Clinical trial NCT00453206: Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer or Other Diseases
Official title: Reduced Intensity Allogeneic Hematopoietic Cell Transplantation for Patients With Hematological Diseases
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
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)
accelerated phase chronic myelogenous leukemia
adult acute myeloid leukemia in remission
blastic phase chronic myelogenous leukemia
primary myelofibrosis
chronic phase chronic myelogenous leukemia
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
de novo myelodysplastic syndromes
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
prolymphocytic leukemia
recurrent adult acute myeloid 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 grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent marginal zone lymphoma
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 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
polycythemia vera
stage III chronic lymphocytic leukemia
recurrent/refractory childhood Hodgkin lymphoma
stage I childhood Hodgkin lymphoma
stage II childhood Hodgkin lymphoma
stage III childhood Hodgkin lymphoma
stage IV childhood Hodgkin lymphoma
recurrent childhood anaplastic large cell lymphoma
stage I childhood anaplastic large cell lymphoma
stage II childhood anaplastic large cell lymphoma
stage III childhood anaplastic large cell lymphoma
stage IV childhood anaplastic large cell lymphoma
recurrent childhood grade III lymphomatoid granulomatosis
recurrent childhood large cell lymphoma
stage I childhood large cell lymphoma
stage II childhood large cell lymphoma
stage III childhood large cell lymphoma
stage IV childhood large cell lymphoma
recurrent childhood lymphoblastic lymphoma
stage I childhood lymphoblastic lymphoma
stage II childhood lymphoblastic lymphoma
stage III childhood lymphoblastic lymphoma
stage IV childhood lymphoblastic lymphoma
childhood nasal type extranodal NK/T-cell lymphoma
recurrent childhood small noncleaved cell lymphoma
stage I childhood small noncleaved cell lymphoma
stage II childhood small noncleaved cell lymphoma
stage III childhood small noncleaved cell lymphoma
stage IV childhood small noncleaved cell lymphoma
Lead sponsor: Wake Forest University Health Sciences
Sponsor class: OTHER
First posted: 2007-03-28
Enrollment: 66
Sex: ALL
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Giving chemotherapy, such as fludarabine, busulfan, and melphalan, before a donor peripheral stem cell transplant or bone marrow transplant helps stop the growth of cancer or abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving tacrolimus, methotrexate, mycophenolate mofetil, and antithymocyte globulin before and after transplant may stop this from happening. Once the donated stem cells begin working, the patient's immune system may see the remaining cancer or abnormal cells as not belonging in the patient's body and destroy them (graft-versus-tumor effect). Giving an infusion of the donor's white blood cells (donor lymphocyte infusion) may boost this effect.

PURPOSE: This phase II trial is studying how well donor stem cell transplant works in treating patients with hematologic cancer or other diseases.

Detailed description: OBJECTIVES:

Primary

* Determine the feasibility (i.e., risk of treatment-related mortality during the first 6 months after transplantation) of administering reduced-intensity allogeneic hematopoietic stem cell transplantation to patients with hematologic cancer or other diseases.

Secondary

* Determine the response rate (partial and complete response), 6- and 12-month probabilities of response, and time to progression in patients treated with this regimen.
* Determine the risk of acute and chronic graft-versus-host disease in patients treated with this regimen.
* Determine other toxicities of this regimen in these patients.
* Determine the overall survival and disease-free survival of patients treated with this regimen.
* Determine the impact of iron status on overall and disease-free survival.
* Determine the influence of quality of life (at time of transplantation) on overall survival.

OUTLINE:

* Preparative regimen: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3. Patients also receive busulfan IV over 2 hours every 6 hours on days -4 and -3 or melphalan IV over 2 hours on day -3.
* Graft-versus-host disease (GVHD) prophylaxis: Patients with matched related donors receive oral tacrolimus twice daily on days -1 to 90 followed by a taper until day 180. Patients also receive methotrexate IV on days 1, 3, and 6. Patients with matched unrelated and 9/10 matched related donors receive oral tacrolimus twice daily on days -1 to 180 followed by a taper; methotrexate IV on days 1, 3, 6, and 11; and oral mycophenolate mofetil twice daily on days -2 to 60 followed by a taper. All patients also receive antithymocyte globulin IV over 4 to 6 hours once a day on days -4 to -1.
* Allogeneic stem cell transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. Patients receive filgrastim (G-CSF) beginning on day 7 and continuing until blood counts recover.
* Lymphocyte infusion: Patients with progressive or stable disease while off immunosuppression and no active GVHD may receive up to 3 donor lymphocyte infusions from the original donor at 8-week intervals beginning on day 180 or 210 .

Quality of life is assessed at baseline.

After completion of study therapy, patients are followed every 3 months for 2 years and then every 6 months for up to 3 years.

PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed hematological disease, including any of the following:

  * Chronic lymphocytic leukemia

    * Absolute lymphocytosis \> 5,000/µL
    * Morphologically mature lymphocytes with \< 55% prolymphocytes
    * Lymphocyte phenotype with expression of CD19 and CD5
    * Absence of CD23 expression allowed provided disease is morphologically distinguished from mantle cell lymphoma
  * Prolymphocytic leukemia

    * Absolute lymphocytosis \> 5,000/µL
    * Morphologically mature lymphocytes with \> 55% prolymphocytes
  * Non-Hodgkin's or Hodgkin's lymphoma

    * Any WHO classification histologic subtype
    * Diagnosis by core biopsy allowed provided there is adequate tissue for diagnosis and immunophenotyping
    * Diagnosis by bone marrow biopsy not acceptable for follicular lymphomas
  * Multiple myeloma

    * Has received ≥ 1 prior treatment regimen
    * Has a partial response or greater by the Blade Criteria
    * Patients who achieved complete remission are eligible
  * Acute myeloid leukemia

    * Documented control (i.e., \< 10% bone marrow blasts and no circulating blasts)
  * Myelodysplastic syndromes

    * Documented disease as defined by WHO or French-American-British Cooperative group criteria
    * Chronic myelogenous leukemia
  * Patients with atypical chronic myelogenous leukemia (i.e., absent Philadelphia chromosome) are eligible
  * Polycythemia vera

    * Documented disease as defined by WHO criteria (i.e., A1 + A2, and any other category A, OR A1 + A2, and any 2 category B):

      * A1: Total red blood cell mass \> 25% above mean normal predicted value OR hemoglobin \> 18.5 g/dL in males, 16.5 g/dL in females (hematocrit ≥ 60% in males or ≥ 56% in females)
      * A2: No cause of secondary erythrocytosis (absence of familial erythrocytosis, no elevation of epoetin alfa \[EPO\] due to hypoxia, high oxygen affinity hemoglobin, truncated EPO receptor, or inappropriate ectopic EPO production)
      * A3: Splenomegaly
      * A4: Clonal genetic abnormality other than the Philadelphia chromosome
      * A5: Endogenous erythroid colony formation in vitro
      * B: Platelet count \> 400,000/mm³, WBC \> 12,000/mm³, bone marrow biopsy with prominent erythroid and megakaryocytic proliferation, and low serum EPO
  * Chronic idiopathic myelofibrosis

    * Documented disease as defined by WHO criteria
    * Must have a HLA-identical donor, a matched unrelated donor, or a HLA 9/10 related donor meeting the following criteria:
    * HLA-identical sibling (6/6)

      * Serologic typing for class I (A, B)
      * Molecular typing for class II (DRB1)
    * 9/10 matched related donor

      * High-resolution molecular typing at HLA-A, B, C, DRB1, and DQB1
      * Only a single mismatch at one class I or II allele allowed
    * 10/10 matched unrelated donor

      * Molecular identity at HLA-A, B, C, DRB1, and DQB1 by high-resolution typing
      * Syngeneic donors are not eligible
* 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 cardiac MRI or echocardiogram with no symptomatic cardiac disease
* Fertile patients willing to use effective contraception

Exclusion Criteria:

* Uncontrolled diabetes mellitus
* Active serious infection
* Known hypersensitivity to E. coli-derived products
* Known HIV positivity
* History of another malignancy\*, meeting the following criteria:

  * Non-skin malignancy or melanoma within the past 5 years
  * Concomitant malignancy that has not been curatively treated
  * NOTE: \*However, cancer survivors who have undergone potentially curative therapy for a prior malignancy at least 5 years before enrollment and are deemed at low risk of \< 30% for recurrence by their treating physicians is considered
* Pregnant or nursing

Primary outcomes:
measure: Treatment-related Mortality Within the First 6 Months After Transplantation
timeFrame: 6 months
Secondary outcomes:
measure: Complete Response
timeFrame: monthly
measure: Overall Survival
timeFrame: monthly
measure: Disease-free Survival
timeFrame: monthly
measure: Graft-versus-host Disease
timeFrame: monthly
measure: Iron Status at the Time of Transplantation
timeFrame: baseline
measure: Quality of Life at the Time of Transplantation
timeFrame: baseline
measure: Treatment-related Mortality at 100 Days After Transplantation
timeFrame: 100 days
Other outcomes:
Locations:
city: Winston-Salem
country: United States
facility: Wake Forest University Comprehensive Cancer Center
state: North Carolina
Study officials:
affiliation: Wake Forest University Health Sciences
name: David Hurd, MD
role: STUDY_CHAIR
References: