Reduced-intensity, Related-donor Bone Marrow Transplantation Followed by High-dose Cyclophosphamide for Hematologic Cancers

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01135329
• Collaborator: (none)
• Enrollment: 15
• Location: 1
• Arm: 1
• Duration (Months): 21
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

This research is being done to learn more about reduced-intensity bone marrow transplantation (BMT), also known as a "mini" transplant for patients with blood cancers, using bone marrow from a relative.

The main goal of the study is to determine how quickly the donor's bone marrow "takes" in your body. Other goals include describing how many people accept the bone marrow and how quickly the blood counts come up; describing Graft-versus-host disease (GVHD) and other complications; and describing how many people survive without progressive cancer and survive overall

Condition or Disease	Intervention/Treatment	Phase
Lymphoma; Leukemia; Myelodysplastic Syndrome	Drug: Fludarabine; Drug: Busulfan; Drug: Cyclophosphamide; Drug: Mycophenolate Mofetil; Drug: Tacrolimus	Phase 2

Detailed Description

At the present time there are few or no cures for people with cancer of the blood or lymph glands outside of a bone marrow transplant (BMT). BMT has developed over several decades of research as an effective treatment of various malignant and nonmalignant hematologic diseases.

This research is being done to learn more about reduced-intensity bone marrow transplantation (BMT), also known as a "mini" transplant for patients with blood cancers, using bone marrow from a relative. The bone marrow for this transplant comes from a relative who is a half-match or "haplo" match to you. Possible donors include parents, siblings, and children.

"Mini" transplants have been given to many people with various cancers but are considered experimental. Over 200 people at Johns Hopkins have received mini transplants with high doses of cyclophosphamide after the transplant. However, the chemotherapy combination and other treatment given before those transplants were different from what is in this study. Although all of the chemotherapy and immune-lowering drugs used in this study are approved by the Food and Drug Administration (FDA), the combination of medications used in this study are not FDA approved and are experimental.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Reduced-intensity, Related-donor Allogeneic BMT With Fludarabine, Busulfan, and High-dose Posttransplantation Cyclophosphamide for Hematologic Malignancies
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: May 1, 2012
• Actual Study Completion Date: May 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Transplant Reduced-intensity transplant with a fludarabine- and busulfan-based preparative regimen. GVHD prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil.

Drug: Fludarabine; 30 mg/m^2 IV daily on Day -6 through Day -2.; Other Names: Fludara Flu ; Drug: Busulfan; 1 mg/kg PO OR 0.8 mg/kg IV four times daily on Day -6 through Day -3.; Other Names: Busulfex Myleran ; Drug: Cyclophosphamide; 50 mg/kg IV daily on Day +3 and Day +4.; Other Names: CTX Cytoxan Cy ; Drug: Mycophenolate Mofetil; 15 mg/kg PO three times daily (max daily dose of 3g) starting on Day +5.; Other Names: MMF CellCept ; Drug: Tacrolimus; Dosed based on drug levels; begin on Day +5 at 1 mg IV daily.; Other Names: FK506 FK-506 Prograf

Outcome Measures

Primary Outcome Measures

1. Chimerism in Unsorted Peripheral Blood [Day 60]

   Percentage of participants achieving full-donor chimerism in unsorted peripheral blood.

2. Chimerism in CD3+ Sorted Peripheral Blood [Day 60]

   Percentage of participants achieving full-donor chimerism in CD3+ sorted peripheral blood

Secondary Outcome Measures

1. Overall Survival [1 year]

   Percentage of participants alive

2. Progression-free Survival [1 year]

   Percentage of participants alive without disease relapse or progression.

3. Incidence of Relapse [1 year]

   Percentage of participants experiencing disease relapse or progression

4. Non-relapse Mortality [1 year]

   Percentage of participants who died due to BMT-related reasons

5. Incidence of Graft-versus-host-disease (GVHD) [1 year]

   Percentage of participants experiencing acute and chronic GVHD. Acute GVHD is graded by Przepiorka criteria. Chronic GVHD is graded by NIH consensus criteria and Seattle criteria.

6. Graft Failure [Day 60]

   Percentage of participants who failed to engraft.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• First-degree related donor who is at minimum HLA haploidentical

• Eligible diagnoses:

1. Low-grade non-Hodgkin's lymphoma or plasma cell neoplasm that has progressed during multiagent therapy, failed at least two prior therapies (excluding single agent rituximab and single agent steroids), or in the case of lymphoma undergone histological conversion:

• Follicular grade 1 or 2 lymphoma

• Follicular lymphoma not otherwise specified

• Marginal zone (or MALT) lymphoma

• Lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia

• Hairy cell leukemia

• Small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL)

• Prolymphocytic leukemia

• Low grade B-cell lymphoma, unspecified

• Multiple myeloma

• Plasma cell leukemia

1. Poor-risk SLL or CLL, defined by an 11q or 17p deletion, histological conversion, or disease progression < 6 months after a purine analog-containing regimen

2. Aggressive lymphoma that has failed at least one prior regimen of multiagent chemotherapy, and patient is either ineligible for autologous BMT or autologous

BMT is not recommended:

• Hodgkin lymphoma

• Follicular grade 3 lymphoma

• Mantle cell lymphoma or leukemia

• Diffuse large B-cell lymphoma (excluding primary CNS lymphoma). Eligible subtypes include primary mediastinal large B-cell lymphoma, T-cell rich large B-cell lymphoma, and large B-cell lymphoma not otherwise specified.

• Burkitt's lymphoma/leukemia

• Atypical Burkitt's lymphoma/leukemia (high grade B-cell lymphoma, unclassified, including that with features intermediate between Burkitt's and diffuse large B-cell lymphoma)

• Anaplastic large cell lymphoma

• Plasmablastic lymphoma

• Peripheral T-cell lymphoma

1. Relapsed or refractory acute leukemia in second or subsequent remission

2. Poor-risk acute leukemia in first remission

3. AML with at least one of the following:

• AML arising from MDS or a myeloproliferative disorder, or secondary AML

• Presence of Flt3 internal tandem duplications

• Poor-risk cytogenetics

• Primary refractory disease

• ALL (leukemia and/or lymphoma) with at least one of the following:

• Adverse cytogenetics

• Clear evidence of hypodiploidy

• Primary refractory disease

• Biphenotypic leukemia

• MDS with at least one of the following features:

• Poor-risk cytogenetics

• IPSS score of INT-2 or greater

• Treatment-related MDS

• MDS diagnosed before age 21 years

• Progression on or lack of response to standard DNA-methyltransferase inhibitor therapy

• Life-threatening cytopenias, including those generally requiring greater than weekly transfusions

1. Interferon- or imatinib-refractory CML in first chronic phase, or non-blast crisis CML beyond first chronic phase

2. Philadelphia chromosome negative myeloproliferative disease (including myelofibrosis)

3. Chronic myelomonocytic leukemia

4. Juvenile myelomonocytic leukemia

• For patients with SLL, CLL, or prolymphocytic leukemia, < 20% of bone marrow cellularity involved by this process

• Adequate end-organ function:

• Left ventricular ejection fraction greater than or equal to 35%

• Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST < 5 x ULN

• FEV1 and FVC > 40% of predicted; or in pediatric patients, if unable to perform pulmonary function tests due to young age, oxygen saturation >92% on room air

• ECOG performance status < 2 or Karnofsky or Lansky score > 60

Exclusion Criteria:

• Pregnant or breast-feeding

• Uncontrolled infection Note: Infection is permitted if there is evidence of response to medication. Eligibility of HIV infected patients will be determined on a case-by-case basis.

• Any previous BMT within 3 months prior to start of conditioning

• Active extra-medullary leukemia or known active Central Nervous System (CNS) involvement by malignancy. Such disease treated into remission is permitted.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Sydney Kimmel Comprehensive Cancer Center	Baltimore	Maryland	United States	21231

Sponsors and Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Investigators

• Principal Investigator: Yvette Kasamon, M.D., Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT01135329
• Other Study ID Numbers: J1046; NA_00039363
• First Posted: Jun 2, 2010
• Last Update Posted: Jul 3, 2018
• Last Verified: Jun 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: Lymphoma; Hodgkin's lymphoma; Non hodgkin's lymphoma; Leukemia; Acute myeloid leukemia (AML); Acute lymphoblastic leukemia(ALL); Chronic myeloid leukemia (CML); Chronic Myelomonocytic (CMML); Myelodysplastic syndrome (MDS); High-risk acute leukemia in first remission; Relapsed leukemia in remission; Cyclophosphamide; High-dose cyclophosphamide; Fludarabine; Busulfan; Allogeneic; Nonmyeloablative; Reduced intensity; Haploidentical; Bone marrow transplant (BMT)
• Additional relevant MeSH terms: Lymphoma; Leukemia; Preleukemia; Myelodysplastic Syndromes; Mycophenolic Acid; Cyclophosphamide; Busulfan; Fludarabine; Tacrolimus

Study Results

Participant Flow

Arm/Group Title	BMT Allogenic Transplantation
Arm/Group Description	Fludarabine, Busulfan, Cyclophosphamide, Tacrolimus,: Fludarabine 30 mg/m2 IV once a day for 4 days Busulfan 0.8 mg/kg IV every 12 hours for 4 days Cyclophosphamide 50 mg/kg IV daily for 2 days
Period Title: Overall Study
STARTED	15
COMPLETED	15
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	BMT Allogenic Transplantation
Arm/Group Description	Fludarabine, Busulfan, Cyclophosphamide, Tacrolimus,: Fludarabine 30 mg/m2 IV once a day for 4 days Busulfan 0.8 mg/kg IV every 12 hours for 4 days Cyclophosphamide 50 mg/kg IV daily for 2 days
Overall Participants	15
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	49
Age (Count of Participants)
<=18 years	1 6.7%
Between 18 and 65 years	12 80%
>=65 years	2 13.3%
Sex/Gender, Customized (participants) [Number]
Female	6 40%
Male	9 60%
Region of Enrollment (participants) [Number]
United States	15 100%

Outcome Measures

1. Primary Outcome

Title	Chimerism in Unsorted Peripheral Blood
Description	Percentage of participants achieving full-donor chimerism in unsorted peripheral blood.
Time Frame	Day 60

Outcome Measure Data

Analysis Population Description

The trial has been terminated early since stopping rule criteria were met (high graft failure rate). Data were not analyzed.

Arm/Group Title	BMT Allogenic Transplantation
Arm/Group Description	Reduced-intensity transplant with a fludarabine- and busulfan-based preparative regimen. GVHD prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil.
Measure Participants	0

2. Primary Outcome

Title	Chimerism in CD3+ Sorted Peripheral Blood
Description	Percentage of participants achieving full-donor chimerism in CD3+ sorted peripheral blood
Time Frame	Day 60

Outcome Measure Data

Analysis Population Description

The trial has been terminated early since stopping rule criteria were met (high graft failure rate). Data were not analyzed.

Arm/Group Title	BMT Allogenic Transplantation
Arm/Group Description	Reduced-intensity transplant with a fludarabine- and busulfan-based preparative regimen. GVHD prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil.
Measure Participants	0

3. Secondary Outcome

Title	Overall Survival
Description	Percentage of participants alive
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The trial has been terminated early since stopping rule criteria were met (high graft failure rate). Data were not analyzed.

Arm/Group Title	BMT Allogenic Transplantation
Arm/Group Description	Reduced-intensity transplant with a fludarabine- and busulfan-based preparative regimen. GVHD prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil.
Measure Participants	0

4. Secondary Outcome

Title	Progression-free Survival
Description	Percentage of participants alive without disease relapse or progression.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The trial has been terminated early since stopping rule criteria were met (high graft failure rate). Data were not analyzed.

Arm/Group Title	BMT Allogenic Transplantation
Arm/Group Description	Reduced-intensity transplant with a fludarabine- and busulfan-based preparative regimen. GVHD prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil.
Measure Participants	0

5. Secondary Outcome

Title	Incidence of Relapse
Description	Percentage of participants experiencing disease relapse or progression
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The trial has been terminated early since stopping rule criteria were met (high graft failure rate). Data were not analyzed.

Arm/Group Title	BMT Allogenic Transplantation
Arm/Group Description	Reduced-intensity transplant with a fludarabine- and busulfan-based preparative regimen. GVHD prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil.
Measure Participants	0

6. Secondary Outcome

Title	Non-relapse Mortality
Description	Percentage of participants who died due to BMT-related reasons
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The trial has been terminated early since stopping rule criteria were met (high graft failure rate). Data were not analyzed.

Arm/Group Title	BMT Allogenic Transplantation
Arm/Group Description	Reduced-intensity transplant with a fludarabine- and busulfan-based preparative regimen. GVHD prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil.
Measure Participants	0

7. Secondary Outcome

Title	Incidence of Graft-versus-host-disease (GVHD)
Description	Percentage of participants experiencing acute and chronic GVHD. Acute GVHD is graded by Przepiorka criteria. Chronic GVHD is graded by NIH consensus criteria and Seattle criteria.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The trial has been terminated early since stopping rule criteria were met (high graft failure rate). Data were not analyzed.

Arm/Group Title	Transplant
Arm/Group Description	Reduced-intensity transplant with a fludarabine- and busulfan-based preparative regimen. GVHD prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil.
Measure Participants	0

8. Secondary Outcome

Title	Graft Failure
Description	Percentage of participants who failed to engraft.
Time Frame	Day 60

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Transplant
Arm/Group Description	Reduced-intensity transplant with a fludarabine- and busulfan-based preparative regimen. GVHD prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil.
Measure Participants	15
Count of Participants [Participants]	8 53.3%

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	Data was collected systematically through at least Day 60 by investigator assessment at protocol-specified visits.
Arm/Group Title	Transplant
Arm/Group Description	Reduced-intensity transplant with a fludarabine- and busulfan-based preparative regimen. GVHD prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil.
All Cause Mortality
	Transplant
	Affected / at Risk (%)	# Events
Total	9/15 (60%)
Serious Adverse Events
	Transplant
	Affected / at Risk (%)	# Events
Total	11/15 (73.3%)
Blood and lymphatic system disorders
Febrile neutropenia	1/15 (6.7%)	1
Gastrointestinal disorders
Diarrhea	1/15 (6.7%)	1
General disorders
Fever	2/15 (13.3%)	2
Chills	1/15 (6.7%)	1
Infections and infestations
Infection	7/15 (46.7%)	7
Sepsis	2/15 (13.3%)	2
Metabolism and nutrition disorders
Dehydration	1/15 (6.7%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/15 (6.7%)	1
Respiratory failure	1/15 (6.7%)	1
Other (Not Including Serious) Adverse Events
	Transplant
	Affected / at Risk (%)	# Events
Total	7/15 (46.7%)
Gastrointestinal disorders
nausea	1/15 (6.7%)	2
General disorders
fever	1/15 (6.7%)	1
Infections and infestations
Infection	4/15 (26.7%)	4
Febrile neutropenia	4/15 (26.7%)	4
Investigations
Elevated liver enzymes	1/15 (6.7%)	1
Elevated total bilirubin	1/15 (6.7%)	1
Nervous system disorders
tremor	1/15 (6.7%)	1
Psychiatric disorders
hallucinations	1/15 (6.7%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia	2/15 (13.3%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.