring maximal cure rates [10]. MRD levels before allogeneic hematopoietic stem cell transplantation (HCT) also predict the risk of relapse post-HCT [25], leading to the clinical practice of reducing MRD levels as much as possible before transplant. By contrast, in children with acute myeloid leukemia (AML), the prognostic value of MRD levels prior to HCT remains unclear.

Our long-term objective is to improve the cure rate for children with AML. The investigators hypothesize that MRD levels before HCT will provide a powerful tool to select the best candidates for transplant, guide decision making in stem cell source and preparative therapy, and optimize the timing of the transplant. Measurements of MRD post-HCT will allow informed decisions about withdrawal of immunosuppressive therapy, administration of donor lymphocyte infusions, or alternative targeted therapies.

  Eligibility

Ages Eligible for Study:   up to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Participating institutions (transplant centers)

Criteria

Inclusion Criteria:

  1. Subject or legal guardian to understand and voluntarily sign an informed consent.
  2. Age 0-21 at time of transplant.
  3. Karnofsky score ≥ 70% (age ≥ 16 years old), or Lansky score ≥ 70% (age<16 years old).
  4. Patients with adequate physical function as measured by:

    • Cardiac: Left ventricular ejection fraction at rest must be > 40%, or shortening fraction > 26%
    • Hepatic: Bilirubin ≤ 2.5 mg/dL; and ALT, AST and Alkaline Phosphatase≤ 5 x ULN
    • Renal: Serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then renal function (creatinine clearance or GFR) > 70 mL/min/1.73 m2.
    • Pulmonary: DLCO, FEV1, FVC (diffusion capacity) > 50% of predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation > 92% in room air.
  5. Acute myelogenous leukemia (AML) at the following stages:

    • High risk first complete remission (CR1), defined as:

      • Having preceding myelodysplasia (MDS) -or-
      • Diagnostic high risk karyotypes: del (5q) -5, -7, abn (3q), t (6;9), abnormalities of 12, t (9:22), complex karyotype (≥3 abnormalities), the presence of a high FLT3 ITD-AR (> 0.4) -or-
      • Having >15% bone marrow blasts after 1st cycle and/or >5% after 2nd cycle before achieving CR -and-
      • <5% blasts in the bone marrow, with peripheral ANC>500
    • Intermediate risk first complete remission (CR1), defined as:

      • Diagnostic karyotypes that are neither high-risk (as defined above) nor low risk (inv(16)/t(16:16); t(8;21); t(15;17)). Included are cases where cytogenetics could not be performed. -and-
      • <5% blasts in the bone marrow, with peripheral ANC>500
    • High risk based upon COG AAML 1031 criteria:

      • High allelic ratio FLT3/ITD+, monosomy 7, del(5q) with any MRD status or standard risk cytogenetics with positive MRD at end of Induction I.
      • <5% blasts in the bone marrow, with peripheral ANC>500
    • Second or greater CR

      • <5% blasts in the bone marrow, with peripheral ANC>500
    • Therapy-related AML at any stage

      • Prior malignancy in remission for >12 months.
      • <5% blasts in the bone marrow, with peripheral ANC>500
  6. Myeloablative preparative regimen, defined as a regimen including one of the following as a backbone agent*:

    • Busulfan ≥ 9mg/kg total dose (IV or PO). PK-based dosing is allowed, if intent is myeloablative dosing OR
    • Total Body Irradiation≥1200cGy fractionated OR
    • Treosulfan ≥ 42g/m2 total dose IV *Regimens may include secondary agents such as, but not limited to Ara-C, Fludarabine, VP-16. Regimens that combine Busulfan and TBI or treosulfan and TBI are allowed as long as the Busulfan or treosulfan meets or exceeds the dose listed and the TBI is below the dose listed.
  7. Graft source:

    • HLA-identical sibling PBSC, BM, or cord blood
    • Adult related or unrelated donor PBSC or BM matched at the allelic level for HLA-A, HLA-B, HLA-C, and HLA-DRB1 with no greater than a single antigen mismatch.
    • One or two unrelated cord blood units:

      • HLA≥4:6 at the low resolution level for HLA-A, HLA-B, at high resolution level at HLA-DRB1 for one or both units.
      • If one unit, must have TNC≥2.5x107/kg; if two units, combination of the two must have TNC≥2.5x107/kg

