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

Acute Myeloid Leukemia Clinical Trial

Official title:

The Role of Minimal Residual Disease Testing Before and After Hematopoietic Cell Transplantation for Pediatric Acute Myeloid Leukemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01385787
• Other study ID #: 09-MRD
• Status: Completed
• Phase: N/A
• First received: June 28, 2011
• Last updated: September 5, 2017
• Start date: October 2011
• Est. completion date: May 2017

Study information

• Verified date: September 2017
• Source: Center for International Blood and Marrow Transplant Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 150
• Est. completion date: May 2017
• Est. primary completion date: May 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 21 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Locations

Country	Name	City	State
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	Hopital Ste. Justine	Montreal	Quebec
Canada	The Montreal Children's Hospital	Montreal	Quebec
Canada	Children's & Women's Health Centre of British Columbia	Vancouver	British Columbia
United States	University of Michigan	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	The Children's Hospital Colorado	Aurora	Colorado
United States	Johns Hopkins	Baltimore	Maryland
United States	The Children's Hospital of Alabama, University of Alabama at Birmingham	Birmingham	Alabama
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cleveland Clinic	Cleveland	Ohio
United States	University Hospitals of Cleveland Case Medical Ctr	Cleveland	Ohio
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Riley Hospital for Children/Indiana University	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Loma Linda University	Loma Linda	California
United States	University of Louisville	Louisville	Kentucky
United States	Miami Children's Hospital	Miami	Florida
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Columbia University - The Morgan Stanley Children's Hospital of New York	New York	New York
United States	Mount Sinai School of Medicine	New York	New York
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Oregon Health & Sciences University - Doerbecher Children's	Portland	Oregon
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Washington University, St. Louis Children's Hospital	Saint Louis	Missouri
United States	All Children's Hospital	Saint Petersburg	Florida
United States	University of Utah - Primary Children's Medical Center	Salt Lake City	Utah
United States	Methodist Children's Hospital of South Texas/Texas Institute of Medicine and Surgery	San Antonio	Texas
United States	University of California San Francisco	San Francisco	California
United States	New York Medical College	Valhalla	New York
United States	Children's National Medical Center	Washington, D.C.	District of Columbia

Sponsors (4)

Lead Sponsor	Collaborator
Center for International Blood and Marrow Transplant Research	Otsuka Pharmaceutical Development & Commercialization, Inc., Pediatric Blood and Marrow Transplant Consortium, St. Baldrick's Foundation

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Two-year Event Free Survival (EFS)	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.	2 years post-HCT
Secondary	Two-year overall survival (OS)	Overall survival is the time from HCT to death from any cause, loss to follow up or end of study, whichever comes first.	2 years post-HCT
Secondary	Disease relapse at 2 years	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.	2 years post-HCT
Secondary	Occurrence of acute grade II-IV and grade III-IV GVHD by 200 days post-HCT	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.	200 days post-HCT
Secondary	Occurrence of chronic GVHD at 2 years post-HCT	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.	2 years post-HCT
Secondary	Time to neutrophil engraftment	1st consecutive day of a sustained ANC = 500/ µL for 3 consecutive days. Death without engraftment and second transplants are considered competing risks.	42 days post-HCT
Secondary	Time to platelet engraftment	1st day of platelet count =20,000/µL that persists =7 days, without transfusion. Death without engraftment and second transplants are considered competing risks.	42 days post-HCT
Secondary	Veno-occlusive Disease	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.	2 years post-HCT
Secondary	Chimerism	Whole blood chimerism and T-cell chimerism will be classified according to full (>95%), mixed (5-95%), or none (<5%) at 100 days.	100 days post-HCT