Donor Stem Cell Transplant in Treating Patients With Relapsed Hematologic Cancer - Full Text View

Sponsor:	Cancer and Leukemia Group B
Collaborator:	National Cancer Institute (NCI)
Information provided by:	Cancer and Leukemia Group B
ClinicalTrials.gov Identifier:	NCT00053196

Purpose

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	Intervention	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 II

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation For Patients With Disease Relapse Or Myelodysplasia After Prior Autologous Transplantation

Resource links provided by NLM:

Genetics Home Reference related topics: aceruloplasminemia hemophilia

MedlinePlus related topics: Acute Myeloid Leukemia Cancer Chronic Myeloid Leukemia Leukemia Lymphoma Multiple Myeloma Myelodysplastic Syndromes

Drug Information available for: Busulfan Methotrexate Allopurinol sodium Fludarabine Fludarabine monophosphate Tacrolimus anhydrous Tacrolimus Mycophenolate mofetil hydrochloride Filgrastim Mycophenolate Mofetil Granulocyte colony-stimulating factor Allopurinol

U.S. FDA Resources

Further study details as provided by Cancer and Leukemia Group B:

Primary Outcome Measures:

Treatment-related mortality [ Time Frame: 6 months post transplant ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Per cent donor chimerism [ Time Frame: 30, 60, 90, 180 days post transplant ] [ Designated as safety issue: No ]
Disease-free survival [ Time Frame: 12 months up to 5 years post study entry ] [ Designated as safety issue: No ]
Graft-versus-host disease incidence [ Time Frame: 6 months post transplant ] [ Designated as safety issue: Yes ]
Response Rates [ Time Frame: 6 and 12 months ] [ Designated as safety issue: No ]

Enrollment:	82
Study Start Date:	December 2002
Study Completion Date:	August 2010
Primary Completion Date:	November 2006 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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 Name: 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

Arms

Assigned Interventions

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 Name: 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

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 6. 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.

PROJECTED ACCRUAL: A total of 20-80 patients will be accrued for this study within 10-40 months.

Eligibility

Ages Eligible for Study:	up to 69 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00053196

Locations

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

Sponsors and Collaborators

Cancer and Leukemia Group B

National Cancer Institute (NCI)

Investigators

Study Chair:

Asad Bashey, MD, PhD

University of California, San Diego

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Publications:

Bashey A, Owzar K, Johnson JL, Edwards PS, Kelly M, Baxter-Lowe LA, Devine S, Farag S, Hurd D, Ball E, McCarthy P, Lister J, Shea TC, Linker C. Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Patients with Hematologic Malignancies Who Relapse following Autologous Transplantation: A Multi-Institutional Prospective Study from the Cancer and Leukemia Group B (CALGB trial 100002). Biol Blood Marrow Transplant. 2010 Jul 29; [Epub ahead of print]

Bashey A, Owzar K, Johnson JL, et al.: Reduced-intensity allogeneic transplantation after failure of autologous transplantation: a prospective multi-center CALGB study. [Abstract] Blood 108 (11): A-3122, 2006.

Responsible Party:	Monica M Bertagnolli, MD, Cancer and Leukemia Group B
ClinicalTrials.gov Identifier:	NCT00053196 History of Changes
Other Study ID Numbers:	CDR0000269301, U10CA031946, CALGB-100002
Study First Received:	January 27, 2003
Last Updated:	April 5, 2011
Health Authority:	United States: Federal Government

Keywords provided by Cancer and Leukemia Group B:

refractory chronic lymphocytic leukemia
prolymphocytic leukemia
recurrent adult Hodgkin lymphoma
stage I multiple myeloma
stage II multiple myeloma
stage III multiple myeloma
refractory multiple myeloma
previously treated myelodysplastic syndromes
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult Burkitt lymphoma
recurrent adult immunoblastic large cell lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma

recurrent grade 3 follicular lymphoma
secondary myelodysplastic syndromes
de novo myelodysplastic syndromes
recurrent adult acute myeloid leukemia
recurrent childhood acute myeloid leukemia
recurrent childhood large cell lymphoma
recurrent childhood lymphoblastic lymphoma
recurrent childhood small noncleaved cell lymphoma
recurrent/refractory childhood Hodgkin lymphoma
atypical chronic myeloid leukemia, BCR-ABL negative
myelodysplastic/myeloproliferative neoplasm, unclassifiable
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma

Additional relevant MeSH terms:

Neoplasms
Leukemia
Lymphoma
Multiple Myeloma
Neoplasms, Plasma Cell
Plasmacytoma
Myelodysplastic Syndromes
Preleukemia
Myeloproliferative Disorders
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Hemostatic Disorders

Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Bone Marrow Diseases
Precancerous Conditions
Allopurinol
Methotrexate
Mycophenolic Acid
Fludarabine monophosphate
Vidarabine
Antilymphocyte Serum
Busulfan

ClinicalTrials.gov processed this record on February 09, 2012