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A Myeloablative Conditioning Regimen Consisting of Cyclophosphamide, Fludarabine and Total Body Irradiation Followed by the Transplantation of Unrelated Donor Double Unit Umbilical Cord Blood Grafts for Patients With Hematological Malignancy


Phase 2
4 Years
50 Years
Open (Enrolling)
Both
Leukemia, Lymphoma, Myelodysplastic Syndromes

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Trial Information

A Myeloablative Conditioning Regimen Consisting of Cyclophosphamide, Fludarabine and Total Body Irradiation Followed by the Transplantation of Unrelated Donor Double Unit Umbilical Cord Blood Grafts for Patients With Hematological Malignancy


OBJECTIVES:

Primary

- Determine, preliminarily, the efficacy of double-unit umbilical cord blood (UCB)
transplantation (UCBT) in patients with hematologic malignancy.

Secondary

- Determine the incidence and rate of donor-derived neutrophil and platelet recovery in
these patients.

- Determine the contribution of each unit of UCB to initial and sustained engraftment in
these patients.

- Determine the incidence and severity of acute graft-vs-host disease (GVHD) at 100 days
in these patients.

- Determine the incidence and severity of chronic GVHD at 1 year in these patients.

- Determine the incidence of treatment-related mortality at 100 and 180 days in these
patients.

- Determine the incidence of malignant relapse in these patients.

- Determine the incidence of serious infectious complications in these patients.

- Determine immune recovery after UCBT and correlate with serious infectious
complications in these patients.

- Determine the probabilities of overall and disease-free survival of these patients at 2
years after UCBT.

- Determine the performance of double-unit correlative laboratory studies and correlate
with engraftment of each unit in these patients.

OUTLINE:

- Myeloablative preparative regimen: Patients receive fludarabine phosphate IV over 30
minutes on days -7 to -5 and cyclophosphamide IV over 30-60 minutes on days -6 and -5.
Patients also undergo total-body irradiation 3 times daily on days -3 to -1 and twice
on day 0.

- Umbilical cord blood (UCB) transplantation: Patients receive UCB IV over 20-60 minutes
on day 0. Patients also receive filgrastim (G-CSF) IV or subcutaneously beginning on
day 1 and continuing until blood counts recover.

- Graft-vs-host (GVHD) prophylaxis: Patients receive cyclosporine IV over 2-4 hours or
orally every 8-12 hours on days -3 to 100 and mycophenolate mofetil IV or orally twice
daily on days -3 to 45.

Blood samples and bone marrow aspirates are collected at baseline and periodically during
and after completion of study treatment. Samples may be examined for engraftment, chimerism
analysis, cytogenetic analysis, recovery of natural killer cells, and immune recovery.
Lymphoid immunophenotyping and function is also determined.

UCB units are examined by flow cytometry and killer immunoglobulin-like receptor (KIR)
genotype analysis.

After completion of study therapy, patients are followed periodically for at least 2 years.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Diagnosis of one of the following:

- Acute myeloid leukemia (AML) meeting 1 of the following criteria:

- Complete first remission (CR1) at high risk for relapse, defined by 1 of
the following:

- Known prior diagnosis of myelodysplastic syndromes (MDS)

- Therapy-related AML

- WBC > 100,000/mm³

- Presence of extramedullary leukemia at diagnosis

- Unfavorable FAB type (M0, M5-7)

- High-risk cytogenetics (those associated with MDS, abnormalities of
Philadelphia chromosomes 5, 7, or 8, or complex karyotype)

- Required ≥ 2 inductions to achieve CR1

- Complete second remission (CR2)

- No AML ≥ CR2

- Acute lymphoblastic leukemia (ALL) meeting 1 of the following criteria:

- CR1 at risk for relapse, defined by 1 of the following:

- WBC > 100,000/mm³ (< 18 years old) OR > 50,000/mm³ (≥ 18 years old)

- Presence of extensive extramedullary disease (excluding CNS disease)

- Presence of high-risk cytogenetic abnormality, such as t(9;22),
t(1;19), t(4;11), or other myelomonocytic leukemia rearrangements
(11q23) or t(8;14) (excluding blastic-phase ALL in pediatric patients)

- Failed to achieve complete remission after 4 weeks of induction
therapy

- CR2 or complete third remission (CR3)

- Not > CR3

- Acute undifferentiated leukemia, infant leukemia, or biphenotypic leukemia in
CR1, CR2, or CR3

- Patients with infant leukemia must be able to receive total-body
irradiation

- Not > CR3

- Juvenile myelomonocytic leukemia with < 30% bone marrow blasts

- Chronic myelogenous leukemia meeting the following criteria:

- Failed prior imatinib mesylate AND in first or second chronic phase or
accelerated phase

- Not in blast crisis

- MDS meeting the following criteria:

- Low (score 0) International Prognostic Scoring System (IPSS) score with
life threatening cytopenia or red cell or platelet-transfusion dependent OR
intermediate (score 1) or high (score 2) IPSS score

- Patients with bone marrow blasts ≥ 10% should have AML induction therapy
with disease response to < 5% blasts and at least partial count recovery

- No MDS with ≥ 10% bone marrow blasts refractory to chemotherapy

- Non-Hodgkin's lymphoma (NHL) meeting 1 of the following criteria:

- High-grade disease in first partial remission (PR) after initial therapy
with biopsy-proven residual disease that is not appropriate for further
chemotherapy or autologous stem cell transplantation

- High-grade or diffuse large cell NHL with recurrent disease after first
remission with chemosensitivity as evidenced by at least PR (defined as >
50% reduction in mass size after therapy)

- No NHL refractory to chemotherapy (less than PR after ≥ 2 regimens)

- No AML evolved from myelofibrosis

- Not a candidate for autologous stem cell transplantation

- No active CNS leukemia

- No bone marrow aplasia (bone marrow cellularity < 5%)

- No acute leukemia with any of the following:

- Morphologic relapse or persistent disease in the bone marrow (cytogenetic
relapse without morphologic evidence of relapse or cytogenetic persistent
disease in the bone marrow is allowed)

- Active extramedullary leukemia

- Required > 2 courses of chemotherapy to obtain present remission status

- No suitably HLA matched related or unrelated volunteer donor available

- Double-unit umbilical cord blood units must meet the following criteria:

- At least 4 of 6 HLA-A and B antigen and DRB1 allele matched with recipient

- At least 3 of 6 HLA-A, B, and DRB1 matched to each other

- Cryopreserved dose of ≥ 1.5 x 10^7 total nucleated cells/recipient body weight
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:

- Karnofsky performance status (PS) 70-100% (age ≥ 16 years) OR Lansky PS 70-100% (age
< 16 years)

- Creatinine clearance ≥ 60 mL/min OR creatinine < 1.5 mg/dL

- Bilirubin < 2.5 mg/dL (unless Gilbert's syndrome)

- ALT and AST < 3 times upper limit of normal

- Albumin ≥ 2.5 g/dL

- LVEF ≥ 50%

- DLCO ≥ 60%

- No uncontrolled viral, bacterial, or fungal infection

- Not HIV positive

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- No prior autologous or allogeneic hematopoietic stem cell transplantation

- No prior radiation therapy rendering the patient ineligible for total-body
irradiation

Type of Study:

Interventional

Study Design:

Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall and disease-free survival at 1 year

Safety Issue:

No

Principal Investigator

Juliet Barker, MBBS

Investigator Role:

Study Chair

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center

Authority:

Unspecified

Study ID:

CDR0000502363

NCT ID:

NCT00388102

Start Date:

March 2006

Completion Date:

Related Keywords:

  • Leukemia
  • Lymphoma
  • 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)
  • chronic phase chronic myelogenous leukemia
  • juvenile myelomonocytic leukemia
  • previously treated myelodysplastic syndromes
  • relapsing chronic myelogenous leukemia
  • secondary acute myeloid leukemia
  • secondary myelodysplastic syndromes
  • adult acute megakaryoblastic leukemia (M7)
  • adult acute minimally differentiated myeloid leukemia (M0)
  • adult acute monoblastic leukemia (M5a)
  • adult acute monocytic leukemia (M5b)
  • adult erythroleukemia (M6a)
  • adult pure erythroid leukemia (M6b)
  • adult acute lymphoblastic leukemia in remission
  • adult acute myeloid leukemia in remission
  • childhood acute lymphoblastic leukemia in remission
  • childhood acute myeloid leukemia in remission
  • accelerated phase chronic myelogenous leukemia
  • childhood chronic myelogenous leukemia
  • de novo myelodysplastic syndromes
  • acute undifferentiated leukemia
  • recurrent adult diffuse large cell lymphoma
  • recurrent adult immunoblastic large cell lymphoma
  • recurrent adult lymphoblastic lymphoma
  • recurrent mantle cell lymphoma
  • recurrent childhood large cell lymphoma
  • childhood diffuse large cell lymphoma
  • recurrent childhood lymphoblastic lymphoma
  • recurrent childhood small noncleaved cell lymphoma
  • Burkitt lymphoma
  • recurrent adult Burkitt lymphoma
  • stage III adult Burkitt lymphoma
  • stage III adult diffuse large cell lymphoma
  • stage III adult immunoblastic large cell lymphoma
  • stage III adult lymphoblastic lymphoma
  • stage III mantle cell lymphoma
  • stage IV adult Burkitt lymphoma
  • stage IV adult diffuse large cell lymphoma
  • stage IV adult immunoblastic large cell lymphoma
  • stage IV adult lymphoblastic lymphoma
  • stage IV mantle cell lymphoma
  • noncontiguous stage II adult Burkitt lymphoma
  • noncontiguous stage II adult diffuse large cell lymphoma
  • noncontiguous stage II adult immunoblastic large cell lymphoma
  • noncontiguous stage II adult lymphoblastic lymphoma
  • noncontiguous stage II mantle cell lymphoma
  • childhood immunoblastic large cell lymphoma
  • childhood myelodysplastic syndromes
  • Leukemia
  • Lymphoma
  • Myelodysplastic Syndromes
  • Preleukemia
  • Lymphoma, Large-Cell, Immunoblastic

Name

Location

Memorial Sloan-Kettering Cancer CenterNew York, New York  10021