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

Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00301834
• Other study ID #: CDR0000462406
• Secondary ID: UCSF-04152UCSF-0
• Status: Completed
• Phase: Phase 2
• First received: March 9, 2006
• Last updated: August 30, 2017
• Start date: January 2005
• Est. completion date: September 2011

Study information

• Verified date: August 2017
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 35
• Est. completion date: September 2011
• Est. primary completion date: September 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 21 Years

Eligibility

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)

• ß-thalassemia major

• Sickle cell anemia

• Hemoglobin E/ß-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)-Drß1 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-Drß1 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 -DRß1 alleles with at least 1 -DRß1 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

Related Conditions & MeSH terms

• Anemia, Diamond-Blackfan
• Congenital Amegakaryocytic Thrombocytopenia
• Diamond-blackfan Anemia
• Leukemia
• Myelodysplastic Syndromes
• Neutropenia
• Preleukemia
• Severe Congenital Neutropenia
• Syndrome
• Thrombocytopenia

Intervention

Biological:
• alemtuzumab

Drug:
• busulfan

• cyclosporine

• fludarabine phosphate

• methotrexate

• methylprednisolone

Procedure:
• allogeneic bone marrow transplantation

• allogeneic hematopoietic stem cell transplantation

• peripheral blood stem cell transplantation

• umbilical cord blood transplantation

Locations

Country	Name	City	State
United States	University of Wisconsin Paul P. Carbone Comprehensive Cancer Center	Madison	Wisconsin
United States	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
University of California, San Francisco	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Achieving Durable Engraftment (Presence of Donor Cells) at 6 Weeks Post Transplantation	Peripheral blood chimerism studies were performed by quantitative real time polymerase chain reaction (qPCR) evaluation of differential short tandem repeat DNA sequences	6 weeks post-transplant
Secondary	Treatment-related Mortality at 100 Days and 1 Year Post Transplantation		100 days and 1 year
Secondary	Toxicity Grade = 3 From Start of Conditioning Through the First Year Post Transplantation		1 year post-transplantation
Secondary	Cytomegalovirus (CMV) Viral Infection and Disease Symptoms	polymerase chain reaction testing for presence of CMV weekly until at least day +100 then every 2 weeks until T-cell reconstitution as defined by cluster of differentiation 4 (CD4) > 200 cells/mm3. Median time to T-cell reconstitution was 6 months.	Up to one year post-transplant
Secondary	Disease-free Survival With Correction of Disease at One Year Post Transplantation	Patients deemed "alive and well" at follow-up timepoint later than 1-year post-transplantation	1 year post-transplantation