Paroxysmal Nocturnal Hemoglobinuria (PNH), Pure Red Cell Aplasia, Severe Aplastic Anemia, Sickle Cell Anemia
Conditions
Keywords
sickle cell anemia, severe aplastic anemia
Brief summary
RATIONALE: Although used primarily to treat malignant disorders of the blood, allogeneic stem cell transplantation can also cure a variety of non-cancerous, inherited or acquired disorders of the blood. Unfortunately, the conventional approach to allogeneic stem cell transplantation is a risky procedure. For some non-cancerous conditions, the risks of this procedure outweigh the potential benefits. This protocol is designed to test a new approach to allogeneic stem cell transplantation. It is hoped that this approach will be better suited for patients with non-cancerous blood and bone marrow disorders.
Detailed description
OBJECTIVES: Primary Objective(s): 1. Evaluate the feasibility in terms of mortality, occurrence of acute graft versus host disease, and grades 3-4/4 toxicity of in vivo and in vitro Campath coupled with concomitantly administered nonmyeloablative fludarabine, cyclophosphamide and total body irradiation (TBI) followed by Human Leukocyte Antigen (HLA) 5-6/6 matched family member allo peripheral blood stem cell transplant (PBSCT). 2. Evaluate the engraftment rate of HLA 5-6/6 matched family member patients who receive in vivo Campath followed by concomitantly administered fludarabine, cyclophosphamide and total body irradiation (TBI) as a conditioning regimen with Campath-treated peripheral blood stem cells (in vitro and in vivo exposure). Secondary Objective(s): 1. Evaluate the response rate and survival of patients who receive a non-myeloablative conditioning regimen of in vivo Campath followed by concomitantly administered fludarabine, cyclophosphamide and total body irradiation (TBI) with Campath-treated peripheral blood stem cells. 2. Evaluate the recovery of immune function post engraftment with this regimen.
Interventions
DRUGCampath, Chemo and/or TBI Allo SCT
Allogeneic PBSC/marrow will be collected/harvested from the donor after granulocyte colony-stimulating factor (G-CSF) priming. The allogeneic PBSCs will be infused as per current institutional practice.
Sponsors
David Rizzieri, MD
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have their clinical material reviewed at the transplanting institution and the diagnosis confirmed * Performance status must be Cancer and Leukemia Group B (CALGB) Performance Status (PS) 0, 1, or 2. * Patients must have a 5/6 to 6/6 HLA matched family member donor who is evaluated and deemed able to provide PBSCs and/or marrow by the transplant team. Donor must have \< 50% Hemoglobin S (HgS) on hemoglobin electrophoresis. Cytomegalovirus (CMV) status of the donor will be assessed, but not used as an exclusion criterion. * Patients must meet the following laboratory parameters unless due to disease status as determined by the treating physician: 1. bilirubin and hepatic transaminases and creatinine must be reviewed by the transplantation center and deemed acceptable. 2. HIV antibody negative. 3. hematocrit, white cell count, platelet counts and hematologic status will be reviewed by the treating physician before patient is deemed acceptable. * Patient must agree to use some form of adequate birth control during the periods that they receive chemotherapy and any post-chemotherapy medications related to the transplant. * Patients must also have a resting multiple gated acquisition scan (MUGA) or echocardiogram and Pulmonary Function Tests (PFTs) with Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) performed before transplant. Recommended minimum standards include an Ejection Fraction (EF) greater than 40% and DLCO greater than 40% for this less toxic regimen. * Appropriate cardiology or pulmonary consultations should be considered if the patient has severe cardiac or lung disease at the initiation of therapy. I) Hemoglobinopathies: (a)Sickle Cell Anemia having history of one or more of the following despite treatment with standard therapies such as hydroxyurea: i) 2 or more episodes of acute chest syndrome since age 13 years ii) pulmonary hypertension as measured by tricuspid regurgitant jet velocity of greater than 2.5m/s iii) 2 or more painful crisis per year requiring medical care and analgesia in excess of what is needed at baseline. iv) history of cerebrovascular accident (b)Thalassemia major: Those eligible will have either cardiac or hepatic sequela of thalassemia as documented by biopsy or functional studies. For those with hepatic damage, this would be an increase in size by 50% of the liver or a doubling of the total bilirubin, aspartate transaminase (AST), alanine aminotransferase (ALT), or alkaline phosphatase. To be eligible for transplant due to cardiac damage, there must be evidence of left ventricular dysfunction as measured by MUGA scan or echocardiography. II) Bone marrow failure Disorders 1. Severe Aplastic Anemia: Cytopenia consisting of at least 2 of the following 3: absolute neutrophil count less than 500/μL, platelet count less than 20,000/μL, and reticulocyte count less than 50,000/μL. 2. Paroxysmal nocturnal hemoglobinuria (PNH): Patients must have a history of either life-threatening thrombosis, cytopenia, transfusion dependence or recurrent, debilitating hemolytic crisis 3. Pure red cell aplasia: Patients must be transfusion dependent.
Exclusion criteria
* pregnant or lactating women, * patients with other major medical or psychiatric illnesses which the treating or transplant physician feels could seriously compromise compliance to this protocol * patients with known history of allergies to murine protein
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Neutrophil Engraftment | 1 year post transplant | Number of patients with neutrophil engraftment: Absolute Neutrophil Count (ANC) \> 500/μL and hemoglobin level remaining above 10 g/dL without transfusion support, with tests showing at least 2.5% donor cells present. Primary graft failure is defined as absence of establishment of adequate donor hematopoiesis by day 42 with bone marrow cellularity \< 5%, peripheral White Blood Count (WBC) \< 500/μL, peripheral ANC \< 100/μL, and/or platelets \< 10,000/μL by day 120 with absence of megakaryocytes in the bone marrow (in the absence of disease relapse). |
| Number of Patients With Platelet Engraftment | 1 year post transplant | Number of patients with platelet engraftment - Platelets \> 20,000/μL and hemoglobin level remaining above 10 g/dL without transfusion support, with tests showing at least 2.5% donor cells present. Primary graft failure is defined as absence of establishment of adequate donor hematopoiesis by day 42 with bone marrow cellularity \< 5%, peripheral White Blood Count (WBC) \< 500/μL, peripheral ANC \< 100/μL, and/or platelets \< 10,000/μL by day 120 with absence of megakaryocytes in the bone marrow (in the absence of disease relapse). |
| Number of Patients With Grade 3-4 Acute Graft Versus Host Disease (GVHD) | 60 days post transplant | Number of patients with Grade 3-4 acute Graft Versus Host Disease (GVHD). GVHD will be monitored at least two times per week through day 45, then weekly through day 60 and graded by 2 persons at each institution, to ensure internal consistency in grading. |
| Number of Participants With Grade 3-4 Unexpected Adverse Events | 45 days post transplant | An unexpected adverse event is one that differs in the nature, severity, or frequency from (a) the research procedures that are described in the protocol-related documents, (such as the IRB-approved research protocol and informed consent document) as expected, and/or (b) the characteristics of the subject population being studied. |
| Number of Participants With Transplant-related Mortality | 100 days | Number of patients who died due to transplant-related complications |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 2 years | Number of patients alive 2 years after transplant |
Countries
United States
Participant flow
Recruitment details
The protocol was reopened in 2003 for non-malignant conditions only. Enrollment closed in 2008 due to lack of enrollment.
Participants by arm
| Arm | Count |
|---|---|
| All Patients | 2 |
| Total | 2 |
Baseline characteristics
| Characteristic | All Patients |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Region of Enrollment United States | 2 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 0 / 2 |
Outcome results
Primary
Number of Participants With Grade 3-4 Unexpected Adverse Events
An unexpected adverse event is one that differs in the nature, severity, or frequency from (a) the research procedures that are described in the protocol-related documents, (such as the IRB-approved research protocol and informed consent document) as expected, and/or (b) the characteristics of the subject population being studied.
Time frame: 45 days post transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients | Number of Participants With Grade 3-4 Unexpected Adverse Events | 0 participants |
Primary
Number of Participants With Transplant-related Mortality
Number of patients who died due to transplant-related complications
Time frame: 100 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients | Number of Participants With Transplant-related Mortality | 0 participants |
Primary
Number of Patients With Grade 3-4 Acute Graft Versus Host Disease (GVHD)
Number of patients with Grade 3-4 acute Graft Versus Host Disease (GVHD). GVHD will be monitored at least two times per week through day 45, then weekly through day 60 and graded by 2 persons at each institution, to ensure internal consistency in grading.
Time frame: 60 days post transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients | Number of Patients With Grade 3-4 Acute Graft Versus Host Disease (GVHD) | 2 participants |
Primary
Number of Patients With Neutrophil Engraftment
Number of patients with neutrophil engraftment: Absolute Neutrophil Count (ANC) \> 500/μL and hemoglobin level remaining above 10 g/dL without transfusion support, with tests showing at least 2.5% donor cells present. Primary graft failure is defined as absence of establishment of adequate donor hematopoiesis by day 42 with bone marrow cellularity \< 5%, peripheral White Blood Count (WBC) \< 500/μL, peripheral ANC \< 100/μL, and/or platelets \< 10,000/μL by day 120 with absence of megakaryocytes in the bone marrow (in the absence of disease relapse).
Time frame: 1 year post transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients | Number of Patients With Neutrophil Engraftment | 2 participants |
Primary
Number of Patients With Platelet Engraftment
Number of patients with platelet engraftment - Platelets \> 20,000/μL and hemoglobin level remaining above 10 g/dL without transfusion support, with tests showing at least 2.5% donor cells present. Primary graft failure is defined as absence of establishment of adequate donor hematopoiesis by day 42 with bone marrow cellularity \< 5%, peripheral White Blood Count (WBC) \< 500/μL, peripheral ANC \< 100/μL, and/or platelets \< 10,000/μL by day 120 with absence of megakaryocytes in the bone marrow (in the absence of disease relapse).
Time frame: 1 year post transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients | Number of Patients With Platelet Engraftment | 2 participants |
Secondary
Overall Survival
Number of patients alive 2 years after transplant
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients | Overall Survival | 2 participants |