Clinical trial NCT00055653: Donor Umbilical Cord Blood Transplantation in Treating Patients With Leukemia, Lymphoma, or Nonmalignant Hematologic Disorders
Official title: Unrelated Umbilical Cord Blood As An Alternate Source Of Stem Cells Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia
Lymphoma
Myelodysplastic Syndromes
Myelodysplastic-Myeloproliferative Diseases
Keywords: refractory anemia with excess blasts in transformation
refractory anemia with excess blasts
refractory anemia with ringed sideroblasts
refractory anemia
chronic myelomonocytic leukemia
childhood acute myeloid leukemia in remission
recurrent childhood acute myeloid leukemia
secondary acute myeloid leukemia
childhood acute lymphoblastic leukemia in remission
recurrent childhood acute lymphoblastic leukemia
accelerated phase chronic myelogenous leukemia
blastic phase chronic myelogenous leukemia
chronic phase chronic myelogenous leukemia
acute undifferentiated leukemia
recurrent/refractory childhood Hodgkin lymphoma
recurrent childhood large cell lymphoma
recurrent childhood lymphoblastic lymphoma
recurrent childhood small noncleaved cell lymphoma
untreated childhood acute lymphoblastic leukemia
untreated childhood acute myeloid leukemia and other myeloid malignancies
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
atypical chronic myeloid leukemia
myelodysplastic/myeloproliferative disease, unclassifiable
Lead sponsor: Roswell Park Cancer Institute
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2003-03-07
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: RATIONALE: Umbilical cord blood transplantation may be able to replace immune cells that were destroyed by the chemotherapy or radiation therapy that was used to kill cancer cells.

PURPOSE: Phase II trial to study the effectiveness of allogeneic umbilical cord blood transplantation in treating patients who have leukemia, lymphoma, or nonmalignant hematologic disorders.

Detailed description: OBJECTIVES:

* Determine 180-day survival in patients with malignant or nonmalignant hematologic diseases treated with allogeneic umbilical cord blood transplantation. (Severe aplastic anemia, Fanconi anemia, and marrow failure syndromes strata are closed to accrual; adult \[over 18 years of age\] patient stratum is closed to accrual.)
* Determine disease-free and long-term survival in patients treated with this regimen.
* Determine the incidence of neutrophil engraftment, primary and secondary graft failure, platelet engraftment, and red blood cell engraftment in patients treated with this regimen.
* Determine the incidence and severity of acute and chronic graft-versus-host disease in patients treated with this regimen.
* Determine the incidence of complications, including infection, veno-occlusive disease, and interstitial pneumonitis, in patients treated with this regimen.
* Determine the incidence of relapse, other malignancies, lymphoproliferative disorders, and posttransplantation myelodysplasia in patients treated with this regimen.
* Determine the immune reconstitution in patients treated with this regimen.

OUTLINE: This is a multicenter study. Patients are grouped according to the following strata:

* Stratum I: Malignant disease, 5/6 or 6/6 HLA match, age 18 and under
* Stratum II: Malignant disease, 4/6 HLA match, age 18 and under
* Stratum III: Malignant disease, 3/6 HLA match, age 18 and under
* Stratum IV: Malignant disease, 2/6 or 1/6 HLA match, age 18 and under
* Stratum V (closed to accrual): Severe aplastic anemia, Fanconi anemia, or other marrow failure syndrome
* Stratum VI: Inborn errors of metabolism/storage diseases and other nonmalignant diseases not included in stratum V
* Stratum VII: Malignant disease receiving alternative conditioning regimen comprising busulfan and melphalan
* Stratum VIII (closed to accrual): Adult patients (over age 18)
* Conditioning therapy: Patients are assigned to 1 of 5 groups according to diagnosis.

  * Group I (malignant disease or severe aplastic anemia \[severe aplastic anemia closed to accrual\]): Patients undergo total body irradiation (TBI) once or twice daily on days -8 to -4. Patients then receive cyclophosphamide IV on days -3 and -2, methylprednisolone IV on days -3 to 0, and antithymocyte globulin (ATG) IV once or twice daily on days -3 to -1.
  * Group II (Fanconi anemia \[closed to accrual\]): Patients undergo TBI on day -6, and then receive cyclophosphamide IV and fludarabine IV on days -5 to -2, and methylprednisolone IV and ATG IV on days -5 to -1.
  * Group III (inborn errors of metabolism/storage disease): Patients receive oral busulfan 4 times daily on days -9 to -6, cyclophosphamide as in group II, and methylprednisolone and ATG as in group I.
  * Group IV (other nonmalignant diseases): Patients receive conditioning therapy as in group III. Patients with familial erythrophagocytic lymphohistiocytosis or Langerhans cell histiocytosis also receive etoposide on days -5 to -3.
  * Group V (non-TBI regimen for leukemia patients under 2 years of age): Patients receive oral busulfan 4 times daily on days -8 to -5, melphalan IV on days -4 to -2, and methylprednisolone and ATG as in group I.
* Allogeneic umbilical cord blood transplantation: All patients undergo umbilical cord blood transplantation on day 0. Beginning on day 0 or 1, patients receive filgrastim (G-CSF) IV or subcutaneously daily until blood counts recover.
* Graft-versus-host disease prophylaxis: Patients receive cyclosporine (IV or oral) beginning between days -3 and -1 and continuing for 1 year after transplantation and methylprednisolone twice daily beginning on day 1 and continuing until blood counts recover.

Patients are followed weekly for 14 weeks, at 100 days, and at 4, 5, 6, 9, 12, 18, 24, and 36 months.

PROJECTED ACCRUAL: A total of 360 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of 1 of the following hematologic malignancies:

  * Acute myeloid leukemia (AML)\*

    * With or without history of myelodysplastic syndromes (MDS)
    * Patients in first complete remission (CR) (no greater than 5% blasts in marrow) with translocations t(8;21) and inv(16) are allowed provided they failed first-line induction therapy
    * Patients in first CR (no greater than 5% blasts in marrow) with translocations t(15;17) are allowed provided at least 1 of the following is true:

      * Failed first-line induction therapy
      * Molecular evidence of persistent disease
    * No patients in first CR and with Down syndrome
  * Acute lymphoblastic leukemia (ALL)\*, meeting 1 of the following criteria:

    * Not in first CR (no greater than 5% blasts in marrow)
    * In first CR and high risk as defined by 1 of the following:

      * Hypoploidy (no more than 44 chromosomes)
      * Pseudodiploidy with translocations or molecular evidence of t(9;22), 11q23, or t(8;14) (excluding B-ALL) or +MLL gene rearrangement
      * One of the following elevated WBC levels:

        * WBC greater than 100,000/mm\^3 if 6 to 12 months of age
        * WBC greater than 200,000/mm\^3 if between 10 and 17 years of age
        * WBC greater than 20,000/mm\^3 if 18 years of age and over (adult \[over 18 years of age\] patient stratum closed to accrual)
      * Failed to achieve CR after 4 weeks of induction therapy
    * B-ALL that is not in first CR or that meets at least 1 of the high-risk criteria specified above

      * No translocation t(8;14)
      * No blasts with surface immunoglobulins
      * CD10 negative
  * Undifferentiated leukemia\*
  * Infant leukemia\*
  * Biphenotypic leukemia\*
  * Chronic myelogenous leukemia, meeting 1 of the following criteria:

    * Accelerated phase
    * Chronic phase

      * At least 1 year from diagnosis without an identified matched unrelated bone marrow donor AND unresponsive to or unable to tolerate interferon
    * Blast crisis\* (greater than 30% promyelocytes plus blasts in the marrow)
  * One of the following MDS:

    * Refractory anemia
    * Refractory anemia with ringed sideroblasts
    * Refractory anemia with excess blasts (RAEB)
    * RAEB in transformation
    * Chronic myelomonocytic leukemia
  * Paroxysmal nocturnal hemoglobinuria
  * Hodgkin's or non-Hodgkin's lymphoma beyond first CR or failed primary induction therapy

    * Tumor displays chemosensitivity (greater than 50% reduction in mass size after the most recent therapy) NOTE: \*Patients in third or greater medullary relapse or refractory disease (other than primary induction failures) or blast crisis receive the study busulfan/melphalan conditioning regimen)

OR

* Diagnosis of one of the following nonmalignant diseases :

  * Acquired severe aplastic anemia (stratum closed to accrual)

    * Unresponsive to medical therapy with anti-thymocyte globulin and/or cyclosporine
  * Inborn errors of metabolism, including, but not limited to the following:

    * Hurler's syndrome
    * Adrenoleukodystrophy
    * Maroteaux-Lamy syndrome
    * Globoid cell leukodystrophy
    * Metachromatic leukodystrophy
    * Fucosidosis
    * Mannosidosis
  * Fanconi anemia documented by increased chromosomal fragility assays and meeting 1 of the following criteria (stratum closed to accrual):

    * Severe pancytopenia

      * Absolute neutrophil count less than 500/mm\^3
      * Platelet count less than 20,000/mm\^3
      * Hemoglobin less than 8 g/dL
    * Morphologic evidence of MDS with clonal chromosomal abnormalities
    * Leukemia transformation
  * Other marrow failure syndromes, including any of the following (stratum closed to accrual):

    * Blackfan-Diamond syndrome that is unresponsive to medical therapy
    * Kostmann's congenital agranulocytosis unresponsive to medical therapy
    * Congenital amegakaryocytic thrombocytopenia
    * Thrombocytopenia absent radius
  * Combined immune deficiencies including, but not limited to the following:

    * Severe combined immunodeficiency (SCID)
    * Wiskott-Aldrich syndrome
    * Leukocyte adhesion defect
    * Chediak-Higashi disease
    * X-linked lymphoproliferative disease
    * Adenosine deaminase deficiency
    * Purine nucleoside phosphorylase deficiency
    * X-linked SCID
    * Common variable immune deficiency
    * Nezeloff's syndrome
    * Cartilage hair hypoplasia
    * Reticular dysgenesis
* No active CNS leukemia (cerebrospinal fluid with WBC greater than 5/mm\^3 and malignant cells on cytospin)
* No SCID patients who do not require cytoreduction
* No dyskeratosis congenita
* No primary myelofibrosis
* No grade 3 or greater myelofibrosis
* Familial erythrophagocytic lymphohistiocytosis patients must not have any of the following:

  * Abnormal brain MRI
  * Neurologic symptoms
  * Lymphocytes and monocytes greater than 7/mm\^3 in the cerebrospinal fluid
* No available 5/6 or 6/6 HLA-matched related donor

PATIENT CHARACTERISTICS:

Age

* 55 and under (over 18 closed to accrual)

Performance status

* Karnofsky 70-100% OR
* Lansky 50-100% (patients under 16 years old)

Life expectancy

* Not specified

Hematopoietic

* See Disease Characteristics

Hepatic

* SGOT less than 5 times upper limit of normal
* Bilirubin less than 2.5 mg/dL

Renal

* Creatinine normal for age OR
* Creatinine clearance or glomerular filtration rate greater than 50% of lower limit of normal

Cardiovascular

* LVEF greater than 40% at rest and must improve with exercise\* OR
* Shortening fraction greater than 26%\* NOTE: \*If symptomatic

Pulmonary

* DLCO greater than 45% of predicted\* (corrected for hemoglobin)
* FEV_1 and FEC greater than 45% of predicted (corrected for hemoglobin) OR
* Room air oxygen saturation greater than 85%\* NOTE: \*If symptomatic

Other

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No uncontrolled viral, bacterial, or fungal infection
* HIV negative

PRIOR CONCURRENT THERAPY:

Biologic therapy

* See Disease Characteristics
* More than 12 months since prior allogeneic stem cell transplantation with cytoreductive preparative therapy
* More than 6 months since prior autologous stem cell transplantation

Chemotherapy

* See Biologic therapy

Endocrine therapy

* Not specified

Radiotherapy

* Not specified

Surgery

* Not specified

Other

* No prior enrollment on this study
* No continuous life support (e.g., mechanical ventilation) within 1 year after study transplantation (for patients with inborn errors of metabolism)

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: Jonsson Comprehensive Cancer Center, UCLA
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Francisco
country: United States
facility: Children's Medical Center, University of California San Francisco
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Indianapolis
country: United States
facility: Indiana University Cancer Center
state: Indiana
city: New Orleans
country: United States
facility: Children's Hospital of New Orleans
state: Louisiana
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
state: Massachusetts
city: Grand Rapids
country: United States
facility: Spectrum Health and DeVos Children's Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Cancer Center
state: Minnesota
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Cardinal Glennon Children's Hospital
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: Rochester
country: United States
facility: James P. Wilmot Cancer Center at University of Rochester Medical Center
state: New York
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Cleveland
country: United States
facility: Ireland Cancer Center
state: Ohio
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: Medical City Dallas Hospital
state: Texas
city: Dallas
country: United States
facility: Children's Medical Center of Dallas
state: Texas
city: San Antonio
country: United States
facility: Texas Transplant Institute
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
Study officials:
affiliation: Roswell Park Cancer Institute
name: Philip L. McCarthy, MD
role: STUDY_CHAIR
References: