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

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT00301834
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 35
• Locations: 2
• Arm: 1
• Duration (Months): 80
• Patients Per Site: 17.5
• Patients Per Site Per Month: 0.2

Study Details

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
• 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: Jan 1, 2005
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Sep 1, 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 [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 [100 days and 1 year]

2. Toxicity Grade ≥ 3 From Start of Conditioning Through the First Year Post Transplantation [1 year post-transplantation]

3. Cytomegalovirus (CMV) Viral Infection and Disease Symptoms [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 [1 year post-transplantation]

   Patients deemed "alive and well" at follow-up timepoint later than 1-year post-transplantation

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115
2	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT00301834
• Other Study ID Numbers: CDR0000462406; UCSF-04152; UCSF-00452; UCSF-H411-25738-02
• First Posted: Mar 13, 2006
• Last Update Posted: Sep 28, 2017
• Last Verified: Aug 1, 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; Cyclosporine; Methylprednisolone; Methotrexate; Fludarabine phosphate; Fludarabine; Busulfan; Alemtuzumab; Cyclosporins

Study Results

Participant Flow

Recruitment Details	Subjects recruited from 9/2005 through 9/2010. Patients identified by the Pediatric BMT (Bone Marrow Transplant) Program and consented by study investigators as outpatients in the BMT clinic.
Pre-assignment Detail	Patients were ineligible if a cord blood was being used for the transplant or if they met any of the other ineligibility criteria in the protocol or did not meet eligibility criteria such as having Fanconi's Anemia.

Arm/Group Title	Single Arm - Transplant Pre-conditioning Per Study Protocol
Arm/Group Description	All eligible patients received pre-transplant conditioning with Alemtuzumab, fludarabine and targeted busulfan followed by allogeneic transplant. The initial dose of busulfan was determined by performing PK (pharmacokinetics) analysis on a test dose of busulfan on the day prior to initiating conditioning. Based on the PK results a starting dose of busulfan was determined. A second PK study was done after the starting dose to ensure that the targeted dose was achieved. If it wasn't achieved, then a dose modification was made and a third PK study done.
Period Title: Overall Study
STARTED	35
COMPLETED	34
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Single Arm - Transplant Pre-conditioning Per Study Protocol
Arm/Group Description	All eligible patients received pre-transplant conditioning with Alemtuzumab, fludarabine and targeted busulfan followed by allogeneic transplant. The initial dose of busulfan was determined by performing PK (pharmacokinetics) analysis on a test dose of busulfan on the day prior to initiating conditioning. Based on the PK results a starting dose of busulfan was determined. A second PK study was done after the starting dose to ensure that the targeted dose was achieved. If it wasn't achieved, then a dose modification was made and a third PK study done.
Overall Participants	35
Age (Count of Participants)
<=18 years	34 97.1%
Between 18 and 65 years	1 2.9%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7.58 (5.25)
Sex: Female, Male (Count of Participants)
Female	13 37.1%
Male	22 62.9%
Region of Enrollment (participants) [Number]
United States	35 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Participants evaluable for engraftment 6 weeks post-transplant; 1 patient died of transplant-related hemorrhage prior to 6 weeks and was not evaluated for this outcome

Arm/Group Title	Single Arm - Transplant Pre-conditioning Per Study Protocol
Arm/Group Description	Conditioning with Alemtuzumab, busulfan and fludarabine followed by allogeneic hematopoietic cell transplant.
Measure Participants	34
Number [participants]	31 88.6%

2. Secondary Outcome

Title	Treatment-related Mortality at 100 Days and 1 Year Post Transplantation
Time Frame	100 days and 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm - Transplant Pre-conditioning Per Study Protocol
Arm/Group Description	Conditioning with Alemtuzumab, busulfan and fludarabine followed by allogeneic hematopoietic cell transplant.
Measure Participants	35
Transplantation-related mortality 0-100 days	2 5.7%
Transplantation-related mortality 100-365 days	1 2.9%

3. Secondary Outcome

Title	Toxicity Grade ≥ 3 From Start of Conditioning Through the First Year Post Transplantation
Time Frame	1 year post-transplantation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm
Arm/Group Description	Conditioning with Alemtuzumab, busulfan and fludarabine followed by allogeneic hematopoietic cell transplant.
Measure Participants	35
Grade 3-4 acute Graft-Versus-Host Disease	2 5.7%
Grade 3-4 mucositis	16 45.7%

4. Secondary Outcome

Title	Cytomegalovirus (CMV) Viral Infection and Disease Symptoms
Description	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.
Time Frame	Up to one year post-transplant

Outcome Measure Data

Analysis Population Description

4 participants were incapable of producing Ab or CMV testing result was indeterminate

Arm/Group Title	CMV Seronegative Participants	CMV Seropositive Participants
Arm/Group Description	"seronegativity" means no detected presence of anti-CMV IgG, indicating no past infection by the virus	"seropositivity" means the presence of anti-CMV IgG, indicating past infection by the virus
Measure Participants	14	17
Positive CMV Viral Load Assay	1 2.9%	12 NaN
Symptomatic CMV disease	0 0%	0 NaN

5. Secondary Outcome

Title	Disease-free Survival With Correction of Disease at One Year Post Transplantation
Description	Patients deemed "alive and well" at follow-up timepoint later than 1-year post-transplantation
Time Frame	1 year post-transplantation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm - Transplant Pre-conditioning Per Study Protocol
Arm/Group Description	Conditioning with Alemtuzumab, busulfan and fludarabine followed by allogeneic hematopoietic cell transplant.
Measure Participants	35
Number [participants]	22 62.9%

Adverse Events

Arm/Group Title	Single Arm - Transplant Pre-conditioning Per Study Protocol
Arm/Group Description	All eligible patients received pre-transplant conditioning with Alemtuzumab, fludarabine and targeted busulfan followed by allogeneic transplant. The initial dose of busulfan was determined by performing PK (pharmacokinetics) analysis on a test dose of busulfan on the day prior to initiating conditioning. Based on the PK results a starting dose of busulfan was determined. A second PK study was done after the starting dose to ensure that the targeted dose was achieved. If it wasn't achieved, then a dose modification was made and a third PK study done.
All Cause Mortality
	Single Arm - Transplant Pre-conditioning Per Study Protocol
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Single Arm - Transplant Pre-conditioning Per Study Protocol
	Affected / at Risk (%)	# Events
Total	7/35 (20%)
Blood and lymphatic system disorders
Pancytopenia and splenomegaly	1/35 (2.9%)	1
Thrombocytopenia	1/35 (2.9%)	1
Graft rejection/failure	1/35 (2.9%)	1
General disorders
aGVHD (acute Graft-Versus-Host Disease)	1/35 (2.9%)	1
Infections and infestations
Aspergillus pneumonia	1/35 (2.9%)	1
Viral Encephalitis	1/35 (2.9%)	1
Renal and urinary disorders
Renal Failure	1/35 (2.9%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory distress associated with Cytomegalovirus infection	1/35 (2.9%)	1
Repiratory failure following ideopathic pneumonia syndrome	1/35 (2.9%)	1
Vascular disorders
Massive intracranial bleed	1/35 (2.9%)	1
Other (Not Including Serious) Adverse Events
	Single Arm - Transplant Pre-conditioning Per Study Protocol
	Affected / at Risk (%)	# Events
Total	33/35 (94.3%)
Gastrointestinal disorders
Mucositis (All grades)	33/35 (94.3%)	33
General disorders
aGVHD	5/35 (14.3%)	5
cGVHD (Chronic graft-versus-host disease)	2/35 (5.7%)	2
Infusion reaction to alemtuzumab	19/35 (54.3%)	19

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.