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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by 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.
Information provided by (Responsible Party):
Center for International Blood and Marrow Transplant Research Identifier:
First received: June 28, 2011
Last updated: September 8, 2014
Last verified: September 2014

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.

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.


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)


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 identifier: NCT01385787

Contact: Alexia Adams 612-884-8735
Contact: Mandi Proue 612-617-8395

  Hide Study Locations
United States, Alabama
The Children's Hospital of Alabama, University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35233
Contact: Hilary Haines, MD    205-939-9364   
Contact: Crystal Turner    205-638-9364   
Principal Investigator: Hilary Haines, MD         
United States, Arizona
Phoenix Children's Hospital Recruiting
Phoenix, Arizona, United States, 85016
Contact: Dorothea Douglas, MD    602-546-0134   
Contact: Alan Holzkopf    (602) 546-3341   
Principal Investigator: Dorothea Douglas, MD         
United States, California
Loma Linda University Recruiting
Loma Linda, California, United States, 92354
Contact: Joan Morris, MD    909-558-7173   
Contact: Nicolle Glover, RN    909-558-7213   
Principal Investigator: Joan Morris, MD         
University of California San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Christopher Dvorak, MD    415-476-2188   
Principal Investigator: Christopher Dvorak, MD         
United States, Colorado
The Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Amy Keating, MD    720-777-6613   
Contact: Teresa Kerwin    720-777-4240   
Principal Investigator: Amy Keating, MD         
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, District of Columbia, United States, 20910
Contact: David A. Jacobsohn, MD, ScM    202-476-6690   
Contact: Divyesh Kukadiya    202-476-6850   
Principal Investigator: David A. Jacobsohn, MD, ScM         
United States, Florida
Miami Children's Hospital Recruiting
Miami, Florida, United States, 33155
Contact: Guillermo DeAngulo, MD    305-243-0850   
Contact: Fabian Castillo    786-624-4146   
Principal Investigator: Guillermo DeAngulo, MD         
All Children's Hospital Recruiting
St. Petersburg, Florida, United States, 33701
Contact: Aleksandra Petrovic, MD   
Contact: Michael Gates, RN    727-767-4178   
Principal Investigator: Aleksandra Petrovic, MD         
United States, Georgia
Children's Healthcare of Atlanta Recruiting
Atlanta, Georgia, United States, 30322
Contact: Ann Haight, MD    404-785-1272   
Contact: Audrey Grizzle    (404) 785-2125   
Principal Investigator: Ann Haight, MD         
United States, Illinois
Lurie Children's Hospital of Chicago Recruiting
Chicago, Illinois, United States, 60611
Contact: Reggie Duerst, MD   
Contact: Colleen Rosen    312.227.4870   
Principal Investigator: Reggie Duerst, MD         
United States, Indiana
Riley Hospital for Children/Indiana University Recruiting
Indianapolis, Indiana, United States, 46202
Contact: David Delgado, MD    317-944-8784   
Contact: Courtney Spiegel, CCRP    317-948-0581   
Principal Investigator: David Delgado, MD         
United States, Kentucky
University of Louisville Recruiting
Louisville, Kentucky, United States, 40202
Contact: Alexandra Cheerva, MD    502-852-8450   
Contact: April Loveall    502-629-6856   
Principal Investigator: Alexandra Cheerva, MD         
United States, Maryland
Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21287
Contact: Allen Chen, MD   
Contact: Tammy Scott    410-614-5990   
Principal Investigator: Allen Chen, MD         
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Steven Margossian, MD   
Contact: Theresa Williams    617-632-4538   
Principal Investigator: Steven Margossian, MD         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Andy Harris, MD    734-764-7127   
Contact: Jessca Yu    734-936-4782   
Principal Investigator: Andy Harris, MD         
Children's Hospital of Michigan Recruiting
Detroit, Michigan, United States, 48201
Contact: Sureyya Savasan, MD    313-745-5515   
Contact: Julie Nucci    313.966.8508   
Principal Investigator: Sureyya Savasan, MD         
United States, Mississippi
University of Mississippi Medical Center Recruiting
Jackson, Mississippi, United States, 39216
Contact: Gail Megason, MD   
Contact: Sarah Elkin    601-984-2701   
Principal Investigator: Gail Megason, MD         
United States, Missouri
Washington University, St. Louis Children's Hospital Recruiting
St. Louis, Missouri, United States, 63110
Contact: Shalini Shenoy, MD    314-454-6018   
Contact: Tia Thomas    314-454-2147   
Principal Investigator: Shalini Shenoy, MD         
United States, New Jersey
Hackensack University Medical Center Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Alfred Gillio, MD    201-996-5600   
Contact: Jeanette Haugh    (201) 996-3457   
Principal Investigator: Alfred Gillio, MD         
United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Barbara Bambach, MD   
Contact: Sandie Ciesla   
Principal Investigator: Barbara Bambach, MD         
Columbia University - The Morgan Stanley Children's Hospital of New York Recruiting
New York, New York, United States, 10032
Contact: Monica Bhatia, MD    212-305-9138   
Contact: Elana Hamburger-Smilow    212-305-8443   
Principal Investigator: Monica Bhatia, MD         
Mount Sinai School of Medicine Recruiting
New York, New York, United States, 10029
Contact: Jaclyn Davis, MD    212-241-7022   
Contact: Rashida Sepagan    212.241.3744   
Principal Investigator: Jaclyn Davis, MD         
New York Medical College Recruiting
Valhalla, New York, United States, 10595
Contact: M. Fevzi Ozkaynak, MD    914-493-7997   
Contact: Phyllis Brand    914-594-3866    Phyllis_Brand@NYMC.EDU   
Principal Investigator: M. Fevzi Ozkaynak, MD         
United States, North Carolina
University of North Carolina at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Kimberly Kasow, DO    919-966-1178   
Contact: James Bradley    919-966-0987   
Principal Investigator: Kimberly Kasow, DO         
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27705
Contact: Paul L. Martin, MD, PhD    919-668-1100   
Contact: Maggie Peterson    919-668-1280   
Principal Investigator: Paul L. Martin, MD, PhD         
United States, Ohio
University Hospitals of Cleveland Case Medical Ctr Recruiting
Cleveland, Ohio, United States, 44106
Contact: Sanjay Ahuja, MD   
Contact: Sharon Spellacy    (216) 844-7176   
Principal Investigator: Sanjay Ahuja, MD         
Cleveland Clinic Recruiting
Cleveland, Ohio, United States, 44195
Contact: Rabi Hanna, MD   
Contact: Patti Baucco   
Principal Investigator: Rabi Hanna, MD         
United States, Oregon
Oregon Health & Sciences University - Doerbecher Children's Recruiting
Portland, Oregon, United States, 97239
Contact: Eneida Nemecek, MD    503-494-0829   
Contact: Christina Burgin    503-418-5337   
Principal Investigator: Eneida Nemecek, MD         
United States, Pennsylvania
Penn State Milton S. Hershey Medical Center Recruiting
Hershey, Pennsylvania, United States, 17033
Contact: Robert Greiner, MD    717-531-6012   
Contact: Jennifer Stokes    (717) 531-7765   
Principal Investigator: Robert Greiner, MD         
United States, South Carolina
Medical University of South Carolina Recruiting
Charleston, South Carolina, United States, 29425
Contact: Michelle Hudspeth, MD    843-792-2957   
Contact: Jared Hortman    843-792-9579   
Principal Investigator: Michelle Hudspeth, MD         
United States, Texas
Methodist Children's Hospital of South Texas/Texas Institute of Medicine and Surgery Recruiting
San Antonio, Texas, United States, 78229
Contact: Veronica Jude, MD    210-575-7268   
Contact: Conschetta Wright    210.575.7865   
Principal Investigator: Veronica Jude, MD         
United States, Utah
University of Utah - Primary Children's Medical Center Recruiting
Salt Lake City, Utah, United States, 84108
Contact: Michael Pulsipher, MD    801-662-4830   
Contact: Suzanne Stradling    801-213-3908   
Principal Investigator: Michael Pulsipher, MD         
United States, Virginia
Virginia Commonwealth University Recruiting
Richmond, Virginia, United States, 23219
Contact: Madhu Gowda, MD    804-828-9607   
Contact: Sabrina Minter    804-628-3094   
Principal Investigator: Madhu Gowda, MD         
United States, Wisconsin
Children's Hospital of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Julie Talano, MD   
Contact: Michelle Martin   
Principal Investigator: Julie Talano, MD         
Canada, Alberta
Alberta Children's Hospital Recruiting
Calgary, Alberta, Canada, T3B 6A8
Contact: Victor Lewis, MD    403-955-7203   
Contact: Karen Mazil, RN, BSN    403.955.2242   
Principal Investigator: Victor Lewiss, MD         
Canada, British Columbia
Children's & Women's Health Centre of British Columbia Recruiting
Vancouver, British Columbia, Canada, V6T 1Z3
Contact: Jeffrey Davis, MD    604-875-2316   
Contact: Colleen Fitzgerald    (604) 875-2000 ext 7277   
Principal Investigator: Jeffrey Davis, MD         
Canada, Quebec
Hopital Ste. Justine Recruiting
Montreal, Quebec, Canada, H3T 1C5
Contact: Pierre Teira, MD    514-345-4969   
Contact: Marion Cortier    514-345-4931 ext 5324   
Principal Investigator: Pierre Teira, MD         
The Montreal Children's Hospital Recruiting
Montreal, Quebec, Canada, H3H 1P3
Contact: David Mitchell, MD    514 412-4445   
Contact: Martine Nagy    514 934-1934 x 23436   
Principal Investigator: David Mitchell, MD         
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.
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 Identifier: NCT01385787     History of Changes
Other Study ID Numbers: 09-MRD
Study First Received: June 28, 2011
Last Updated: September 8, 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, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms processed this record on October 01, 2014