Aplastic Anemia
Conditions
Keywords
Thymoglobuline, Rabbit ATG, Ciclosporin, Aplastic Anemia
Brief summary
To assess the tolerability and effectiveness of rabbit antithymocyte globulin (ATG, Thymoglobuline) with ciclosporin in the first line treatment of patients with acquired severe aplastic anaemia, and patients with non-severe aplastic anaemia and who are transfusion dependent.
Detailed description
Traditionally horse antithymocyte globulin (ATG) has been the preferred animal source of ATG as first line treatment for acquired aplastic anaemia (AA) patients who are ineligible for bone marrow transplantation (BMT). For severe AA (SAA) the combination of ATG and Ciclosporin (CSA) results in response in 60-75% of patients and the response is superior to using either agent alone. The addition of granulocyte colony stimulating factor (G-CSF) to the combination of ATG and CSA has so far shown no significant benefit in terms of response and survival, but an European Group for Blood and Marrow Transplantation (EBMT) prospective study is currently evaluating this further in a larger number of patients. For patients with non-severe aplastic anaemia (NSAA) who are transfusion dependent, the combination of ATG and CSA was shown to be superior to CSA alone in an EBMT prospective randomised study, with a higher response rate, superior blood counts and improved disease free survival using the combination of ATG with CSA. There have been no phase II studies of rabbit ATG (Thymoglobuline®) in the treatment of AA as first line therapy. Preliminary results from a small single centre study compared horse ATG (ATGAM) with rabbit ATG (Fresenius) in children and showed response rates of 93% and 47%, respectively, but it is likely that different preparations of rabbit ATG will vary in their efficacy. Rabbit ATG is more commonly used for a second course following relapse or lack of response to a first course of horse ATG. Rabbit ATG in combination with CSA and G-CSF was used in patients with SAA who had failed to respond to a course of horse ATG with CSA and G-CSF. Overall response (transfusion independence) was seen in 23/30 (77%) of patients after a median of 95 days and complete response (neutrophils \> 2.0, haemoglobin \> 11, and platelets \> 100) in 9/30 (30%). Rabbit ATG was well tolerated; no anaphylaxis or severe side effects were reported. Another study of 43 patients treated with rabbit ATG and CSA following non-response or relapse after horse ATG and CSA, showed 30% response rate among non-responding patients and 65% response rate for relapsing patients. Studies comparing the antibody specificities between Thymoglobuline® and Lymphoglobuline® are in broad agreement, but (a) Lymphoglobuline® has fewer studies and those reported are older, because the product is older and has been less extensively developed (b) antibodies against certain epitopes are inconsistently present (c) not all antibody specificities have been examined in some studies and (d) different methods of testing have been used. There is a view that it is the immunogen and not the animal species which is most important in creating differences between different ATGs.
Interventions
1.5 vials/10kg daily for 5 days
Sponsors
Genzyme, a Sanofi Company
European Society for Blood and Marrow Transplantation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Must fulfil definition of aplastic anaemia: There must be at least two of the following: * haemoglobin \< 10g/dl * platelet count \< 50 x 109/l * neutrophil count \< 1.5 x 109/l, and a hypocellular bone marrow on bone marrow biopsy SAA as defined by a hypocellular bone marrow of \<25% cellularity and two of the following: * neutrophil count \< 0.5 x 109/l * platelets \< 20 x 109/l * reticulocytes \< 20 x 109/l NSAA as defined by a hypocellular bone marrow and cytopenia in at least two cell lines and neutrophil count \> 0.5 x 109/l, and red cell and/or platelet transfusion dependence 2. Have acquired aplastic anaemia 3. Time from diagnosis to study registration maximum 6 months 4. No prior treatment except for haemopoietic growth factors given for no more than four weeks, and androgens 5. Age minimum 16 years with no upper age limit
Exclusion criteria
1. Eligibility for an human leukocyte antigens (HLA)-matched sibling donor transplant for SAA patients 2. Prior therapy with ATG or CSA 3. Haematopoeitic growth factors more than 4 weeks before study enrolment 4. Diagnosis of Fanconi anaemia, dyskeratosis congenita or congenital bone marrow failure syndrome 5. Evidence of myelodysplastic disease 6. Paroxysmal nocturnal haemoglobinuria with evidence of significant haemolysis, history of Paroxysmal Nocturnal Hemoglobinuria (PNH) associated thrombosis or a PNH clone \>50% by flow cytometry 7. Diagnosis or previous history of carcinoma (except local cervical, basal cell, squamous cells, or melanoma) 8. Subject is pregnant (e.g. positive Human Chorionic Gonadotropin (HCG) test) or is breast feeding 9. Severe uncontrolled infection or unexplained fever \>38 degrees Celsius 10. Subjects who have hepatic, renal cardiac, metabolic or other concurrent diseases of such severity that life expectancy is less than 3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Response to Rabbit Antithymocyte Globulin (Thymoglobuline) | at 6months | Complete Response (CR) defined as: Haemoglobin normal for age and gender, neutrophils \> 1.5 x 10E9/l, platelets \> 150 x 10E9/l. Partial Response (PR) defined as: * transfusion independence (if previously dependent) or * doubling or normalisation of at least one cell line or * increase of baseline haemoglobin of \> 3 g/dl (if initially \<6) + neutrophils of \> 0.5 x 10E9/l + platelets of \> 20 x 10E9/l (if initially \< 20) No Response (MR) is defined as: worse or not meeting criteria above |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Failure Free and Overall Survival of Participants to Rabbit Antithymocyte Globulin (Thymoglobuline) | at 2 years | Failure free survival is defined as a failure of the protocol: no achievement of response, relapse, disease progression requiring a second course of immune suppressive therapy (IST) or a stem cell transplant, death, or later clonal disorders such as Paroxysmal Nocturnal Hemoglobinuria (PNH), Myelodysplastic Syndrome (MDS) and Acute Myeloblastic Leukemia (AML). |
Countries
France, Germany, Italy, Saudi Arabia, Switzerland, United Kingdom
Participant flow
Recruitment details
14 sites in 6 countries were open to include patients; in the end 10 sites entered all 35 patients. First Patient In (FPI) 04-Aug-2008, Last Patient In (LPI) 30-Sep-2010
Pre-assignment details
Naive aplastic anaemia patients
Participants by arm
| Arm | Count |
|---|---|
| Treatment Arm Antithymocyte globulin with cyclosporin in first line treatment of patients with acquired severe aplastic anaemia and patients with non-severe aplastic anaemia who are transfusion dependent; the results were compared with historical controls from the EBMT database. Patients were matched for age and disease status (NSAA, SAA, VSAA) | 35 |
| Total | 35 |
Baseline characteristics
| Characteristic | Treatment Arm |
|---|---|
| Age, Categorical <=18 years | 2 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 30 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 | 0 / 35 |
| serious Total, serious adverse events | 27 / 35 |
Outcome results
Primary
Number of Participants With Response to Rabbit Antithymocyte Globulin (Thymoglobuline)
Complete Response (CR) defined as: Haemoglobin normal for age and gender, neutrophils \> 1.5 x 10E9/l, platelets \> 150 x 10E9/l. Partial Response (PR) defined as: * transfusion independence (if previously dependent) or * doubling or normalisation of at least one cell line or * increase of baseline haemoglobin of \> 3 g/dl (if initially \<6) + neutrophils of \> 0.5 x 10E9/l + platelets of \> 20 x 10E9/l (if initially \< 20) No Response (MR) is defined as: worse or not meeting criteria above
Time frame: at 6months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment Arm | Number of Participants With Response to Rabbit Antithymocyte Globulin (Thymoglobuline) | PR | 11 Participants |
| Treatment Arm | Number of Participants With Response to Rabbit Antithymocyte Globulin (Thymoglobuline) | CR | 1 Participants |
| Treatment Arm | Number of Participants With Response to Rabbit Antithymocyte Globulin (Thymoglobuline) | NR | 18 Participants |
| Treatment Arm | Number of Participants With Response to Rabbit Antithymocyte Globulin (Thymoglobuline) | Transplanted | 3 Participants |
| Treatment Arm | Number of Participants With Response to Rabbit Antithymocyte Globulin (Thymoglobuline) | Dead | 2 Participants |
Secondary
Failure Free and Overall Survival of Participants to Rabbit Antithymocyte Globulin (Thymoglobuline)
Failure free survival is defined as a failure of the protocol: no achievement of response, relapse, disease progression requiring a second course of immune suppressive therapy (IST) or a stem cell transplant, death, or later clonal disorders such as Paroxysmal Nocturnal Hemoglobinuria (PNH), Myelodysplastic Syndrome (MDS) and Acute Myeloblastic Leukemia (AML).
Time frame: at 2 years