Outcomes of immunosuppressant therapy with lower dose of antithymocyte globulin and cyclosporine in aplastic anemia Pankaj Malhotra1 , Vijay Bodh1, Guru Subramanian Guru Murthy 1, Anup Kumar Datta 1, Neelam Varma 2, Subhash Varma1 1
Department of Internal Medicine, PGIMER, Chandigarh, India, 2Department of Hematology, PGIMER
Objective: Immunosuppressant therapy (IST) with antithymocyte globulin (ATG) and cyclosporine is an established treatment option for patients with aplastic anemia (AA), who are not eligible for allogeneic stem cell transplantation. However, data on the dose of ATG and its efficacy from the developing countries is minimal. Methods: We performed a retrospective analysis of all AA patients (age >12 years), treated with equine ATG and cyclosporine from a single center in India. Patients who received or were eligible for stem cell transplantation were excluded. The overall response rate (ORR) to IST was calculated at 3 and 6 months. We also determined the influence of using a lower dose of Atgam ATG (25 mg/kg/day × 4 days) and compared its efficacy against the standard dose of locally manufactured Thymogam ATG (40 mg/kg/ day × 4 days). Factors influencing the ORR were analyzed using Fisher’s exact test with a significant P < 0.05. Results: Thirty-nine patients with AA treated with ATG and cyclosporine were studied. Median age was 31 years with a male:female ratio of 0.85:1. The ORR was 58% at 3 months, 77% at 6 months and was similar with lower dose Atgam and standard dose Thymogam. On multivariate analysis of ORR at 6 months, the interval between the onset of symptoms to the initiation of therapy was close to attaining statistical significance (odds ratio 23.53, P value 0.053) while the other variables did not attain significance. Conclusions: IST with equine ATG in a lower dose (25 mg/kg/day × 4 days) and cyclosporine is a feasible and effective treatment option for AA in resource-constrained settings.
Introduction Aplastic anemia (AA) is a hematological disorder characterized by pancytopenia with a hypocellular bone marrow in the absence of any abnormal infiltrate or increase in marrow reticulin. Several congenital and acquired causes can predispose to this condition, the commonest etiology being idiopathic or immunomediated suppression of hematopoiesis.1–2 Although this disorder is seen in most parts of the world, there are geographic differences in its incidence with more number of cases being reported from the eastern countries compared with the west.3 This difference is thought to be due to variations in socioeconomic conditions, genetic factors, and the degree of exposure to various factors associated with AA.4 While supportive care is helpful in dealing with the complications of this disorder,5–7 treatments aimed at disease pathogenesis would provide long-term benefits with freedom from transfusions, infections, and potentially curing this condition. To date, allogeneic stem cell transplantation Correspondence to: Pankaj Malhotra, Dept. of Internal Medicine, PGIMER, Chandigarh 160012, India. Email: [email protected]
© W. S. Maney & Son Ltd 2015 DOI 10.1179/1607845414Y.0000000196
from an HLA-matched sibling donor is the definitive therapy for this disorder resulting in a longterm survival of >80% in these patients.8 However, the patient’s candidacy for transplant is often limited by lack of appropriate donor and factors like patient’s age and co-morbidities. Immunosuppressant therapy (IST) with antithymocyte globulin (ATG) and cyclosporine is another promising approach for those patients in whom transplant is not an appropriate option.9 While studies from the developed countries indicate a better survival with allogeneic transplant and IST in patients with AA, the treatment outcomes in developing countries is still uncertain. Key factors like the cost of therapy, availability of resources for stem cell transplantation, and the patient’s willingness to undergo therapy influence the outcomes of this disorder in developing countries like India.10 Similarly, the dose and the type of ATG used are also important factors that are considered to influence the overall outcome. While the ideal dose of ATG has not been well established, it is commonly used in the dose of 40 mg/kg/ day over 4 days. However, a lower dose of ATG
Hematology
2015
VOL.
20
NO.
4
239
Malhotra et al.
Outcomes of IST with ATG and cyclosporine in aplastic anemia
could be cost saving if it can produce similar overall response rates (ORRs). In this study, we have retrospectively analyzed the outcomes of IST and the factors associated with treatment response in a cohort of patients with AA from India. Moreover, we aimed to determine the influence of using a lower dose of Atgam ATG and compared its efficacy against the standard dose of another equine ATG preparation called Thymogam, which is commonly used in resource-constrained settings.
Materials and methods Patients Patients with newly diagnosed AA who were treated with IST as the first-line therapy were studied. These patients received treatment at the Postgraduate Institute of Medical Education and Research (PGMER, Chandigarh, India) from the years 2003 through 2010. Our center is located in the northwestern part of India and is a tertiary care referral institution. The patients included were of age >12 years at diagnosis, and received IST with ATG and cyclosporine. Although most patients had severe or very severe AA requiring IST, patients with non-severe AA who had declining trends in their blood counts with a high transfusion requirement requiring IST were also included. We excluded patients who had either received or planned for stem cell transplantation, hypersensitivity to ATG or cyclosporine, preexisting renal failure, and constitutional AA. The study was approved by the Institutional Ethics Committee. Informed consent was obtained from all adult subjects and from the parents of patients
Department of Internal Medicine, PGIMER, Chandigarh, India, 2Department of Hematology, PGIMER
Objective: Immunosuppressant therapy (IST) with antithymocyte globulin (ATG) and cyclosporine is an established treatment option for patients with aplastic anemia (AA), who are not eligible for allogeneic stem cell transplantation. However, data on the dose of ATG and its efficacy from the developing countries is minimal. Methods: We performed a retrospective analysis of all AA patients (age >12 years), treated with equine ATG and cyclosporine from a single center in India. Patients who received or were eligible for stem cell transplantation were excluded. The overall response rate (ORR) to IST was calculated at 3 and 6 months. We also determined the influence of using a lower dose of Atgam ATG (25 mg/kg/day × 4 days) and compared its efficacy against the standard dose of locally manufactured Thymogam ATG (40 mg/kg/ day × 4 days). Factors influencing the ORR were analyzed using Fisher’s exact test with a significant P < 0.05. Results: Thirty-nine patients with AA treated with ATG and cyclosporine were studied. Median age was 31 years with a male:female ratio of 0.85:1. The ORR was 58% at 3 months, 77% at 6 months and was similar with lower dose Atgam and standard dose Thymogam. On multivariate analysis of ORR at 6 months, the interval between the onset of symptoms to the initiation of therapy was close to attaining statistical significance (odds ratio 23.53, P value 0.053) while the other variables did not attain significance. Conclusions: IST with equine ATG in a lower dose (25 mg/kg/day × 4 days) and cyclosporine is a feasible and effective treatment option for AA in resource-constrained settings.
Introduction Aplastic anemia (AA) is a hematological disorder characterized by pancytopenia with a hypocellular bone marrow in the absence of any abnormal infiltrate or increase in marrow reticulin. Several congenital and acquired causes can predispose to this condition, the commonest etiology being idiopathic or immunomediated suppression of hematopoiesis.1–2 Although this disorder is seen in most parts of the world, there are geographic differences in its incidence with more number of cases being reported from the eastern countries compared with the west.3 This difference is thought to be due to variations in socioeconomic conditions, genetic factors, and the degree of exposure to various factors associated with AA.4 While supportive care is helpful in dealing with the complications of this disorder,5–7 treatments aimed at disease pathogenesis would provide long-term benefits with freedom from transfusions, infections, and potentially curing this condition. To date, allogeneic stem cell transplantation Correspondence to: Pankaj Malhotra, Dept. of Internal Medicine, PGIMER, Chandigarh 160012, India. Email: [email protected]
© W. S. Maney & Son Ltd 2015 DOI 10.1179/1607845414Y.0000000196
from an HLA-matched sibling donor is the definitive therapy for this disorder resulting in a longterm survival of >80% in these patients.8 However, the patient’s candidacy for transplant is often limited by lack of appropriate donor and factors like patient’s age and co-morbidities. Immunosuppressant therapy (IST) with antithymocyte globulin (ATG) and cyclosporine is another promising approach for those patients in whom transplant is not an appropriate option.9 While studies from the developed countries indicate a better survival with allogeneic transplant and IST in patients with AA, the treatment outcomes in developing countries is still uncertain. Key factors like the cost of therapy, availability of resources for stem cell transplantation, and the patient’s willingness to undergo therapy influence the outcomes of this disorder in developing countries like India.10 Similarly, the dose and the type of ATG used are also important factors that are considered to influence the overall outcome. While the ideal dose of ATG has not been well established, it is commonly used in the dose of 40 mg/kg/ day over 4 days. However, a lower dose of ATG
Hematology
2015
VOL.
20
NO.
4
239
Malhotra et al.
Outcomes of IST with ATG and cyclosporine in aplastic anemia
could be cost saving if it can produce similar overall response rates (ORRs). In this study, we have retrospectively analyzed the outcomes of IST and the factors associated with treatment response in a cohort of patients with AA from India. Moreover, we aimed to determine the influence of using a lower dose of Atgam ATG and compared its efficacy against the standard dose of another equine ATG preparation called Thymogam, which is commonly used in resource-constrained settings.
Materials and methods Patients Patients with newly diagnosed AA who were treated with IST as the first-line therapy were studied. These patients received treatment at the Postgraduate Institute of Medical Education and Research (PGMER, Chandigarh, India) from the years 2003 through 2010. Our center is located in the northwestern part of India and is a tertiary care referral institution. The patients included were of age >12 years at diagnosis, and received IST with ATG and cyclosporine. Although most patients had severe or very severe AA requiring IST, patients with non-severe AA who had declining trends in their blood counts with a high transfusion requirement requiring IST were also included. We excluded patients who had either received or planned for stem cell transplantation, hypersensitivity to ATG or cyclosporine, preexisting renal failure, and constitutional AA. The study was approved by the Institutional Ethics Committee. Informed consent was obtained from all adult subjects and from the parents of patients
