Clinical trial NCT00290641: Chemotherapy and Total-Body Irradiation Followed by Donor Umbilical Cord Blood Transplant, Cyclosporine, and Mycophenolate Mofetil in Treating Patients With Hematologic Cancer
Official title: A Cyclophosphamide/Fludarabine/Total Body Irradiation Preparative Regimen for Patients With Hematological Malignancy Receiving Unrelated Donor Umbilical Cord Blood Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Myelodysplastic Syndromes
Keywords: adult acute myeloid leukemia in remission
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)
childhood acute myeloid leukemia in remission
secondary acute myeloid leukemia
accelerated phase chronic myelogenous leukemia
childhood chronic myelogenous leukemia
chronic phase chronic myelogenous leukemia
relapsing chronic myelogenous leukemia
refractory anemia with excess blasts
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
noncontiguous stage II adult Burkitt lymphoma
recurrent adult Burkitt lymphoma
stage III adult Burkitt lymphoma
stage IV adult Burkitt lymphoma
noncontiguous stage II adult diffuse large cell lymphoma
recurrent adult diffuse large cell lymphoma
stage III adult diffuse large cell lymphoma
stage IV adult diffuse large cell lymphoma
noncontiguous stage II adult diffuse mixed cell lymphoma
recurrent adult diffuse mixed cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage IV adult diffuse mixed cell lymphoma
noncontiguous stage II adult diffuse small cleaved cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
contiguous stage II adult lymphoblastic lymphoma
noncontiguous stage II adult lymphoblastic lymphoma
stage III adult lymphoblastic lymphoma
stage IV adult lymphoblastic lymphoma
noncontiguous stage II grade 3 follicular lymphoma
recurrent grade 3 follicular lymphoma
stage III grade 3 follicular lymphoma
stage IV grade 3 follicular lymphoma
noncontiguous stage II mantle cell lymphoma
recurrent mantle cell lymphoma
stage III mantle cell lymphoma
stage IV mantle cell lymphoma
recurrent childhood large cell lymphoma
recurrent childhood lymphoblastic lymphoma
recurrent childhood small noncleaved cell lymphoma
adult acute lymphoblastic leukemia in remission
childhood acute lymphoblastic leukemia in remission
refractory anemia with excess blasts in transformation
refractory cytopenia with multilineage dysplasia
recurrent adult acute myeloid leukemia
recurrent childhood acute myeloid leukemia
noncontiguous stage II adult immunoblastic large cell lymphoma
recurrent adult immunoblastic large cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage IV adult immunoblastic large cell lymphoma
blastic phase chronic myelogenous leukemia
chronic idiopathic myelofibrosis
chronic eosinophilic leukemia
chronic neutrophilic leukemia
contiguous stage II adult Burkitt lymphoma
stage I adult Burkitt lymphoma
contiguous stage II adult diffuse large cell lymphoma
stage I adult diffuse large cell lymphoma
contiguous stage II adult diffuse mixed cell lymphoma
stage I adult diffuse mixed cell lymphoma
contiguous stage II adult diffuse small cleaved cell lymphoma
stage I adult diffuse small cleaved cell lymphoma
contiguous stage II adult immunoblastic large cell lymphoma
stage I adult immunoblastic large cell lymphoma
stage I adult lymphoblastic lymphoma
stage I childhood lymphoblastic lymphoma
stage II childhood lymphoblastic 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
contiguous stage II grade 3 follicular lymphoma
stage I grade 3 follicular lymphoma
contiguous stage II mantle cell lymphoma
stage I mantle 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
stage III childhood lymphoblastic lymphoma
stage IV childhood lymphoblastic lymphoma
recurrent adult lymphoblastic lymphoma
childhood myelodysplastic syndromes
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2006-02-13
Enrollment: 68
Sex: ALL
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: RATIONALE: Giving low doses of chemotherapy, such as cyclophosphamide and fludarabine, and radiation therapy before a donor umbilical cord blood stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system 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 cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.

PURPOSE: This clinical trial is studying how well giving chemotherapy together with total-body irradiation followed by donor umbilical cord blood transplant, cyclosporine, and mycophenolate mofetil works in treating patients with hematologic cancer.

Detailed description: OBJECTIVES:

Primary

* Determine the engraftment potential of unrelated allogeneic umbilical cord blood (UCB) using nonmyeloablative conditioning comprising fludarabine, cyclophosphamide, and total-body irradiation followed by post-transplant immunosuppression comprising cyclosporine and mycophenolate mofetil in patients with hematologic malignancies.

Secondary

* Determine the rate of neutrophil and platelet recovery and the completeness of donor cell engraftment in patients treated with this regimen.
* Determine the incidence and severity of acute and chronic graft-versus-host disease (GVHD) in patients treated with this regimen.
* Determine the incidence of malignant relapse in patients treated with this regimen.
* Determine the 1- and 2-year survival and event-free survival of patients treated with this regimen.
* Determine the phenotype and function of immune cells recovering after UCB transplantation in patients treated with this regimen.
* Determine the toxicity of this regimen in these patients.

