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

• ClinicalTrials.gov Identifier: NCT00301834
• Recruitment Status: Completed
• First Posted: March 13, 2006
• Results First Posted: May 16, 2013
• Last Update Posted: September 28, 2017
• Sponsor: University of California, San Francisco
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): University of California, San Francisco

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Congenital Amegakaryocytic Thrombocytopenia; Diamond-blackfan Anemia; Leukemia; Myelodysplastic Syndromes; Severe Congenital Neutropenia	Biological: alemtuzumab; Drug: busulfan; Drug: cyclosporine; Drug: fludarabine phosphate; Drug: methotrexate; Drug: methylprednisolone; Procedure: allogeneic bone marrow transplantation; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation; Procedure: umbilical cord blood transplantation	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: January 2005
• Actual Primary Completion Date: September 2011
• Actual Study Completion Date: September 2011

Arms and Interventions

Arm

Intervention/treatment

Experimental: Single arm - conditioning and transplant; 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.

Biological: alemtuzumab; Drug: busulfan; Drug: cyclosporine; Drug: fludarabine phosphate; Drug: methotrexate; Drug: methylprednisolone; Procedure: allogeneic bone marrow transplantation; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation; Procedure: umbilical cord blood transplantation

Outcome Measures

Primary Outcome Measures :

1. Number of Participants Achieving Durable Engraftment (Presence of Donor Cells) at 6 Weeks Post Transplantation [ Time Frame: 6 weeks post-transplant ]
   Peripheral blood chimerism studies were performed by quantitative real time polymerase chain reaction (qPCR) evaluation of differential short tandem repeat DNA sequences

Secondary Outcome Measures :

1. Treatment-related Mortality at 100 Days and 1 Year Post Transplantation [ Time Frame: 100 days and 1 year ]
2. Toxicity Grade ≥ 3 From Start of Conditioning Through the First Year Post Transplantation [ Time Frame: 1 year post-transplantation ]
3. Cytomegalovirus (CMV) Viral Infection and Disease Symptoms [ Time Frame: Up to one year post-transplant ]
   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.
4. Disease-free Survival With Correction of Disease at One Year Post Transplantation [ Time Frame: 1 year post-transplantation ]
   Patients deemed "alive and well" at follow-up timepoint later than 1-year post-transplantation

Eligibility Criteria

• Ages Eligible for Study: up to 21 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, California

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, California, United States, 94115

United States, Wisconsin

University of Wisconsin Paul P. Carbone Comprehensive Cancer Center

Madison, Wisconsin, United States, 53792-6164

Sponsors and Collaborators

University of California, San Francisco

National Cancer Institute (NCI)

Investigators

• Study Chair: Morton J. Cowan, MD; University of California, San Francisco

More Information

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT00301834
• Other Study ID Numbers: CDR0000462406; UCSF-04152 ( Other Identifier: UCSF Helen Diller Family Comprehensive Cancer Center ); UCSF-00452 ( Other Identifier: UCSF Helen Diller Family Comprehensive Cancer Center ); UCSF-H411-25738-02 ( Other Identifier: UCSF Committee on Human Research (CHR) )
• First Posted: March 13, 2006
• Results First Posted: May 16, 2013
• Last Update Posted: September 28, 2017
• Last Verified: August 2017

Keywords provided by University of California, San Francisco:

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

Additional relevant MeSH terms:

Leukemia; Preleukemia; Myelodysplastic Syndromes; Thrombocytopenia; Neutropenia; Anemia, Diamond-Blackfan; Syndrome; Disease; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Anemia; Hematologic Diseases; Bone Marrow Diseases; Precancerous Conditions; Blood Platelet Disorders; Agranulocytosis; Leukopenia; Leukocyte Disorders; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Red-Cell Aplasia, Pure; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Genetic Diseases, Inborn; Cyclosporine; Methylprednisolone; Methotrexate; Fludarabine phosphate; Fludarabine