Donor Stem Cell Transplant in Treating Patients With Relapsed Hematologic Cancer

Sponsor

Alliance for Clinical Trials in Oncology (Other)

Overall Status

Completed

CT.gov ID

NCT00053196

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

Duration (Months)

6.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Giving low doses of chemotherapy, such as fludarabine and busulfan, before a donor bone marrow or peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving immunosuppressive therapy after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well donor bone marrow or peripheral stem cell transplant works in treating patients with relapsed hematologic cancer after treatment with chemotherapy and autologous stem cell transplant.

Condition or Disease	Intervention/Treatment	Phase
Leukemia Lymphoma Multiple Myeloma Plasma Cell Neoplasm Myelodysplastic Syndromes Myeloproliferative Neoplasms	Biological: anti-thymocyte globulin Biological: G-CSF Drug: busulfan Drug: fludarabine phosphate Drug: methotrexate Drug: mycophenolate mofetil Drug: tacrolimus Procedure: allogeneic cell transplantation Drug: allopurinol	Phase 2

Detailed Description

OBJECTIVES:

Determine the feasibility of non-myeloablative allogeneic hematopoietic stem cell transplantation by demonstrating that the risk of treatment-related mortality during the first 6 months is an acceptable rate of less than 40% in patients with relapsed hematologic malignancies after prior high-dose chemotherapy and autologous stem cell transplantation.
Determine the response rates (disease-specific partial and complete response) in patients treated with this regimen.
Determine the 6-month and 12-month probabilities of response in patients treated with this regimen.
Determine the distribution of time-to-progression in patients responding to this regimen.
Determine the percent donor chimerism in patients treated with this regimen.
Determine the risk of acute and chronic graft-vs-host disease in patients treated with this regimen.
Determine the toxic effects of this regimen in these patients.
Determine the disease-free and overall survival of patients treated with this regimen.

OUTLINE: This is an open-label study.

Preparative Regimen: Patients receive fludarabine IV over 30 minutes on days -7 to -3 and busulfan IV over 2 hours every 6 hours (for a total of 8 doses) on days -4 and -3.
Graft vs Host Disease (GVHD) Prophylaxis: Patients who have an HLA-identical donor receive oral (or IV if unable to tolerate oral administration) tacrolimus twice daily on days -1 to 90 followed by a taper^* until day 150 and methotrexate IV on days 1, 3, and

Patients with a matched related or matched unrelated donor receive oral (or IV if unable to tolerate oral administration) tacrolimus twice daily on days -1 to 180 followed by a taper^* as tolerated; methotrexate IV on days 1, 3, 6, and 11; oral mycophenolate mofetil twice daily on days -2 to 60 followed by a taper; and rabbit anti-thymocyte globulin IV over 4-6 hours on days -4 to -1 (for a total of 4 doses).

NOTE: *Tacrolimus may be tapered on days 60-90 if donor chimerism of CD3+ cells is less than 50% at day 60 or patient has progressive disease

Allogeneic Stem Cell Transplantation: Patients undergo allogeneic bone marrow or peripheral blood stem cell transplantation on days 0 and 1. Patients then receive filgrastim (G-CSF) subcutaneously daily beginning on day 7 and continuing until blood counts recover.
Donor Lymphocyte Infusion (DLI): After day 180 (or day 210 for patients without an HLA-identical donor), patients with stable or progressive disease and no active GVHD may receive up to 3 DLIs every 8 weeks.

Patients are followed within 2-3 months, every 3 months for 2 years, and then every 6 months for 3 years.

Study Design

Study Type:

Interventional

Actual Enrollment :

82 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation For Patients With Disease Relapse Or Myelodysplasia After Prior Autologous Transplantation

Study Start Date :

Dec 1, 2002

Actual Primary Completion Date :

Nov 1, 2006

Actual Study Completion Date :

Aug 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Non myeloblative allogeneic transplant Non myeloblative allogeneic hematopoietic cell transplantation after prior autologous transplantation	Biological: anti-thymocyte globulin 2.5mg/kg/day IV infusion over 6 hrs x 4 doses Days -4 to -1 (for MUD and 9/10 related donor transplants only) Biological: G-CSF 5 ug/kg/day subQ injection Day 7 until ANC> 1000/uL for 3 consec days Other Names: filgrastim Drug: busulfan 0.8mg/kg IV infusion over 2 hrs q 6 hrs x 8 doses Days -4 thru -3 Drug: fludarabine phosphate 30 mg/sq m/day IVBP over 30 min Days -7 thru -3 Drug: methotrexate 5 mg/sq m/day IV infusion Days 1, 3, & 6 for HLA-identical donor transplants and Days 1, 3, 6, & 11 for MUD & 9/10 related donor transplants Drug: mycophenolate mofetil 15mg/kg PO bid Day -2 to Day 60, then taper as tolerated (for MUD and 9/10 related donor transplants only) Drug: tacrolimus target serum level is 5-10 ng/mL. Start with 0.03mg/kg PO bid Day -1 to Day 90, then taper thru Day 150 for HLA identical donor transplants and Day -1 to Day 180 then taper for MUD and 9/10 related donor transplants Procedure: allogeneic cell transplantation 2,000,000-8,000,000 CD34+ cells total via infusion Days 0 and 1 Drug: allopurinol 300 mg/day PO Days -8 thru -1

Arm

Intervention/Treatment

Experimental: Non myeloblative allogeneic transplant

Non myeloblative allogeneic hematopoietic cell transplantation after prior autologous transplantation

Biological: anti-thymocyte globulin

2.5mg/kg/day IV infusion over 6 hrs x 4 doses Days -4 to -1 (for MUD and 9/10 related donor transplants only)

Biological: G-CSF

5 ug/kg/day subQ injection Day 7 until ANC> 1000/uL for 3 consec days

Other Names:

filgrastim

Drug: busulfan

0.8mg/kg IV infusion over 2 hrs q 6 hrs x 8 doses Days -4 thru -3

Drug: fludarabine phosphate

30 mg/sq m/day IVBP over 30 min Days -7 thru -3

Drug: methotrexate

5 mg/sq m/day IV infusion Days 1, 3, & 6 for HLA-identical donor transplants and Days 1, 3, 6, & 11 for MUD & 9/10 related donor transplants

Drug: mycophenolate mofetil

15mg/kg PO bid Day -2 to Day 60, then taper as tolerated (for MUD and 9/10 related donor transplants only)

Drug: tacrolimus

target serum level is 5-10 ng/mL. Start with 0.03mg/kg PO bid Day -1 to Day 90, then taper thru Day 150 for HLA identical donor transplants and Day -1 to Day 180 then taper for MUD and 9/10 related donor transplants

Procedure: allogeneic cell transplantation

2,000,000-8,000,000 CD34+ cells total via infusion Days 0 and 1

Drug: allopurinol

300 mg/day PO Days -8 thru -1

Outcome Measures

Primary Outcome Measures

Treatment-related mortality [6 months post transplant]

Secondary Outcome Measures

Per cent donor chimerism [30, 60, 90, 180 days post transplant]
Disease-free survival [12 months up to 5 years post study entry]
Graft-versus-host disease incidence [6 months post transplant]
Response Rates [6 and 12 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 69 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed hematologic malignancy, including one of the following:
Chronic lymphocytic leukemia (CLL)
Absolute lymphocytosis greater than 5,000/mm^3
Lymphocytes must appear morphologically mature with less than 55% prolymphocytes
Lymphocyte phenotype with expression of CD19 and CD5
Prolymphocytic leukemia (PLL)
Morphologically confirmed
Absolute lymphocytosis greater than 5,000/mm^3
More than 55% prolymphocytes
Non-Hodgkin's lymphoma or Hodgkin's lymphoma
Any WHO histologic subtype allowed except mantle cell lymphoma
Core biopsies allowed if they contain adequate tissue for primary diagnosis and immunophenotyping
No bone marrow biopsy as the sole diagnostic means for follicular lymphoma
Multiple myeloma
Active disease requiring treatment
Durie-Salmon stage I, II, or III
Acute myeloid leukemia
Documented control (i.e., less than 10% bone marrow blasts and no circulating blasts)
Myelodysplastic syndromes
Documented disease by WHO criteria
Must have evidence of relapse/progression at least 6 months after prior high-dose chemotherapy with autologous hematopoietic stem cell support
Absence of CD23 expression for CLL or PLL allowed provided there is no morphologic evidence of mantle cell lymphoma
Availability of any of the following donor types:
HLA-identical sibling (6/6)
9/10 matched related donor by high-resolution molecular typing at HLA A, B, C, DRB1, and DQB1 loci
Only a single mismatch at one class I or II allele allowed
10/10 matched unrelated donor by high-resolution molecular typing at HLA A, B, C, DRB1, and DQB1 loci
No syngeneic donors

PATIENT CHARACTERISTICS:

Age

Under 70

Performance status

Not specified

Life expectancy

Not specified

Hematopoietic

See Disease Characteristics

Hepatic

Bilirubin no greater than 3 times upper limit of normal (ULN)
AST no greater than 3 times ULN

Renal

Creatinine clearance at least 40 mL/min

Cardiovascular

LVEF at least 30% by MUGA

Pulmonary

DLCO greater than 40%
No symptomatic pulmonary disease

Other

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
HIV negative
No uncontrolled diabetes mellitus
No active serious infection
No known hypersensitivity to E. coli-derived products

PRIOR CONCURRENT THERAPY:

Biologic therapy

See Disease Characteristics

Chemotherapy

See Disease Characteristics
More than 4 weeks since prior chemotherapy

Endocrine therapy

Not specified

Radiotherapy

More than 4 weeks since prior radiotherapy

Surgery

More than 4 weeks since prior surgery

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rebecca and John Moores UCSD Cancer Center	La Jolla	California	United States	92093-0658
2	Beebe Medical Center	Lewes	Delaware	United States	19958
3	CCOP - Christiana Care Health Services	Newark	Delaware	United States	19713
4	St. Francis Hospital	Wilmington	Delaware	United States	19805
5	Union Hospital Cancer Center at Union Hospital	Elkton MD	Maryland	United States	21921
6	Siteman Cancer Center at Barnes-Jewish Hospital	St Louis	Missouri	United States	63110
7	Cancer Institute of New Jersey at the Cooper University Hospital - Voorhees	Voorhees	New Jersey	United States	08043
8	Roswell Park Cancer Institute	Buffalo	New York	United States	14263-0001
9	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157-1096
10	Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University	Columbus	Ohio	United States	43210-1240
11	Western Pennsylvania Cancer Institute at Western Pennsylvania Hospital	Pittsburgh	Pennsylvania	United States	15224-1791
12	Massey Cancer Center at Virginia Commonwealth University	Richmond	Virginia	United States	23298-0037