Alemtuzumab, Fludarabine, and Busulfan Followed By Donor Stem Cell Transplant in Treating Young Patients With Hematologic Disorders

University of California San Francisco (UCSF)

Status and phase

Completed

Phase 2

Conditions

Diamond-blackfan Anemia

Congenital Amegakaryocytic Thrombocytopenia

Leukemia

Myelodysplastic Syndromes

Severe Congenital Neutropenia

Treatments

Drug: busulfan

Drug: methotrexate

Biological: alemtuzumab

Procedure: umbilical cord blood transplantation

Drug: methylprednisolone

Drug: fludarabine phosphate

Procedure: allogeneic bone marrow transplantation

Drug: cyclosporine

Procedure: peripheral blood stem cell transplantation

Procedure: allogeneic hematopoietic stem cell transplantation

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00301834

UCSF-H411-25738-02 (Other Identifier)

UCSF-04152 (Other Identifier)

UCSF-00452 (Other Identifier)

CDR0000462406

Details and patient eligibility

About

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.

Full 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.

Enrollment

35 patients

Sex

All

Ages

Under 21 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

35 participants in 1 patient group

Single arm - conditioning and transplant

Experimental group

Description:

Alemtuzumab 0.5 mg/kg (maximum 15 mg) daily for 3 days; Busulfan i.v. every 6 hours from day -9 to day -6 for 16 total doses; Fludarabine phosphate from day -5 for 4 days at 1.3 mg/kg (if patient was less than 12 kg) or 40 mg/m\*2 per dose; Cyclosporine continuous infusion 3 mg/kg/Day beginning day -1 for GVHD prophylaxis; Methotrexate at 15 mg/m\*2 on day +1, 10 mg/m\*2 on days +3, +6, and (only for MUDs) day +11 also for GVHD prophylaxis; Methylprednisolone only as required for GVHD prophylaxis; allogeneic bone marrow transplantation or allogeneic hematopoietic stem cell transplantation or peripheral blood stem cell transplantation or umbilical cord blood transplantation.

Treatment: