Bone Marrow Transplant From Partially Matched Donors and Nonmyeloablative Conditioning for Blood Cancers (BMT CTN 0603)

• Sponsor: Medical College of Wisconsin (Other)
• Overall Status: Completed
• CT.gov ID: NCT00849147
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), Blood and Marrow Transplant Clinical Trials Network (Other), National Cancer Institute (NCI) (NIH), National Marrow Donor Program (Other)
• Enrollment: 55
• Locations: 17
• Arm: 1
• Duration (Months): 61
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Bone marrow transplants are one treatment option for people with leukemia or lymphoma. Family members or unrelated donors with a similar type of bone marrow usually donate their bone marrow to the transplant patients. This study will evaluate the effectiveness of a new type of bone marrow transplant-one that uses lower doses of chemotherapy and bone marrow donated from family members with only partially matched bone marrow-in people with leukemia or lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Burkitt Lymphoma; Lymphoma, B-Cell; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse	Biological: Haploidentical Bone Marrow Transplantation; Biological: GVHD prophylaxis	Phase 2

Detailed Description

Leukemia and lymphoma are types of blood cancers. Chemotherapy is a common treatment option for people with these types of cancers, but if the cancer does not respond well to chemotherapy, or if the cancer returns, a bone marrow transplant is another treatment option. In a bone marrow transplant procedure, healthy bone marrow is taken from a donor and transplanted into the patient. Bone marrow can be donated by a family member or an unrelated donor who has a similar type of bone marrow. Most bone marrow transplants are performed using a donor who is a perfect or close-to-perfect tissue match. However, for participants in this study, researchers have determined that a completely matched donor is unavailable within participants' families, and an unrelated donor match has not been found either. Participants do, however, have a family member who is a partial tissue match. Typically, people who are undergoing a bone marrow transplant receive high doses of chemotherapy before the transplant to prepare their bodies to accept the donor bone marrow. In this study, participants will undergo a new type of bone marrow transplant called a nonmyeloablative transplant, which is a reduced intensity method of transplantation that does not require high doses of chemotherapy. The purpose of the study is to examine the safety and effectiveness of a nonmyeloablative bone marrow transplant that uses partially matched bone marrow donated by a family member as a treatment option for people with leukemia or lymphoma.

This study will enroll people with leukemia or lymphoma who have a family member with a partial tissue match. Participants will be admitted to the hospital and will first receive a type of chemotherapy called fludarabine, which will be given intravenously for 5 days. In addition, another type of chemotherapy, cyclophosphamide, will be given intravenously on the first and second day. After 5 days, participants will receive a small dose of radiation. The next day, participants will undergo the bone marrow transplant. The third and fourth day after the transplant, participants will receive high doses of cyclophosphamide to help prevent two complications, graft rejection, which occurs when the body's immune system rejects the donor bone marrow, and graft-versus-host disease (GVHD), which is an attack by the donor cells on the body's normal tissues. On the fifth day after the transplant, participants will receive two additional medications, tacrolimus and mycophenolate mofetil (MMF), to help prevent GVHD; some participants may receive cyclosporine instead of tacrolimus. Participants will receive MMF for about 5 weeks and tacrolimus for about 6 months. Also beginning on the fifth day after the transplant, participants will receive daily injections of a growth factor called granulocyte-colony stimulating factor (G-CSF), which is a natural protein that increases the white blood cell count; G-CSF will be continued until a participant's white blood cell count is normal again.

Participants will remain in the hospital for approximately 2 to 3 months, but possibly longer if there are complications. While participants are in the hospital, blood samples will be collected regularly to evaluate the response and possible side effects to treatment, including GVHD. If necessary, participants will receive platelet and red blood cell transfusions. Follow-up study visits will occur 6 months and 1 year after the transplant. At Months 1, 2, 6, and 12 after the transplant, blood or bone marrow samples will be obtained. Study researchers will keep track of participants' medical condition through phone calls or mailings to participants and their doctors once a year for the rest of the participants' lives.

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-Center, Phase II Trial of Nonmyeloablative Conditioning (NST) and Transplantation of Partially HLA-Mismatched Bone Marrow From Related Donors for Patients With Hematologic Malignancies (BMT CTN #0603)
• Study Start Date: Oct 1, 2008
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Nov 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Haploidentical Bone Marrow Transplant Participants will receive a human leucocyte antigen (HLA) haploidentical bone marrow transplantation using a non-myeloablative preparative regimen, GVHD prophylaxis.

Biological: Haploidentical Bone Marrow Transplantation; The transplant preparative regimen is listed below. The - sign is the number of days before the transplant. Fludarabine: 30 mg/m2 intravenously (IV) on Days -6, -5, -4, -3, and -2 Cyclophosphamide (Cy): 14.5 mg/kg IV on Days -6 and -5 Total body irradiation (TBI): 200 centigray (cGy) on Day -1 Day 0 is the day of the infusion of non-T-cell depleted bone marrow. The bone marrow will be obtained from haploidentical related donor.; Biological: GVHD prophylaxis; The GVHD prophylaxis regimen will consist of the following: Cy: 50 mg/kg IV on Days 3 and 4 Tacrolimus: (IV or orally) beginning on Day 5 with dose adjusted to maintain a level of 5 to 15 mg/mL Mycophenolate mofetil (MMF): 15 mg/kg orally three times a day (TID) beginning on Day 5; maximum dose will be 1 g orally TID Granulocyte-colony stimulating factor (G-CSF) 5 mcg/kg/day beginning on Day 5 until absolute neutrophil count (ANC) is greater than or equal to 1,000/mm^3 for 3 consecutive days

Outcome Measures

Primary Outcome Measures

1. Overall Survival at 180 Days From the Time of Transplant [Measured at Month 6 and Year 1]

Secondary Outcome Measures

1. Neutrophil Recovery [Measured at Days 28, 56, 90, and 100]

   Cumulative incidence of neutrophil recovery >500/μL at day +56

2. Primary Graft Failure [Measured at Day 67]

   Primary graft failure is defined as < 5% donor chimerism on all measurements.

3. Secondary Graft Failure [Measured at Day 100]

   Secondary graft failure is defined as initial recovery followed by neutropenia with < 5% donor chimerism. If no chimerism assays were performed and absolute neutrophil count is < 500/mm3, then it will be counted as a secondary graft failure.

4. Platelet Recovery [Measured at Days 56, 90, and 100]

   Platelet Recovery to 20K

5. Platelet Recovery [Measured at Days 56, 90, and 100]

   Platelet Recovery to 50K

6. Donor Cell Engraftment [Measured at Day 56]

   Marrow or Blood Sample. Donor cell engraftment is defined as donor chimerism ≥ 5% on Day ≥ 56 after transplantation. Chimerism should be evaluated on Days ~28, ~56, ~180, and ~365 after transplantation. Chimerism may be evaluated in whole blood or mononuclear fraction.

7. Acute Graft-versus-host Disease (GVHD) [Measured at Day 100]

8. Chronic GVHD [Measured at Year 1]

9. Progression-free Survival [Measured at Year 1]

   Progression-free survival is defined as the minimum time interval of the times to relapse/recurrence, to death or to last follow-up.

10. Treatment-related Mortality (TRM) [Measured at 6 months and 1 year]

11. Infections [Measured at Year 1]

    Number of infections; infections will be reported by anatomic site, date of onset, organism and resolution, if any. Patients will be followed for infection for 1 year post-transplant.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participants must be 21 to 70 years old; participants 1 to 21 years old are also eligible if they are ineligible for BMT CTN #0501 (NCT00412360)

• Donor must be at least 18 years of age

• Human leucocyte antigen (HLA) typing will be performed at high resolution (allele level) for the HLA-A, -B, Cw, DRB1, and -DQB1 loci. A minimum match of 5/10 is required. An unrelated donor search is not required for a person to be eligible for this study if the clinical situation dictates an urgent transplant. Clinical urgency is defined as 6 to 8 weeks from referral to transplant center or low likelihood of finding a matched, unrelated donor. The donor and recipient must be identical, as determined by high resolution typing, on at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. Fulfillment of this criterion shall be considered sufficient evidence that the donor and recipient share one HLA haplotype, and typing of additional family members is not required.

• Must have received cytotoxic chemotherapy within 3 months of the consent date (measured from the start date of chemotherapy)

• Acute leukemias (includes T lymphoblastic lymphoma) in the second or subsequent complete remission (CR)

• Burkitt's lymphoma in the second or subsequent CR

• Lymphoma

• Patients with adequate physical function as measured by the following:

1. Heart: left ventricular ejection fraction at rest must be greater than or equal to 35%, or shortening fraction greater than 25%

2. Liver: bilirubin less than or equal to 2.5 mg/dL and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase less than five times the upper limit of normal

3. Kidney: serum creatinine within normal range for age, or if serum creatinine is outside the normal range for age, then kidney function (creatinine clearance or glomerular filtration rate (GFR) is greater than 40 mL/min/1.73m^2

4. Pulmonary: forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) greater than 50% predicted (corrected for hemoglobin). If unable to perform pulmonary function tests, then oxygen (O2) saturation must be greater than 92% on room air.

5. Performance status: Karnofsky/Lansky score greater than or equal to 60%

Exclusion Criteria:

• Have an HLA-matched, related, or 7 or 8/8 allele matched (HLA-A, -B, -Cw, -DRB1) related donor able to donate

• Had an autologous hematopoietic stem cell transplant in the 3 months before study entry

• Pregnant or breastfeeding

• Evidence of HIV infection or known HIV positive serology

• Current uncontrolled bacterial, viral, or fungal infection (i.e., currently taking medication with evidence of progression of clinical symptoms or radiologic findings)

• Prior allogeneic hematopoietic stem cell transplant

• History of primary idiopathic myelofibrosis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope National Medical Center	Duarte	California	United States	91010-3000
2	University of California San Diego Medical Center	La Jolla	California	United States	92093
3	University of Florida College of Medicine (Shands)	Gainesville	Florida	United States	32610-0277
4	Bone Marrow Transplant Group of Georgia, Northside Hospital	Atlanta	Georgia	United States	30342
5	Kapi'olani Medical Center for Women and Children, University of Hawaii	Honolulu	Hawaii	United States	96826
6	University of Maryland, Greenbaum Cancer Center	Baltimore	Maryland	United States	21201
7	Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center (SKCCC)	Baltimore	Maryland	United States	21231
8	DFCI, Massachusetts General Hospital	Boston	Massachusetts	United States	02114
9	Karmanos Cancer Institute, Children's Hospital of Michigan	Detroit	Michigan	United States	48201
10	Washington University, Barnes Jewish Hospital	Saint Louis	Missouri	United States	63110
11	Oregon Health & Science University	Portland	Oregon	United States	97239-3098
12	Fox Chase, Temple University	Philadelphia	Pennsylvania	United States	19111-2442
13	Medical University of South Carolina	Charleston	South Carolina	United States	29425
14	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232-8210
15	Baylor University Medical Center	Dallas	Texas	United States	75246
16	Texas Transplant Institute	San Antonio	Texas	United States	78229
17	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109-1024

Sponsors and Collaborators

• Medical College of Wisconsin
• National Heart, Lung, and Blood Institute (NHLBI)
• Blood and Marrow Transplant Clinical Trials Network
• National Cancer Institute (NCI)
• National Marrow Donor Program

Investigators

• Study Director: Mary Horowitz, MD, MS, Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here for the Blood and Marrow Transplant (BMT) Clinical Trials Network (CTN) Web site
• National Marrow Donor Program

Publications

None provided.

• Responsible Party: Medical College of Wisconsin
• ClinicalTrials.gov Identifier: NCT00849147
• Other Study ID Numbers: BMTCTN0603; U01HL069294; 5U24CA076518
• First Posted: Feb 23, 2009
• Last Update Posted: Dec 22, 2017
• Last Verified: Aug 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Medical College of Wisconsin: Acute Lymphoblastic Leukemia/Lymphoma; Acute Myelogenous Leukemia; Mantel-Cell Lymphoma; Hematopoietic Transplant; Haplo-Identical Transplant; Non-Myeloablative Transplant
• Additional relevant MeSH terms: Burkitt Lymphoma; Lymphoma; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma

Study Results

Participant Flow

Arm/Group Title	Haplo-marrow Transplantation
Arm/Group Description	Haploidentical bone marrow transplantation using a non-myeloablative preparative regimen.
Period Title: Overall Study
STARTED	55
COMPLETED	50
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Haplo-marrow Transplantation
Arm/Group Description	Haploidentical bone marrow transplantation using a non-myeloablative preparative regimen.
Overall Participants	50
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.4 (18.1)
Sex: Female, Male (Count of Participants)
Female	18 36%
Male	32 64%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 10%
Not Hispanic or Latino	38 76%
Unknown or Not Reported	7 14%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 4%
Native Hawaiian or Other Pacific Islander	1 2%
Black or African American	6 12%
White	40 80%
More than one race	0 0%
Unknown or Not Reported	1 2%
Karnofsky Performance-status score (participants) [Number]
100%	19 38%
90%	19 38%
80%	9 18%
70%	3 6%
Primary Disease (participants) [Number]
Acute Lymphoblastic Leukemia	6 12%
Acute Myelogeneous Leukemia	22 44%
Biphenotypic/Undifferentiated Leukemia	3 6%
Hodgkins Lymphoma	7 14%
Large Cell Lymphoma	8 16%
Marginal Zone B-cell Lymphoma	1 2%
Mantle Cell Lymphoma	3 6%
Human leucocyte antigen (HLA) Typing Match Score - GVH direction (participants) [Number]
5/10	28 56%
6/10	12 24%
7/10	9 18%
8/10	1 2%
HLA Typing Match Score - Host vs Graft (HVG) direction (participants) [Number]
5/10	22 44%
6/10	22 44%
7/10	3 6%
8/10	1 2%
9/10	1 2%
10/10	1 2%
Weight (kilograms) [Median (Full Range) ]
Median (Full Range) [kilograms]	78

Outcome Measures

1. Primary Outcome

Title	Overall Survival at 180 Days From the Time of Transplant
Time Frame	Measured at Month 6 and Year 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Haplo-marrow Transplantation
Arm/Group Description	Haploidentical bone marrow transplantation using a non-myeloablative preparative regimen.
Measure Participants	50
6 months	83.7 167.4%
1 year	62.0 124%

2. Secondary Outcome

Title	Neutrophil Recovery
Description	Cumulative incidence of neutrophil recovery >500/μL at day +56
Time Frame	Measured at Days 28, 56, 90, and 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Haplo-marrow Transplantation
Arm/Group Description	Haploidentical bone marrow transplantation using a non-myeloablative preparative regimen.
Measure Participants	50
Day 28	96.0 192%
Day 56	96.0 192%
Day 90	100.0 200%
Day 100	100.0 200%

3. Secondary Outcome

Title	Primary Graft Failure
Description	Primary graft failure is defined as < 5% donor chimerism on all measurements.
Time Frame	Measured at Day 67

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Haplo-marrow Transplantation
Arm/Group Description	Haploidentical bone marrow transplantation using a non-myeloablative preparative regimen.
Measure Participants	50
Number [participants]	1 2%

4. Secondary Outcome

Title	Secondary Graft Failure
Description	Secondary graft failure is defined as initial recovery followed by neutropenia with < 5% donor chimerism. If no chimerism assays were performed and absolute neutrophil count is < 500/mm3, then it will be counted as a secondary graft failure.
Time Frame	Measured at Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Haplo-marrow Transplantation
Arm/Group Description	Haploidentical bone marrow transplantation using a non-myeloablative preparative regimen.
Measure Participants	50
Number [participants]	0 0%

5. Secondary Outcome

Title	Platelet Recovery
Description	Platelet Recovery to 20K
Time Frame	Measured at Days 56, 90, and 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Haplo-marrow Transplantation
Arm/Group Description	Haploidentical bone marrow transplantation using a non-myeloablative preparative regimen.
Measure Participants	50
Day 56	96.0 192%
Day 90	96.0 192%
Day 100	98.0 196%

6. Secondary Outcome

Title	Platelet Recovery
Description	Platelet Recovery to 50K
Time Frame	Measured at Days 56, 90, and 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Haplo-marrow Transplantation
Arm/Group Description	Haploidentical bone marrow transplantation using a non-myeloablative preparative regimen.
Measure Participants	50
Day 56	76.0 152%
Day 90	76.0 152%
Day 100	76.0 152%

7. Secondary Outcome

Title	Donor Cell Engraftment
Description	Marrow or Blood Sample. Donor cell engraftment is defined as donor chimerism ≥ 5% on Day ≥ 56 after transplantation. Chimerism should be evaluated on Days ~28, ~56, ~180, and ~365 after transplantation. Chimerism may be evaluated in whole blood or mononuclear fraction.
Time Frame	Measured at Day 56

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Haplo-marrow Transplantation
Arm/Group Description	Haploidentical bone marrow transplantation using a non-myeloablative preparative regimen.
Measure Participants	50
Chimerism Performed	42 84%
Donor Percentage ≥95%	39 78%
Donor Percentage 5%-95%	2 4%
Donor Percentage <5%	1 2%

8. Secondary Outcome

Title	Acute Graft-versus-host Disease (GVHD)
Time Frame	Measured at Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Haplo-marrow Transplantation
Arm/Group Description	Haploidentical bone marrow transplantation using a non-myeloablative preparative regimen.
Measure Participants	50
Grade II-IV Acute GVHD	32.0 64%
Grade III-IV Acute GVHD	0.0 0%

9. Secondary Outcome

Title	Chronic GVHD
Time Frame	Measured at Year 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Haplo-marrow Transplantation
Arm/Group Description	Haploidentical bone marrow transplantation using a non-myeloablative preparative regimen.
Measure Participants	50
Number (95% Confidence Interval) [percentage of participants]	12.9 25.8%

10. Secondary Outcome

Title	Progression-free Survival
Description	Progression-free survival is defined as the minimum time interval of the times to relapse/recurrence, to death or to last follow-up.
Time Frame	Measured at Year 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Haplo-marrow Transplantation
Arm/Group Description	Haploidentical bone marrow transplantation using a non-myeloablative preparative regimen.
Measure Participants	50
Number (95% Confidence Interval) [percentage of participants]	47.9 95.8%

11. Secondary Outcome

Title	Treatment-related Mortality (TRM)
Time Frame	Measured at 6 months and 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Haplo-marrow Transplantation
Arm/Group Description	Haploidentical bone marrow transplantation using a non-myeloablative preparative regimen.
Measure Participants	50
6 months	4.0 8%
1 year	7.0 14%

12. Secondary Outcome

Title	Infections
Description	Number of infections; infections will be reported by anatomic site, date of onset, organism and resolution, if any. Patients will be followed for infection for 1 year post-transplant.
Time Frame	Measured at Year 1

Outcome Measure Data

Analysis Population Description

36 patients incurred a total number of 108 infection events.

Arm/Group Title	Haplo-marrow Transplantation
Arm/Group Description	Haploidentical bone marrow transplantation using a non-myeloablative preparative regimen.
Measure Participants	50
1 Infection	14 28%
2 Infections	6 12%
3 Infections	10 20%
4 Infections	2 4%
5 Infections	1 2%
6-10 Infections	2 4%
>10 Infections	1 2%

Adverse Events

Time Frame	1-year post-transplant
Adverse Event Reporting Description	Serious adverse events are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event.
Arm/Group Title	Haplo-marrow Transplantation
Arm/Group Description	Haploidentical bone marrow transplantation using a non-myeloablative preparative regimen.
All Cause Mortality
	Haplo-marrow Transplantation
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Haplo-marrow Transplantation
	Affected / at Risk (%)	# Events
Total	5/52 (9.6%)
Cardiac disorders
Atrial fibrillation	1/52 (1.9%)	1
Cardiac failure congestive	1/52 (1.9%)	1
Infections and infestations
Pseudomonas infection	1/52 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory distress	1/52 (1.9%)	1
Respiratory failure	1/52 (1.9%)	1
Other (Not Including Serious) Adverse Events
	Haplo-marrow Transplantation
	Affected / at Risk (%)	# Events
Total	1/52 (1.9%)
Nervous system disorders
Headache	1/52 (1.9%)	1

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.