Clinical trial NCT00448201: Reduced-Intensity Busulfan and Fludarabine With or Without Antithymocyte Globulin Followed by Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer or Other Disease
Official title: Allogeneic Hematopoietic Cell Transplantation for Patients With Hematologic Disorders Who Are Ineligible or Inappropriate for Treatment With a More Intensive Therapeutic Regimen
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Keywords: adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
prolymphocytic leukemia
accelerated phase chronic myelogenous leukemia
adult acute lymphoblastic leukemia in remission
adult acute myeloid leukemia in remission
blastic phase chronic myelogenous leukemia
childhood acute lymphoblastic leukemia in remission
childhood acute myeloid leukemia in remission
childhood chronic myelogenous leukemia
chronic phase chronic myelogenous leukemia
de novo myelodysplastic syndromes
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
noncontiguous stage II adult Burkitt lymphoma
noncontiguous stage II adult diffuse large cell lymphoma
noncontiguous stage II adult diffuse mixed cell lymphoma
noncontiguous stage II adult diffuse small cleaved cell lymphoma
noncontiguous stage II adult immunoblastic large cell lymphoma
noncontiguous stage II adult lymphoblastic lymphoma
noncontiguous stage II grade 1 follicular lymphoma
noncontiguous stage II grade 2 follicular lymphoma
noncontiguous stage II grade 3 follicular lymphoma
noncontiguous stage II mantle cell lymphoma
noncontiguous stage II marginal zone lymphoma
noncontiguous stage II small lymphocytic lymphoma
previously treated myelodysplastic syndromes
recurrent adult acute lymphoblastic leukemia
recurrent adult Burkitt lymphoma
recurrent adult Hodgkin lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent adult acute myeloid leukemia
recurrent childhood acute myeloid leukemia
recurrent/refractory childhood Hodgkin lymphoma
recurrent childhood acute lymphoblastic leukemia
recurrent childhood large cell lymphoma
recurrent childhood lymphoblastic lymphoma
recurrent childhood small noncleaved cell lymphoma
recurrent cutaneous T-cell non-Hodgkin lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent marginal zone lymphoma
recurrent mycosis fungoides/Sezary syndrome
recurrent small lymphocytic lymphoma
refractory chronic lymphocytic leukemia
refractory multiple myeloma
relapsing chronic myelogenous leukemia
secondary acute myeloid leukemia
secondary myelodysplastic syndromes
splenic marginal zone lymphoma
stage I multiple myeloma
stage II multiple myeloma
stage III adult Burkitt lymphoma
stage III adult Hodgkin lymphoma
stage III adult diffuse large cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage III adult lymphoblastic lymphoma
stage III chronic lymphocytic leukemia
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage III mantle cell lymphoma
stage III marginal zone lymphoma
stage III multiple myeloma
stage III small lymphocytic lymphoma
stage IV adult Burkitt lymphoma
stage IV adult Hodgkin lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV adult lymphoblastic lymphoma
stage IV chronic lymphocytic leukemia
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage IV mantle cell lymphoma
stage IV marginal zone lymphoma
stage IV small lymphocytic lymphoma
primary myelofibrosis
Waldenstrom macroglobulinemia
adult nasal type extranodal natural killer (NK)/T-cell lymphoma
recurrent adult grade III lymphomatoid granulomatosis
childhood myelodysplastic syndromes
Lead sponsor: UNC Lineberger Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-03-16
Enrollment: 71
Sex: ALL
Minimum age (years): 10
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 busulfan and fludarabine, before a donor stem cell transplant helps stop the growth of cancer and abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer or abnormal cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Immunosuppressive therapy may improve bone marrow function and may be an effective treatment for hematologic cancer or other disease.

PURPOSE: This clinical trial is studying the side effects and how well giving busulfan and fludarabine with or without antithymocyte globulin followed by donor stem cell transplant works in treating patients with hematologic cancer or other disease.

Detailed description: OBJECTIVES:

Primary

* Determine the clinical efficacy and toxicity profiles of a nonmyeloablative preparative regimen comprising busulfan and fludarabine with or without anti-thymocyte globulin followed by allogeneic hematopoietic stem cell transplantation in patients with hematologic cancers or other diseases.
* Determine the feasibility of this regimen in these patients.
* Establish a treatment-related mortality during the first 6 months that is less than 20% in patients treated with this regimen.

Secondary

* Determine the response rates (disease-specific partial response and complete response) in patients treated with this regimen.
* Determine overall and progression-free survival of patients treated with this regimen.
* Determine the percent donor chimerism and immunologic recovery, including dendritic cell recovery, in patients treated with this regimen.
* Determine the risk of acute and chronic graft-versus-host disease and other toxicities in patients treated with this regimen.
* Assess the overall nonhematologic grades 3 and 4 toxicity of this regimen, including the incidence of veno-occlusive disease and pulmonary toxicity, in these patients.

OUTLINE: Patients are assigned to 1 of 4 treatment groups according to disease type and donor type.

* Preparative regimen:

  * Group 1 (patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), IPSS (International Prognostic Scoring System score) high-risk myelodysplastic syndromes (HR MDS), or chronic myelogenous leukemia (CML) with an human leukocyte antigen (HLA)-matched related donor (MRD): Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and busulfan IV continuously over 48 hours on days -6 and -5.
  * Group 2 (patients with AML, ALL, IPSS HR MDS, or CML with an HLA-matched unrelated donor (MUD) or mismatched related donor (MMRD)): Patients receive fludarabine phosphate and busulfan as in group 1 and anti-thymocyte globulin IV over 4 hours on day -8.
  * Group 3 (patients with all other diseases with a MRD): Patients receive fludarabine phosphate and busulfan as in group 1 and anti-thymocyte globulin as in group 2.
  * Group 4 (patients with all other disease with a MUD or MMRD): Patients receive fludarabine phosphate and busulfan as in group 1 and anti-thymocyte globulin IV over 4 hours on days -8 and -7.
* Allogeneic stem cell transplantation: All patients undergo allogeneic peripheral blood stem cell transplantation on day 0. Patients then receive sargramostim (GM-CSF) subcutaneously once daily beginning on day 5 (groups 1 and 2) or day 7 (groups 3 and 4) and continuing until blood counts recover.
* Graft-vs-host disease (GVHD) prophylaxis: All patients receive oral tacrolimus twice daily on days -1 to 120 followed by a taper until day 180. Patients in groups 1 and 2 also receive methotrexate IV on days 1, 3, and 6.
* Donor lymphocyte infusion (DLI): After day 120, patients with progressive disease or stable disease while off immunosuppression and with no evidence of active GVHD may receive DLI. Treatment with DLI may repeat every 8 weeks for up to 3 total infusions in the absence of disease response or GVHD.

Peripheral blood and/or bone marrow samples are collected at baseline and then at 30, 60, 90, 120, and 180 days post-transplantation. Chimerism (including the following subsets: whole blood, T-cells as defined by cluster of differentiation 3 (CD3) positivity, B-cells as defined by Cluster of Differentiation 19 (CD19) positivity, and myeloid cells as defined by Cluster of Differentiation 14 (CD14) and Cluster of Differentiation 15 (CD15) positivity is analyzed by polymerase chain reaction technology.

After restaging between Days 90 and 100 and between Days 150 to 180, patients are followed every 6 months for 1 years and then yearly for a maximum of 5 years from study entry.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed diagnosis of 1 of the following:

  * Chronic lymphocytic leukemia (CLL), meeting the following criteria:

    * Absolute lymphocyte count \> 5,000/mm³
    * Lymphocytes must appear morphologically mature with \< 55% prolymphocytes
    * Lymphocyte phenotype with expression of CD19 and cluster of differentiation 5 (CD5)
  * Prolymphocytic leukemia (PLL), meeting the following criteria:

    * Absolute lymphocyte count \> 5,000/mm³
    * More than 55% prolymphocytes
    * Morphologically diagnosed
  * Chronic myelogenous leukemia (CML), meeting the following criteria:

    * Diagnosis of CML or similar myeloproliferative disorders based on t(9;22) or related t(9;12) cytogenetic abnormalities AND characterized by elevated white blood cell (WBC) counts in peripheral blood or bone marrow
    * In first chronic phase CML and a candidate for treatment with reduced-dose busulfan
    * Patients with other cytogenetic abnormalities, such as t(9;12), that are associated with an aggressive clinical course are eligible
  * Non-Hodgkin's lymphoma (NHL), meeting the following criteria:

    * Any World Health Organization (WHO) class histologic subtype allowed
    * Core biopsies are acceptable provided they contain adequate tissue for primary diagnosis and immunophenotyping
    * Bone marrow biopsies as sole means of diagnosis are not allowed for follicular lymphoma
  * Hodgkin's lymphoma, meeting the following criteria:

    * Any WHO class histologic subtype allowed
    * Core biopsies are acceptable provided they contain adequate tissue for primary diagnosis and immunophenotyping
  * Multiple myeloma, meeting the following criteria:

    * Active disease requiring treatment (Durie-Salmon stages I, II, or III)
  * Acute myeloid leukemia with documented control, defined as \< 10% bone marrow blasts and no circulating blasts
  * Acute lymphoblastic leukemia, meeting the following criteria:

    * In early first relapse or beyond OR in first complete remission and has 1 of the following high-risk features:

      * t(9;22) or t(4;11)
      * WBC count \> 30,000/mm³ at presentation
      * Non-T-cell phenotype
      * More than 30 years of age
  * Agnogenic myeloid metaplasia/myelofibrosis

    * Patients who are transfusion dependent or who have evolving myelodysplastic or leukemic features or high-risk cytogenetic abnormalities are eligible
  * Myelodysplastic syndromes (MDS) as defined by WHO criteria
* Meets 1 of the following criteria:

  * Over 55 years of age
  * Ineligible for busulfan-based therapy based on diminished organ function or poor performance status
  * Indolent and chemotherapy-responsive CLL, low-grade NHL, small lymphocytic lymphoma, or PLL
* Patients who have undergone prior autologous stem cell transplantation are preferentially enrolled on clinical trial CALGB-100002, if available and patient is eligible
* HLA-matched or mismatched related donor or HLA-matched unrelated donor available

  * HLA-identical sibling (6/6 or 9/10) (minimal serologic typing required for class I \[A, B\]; molecular typing required for class II (DRB1))
  * 9/10 matched unrelated donor (MUD) (molecular analysis at HLA A, B, C, DRB1, and DQB1 by high resolution typing required)
  * 5/6 MUD (molecular analysis at HLA A, B, and DRB1 required)
  * No syngeneic donors

PATIENT CHARACTERISTICS:

* Creatinine clearance ≥ 40 mL/min
* Bilirubin ≤ 3 times upper limit of normal (ULN)
* aspartate aminotransferase (AST) ≤ 3 times ULN
* Diffusing capacity of the lungs for carbon monoxide (DLCO) \> 40% with no symptomatic pulmonary disease
* Left ventricular ejection fraction (LVEF) ≥ 30% by multigated acquisition scan (MUGA)
* No uncontrolled diabetes mellitus or active serious infection
* No known hypersensitivity to Escherichia coli-derived products
* No HIV infection
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* More than 4 weeks since prior chemotherapy, radiotherapy (except prophylactic cranial x-ray therapy), or surgery

Primary outcomes:
measure: Treatment-related Mortality
timeFrame: 6 months
Secondary outcomes:
measure: Complete Response at 6 and 12 Months Post-transplant
timeFrame: 6 and 12 months
measure: Complete or Mixed Donor Chimerism at 30, 60, and 90 Days Post-transplant
timeFrame: Days 30, 60, and 90
measure: 5-year Disease-free Survival
timeFrame: Year 5
measure: Graft-vs-host Disease at 6 Months Post-transplant
timeFrame: 6 Months
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
state: North Carolina
Study officials:
affiliation: UNC Lineberger Comprehensive Cancer Center
name: Thomas C. Shea, MD
role: PRINCIPAL_INVESTIGATOR
References: