Congenital Amegakaryocytic Thrombocytopenia, Diamond-blackfan Anemia, Leukemia, Myelodysplastic Syndromes, Severe Congenital Neutropenia
Conditions
Keywords
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
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.
Interventions
BIOLOGICALalemtuzumab
DRUGbusulfan
DRUGcyclosporine
DRUGfludarabine phosphate
DRUGmethotrexate
DRUGmethylprednisolone
PROCEDUREallogeneic bone marrow transplantation
PROCEDUREallogeneic hematopoietic stem cell transplantation
PROCEDUREperipheral blood stem cell transplantation
PROCEDUREumbilical cord blood transplantation
Sponsors
National Cancer Institute (NCI)
University of California, San Francisco
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Treatment-related Mortality at 100 Days and 1 Year Post Transplantation | 100 days and 1 year | — |
| Toxicity Grade ≥ 3 From Start of Conditioning Through the First Year Post Transplantation | 1 year post-transplantation | — |
| 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. |
| 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 |
Countries
United States
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 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.
Participants by arm
| Arm | Count |
|---|---|
| Single Arm - Transplant Pre-conditioning Per Study Protocol 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. | 35 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
Baseline characteristics
| Characteristic | Single Arm - Transplant Pre-conditioning Per Study Protocol |
|---|---|
| Age, Categorical <=18 years | 34 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 7.58 years STANDARD_DEVIATION 5.25 |
| Region of Enrollment United States | 35 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 33 / 35 |
| serious Total, serious adverse events | 7 / 35 |
Outcome results
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
Time frame: 6 weeks post-transplant
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Single Arm - Transplant Pre-conditioning Per Study Protocol | Number of Participants Achieving Durable Engraftment (Presence of Donor Cells) at 6 Weeks Post Transplantation | 31 participants |
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.
Time frame: Up to one year post-transplant
Population: 4 participants were incapable of producing Ab or CMV testing result was indeterminate
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Single Arm - Transplant Pre-conditioning Per Study Protocol | Cytomegalovirus (CMV) Viral Infection and Disease Symptoms | Positive CMV Viral Load Assay | 1 participants |
| Single Arm - Transplant Pre-conditioning Per Study Protocol | Cytomegalovirus (CMV) Viral Infection and Disease Symptoms | Symptomatic CMV disease | 0 participants |
| CMV Seropositive Participants | Cytomegalovirus (CMV) Viral Infection and Disease Symptoms | Positive CMV Viral Load Assay | 12 participants |
| CMV Seropositive Participants | Cytomegalovirus (CMV) Viral Infection and Disease Symptoms | Symptomatic CMV disease | 0 participants |
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
Time frame: 1 year post-transplantation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Arm - Transplant Pre-conditioning Per Study Protocol | Disease-free Survival With Correction of Disease at One Year Post Transplantation | 22 participants |
Secondary
Toxicity Grade ≥ 3 From Start of Conditioning Through the First Year Post Transplantation
Time frame: 1 year post-transplantation
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Single Arm - Transplant Pre-conditioning Per Study Protocol | Toxicity Grade ≥ 3 From Start of Conditioning Through the First Year Post Transplantation | Grade 3-4 acute Graft-Versus-Host Disease | 2 participants |
| Single Arm - Transplant Pre-conditioning Per Study Protocol | Toxicity Grade ≥ 3 From Start of Conditioning Through the First Year Post Transplantation | Grade 3-4 mucositis | 16 participants |
Secondary
Treatment-related Mortality at 100 Days and 1 Year Post Transplantation
Time frame: 100 days and 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Single Arm - Transplant Pre-conditioning Per Study Protocol | Treatment-related Mortality at 100 Days and 1 Year Post Transplantation | Transplantation-related mortality 0-100 days | 2 participants |
| Single Arm - Transplant Pre-conditioning Per Study Protocol | Treatment-related Mortality at 100 Days and 1 Year Post Transplantation | Transplantation-related mortality 100-365 days | 1 participants |