OUTLINE: Patients are stratified according to HLA disparity (0-1 vs 2) and number of graft units (1 vs 2).

* Nonmyeloablative conditioning: Patients receive nonmyeloablative conditioning comprising fludarabine IV over 1 hour on days -8 to -6 and cyclophosphamide IV over 2 hours on days -7 and -6. Patients undergo total-body irradiation twice daily on days -4 to -1.
* Unrelated allogeneic umbilical cord blood transplantation (UCBT): Patients undergo 1 or 2 unrelated allogeneic UCBTs on day 0.
* Immunosuppression: Patients receive cyclosporine orally or IV over 2 hours 2-3 times daily beginning on day -3 and continuing until day 100, followed by a taper in the absence of graft-vs-host disease (GVHD). Patients also receive mycophenolate mofetil orally or IV twice daily on days -3 to 30, continuing beyond day 30 if no donor engraftment. Patients also receive filgrastim (G-CSF) IV or subcutaneously beginning on day 1 and continuing until blood counts recover.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 100 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of a hematologic malignancy of 1 of the following types:

  * Acute myeloid leukemia (AML), meeting the following criteria:

    * In complete remission (CR) by morphology (\< 5% blasts in the bone marrow), as defined by 1 of the following:

      * In first CR (CR1) and meets ≥ 1 of the following high-risk criteria:

        * High-risk cytogenetics (e.g., those associated with myelodysplastic syndromes \[MDS\] or complex karotype)
        * Preceding MDS
        * More than 2 courses of therapy was required to obtain CR
      * In second or greater CR
    * No morphologic relapse

      * Cytogenetic relapse or persistent disease allowed
  * Acute lymphocytic leukemia (ALL), meeting the following criteria:

    * In CR, as defined by 1 of the following:

      * In CR1 and meets ≥ 1 of the following high-risk criteria:

        * Unfavorable high-risk cytogenetics \[t(9;22), t(1;19), t(4;11) or other MLL rearrangements\]
        * More than 1 course of therapy was required to obtain CR
      * In second or greater CR
    * No morphologic relapse or persistent disease
  * Chronic myelogenous leukemia (CML), excluding refractory blast crisis
  * Advanced myelofibrosis
  * Advanced myelodysplasia (blasts \< 10% \[otherwise need AML induction pre-transplant\]), meeting ≥ 1 of the following criteria:

    * Refractory anemia with excess blasts (RAEB)
    * RAEB in transformation
    * Refractory anemia with severe pancytopenia
    * High-risk cytogenetics
  * Non-Hodgkin's lymphoma (NHL), meeting the following criteria:

    * One of the following histologic subtypes:

      * Mantle cell NHL

        * Disease progression after initial therapy (e.g., CHOP)
        * Beyond CR1 or beyond first partial remission (PR)
      * Intermediate-grade NHL in second or greater CR or PR
      * High-grade NHL

        * Stage III or IV disease AND received initial therapy
        * Stage I or II disease at diagnosis that subsequently progressed after a prior response duration of \< 1 year
    * No chemotherapy-refractory NHL (i.e., \< progressive disease after \> 2 salvage regimens)
* Donor available, meeting the following criteria:

  * No other existing HLA-identical related donor available
  * 4-6/6 HLA-A, -B, and -DRB1, matched unrelated donor by molecular techniques

    * A and B to antigen level resolution
    * DR to allele resolution
  * Umbilical cord blood (UCB) graft may consist of one or two UCB units 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 score 80-100% (for adults) OR
* Lansky score 50-100% (for children)
* Creatinine ≤ 2.0 mg/dL (for adults) OR creatinine clearance \> 40 mL/min (for children)

  * Adults with a creatinine \> 1.2 mg/dL or a history of renal dysfunction must have a creatinine clearance \> 40 mL/min
* Bilirubin ≤ 2 times normal
* AST and ALT ≤ 2 times normal
* Alkaline phosphatase ≤ 2 times normal
* Pulmonary function \> 50 % of normal
* LVEF ≥ 45%
* No active infection, including Aspergillus or other mold, within the past 30 days
* No history of HIV infection
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* No prior myeloablative transplant within the past 6 months if ≤ 18 years old
* No prior myeloablative allotransplant or autologous transplant if \> 18 years old
* No prior extensive therapy (e.g., \> 12 months of alkylating therapy or \> 6 months of alkylating therapy with extensive radiation)

Primary outcomes:
measure: Engraftment as measured by an absolute neutrophil count of donor origin > 0.5 x 109 /L for 3 days by day 42
Secondary outcomes:
measure: Incidence and severity of acute or chronic graft-versus-host-disease, relapse, or mortality at day 100
measure: Survival and event-free survival by Kaplan-Meier estimation at 1 and 2 years after umbilical cord blood (UCB) transplant
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: University of Minnesota Cancer Center
state: Minnesota
Study officials:
affiliation: Masonic Cancer Center, University of Minnesota
name: Claudio G. Brunstein, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, McGlave PB, Miller JS, Verfaillie CM, Wagner JE. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood. 2005 Feb 1;105(3):1343-7. doi: 10.1182/blood-2004-07-2717. Epub 2004 Oct 5.