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

Sponsor

Center for International Blood and Marrow Transplant Research (Other)

Overall Status

Completed

CT.gov ID

NCT01385787

Collaborator

Pediatric Blood and Marrow Transplant Consortium (Other), St. Baldrick's Foundation (Other), Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)

150

Enrollment

Locations

Actual Duration (Months)

3.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia

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.

Study Design

Study Type:

Observational

Actual Enrollment :

150 participants

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

Actual Study Start Date :

Oct 1, 2011

Actual Primary Completion Date :

May 1, 2017

Actual Study Completion Date :

May 1, 2017

Outcome Measures

Primary Outcome Measures

Two-year Event Free Survival (EFS) [2 years post-HCT]
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) [2 years post-HCT]
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 [2 years post-HCT]
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 [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.
Occurrence of chronic GVHD at 2 years post-HCT [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.
Time to neutrophil engraftment [42 days post-HCT]
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 [42 days post-HCT]
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 [2 years post-HCT]
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 [100 days post-HCT]
Whole blood chimerism and T-cell chimerism will be classified according to full (>95%), mixed (5-95%), or none (<5%) at 100 days.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subject or legal guardian to understand and voluntarily sign an informed consent.
Age 0-21 at time of transplant.
Karnofsky score ≥ 70% (age ≥ 16 years old), or Lansky score ≥ 70% (age<16 years old).
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.

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

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.

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:

Women who are pregnant (positive HCG) or breastfeeding.
Evidence of HIV infection or HIV positive serology.
Positive viral load (PCR) for Hepatitis B or C (negative serology, surface antigen, and core antibody may substitute for PCR).
Current uncontrolled bacterial, viral or fungal infection (currently taking medication and progression of clinical symptoms).
Autologous transplant < 12 months prior to enrollment.
Prior allogeneic hematopoietic stem cell transplant.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Children's Hospital of Alabama, University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016
3	Loma Linda University	Loma Linda	California	United States	92354
4	University of California San Francisco	San Francisco	California	United States	94143
5	The Children's Hospital Colorado	Aurora	Colorado	United States	80045
6	Children's National Medical Center	Washington, D.C.	District of Columbia	United States	20910
7	Miami Children's Hospital	Miami	Florida	United States	33155
8	All Children's Hospital	Saint Petersburg	Florida	United States	33701
9	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30322
10	Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
11	Riley Hospital for Children/Indiana University	Indianapolis	Indiana	United States	46202
12	University of Louisville	Louisville	Kentucky	United States	40202
13	Johns Hopkins	Baltimore	Maryland	United States	21287
14	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
15	University of Michigan	Ann Arbor	Michigan	United States	48109
16	Children's Hospital of Michigan	Detroit	Michigan	United States	48201
17	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
18	Washington University, St. Louis Children's Hospital	Saint Louis	Missouri	United States	63110
19	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
20	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
21	Mount Sinai School of Medicine	New York	New York	United States	10029
22	Columbia University - The Morgan Stanley Children's Hospital of New York	New York	New York	United States	10032
23	New York Medical College	Valhalla	New York	United States	10595
24	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
25	Duke University Medical Center	Durham	North Carolina	United States	27705
26	University Hospitals of Cleveland Case Medical Ctr	Cleveland	Ohio	United States	44106
27	Cleveland Clinic	Cleveland	Ohio	United States	44195
28	Oregon Health & Sciences University - Doerbecher Children's	Portland	Oregon	United States	97239
29	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033
30	Medical University of South Carolina	Charleston	South Carolina	United States	29425
31	Methodist Children's Hospital of South Texas/Texas Institute of Medicine and Surgery	San Antonio	Texas	United States	78229
32	University of Utah - Primary Children's Medical Center	Salt Lake City	Utah	United States	84108
33	Virginia Commonwealth University	Richmond	Virginia	United States	23219
34	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
35	Alberta Children's Hospital	Calgary	Alberta	Canada	T3B 6A8
36	Children's & Women's Health Centre of British Columbia	Vancouver	British Columbia	Canada	V6T 1Z3
37	The Montreal Children's Hospital	Montreal	Quebec	Canada	H3H 1P3
38	Hopital Ste. Justine	Montreal	Quebec	Canada	H3T 1C5