Clinical trial NCT00301834: Alemtuzumab, Fludarabine, and Busulfan Followed By Donor Stem Cell Transplant in Treating Young Patients With Hematologic Disorders
Official title: Evaluation of Fludarabine, Busulfan and Alemtuzumab as a Reduced Toxicity Ablative Bone Marrow Stem Cell Transplant Regimen for Children With Stem Cell Defects, Marrow Failure Syndromes, or Myelodysplastic Syndrome (MDS)/Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Congenital Amegakaryocytic Thrombocytopenia
Diamond-blackfan Anemia
Leukemia
Myelodysplastic Syndromes
Severe Congenital Neutropenia
Keywords: de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
childhood acute myeloid leukemia in remission
childhood chronic myelogenous leukemia
congenital amegakaryocytic thrombocytopenia
Diamond-Blackfan anemia
severe congenital neutropenia
secondary acute myeloid leukemia
chronic phase chronic myelogenous leukemia
childhood myelodysplastic syndromes
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2006-03-13
Enrollment: 35
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Monoclonal antibodies, such as alemtuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as fludarabine and busulfan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. A peripheral stem cell, bone marrow , or umbilical cord blood transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine together with methotrexate and methylprednisolone may stop this from happening.

PURPOSE: This phase II trial is studying how well giving alemtuzumab together with fludarabine and busulfan works when given before donor stem cell transplant in treating young patients with hematologic disorders.

Detailed description: OBJECTIVES:

Primary

* Determine the engraftment rate with reduced toxicity ablative conditioning regimen comprising alemtuzumab, fludarabine, and busulfan followed by allogeneic stem cell transplantation in pediatric patients with stem cell defects, marrow failure syndromes, hemoglobinopathy, severe immunodeficiency syndromes (nonsevere combined immunodeficiency disorders), myelodysplastic syndromes, or myeloid leukemia.

Secondary

* Determine the acute reactions, incidence of infections, and rate of immune reconstitution in patients treated with this regimen.

OUTLINE: This is a multicenter study.

* Conditioning regimen: Patients receive alemtuzumab IV over 6 hours on days -12 to -10, high-dose busulfan IV over 2 hours 4 times daily on days -9 to -6, and fludarabine IV over 30 minutes on days -5 to -2.
* Allogeneic stem cell transplantation: Two days after the completion of conditioning regimen, patients undergo allogeneic bone marrow, peripheral blood stem cell, or umbilical cord blood transplantation on day 0. Patients receive filgrastim (G-CSF) subcutaneously beginning on day 5 and continuing until blood counts recover.
* Graft-vs-host disease (GVHD) prophylaxis:

  * Most transplantations (bone marrow or peripheral blood stem cell transplantation): Patients receive cyclosporine IV continuously beginning on day -1 until at least day 50 followed by a taper at either 2 months, 9 months, or 1 year in the absence of GVHD. Patients also receive methotrexate on days 1, 3, and 6.
  * Umbilical cord blood transplantation: Patients receive cyclosporine as in most transplantations, and methylprednisolone IV twice daily on days 0-21 followed by a weekly taper.

After transplantation, patients are followed periodically for up to 20 years.

PROJECTED ACCRUAL: A total of 35 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of 1 of the following hematologic conditions:

  * Aplastic anemia with marrow aplasia, meeting all of the following criteria:

    * Absolute neutrophil count \< 500/mm\^3
    * Platelet and/or red cell transfusion dependent
  * Chronic aplastic anemia, meeting all of the following criteria:

    * Transfusion dependent
    * Unresponsive to immunosuppressive therapy
    * Alternative matched unrelated donor has been identified
  * Congenital marrow failure syndrome, including any of the following (with closely matched related or unrelated donor):

    * Primary red cell aplasia (Diamond-Blackfan syndrome)
    * Congenital neutropenia (Kostmann's syndrome)
    * Amegakaryocytic thrombocytopenia
    * Congenital dyserythropoietic anemias
    * Other severe acquired cytopenias in which a transplantation using a combined busulfan/cyclophosphamide conditioning regimen is indicated
  * Hemoglobinopathy (with closely matched related or unrelated donor)

    * β-thalassemia major
    * Sickle cell anemia
    * Hemoglobin E/β-thalassemia
  * Severe immunodeficiency disease

    * Chediak-Higashi disease
    * Wiskott-Aldrich syndrome
    * Combined immunodeficiency disease (Nezelof's)
    * Hyper immunoglobulin M (IgM) syndrome
    * Bare lymphocyte syndrome
    * Chronic granulomatous disease
    * Familial erythrohemophagocytic lymphohistiocytosis
  * Other stem cell defects (e.g., osteopetrosis)
  * Severe immune dysregulation/autoimmune disorders

    * Achieved a transient response to prior immunosuppressive therapy
  * Chronic myelogenous leukemia

    * Disease in first chronic phase
  * Acute myeloid leukemia

    * Disease in first remission
  * Myelodysplastic syndromes
  * Inborn errors of metabolism
  * Histiocytosis
* No severe combined immunodeficiency disease
* Matched related or unrelated donor available by high resolution DNA typing

  * Related donor, meeting both of the following criteria:

    * Matched at both human leukocyte antigen (HLA)-Drβ1 alleles
    * No more than 1 mismatch at the 4 HLA-A and -B alleles
  * Unrelated donor, meeting 1 of the following criteria:

    * Marrow matched at both HLA-Drβ1 alleles AND no more than 1 mismatch at the 4 HLA-A and -B alleles
    * Umbilical cord blood matched at 5/6 HLA-A, -B, and -DRβ1 alleles with at least 1 -DRβ1 match AND there are ≥ 3x10\^5 CD34+ (Cluster of differentiation 34-positive) cells per kg body weight of recipient available at the time of cryopreservation

PATIENT CHARACTERISTICS:

* Cardiac ejection fraction ≥ 27%
* Creatinine clearance ≥ 50 mL/min by 24-hour urine collection or glomerular filtration rate
* DLCO (diffusion capacity of lung for carbon monoxide) ≥ 50% of predicted (corrected for anemia/lung volume)

PRIOR CONCURRENT THERAPY:

* No prior transplantation for leukemia from which patient remains engrafted and alemtuzumab is not needed as part of the conditioning regimen

Primary outcomes:
measure: Number of Participants Achieving Durable Engraftment (Presence of Donor Cells) at 6 Weeks Post Transplantation
timeFrame: 6 weeks post-transplant
Secondary outcomes:
measure: Treatment-related Mortality at 100 Days and 1 Year Post Transplantation
timeFrame: 100 days and 1 year
measure: Toxicity Grade ≥ 3 From Start of Conditioning Through the First Year Post Transplantation
timeFrame: 1 year post-transplantation
measure: Cytomegalovirus (CMV) Viral Infection and Disease Symptoms
timeFrame: Up to one year post-transplant
measure: Disease-free Survival With Correction of Disease at One Year Post Transplantation
timeFrame: 1 year post-transplantation
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
city: Madison
country: United States
facility: University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
state: Wisconsin
Study officials:
affiliation: University of California, San Francisco
name: Morton J. Cowan, MD
role: STUDY_CHAIR
References: