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

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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:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
University of California, San Francisco

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Congenital Amegakaryocytic Thrombocytopenia
Diamond-blackfan Anemia
Leukemia
Myelodysplastic Syndromes
Severe Congenital Neutropenia
Interventions 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
Enrollment 35
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 Details 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
Hide 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
Reason Not Completed
Death             1
Arm/Group Title Single Arm - Transplant Pre-conditioning Per Study Protocol
Hide 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 Number of Baseline Participants 35
Hide Baseline Analysis Population Description
Thirty-five children undergoing allogeneic hemotopoietic stem cell transplants (HSCTs) for malignant and nonmalignant diseases; 12 with HLA-matched related donors (MRDs), 16 with 10 of 10 HLA allele-matched unrelated donors (MUDs), 7 with 9 of 10 allele MUDs.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 35 participants
<=18 years
34
  97.1%
Between 18 and 65 years
1
   2.9%
>=65 years
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 35 participants
7.58  (5.25)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 35 participants
Female
13
  37.1%
Male
22
  62.9%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 35 participants
35
1.Primary Outcome
Title Number of Participants Achieving Durable Engraftment (Presence of Donor Cells) at 6 Weeks Post Transplantation
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide Arm/Group Description:
Conditioning with Alemtuzumab, busulfan and fludarabine followed by allogeneic hematopoietic cell transplant.
Overall Number of Participants Analyzed 34
Measure Type: Number
Unit of Measure: participants
31
2.Secondary Outcome
Title Treatment-related Mortality at 100 Days and 1 Year Post Transplantation
Hide Description [Not Specified]
Time Frame 100 days and 1 year
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Hide Analysis Population Description
[Not Specified]
Arm/Group Title Single Arm - Transplant Pre-conditioning Per Study Protocol
Hide Arm/Group Description:
Conditioning with Alemtuzumab, busulfan and fludarabine followed by allogeneic hematopoietic cell transplant.
Overall Number of Participants Analyzed 35
Measure Type: Number
Unit of Measure: participants
Transplantation-related mortality 0-100 days 2
Transplantation-related mortality 100-365 days 1
3.Secondary Outcome
Title Toxicity Grade ≥ 3 From Start of Conditioning Through the First Year Post Transplantation
Hide Description [Not Specified]
Time Frame 1 year post-transplantation
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Hide Analysis Population Description
[Not Specified]
Arm/Group Title Single Arm
Hide Arm/Group Description:
Conditioning with Alemtuzumab, busulfan and fludarabine followed by allogeneic hematopoietic cell transplant.
Overall Number of Participants Analyzed 35
Measure Type: Number
Unit of Measure: participants
Grade 3-4 acute Graft-Versus-Host Disease 2
Grade 3-4 mucositis 16
4.Secondary Outcome
Title Cytomegalovirus (CMV) Viral Infection and Disease Symptoms
Hide 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
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Hide 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
Hide 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
Overall Number of Participants Analyzed 14 17
Measure Type: Number
Unit of Measure: participants
Positive CMV Viral Load Assay 1 12
Symptomatic CMV disease 0 0
5.Secondary Outcome
Title Disease-free Survival With Correction of Disease at One Year Post Transplantation
Hide Description Patients deemed "alive and well" at follow-up timepoint later than 1-year post-transplantation
Time Frame 1 year post-transplantation
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Hide Analysis Population Description
[Not Specified]
Arm/Group Title Single Arm - Transplant Pre-conditioning Per Study Protocol
Hide Arm/Group Description:
Conditioning with Alemtuzumab, busulfan and fludarabine followed by allogeneic hematopoietic cell transplant.
Overall Number of Participants Analyzed 35
Measure Type: Number
Unit of Measure: participants
22
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Single Arm - Transplant Pre-conditioning Per Study Protocol
Hide 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 (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Single Arm - Transplant Pre-conditioning Per Study Protocol
Affected / at Risk (%) # Events
Total   7/35 (20.00%)    
Blood and lymphatic system disorders   
Pancytopenia and splenomegaly * [1]  1/35 (2.86%)  1
Thrombocytopenia * [2]  1/35 (2.86%)  1
Graft rejection/failure  [3]  1/35 (2.86%)  1
General disorders   
aGVHD (acute Graft-Versus-Host Disease)  [4]  1/35 (2.86%)  1
Infections and infestations   
Aspergillus pneumonia * [5]  1/35 (2.86%)  1
Viral Encephalitis *  1/35 (2.86%)  1
Renal and urinary disorders   
Renal Failure * [6]  1/35 (2.86%)  1
Respiratory, thoracic and mediastinal disorders   
Respiratory distress associated with Cytomegalovirus infection * [7]  1/35 (2.86%)  1
Repiratory failure following ideopathic pneumonia syndrome * [8]  1/35 (2.86%)  1
Vascular disorders   
Massive intracranial bleed * [9]  1/35 (2.86%)  1
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
[1]
Child presented with fever and pancytopenia, splenomegaly and was admitted for possible recurrent disease.
[2]
Sudden onset of thrombocytopenia of unknown etiology.
[3]
initially, cells recovered normally with neutrophil count >500 by day +12 post-transplant. By day +20 they began a slow decline and by day +40 the neutrophil count was <500 with 99% host CD3+ (cluster of differentiation 3-positive) cells.
[4]
acute Graft-Versus-Host Disease
[5]
Patient admitted with cough and fever and diagnosed with Aspergillus pneumonia.
[6]
Patient developed renal failure and is required dialysis
[7]
After 4th unrelated donor transplant (off study), patient developed respiratory distress that was associated with a CMV infection. Respiratory distress worsened in spite of maximal therapy. The parents elected to withdraw therapy and he died.
[8]
Worsening respiratory status despite maximal support, at parent's request, patient was removed from mechanical ventilation, and the patient died quickly and peacefully.
[9]
Child died from a massive intracranial bleed, probably due to Evan's syndrome and myeloablation; possible viral encephalitis possibly increased risk of intracranial hemorrhage.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Single Arm - Transplant Pre-conditioning Per Study Protocol
Affected / at Risk (%) # Events
Total   33/35 (94.29%)    
Gastrointestinal disorders   
Mucositis (All grades)  [1]  33/35 (94.29%)  33
General disorders   
aGVHD  [2]  5/35 (14.29%)  5
cGVHD (Chronic graft-versus-host disease)   2/35 (5.71%)  2
Infusion reaction to alemtuzumab   19/35 (54.29%)  19
Indicates events were collected by systematic assessment
[1]
< Grade III - 17 participants; Grade III - 15 participants; Grade IV - 1 participant
[2]
aGVHD < Grade IV
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Dr. Morton Cowan
Organization: University of California San Francisco
Phone: 4154762188
Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT00301834     History of Changes
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 Submitted: March 9, 2006
First Posted: March 13, 2006
Results First Submitted: January 31, 2013
Results First Posted: May 16, 2013
Last Update Posted: September 28, 2017