Clinical trial NCT01385787: MRD Testing Before and After Hematopoietic Cell Transplantation for Pediatric Acute Myeloid Leukemia
Official title: The Role of Minimal Residual Disease Testing Before and After Hematopoietic Cell Transplantation for Pediatric Acute Myeloid Leukemia
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Acute Myeloid Leukemia
Keywords: Pediatric (ages 0-21 years)
myeloablative HCT
PBMTC sites
Lead sponsor: Center for International Blood and Marrow Transplant Research
Sponsor class: NETWORK
Collaborators: name: Pediatric Blood and Marrow Transplant Consortium
name: St. Baldrick's Foundation
name: Otsuka Pharmaceutical Development & Commercialization, Inc.
First posted: 2011-06-30
Enrollment: 150
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Participating institutions (transplant centers)

Brief summary: 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.

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 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.

Primary outcomes:
measure: Two-year Event Free Survival (EFS)
timeFrame: 2 years post-HCT
Secondary outcomes:
measure: Two-year overall survival (OS)
timeFrame: 2 years post-HCT
measure: Disease relapse at 2 years
timeFrame: 2 years post-HCT
measure: Occurrence of acute grade II-IV and grade III-IV GVHD by 200 days post-HCT
timeFrame: 200 days post-HCT
measure: Occurrence of chronic GVHD at 2 years post-HCT
timeFrame: 2 years post-HCT
measure: Time to neutrophil engraftment
timeFrame: 42 days post-HCT
measure: Time to platelet engraftment
timeFrame: 42 days post-HCT
measure: Veno-occlusive Disease
timeFrame: 2 years post-HCT
measure: Chimerism
timeFrame: 100 days post-HCT
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: The Children's Hospital of Alabama, University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Loma Linda
country: United States
facility: Loma Linda University
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Aurora
country: United States
facility: The Children's Hospital Colorado
state: Colorado
city: Washington, D.C.
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Miami
country: United States
facility: Miami Children's Hospital
state: Florida
city: Saint Petersburg
country: United States
facility: All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Chicago
country: United States
facility: Lurie Children's Hospital of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children/Indiana University
state: Indiana
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Saint Louis
country: United States
facility: Washington University, St. Louis Children's Hospital
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: New York
country: United States
facility: Columbia University - The Morgan Stanley Children's Hospital of New York
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals of Cleveland Case Medical Ctr
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Sciences University - Doerbecher Children's
state: Oregon
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: San Antonio
country: United States
facility: Methodist Children's Hospital of South Texas/Texas Institute of Medicine and Surgery
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah - Primary Children's Medical Center
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Children's & Women's Health Centre of British Columbia
state: British Columbia
city: Montreal
country: Canada
facility: The Montreal Children's Hospital
state: Quebec
city: Montreal
country: Canada
facility: Hopital Ste. Justine
state: Quebec
Study officials:
affiliation: Children's National Research Institute
name: David A. Jacobsohn, MD, ScM
role: PRINCIPAL_INVESTIGATOR
References: