Acute Myeloid Leukemia T Cell Depletion to Improve Transplants in Adults With Acute Myeloid Leukemia (BMT CTN 0303)

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00201240
• Collaborator: Blood and Marrow Transplant Clinical Trials Network (Other), National Cancer Institute (NCI) (NIH)
• Enrollment: 47
• Locations: 8
• Arm: 1
• Duration (Months): 102
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study is a single arm Phase II, multicenter trial. It is designed to determine whether the anticipated endpoints for a T cell depleted transplant arm of a planned prospective randomized trial comparing T cell depleted and unmodified hematopoietic allografts are likely to be achieved in a multicenter study conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN or Network). The study population is patients with acute myeloid leukemia (AML) in first or second morphologic complete remission. The enrollment is 45 patients.

Based on published results of unmodified transplants from HLA-matched siblings applied to patients with AML in first or second morphologic complete remission, a significant improvement in results with a graft modified as specified in this protocol would be expected if disease-free survival (DFS) at 6 months was greater than 75%, the true incidence of transplant-related mortality at 1 year was less than 30%, and the DFS rate at 2 years was greater 70% for patients transplanted in first remission and less than 60% for patients transplanted in second remission. Additional secondary endpoints include the following: graft failure rate and incidences of acute grade II-IV and chronic graft-versus-host disease (GVHD). Additionally, the trial will have target specific doses of CD34+ progenitors and CD3+ T cells to be obtained following fractionation with the CliniMACS system. Based on the results of this trial, a Phase III trial comparing T cell depleted peripheral blood stem cell transplants (PBSCT) with unmanipulated bone marrow or unmanipulated PBSCT will be designed.

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Myelocytic, Acute	Biological: CD34+ selection with CliniMACS device	Phase 2

Detailed Description

BACKGROUND:

Allogeneic hematopoietic cell transplantation is an accepted therapy for AML. Transplants of unmodified HLA-matched related bone marrow or peripheral blood stem cells following conditioning with total body irradiation (TBI) and cyclophosphamide or VP-16 or busulfan and cyclophosphamide have led to sustained DFS rates of 45-60% for adults transplanted in first complete remission (CR1) and 40-53% for patients transplanted in second complete remission (CR2). In several single center and multicenter cooperative group prospective trials comparing HLA-matched allogeneic transplants to chemotherapy in the treatment of AML in CR1, DFS rates for the transplant arm were almost invariably superior; however, these advantages were statistically significant in only a minority of the cooperative group studies conducted. In each study, the risk of relapse was significantly lower for patients receiving allogeneic transplants. However, this advantage was counterbalanced by transplant-related mortality, principally reflecting infections complicating GVHD and its treatment.

DESIGN NARRATIVE:

Despite increased risks of infection, development of effective T cell depletion (TCD) techniques for prevention of GVHD and tolerable modifications of regimens for pre-transplant cytoreduction that secure consistent engraftment offer the potential for significant decreases in transplant-related mortality. Furthermore, the use of TCD transplants in the treatment of patients with AML is not associated with substantial increases in the incidence of relapse. Several single center trials indicate highly encouraging long-term results, particularly for patients with AML in CR1 or CR2. Although the number of cases in each single center series is limited, the consistency of the results suggests that the use of an effective technique for TCD together with an adequate cytoreductive regimen might yield transplant results superior to those achieved with unmodified grafts.

Study Design

• Study Type: Interventional
• Actual Enrollment: 47 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Single Arm Trial of HLA-Matched Transplants, CD34+ Enriched, T-Cell Depleted Peripheral Blood Stem Cells Isolated by CliniMACS System in the Treatment of Patients With AML in 1st or 2nd Morphologic Complete Remission (BMTCTN0303)
• Study Start Date: Jun 1, 2005
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CD34+ selection with CliniMACS device T cell depletion using Miltenyi device	Biological: CD34+ selection with CliniMACS device; CD34+ cell selection will be performed according to procedures given in the CliniMACS Users Operating Manual and institutional Standard Operating Procedures (SOPs) in place and validated at the study sites. CliniMACS (Miltenyi device) to target CD34+ >5 x 10*6/kg and CD3+ < 1 x 10*5/kg; Other Names: T Cell Depletion

Outcome Measures

Primary Outcome Measures

1. Probability of Disease-free Survival (DFS) at 6 Months Post-transplant (Death or Relapse Will be Considered Events for This Endpoint) [6 months]

   The primary analysis will consist of estimating the 6-month DFS (from day of enrollment) probability based on the Kaplan-Meier product limit estimator. The 6-month DFS probability and confidence interval will be calculated. All registered patients will be considered for this analysis.

Secondary Outcome Measures

1. Leukemia Relapse [Months 12 and 36]

   To assess the incidence of acute leukemia relapse from day of transplant, a cumulative incidence curve will be computed along with a 95% confidence interval. Death prior to relapse will be considered as a competing risk.

2. Neutrophil Engraftment [28 day]

   Time to neutrophil engraftment is measured by determining the first of three consecutive measurements of absolute neutrophil count ≥ 500/uL following conditioning regimen induced nadir, starting from Day 0.

3. Platelet Engraftment [6 Months]

   Time to platelet engraftment is measured by determining the first of three consecutive measurements of platelet count ≥ 20,000/uL without platelet transfusion support for seven days, starting from Day 0.

4. Graft Failure [Day 100]

   Primary graft failure is defined as the failure to achieve an ANC > 500 cells/µL by Day +30. Secondary graft failure is defined as initial neutrophil engraftment followed by subsequent decline in neutrophil counts < 500 cells/µL, unresponsive to growth factor therapy.

5. Acute Graft Versus Host Disease (GVHD) [Day 100]

   Incidence and severity of acute GVHD will be graded according to the BMT CTN MOP.

6. Chronic Graft Versus Host Disease (GVHD) [Year 2]

   Incidence and severity of chronic GVHD will be scored according to the BMT CTN MOP.

7. Transplant Related Mortality [Months 12, 24, and 36]

   Death occurring in a patient in continuing complete remission.

8. Determination of Infusional Toxicity [28 day]

9. Disease-free Survival (DFS) [Months 6, 12, and 36]

   DFS is defined as the minimum time interval of times to relapse/recurrence, to death or to the last follow-up, from the time of transplant.

10. Overall Survival [Months 12 and 36]

    Overall survival is defined as time from transplant to death or last follow-up.

11. CD34+ and CD3+ Cell Doses [Day 0]

    Total CD34+ and CD3+ cell doses will be calculated based on results of flow cytometric analysis.

12. Post-transplant Lymphoproliferative Disorder (PTLD) [Year 2]

    PTLD is defined as increased Epstein Barr Virus viremia requiring clinical intervention.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with AML with or without prior history of myelodysplastic syndrome based on the World Health Organization criteria at the following stages:

• First morphologic complete remission (CR)

• Second morphologic CR

• If prior history of central nervous system (CNS) involvement, no evidence of active CNS leukemia during the pre-transplant evaluation (no evidence of leukemic blasts in cerebrospinal fluid)

• First or second CR was achieved after no more than two cycles of induction (or re-induction for patients in second CR) chemotherapy

• No more than 6 months elapsed from documentation of CR to transplant for patients in first CR, or 3 months for patients in second CR.

• A 6/6 HLA antigen (A, B, DRB1)-compatible sibling donor; the match may be determined at serologic level for HLA-A and HLA-B loci; DRB1 must be matched at least at low-resolution using DNA typing techniques; HLA-C will be typed at the serologic level, but not included in the match algorithm

• Karnofsky performance status greater than 70%

• Life expectancy greater than 8 weeks

• Diffusing capacity of the lung for carbon monoxide (DLCO) of at least 40% (corrected for hemoglobin) with no symptomatic pulmonary disease

• Left ventricular ejection fraction (LVEF) by Multi Gated Acquisition Scan (MUGA) or echocardiogram greater than 40%

• Serum creatinine greater than 2 mg/dL, bilirubin greater than 2 mg/dL, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at least 3 times the upper limit of normal at time of enrollment

• Willingness of both the patient and the donor to participate

Exclusion Criteria:

• M3-AML (acute promyelocytic leukemia) in first CR

• Acute leukemia following blast transformation of prior chronic myelogenous leukemia (CML) or other myeloproliferative disease

• M4Eo-AML with inv 16 in first CR

• AML with t(8;21) in first CR

• Participation in other clinical trials that involve investigational drugs or devices except with permission from the Medical Monitor

• Evidence of active Hepatitis B or C infection or evidence of cirrhosis

• HIV positive

• Uncontrolled diabetes mellitus

• If proven or probable invasive fungal infection, infection must be controlled; patients may be on prophylactic anti-fungal agents, but are not permitted to be on anti-fungal agents for therapeutic purposes (i.e., active treatment for disease)

• Uncontrolled viral or bacterial infection (currently taking medication without clinical improvement)

• Documented allergy to iron dextran or murine proteins

• Pregnant or breastfeeding; women of childbearing age must avoid becoming pregnant while in the study

• Prior autologous or allogeneic hematopoietic stem cell transplantation (HSCT)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope National Medical Center	Duarte	California	United States	91010
2	University of California, San Francisco	San Francisco	California	United States	94143
3	Dana Farber Cancer Institute/Brigham & Women's Hospital	Boston	Massachusetts	United States	02114
4	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10021
5	University Hospitals of Cleveland/Case Western	Cleveland	Ohio	United States	44106
6	Ohio State/Arthur G. James Cancer Hospital	Columbus	Ohio	United States	43210
7	University of Pennsylvania Cancer Center	Philadelphia	Pennsylvania	United States	19104
8	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53211

Sponsors and Collaborators

• National Heart, Lung, and Blood Institute (NHLBI)
• Blood and Marrow Transplant Clinical Trials Network
• National Cancer Institute (NCI)

Investigators

• Study Chair: Steven Devine, MD, Ohio State/Arthur G. James Cancer Hospital
• Principal Investigator: Parameswaran Hari, MD, Medical College of Wisconsin
• Principal Investigator: Hillard Lazarus, MD, University Hospitals of Cleveland/Case Western
• Principal Investigator: Lloyd Damon, MD, University of California, San Francisco
• Study Chair: Richard O'Reilly, MD, Memorial Sloan Kettering Cancer Center
• Principal Investigator: Robert Soiffer, MD, Dana Farber Cancer Institute/Brigham & Women's Hospital
• Principal Investigator: Anthony Stein, MD, City of Hope National Medical Center
• Principal Investigator: John DiPersio, MD, PhD, Washington University/Barnes Jewish Hospital
• Principal Investigator: Edward Stadtmauer, MD, University of Pennsylvania

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Nov 13, 2006

More Information

Additional Information:

• Blood and Marrow Transplant Clinical Trials Network Website

Publications

None provided.

• Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
• ClinicalTrials.gov Identifier: NCT00201240
• Other Study ID Numbers: BMTCTN0303; U01HL069254; U01HL069249; U01HL069278; U01HL069294; U01HL069315; U01HL069348; 284
• First Posted: Sep 20, 2005
• Last Update Posted: Nov 1, 2021
• Last Verified: Aug 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute

Study Results

Participant Flow

Recruitment Details	Patients were recruited from October2005 through December 2008

Arm/Group Title	T Cell Depletion
Arm/Group Description	T cell depletion using Miltenyi device for patients with acute myeloid leukemia (AML) in first or second complete remission
Period Title: Overall Study
STARTED	47
COMPLETED	44
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	T Cell Depletion
Arm/Group Description	T cell depletion using Miltenyi device for patients with AML in first or second complete remission
Overall Participants	44
Age, Customized (participants) [Number]
<20	0 0%
20-29	7 15.9%
30-39	4 9.1%
40-49	14 31.8%
50-59	19 43.2%
Sex: Female, Male (Count of Participants)
Female	28 63.6%
Male	16 36.4%
Race/Ethnicity, Customized (participants) [Number]
White	42 95.5%
Other	2 4.5%
Region of Enrollment (participants) [Number]
United States	44 100%
Karnofsky Performance Status (participants) [Number]
100%	17 38.6%
90%	17 38.6%
80%	8 18.2%
70%	2 4.5%
Leukemia stage (participants) [Number]
CR1	37 84.1%
CR2	7 15.9%
Cytogenetic risk (participants) [Number]
Favorable	1 2.3%
Intermediate	28 63.6%
Unfavorable	14 31.8%
Unknown	1 2.3%
Recipient CMV Status (participants) [Number]
Positive	17 38.6%
Negative	27 61.4%

Outcome Measures

1. Primary Outcome

Title	Probability of Disease-free Survival (DFS) at 6 Months Post-transplant (Death or Relapse Will be Considered Events for This Endpoint)
Description	The primary analysis will consist of estimating the 6-month DFS (from day of enrollment) probability based on the Kaplan-Meier product limit estimator. The 6-month DFS probability and confidence interval will be calculated. All registered patients will be considered for this analysis.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

All transplanted patients

Arm/Group Title	T Cell Depletion
Arm/Group Description	T cell depletion using Miltenyi device for patients with AML in first or second complete remission
Measure Participants	44
Number (95% Confidence Interval) [percentage of patients]	81.8

2. Secondary Outcome

Title	Leukemia Relapse
Description	To assess the incidence of acute leukemia relapse from day of transplant, a cumulative incidence curve will be computed along with a 95% confidence interval. Death prior to relapse will be considered as a competing risk.
Time Frame	Months 12 and 36

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Depletion
Arm/Group Description	T cell depletion using Miltenyi device for patients with AML in first or second complete remission
Measure Participants	44
12 months	20.6 46.8%
36 months	23.7 53.9%

3. Secondary Outcome

Title	Neutrophil Engraftment
Description	Time to neutrophil engraftment is measured by determining the first of three consecutive measurements of absolute neutrophil count ≥ 500/uL following conditioning regimen induced nadir, starting from Day 0.
Time Frame	28 day

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Depletion
Arm/Group Description	T cell depletion using Miltenyi device for patients with AML in first or second complete remission
Measure Participants	44
Median (Full Range) [days]	12

4. Secondary Outcome

Title	Platelet Engraftment
Description	Time to platelet engraftment is measured by determining the first of three consecutive measurements of platelet count ≥ 20,000/uL without platelet transfusion support for seven days, starting from Day 0.
Time Frame	6 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Depletion
Arm/Group Description	T cell depletion using Miltenyi device for patients with AML in first or second complete remission
Measure Participants	44
Median (Full Range) [days]	16

5. Secondary Outcome

Title	Graft Failure
Description	Primary graft failure is defined as the failure to achieve an ANC > 500 cells/µL by Day +30. Secondary graft failure is defined as initial neutrophil engraftment followed by subsequent decline in neutrophil counts < 500 cells/µL, unresponsive to growth factor therapy.
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Depletion
Arm/Group Description	T cell depletion using Miltenyi device for patients with AML in first or second complete remission
Measure Participants	44
Primary Graft Failure	0 0%
Secondary Graft Failure	1 2.3%

6. Secondary Outcome

Title	Acute Graft Versus Host Disease (GVHD)
Description	Incidence and severity of acute GVHD will be graded according to the BMT CTN MOP.
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Depletion
Arm/Group Description	T cell depletion using Miltenyi device for patients with AML in first or second complete remission
Measure Participants	44
Grades II - IV	22.7 51.6%
Grades III - IV	4.5 10.2%

7. Secondary Outcome

Title	Chronic Graft Versus Host Disease (GVHD)
Description	Incidence and severity of chronic GVHD will be scored according to the BMT CTN MOP.
Time Frame	Year 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Depletion
Arm/Group Description	T cell depletion using Miltenyi device for patients with AML in first or second complete remission
Measure Participants	44
Limited/extensive	19.0 43.2%
Extensive only	6.8 15.5%

8. Secondary Outcome

Title	Transplant Related Mortality
Description	Death occurring in a patient in continuing complete remission.
Time Frame	Months 12, 24, and 36

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Depletion
Arm/Group Description	T cell depletion using Miltenyi device for patients with AML in first or second complete remission
Measure Participants	44
12 months	14 31.8%
24 months	20 45.5%
36 months	23.2 52.7%

9. Secondary Outcome

Title	Determination of Infusional Toxicity
Time Frame	28 day

Outcome Measure Data

Analysis Population Description

No data collected

Arm/Group Title	T Cell Depletion
Arm/Group Description	T cell depletion using Miltenyi device for patients with AML in first or second complete remission
Measure Participants	0

10. Secondary Outcome

Title	Disease-free Survival (DFS)
Description	DFS is defined as the minimum time interval of times to relapse/recurrence, to death or to the last follow-up, from the time of transplant.
Time Frame	Months 6, 12, and 36

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Depletion
Arm/Group Description	T cell depletion using Miltenyi device for patients with AML in first or second complete remission
Measure Participants	44
6 months	81.8 185.9%
12 months	66 150%
36 months	53 120.5%

11. Secondary Outcome

Title	Overall Survival
Description	Overall survival is defined as time from transplant to death or last follow-up.
Time Frame	Months 12 and 36

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Depletion
Arm/Group Description	T cell depletion using Miltenyi device for patients with AML in first or second complete remission
Measure Participants	44
12 months	77 175%
36 months	56 127.3%

12. Secondary Outcome

Title	CD34+ and CD3+ Cell Doses
Description	Total CD34+ and CD3+ cell doses will be calculated based on results of flow cytometric analysis.
Time Frame	Day 0

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Depletion
Arm/Group Description	T cell depletion using Miltenyi device for patients with acute myeloid leukemia (AML) in first or second complete remission
Measure Participants	44
CD34+ (x10^6)	7.9
CD3+ (x10^3)	6.6

13. Secondary Outcome

Title	Post-transplant Lymphoproliferative Disorder (PTLD)
Description	PTLD is defined as increased Epstein Barr Virus viremia requiring clinical intervention.
Time Frame	Year 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Depletion
Arm/Group Description	T cell depletion using Miltenyi device for patients with AML in first or second complete remission
Measure Participants	44
Number [participants]	8 18.2%

Adverse Events

Arm/Group Title	T Cell Depletion
Arm/Group Description	T cell depletion using Miltenyi device for patients with AML in first or second complete remission
All Cause Mortality
	T Cell Depletion
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	T Cell Depletion
	Affected / at Risk (%)	# Events
Total	0/47 (0%)
Other (Not Including Serious) Adverse Events
	T Cell Depletion
	Affected / at Risk (%)	# Events
Total	0/47 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.