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

Brief Title

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

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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Number of Participants Achieving Durable Engraftment (Presence of Donor Cells) at 6 Weeks Post Transplantation

Secondary Outcome

 Treatment-related Mortality at 100 Days and 1 Year Post Transplantation

Condition

Congenital Amegakaryocytic Thrombocytopenia

Intervention

alemtuzumab

Study Arms / Comparison Groups

 Single arm - conditioning and transplant
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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

35

Start Date

January 2005

Completion Date

September 2011

Primary Completion Date

September 2011

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
      

Gender

All

Ages

N/A - 21 Years

Accepts Healthy Volunteers

No

Contacts

Morton J. Cowan, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00301834

Organization ID

CDR0000462406

Secondary IDs

UCSF-04152

Responsible Party

Sponsor

Study Sponsor

University of California, San Francisco

Collaborators

 National Cancer Institute (NCI)

Study Sponsor

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


Verification Date

August 2017