Exclusion Criteria:

  1. Women who are pregnant (positive HCG) or breastfeeding.
  2. Evidence of HIV infection or HIV positive serology.
  3. Positive viral load (PCR) for Hepatitis B or C (negative serology, surface antigen, and core antibody may substitute for PCR).
  4. Current uncontrolled bacterial, viral or fungal infection (currently taking medication and progression of clinical symptoms).
  5. Autologous transplant < 12 months prior to enrollment.
  6. Prior allogeneic hematopoietic stem cell transplant.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01385787

  Hide Study Locations
Locations
United States, Alabama
The Children's Hospital of Alabama, University of Alabama at Birmingham
Birmingham, Alabama, United States, 35233
United States, Arizona
Phoenix Children's Hospital
Phoenix, Arizona, United States, 85016
United States, California
Loma Linda University
Loma Linda, California, United States, 92354
University of California San Francisco
San Francisco, California, United States, 94143
United States, Colorado
The Children's Hospital Colorado
Aurora, Colorado, United States, 80045
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20910
United States, Florida
Miami Children's Hospital
Miami, Florida, United States, 33155
All Children's Hospital
St. Petersburg, Florida, United States, 33701
United States, Georgia
Children's Healthcare of Atlanta
Atlanta, Georgia, United States, 30322
United States, Illinois
Lurie Children's Hospital of Chicago
Chicago, Illinois, United States, 60611
United States, Indiana
Riley Hospital for Children/Indiana University
Indianapolis, Indiana, United States, 46202
United States, Kentucky
University of Louisville
Louisville, Kentucky, United States, 40202
United States, Maryland
Johns Hopkins
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
Children's Hospital of Michigan
Detroit, Michigan, United States, 48201
United States, Mississippi
University of Mississippi Medical Center
Jackson, Mississippi, United States, 39216
United States, Missouri
Washington University, St. Louis Children's Hospital
St. Louis, Missouri, United States, 63110
United States, New Jersey
Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Columbia University - The Morgan Stanley Children's Hospital of New York
New York, New York, United States, 10032
Mount Sinai School of Medicine
New York, New York, United States, 10029
New York Medical College
Valhalla, New York, United States, 10595
United States, North Carolina
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States, 27599
Duke University Medical Center
Durham, North Carolina, United States, 27705
United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195
University Hospitals of Cleveland Case Medical Ctr
Cleveland, Ohio, United States, 44106
United States, Oregon
Oregon Health & Sciences University - Doerbecher Children's
Portland, Oregon, United States, 97239
United States, Pennsylvania
Penn State Milton S. Hershey Medical Center
Hershey, Pennsylvania, United States, 17033
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Texas
Methodist Children's Hospital of South Texas/Texas Institute of Medicine and Surgery
San Antonio, Texas, United States, 78229
United States, Utah
University of Utah - Primary Children's Medical Center
Salt Lake City, Utah, United States, 84108
United States, Virginia
Virginia Commonwealth University
Richmond, Virginia, United States, 23219
United States, Wisconsin
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Canada, Alberta
Alberta Children's Hospital
Calgary, Alberta, Canada, T3B 6A8
Canada, British Columbia
Children's & Women's Health Centre of British Columbia
Vancouver, British Columbia, Canada, V6T 1Z3
Canada, Quebec
Hopital Ste. Justine
Montreal, Quebec, Canada, H3T 1C5
The Montreal Children's Hospital
Montreal, Quebec, Canada, H3H 1P3
Sponsors and Collaborators
Center for International Blood and Marrow Transplant Research
Resource for Clinical Investigations in Blood and Marrow Transplantation (RCI-BMT)
Pediatric Blood and Marrow Transplant Consortium
St. Baldrick's Foundation
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigators
Principal Investigator: David A. Jacobsohn, MD, ScM Children's Research Institute
  More Information

No publications provided

Responsible Party: Center for International Blood and Marrow Transplant Research
ClinicalTrials.gov Identifier: NCT01385787     History of Changes
Other Study ID Numbers: 09-MRD
Study First Received: June 28, 2011
Last Updated: October 31, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Center for International Blood and Marrow Transplant Research:
Pediatric (ages 0-21 years)
myeloablative HCT
PBMTC sites

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms
Neoplasms by Histologic Type

ClinicalTrials.gov processed this record on November 25, 2014