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Allogeneic Hematopoietic Cell Transplantation for Patients With Hematologic Disorders Who Are Ineligible or Inappropriate for Treatment With a More Intensive Therapeutic Regimen


Phase 2
10 Years
N/A
Open (Enrolling)
Both
Chronic Myeloproliferative Disorders, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes

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Trial Information

Allogeneic Hematopoietic Cell Transplantation for Patients With Hematologic Disorders Who Are Ineligible or Inappropriate for Treatment With a More Intensive Therapeutic Regimen


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
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 CD3 positivity, B-cells as defined by CD19 positivity,
and myeloid cells as defined by CD14 and 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.

Inclusion 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 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
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 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)

- AST ≤ 3 times ULN

- DLCO > 40% with no symptomatic pulmonary disease

- LVEF ≥ 30% by 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

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Treatment-related mortality

Outcome Time Frame:

6 months

Safety Issue:

No

Principal Investigator

Thomas C. Shea, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UNC Lineberger Comprehensive Cancer Center

Authority:

United States: Institutional Review Board

Study ID:

LCCC 0306

NCT ID:

NCT00448201

Start Date:

November 2003

Completion Date:

July 2014

Related Keywords:

  • Chronic Myeloproliferative Disorders
  • Leukemia
  • Lymphoma
  • Multiple Myeloma and Plasma Cell Neoplasm
  • Myelodysplastic Syndromes
  • 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 NK/T-cell lymphoma
  • recurrent adult grade III lymphomatoid granulomatosis
  • childhood myelodysplastic syndromes
  • Neoplasms
  • Leukemia
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Plasmacytoma
  • Myelodysplastic Syndromes
  • Preleukemia
  • Myeloproliferative Disorders
  • Lymphoma, Large-Cell, Immunoblastic

Name

Location

Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel HillChapel Hill, North Carolina  27599-7570