Clinical trial NCT00053196: Donor Stem Cell Transplant in Treating Patients With Relapsed Hematologic Cancer
Official title: Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation For Patients With Disease Relapse Or Myelodysplasia After Prior Autologous Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia
Lymphoma
Multiple Myeloma
Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myeloproliferative Neoplasms
Keywords: 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
splenic marginal zone lymphoma
adult acute myeloid leukemia with t(8;21)(q22;q22)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with t(15;17)(q22;q12)
childhood myelodysplastic syndromes
Lead sponsor: Alliance for Clinical Trials in Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-01-28
Enrollment: 82
Sex: ALL
Maximum age (years): 69
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Treatment-related mortality
timeFrame: 6 months post transplant
Secondary outcomes:
measure: Per cent donor chimerism
timeFrame: 30, 60, 90, 180 days post transplant
measure: Disease-free survival
timeFrame: 12 months up to 5 years post study entry
measure: Graft-versus-host disease incidence
timeFrame: 6 months post transplant
measure: Response Rates
timeFrame: 6 and 12 months
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Rebecca and John Moores UCSD Cancer Center
state: California
city: Lewes
country: United States
facility: Beebe Medical Center
state: Delaware
city: Newark
country: United States
facility: CCOP - Christiana Care Health Services
state: Delaware
city: Wilmington
country: United States
facility: St. Francis Hospital
state: Delaware
city: Elkton MD
country: United States
facility: Union Hospital Cancer Center at Union Hospital
state: Maryland
city: St Louis
country: United States
facility: Siteman Cancer Center at Barnes-Jewish Hospital
state: Missouri
city: Voorhees
country: United States
facility: Cancer Institute of New Jersey at the Cooper University Hospital - Voorhees
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University Comprehensive Cancer Center
state: North Carolina
city: Columbus
country: United States
facility: Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University
state: Ohio
city: Pittsburgh
country: United States
facility: Western Pennsylvania Cancer Institute at Western Pennsylvania Hospital
state: Pennsylvania
city: Richmond
country: United States
facility: Massey Cancer Center at Virginia Commonwealth University
state: Virginia
Study officials:
affiliation: University of California, San Diego
name: Asad Bashey, MD, PhD
role: STUDY_CHAIR
References:
citation: 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. 2011 Apr;17(4):558-65. doi: 10.1016/j.bbmt.2010.07.015. Epub 2010 Jul 30.
citation: 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.