Clinical trial NCT00134004: Fludarabine, Cyclophosphamide, and Total-Body Irradiation in Treating Patients Who Are Undergoing a Donor Bone Marrow Transplant for Hematologic Cancer
Official title: A Phase II Trial of Non-Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched Bone Marrow for Patients With Hematologic Malignancies
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 lymphoblastic leukemia in remission
adult acute myeloid leukemia in remission
childhood acute lymphoblastic leukemia in remission
childhood acute myeloid leukemia in remission
childhood chronic myelogenous leukemia
chronic phase chronic myelogenous leukemia
refractory chronic lymphocytic leukemia
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
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)
chronic idiopathic myelofibrosis
chronic myelomonocytic leukemia
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
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
recurrent adult Burkitt lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult Hodgkin lymphoma
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent/refractory childhood Hodgkin lymphoma
recurrent childhood large cell lymphoma
recurrent childhood lymphoblastic lymphoma
recurrent childhood small noncleaved cell lymphoma
nodal marginal zone B-cell 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 multiple myeloma
relapsing chronic myelogenous leukemia
secondary myelodysplastic syndromes
splenic marginal zone lymphoma
stage I multiple myeloma
stage II multiple myeloma
stage III multiple myeloma
stage III adult Burkitt 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 Hodgkin 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
polycythemia vera
essential thrombocythemia
stage III small lymphocytic lymphoma
stage IV mantle cell lymphoma
stage IV marginal zone lymphoma
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage IV adult Burkitt 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 small lymphocytic lymphoma
stage IV adult Hodgkin lymphoma
childhood myelodysplastic syndromes
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2005-08-24
Enrollment: 210
Sex: ALL
Minimum age (years): 6
Maximum age (years): 74
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Giving low doses of chemotherapy, such as fludarabine and cyclophosphamide, and radiation therapy before a donor bone marrow transplant helps stop the growth of cancer cells. Giving chemotherapy or radiation therapy before or after transplant also stops the patient's immune system from rejecting the donor's bone marrow stem cells. The donated stem cells may replace the patient's immune system cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus and mycophenolate mofetil after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation works in treating patients who are undergoing a donor bone marrow transplant for hematologic cancer.

Detailed description: OBJECTIVES:

* Determine transplant-related mortality, risk of relapse, and progression-free survival of patients with standard- or high-risk hematologic malignancies undergoing nonmyeloablative conditioning comprising fludarabine, cyclophosphamide, and total-body irradiation followed by HLA-haploidentical allogeneic bone marrow transplantation.
* Determine donor hematopoietic chimerism in patients' peripheral blood at 30, 60, and 180 days after transplantation.
* Determine hematologic and nonhematologic toxic effects of this regimen in these patients.
* Determine, when feasible, surface expression of HLA molecules and death receptors, sensitivity to cytotoxic lymphocytes, and expression of anti-apoptotic genes (e.g., Bcl-2, Bcl-xL, X-IAP, and c-FLIP) in cancer cells from patients who relapse after treatment with this regimen.

OUTLINE: This is a multicenter study. Patients are stratified according to risk of relapse (standard \[defined as ≤ 30% risk\] vs high \[defined as ≥ 70% risk\]).

* Nonmyeloablative conditioning regimen: Patients receive fludarabine IV over 30 minutes on days -6 to -2 and cyclophosphamide IV over 1-2 hours on days -6 and -5. Patients undergo total body irradiation on day -1.
* Allogeneic bone marrow transplantation: Patients undergo donor bone marrow infusion on day 0.
* Post-transplantation therapy: Patients receive cyclophosphamide IV over 1-2 hours on days 3 and 4.
* Graft-vs-host disease prophylaxis: Beginning on day 5, patients receive oral mycophenolate mofetil 3 times daily until day 35 and tacrolimus IV (then changing to orally) twice daily until day 180.

Treatment continues in the absence of disease progression.

After completion of study transplantation, patients are followed on days 30, 60, 100, and 180; at 1 year; and then annually for 4 additional years.

PROJECTED ACCRUAL: A total of 75-100 patients will be accrued for this study within 3-4 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of 1 of the following hematologic malignancies:

  * Acute leukemia

    * In second or subsequent complete remission (CR), as defined by absence of abnormal blast population by flow cytometry
    * In first CR with any of the following poor-risk cytogenetic features:

      * Alteration of chromosome 5 or 7
      * Multiple abnormalities
      * Philadelphia chromosome positive
  * Chronic phase chronic myelogenous leukemia (CML)

    * In first chronic phase and refractory to interferon alfa or imatinib mesylate
    * In second or subsequent chronic phase
  * Chronic lymphocytic leukemia, meeting 1 of the following criteria:

    * Received prior chemotherapy with a nucleoside analog and had remission lasting \< 6 months
    * Received 1 prior therapy and has any of the following high-risk features:

      * Cytogenetic abnormalities of 17p, 11q
      * Mutations of the Zap70 gene
      * Somatically unmutated immunoglobulin heavy chain variable region genes
  * Hodgkin's lymphoma

    * Ineligible for autologous stem cell transplantation (SCT) due to any of the following exclusion factors:

      * LVEF \< 45%
      * FEV_1 or FVC \< 50% of predicted (75% of predicted in patients with prior thoracic or mantle radiotherapy)
      * Total bilirubin \> 2.0 mg/dL (unless documented Gilbert's disease)
      * Creatinine \> 2.0 mg/dL
  * Non-Hodgkin's lymphoma (NHL)

    * Low-grade NHL allowed provided patient had a remission duration of \< 1 year after administration of any established, multi-agent chemotherapy regimen (e.g., CVP, CHOP, or rituximab in combination with CHOP)
    * Intermediate- or high-grade NHL allowed provided patient is ineligible for autologous SCT according to the criteria listed above
  * Multiple myeloma
  * Myelodysplastic syndromes
  * Paroxysmal nocturnal hemoglobinuria
  * Chronic myeloproliferative disorders other than CML, including any of the following:

    * Chronic myelomonocytic leukemia
    * Agnogenic myeloid metaplasia (or myeloid metaplasia with myelofibrosis), with hemoglobin \< 10 g/dL OR WBC \< 4,000/mm\^3 or \> 30,000/mm\^3
    * Polycythemia vera or essential thrombocythemia in "spent" phase, with a history of 2 of the following:

      * Marrow fibrosis
      * Splenomegaly
      * Cytopenia (i.e., absolute neutrophil count \< 1,500/mm\^3, platelet count \< 100,000/mm\^3, hemoglobin \< 10 g/dL)
    * Polycythemia vera or essential thrombocythemia with transformation to myelodysplastic syndromes or acute myeloid leukemia (requires treatment to achieve \< 20% blasts in marrow)
* No smoldering myeloma
* Patients with acute myeloid leukemia or myelodysplastic syndromes must have had comprehensive cytogenetic evaluation of bone marrow specimen during active disease
* Ineligible for or refused bone marrow transplantation from an HLA-matched sibling or unrelated donor
* Ineligible for or refused autologous SCT
* Must have an HLA mismatched (i.e., 3/6, 4/6, or 5/6) related (first-degree relative)\* donor available

  * Donor ≥ 18 years of age NOTE: \*Patients with an inherited recombinant HLA haplotype may receive marrow from the parent in whose gamete the recombination occurred

NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.

PATIENT CHARACTERISTICS:

Age

* 6 months to 74 years

Performance status

* ECOG 0-1

Life expectancy

* Not specified

Hematopoietic

* See Disease Characteristics

Hepatic

* See Disease Characteristics
* Bilirubin \< 3.1 mg/dL

Renal

* See Disease Characteristics

Cardiovascular

* See Disease Characteristics
* LVEF ≥ 35%

Pulmonary

* See Disease Characteristics
* FEV_1 or FVC ≥ 40% of predicted in patients without prior thoracic or mantle radiotherapy (60% of predicted in patients with prior thoracic or mantle radiotherapy)

Other

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* HIV negative
* Geographically accessible
* No debilitating medical or psychiatric illness that would preclude giving informed consent or receiving optimal treatment or follow-up

PRIOR CONCURRENT THERAPY:

Biologic therapy

* See Disease Characteristics
* No prior transfusions from donor

Chemotherapy

* See Disease Characteristics

Endocrine therapy

* Not specified

Radiotherapy

* See Disease Characteristics

Surgery

* Not specified

Primary outcomes:
measure: Transplant-related Mortality
timeFrame: Cumulative incidence for the entire study, up to 11 years
measure: Relapse Rate
timeFrame: Cumulative incidence for the entire study, up to 11 years
measure: Progression-free Survival
timeFrame: 2 years
Secondary outcomes:
measure: Graft Failure Rate
timeFrame: Cumulative incidence for the entire study, up to 11 years
measure: Hematologic and Non-hematologic Toxicities as Measured by NCI Common Toxicity Criteria for Adverse Events, v 3.0 Weekly Until 1 Year After Transplantation
timeFrame: 1 year
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Blood and Marrow Transplant Program at Northside Hospital
state: Georgia
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Philadelphia
country: United States
facility: Hahnemann University Hospital
state: Pennsylvania
Study officials:
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
name: Ephraim J. Fuchs, MD
role: STUDY_CHAIR
References: