• Users Online: 285
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
Year : 2015  |  Volume : 6  |  Issue : 2  |  Page : 53-57

Acquired severe aplastic anemia treated with antithymocyte globulin and cyclosporine: An experience of regional cancer center, Western India

Department of Medical and Paediatric Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India

Date of Web Publication7-Jul-2015

Correspondence Address:
Ankit B Patel
Medical OPD Room No. 80, Gujarat Cancer and Research Institute, New Civil Campus, Asarwa, Ahmedabad, Gujarat
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1658-5127.160198

Rights and Permissions

Severe aplastic anemia (SAA) is a serious bone marrow disease that needs a comprehensive and service-intense treatment with either bone marrow transplantation (BMT) or immunosuppressive therapy (IST); both are difficult to optimally offer in resources-limited countries. Here, we report the outcome of IST using horse Antithymocyte globulin (ATG) in 18 (7 children; 11 adults) patients with SAA referred to our center in west India. Only 18 patients out of 102 diagnosed as AA in 2 years could receive IST, largely due to costs restraints. Although CR was seen in 30% in adults and 33% in pediatric cases, but overall 50% cases were able to enjoy transfusion-independence, requiring no further treatment. Treatment related mortality occurred in 6.2%, relapse in 6.2% and 6.2% had clonal evolution. This makes IST a valuable option for managing SAA in absence of bone marrow transplantation.

Keywords: Antithymocyte globulin, aplastic anemia, cyclosporine, Western India

How to cite this article:
Patel AB, Panchal HP, Anand AS, Patel AA, Parikh SP, Shah SA. Acquired severe aplastic anemia treated with antithymocyte globulin and cyclosporine: An experience of regional cancer center, Western India. J Appl Hematol 2015;6:53-7

How to cite this URL:
Patel AB, Panchal HP, Anand AS, Patel AA, Parikh SP, Shah SA. Acquired severe aplastic anemia treated with antithymocyte globulin and cyclosporine: An experience of regional cancer center, Western India. J Appl Hematol [serial online] 2015 [cited 2022 Dec 9];6:53-7. Available from: https://www.jahjournal.org/text.asp?2015/6/2/53/160198

  Introduction Top

Aplastic anemia (AA) is an uncommon but serious disorder characterized by peripheral blood (PB) cytopenias resulting from acquired factors causing failure of the bone marrow (BM) to produce blood cells. BM transplantation (BMT) is the treatment of choice for the majority of patients especially young patients but is unfortunately limited due to various factors including the cost of treatment, non-availability of expertise or matched donors. As acquired AA is thought to be caused by immune damage including T-cell related immune destruction, immunosuppressive therapy (IST) has a role. Several studies have shown encouraging results with a combination of antithymocyte globulin (ATG) and cyclosporine (CSA) [1],[2] in improving survival compared with supportive care alone, [3],[4] with response rates vary between 40% and 70% and short-term survival similar to unselected patients treated with BMT. [5],[6]

  Subjects and methods Top

In this retrospective study, all patients who were treated with ATG and CSA from January 2011 to December 2012 were included and followed up for at least 1 year at Gujarat Cancer and Research Institute, Ahmedabad with permission of Institutional Review Board. The disease was considered severe AA (SAA) if hypocellular marrow was associated with at least two of the following: a neutrophil count of <0.5 × 10 9 /L, a platelet count of <20 × 10 9 /L, and a reticulocyte count of <1%. [7] AA was considered very SAA (VSAA) if the criteria for severe disease were fulfilled and the neutrophil count was below 0.2 × 10 9 L. Chromosomal fragility test was not available. However, patients were screened for any phenotypic manifestation of Fanconi's and all had no family history of intrinsic BM failure syndrome or of consanguinity. Only 4 patients were screened for paroxysmal nocturnal hemoglobinuria by immunophenotyping and the rest had a negative sucrose lysis test. Viral markers HIV, HBsAg, HCV were negative in all patients and history of chemical and radiation exposure was ruled out. No specific cause was found all patients.

All patients were treated with horse ATG at a dose of 40 mg/kg for 8 days or 80 mg/kg for 4 days through a central line over 4-6 h infusion. A test dose of ATG (0.1 ml in 10 ml on forearm) was given before first course of ATG. Premedication with hydrocortisone and pheniramine maleate was given before daily dose of ATG. For the prevention of serum sickness, intravenous methylprednisolone was given at 2 mg/kg divided into 0.5 mg/kg 6 hourly doses over 8 days followed by tapering protocol of 1.5 mg/kg divided into two equal doses on day 9, 10 then 1.0 mg/kg divided on day 11, 12; 0.5 mg/kg on day 13, 14, and 0.25 mg/kg given on 15 th day. CSA was started at 10 mg/kg orally on day 1 and continued for responding patients until they become transfusion independent and for at least 1 year with monitoring of CSA level every week for the first 2 weeks and then once every 2 weeks for the remainder of the treatment or as necessary to maintain a whole-blood CSA level between 200 and 500 ng/ml. Those who failed to respond discontinued treatment after 6 months of treatment.

Response Criteria and Toxicity

Complete response (CR) was defined as transfusion independence and a neutrophil count >1.5 × 10 9 /L, a platelet count >100 × 10 9 /L, and a hemoglobin (Hb) level of >10 g/dl. Partial response (PR) was defined as transfusion independence and an unsupported increase of counts of at least one cell line over baseline values (Hb by at least 2 g/dl and actual value ≥8 g/dl: neutrophils by at least 0.5 × 10 9 /L and platelets >30 × 10 9 /L, if previously lower than 20 × 10 9 /L) in patients with SAA or VSAA. [1],[2],[8],[9] All remissions were confirmed by 2 blood counts at least 4 weeks apart. Clinical relapse was defined by the return of PB counts to levels meeting the definition of severe or moderate AA and the requirement for blood transfusion. [1],[2] Toxicity of treatment was evaluated and graded according to the criteria of World Health Organization. [10]

  Results Top

There were 18 patients. Of which, 7 were pediatric (4 male: 3 female) and 11 were adult patients (8 male: 3 female), who were treated for aplastic anemia with ATG and CSA between January 2011 and December 2012. Median age of pediatric patients was 9 years and of adult patients was 35 years. Pretreatment characteristics of study population are shown in [Table 1]. The median follow-up time was 20 months (13-35). One pediatric patient died within 1 month due to intracranial hemorrhage and one adult patient was lost to follow-up (LFU) within 1 month after taking ATG, so 2 patients were excluded from analysis. Finally, 10 adults (9 AA: 1 VSAA) and 6 pediatrics (5 AA: 1 VSAA) were analyzed for response [Table 2]. 6 months after treatment, 6 out of 10 (60%) adult patients had remission (1 had CR and 5 had PR) and in pediatric subset, only 1 patient out of 6 (16.7%) had PR. At the end of 1 year, 5 out of 10 (50%) adult patients had remission - 3 CR and 2 PR (2 PR converted in CR and 1 patient had relapse on 200 days and in pediatric subset 2 out of 6 (33%) had remission - 1 had CR and 1 had PR. One child had delayed response achieving CR at 430 days. So finally, 50% response rate in pediatric patients (2 CR: 1 PR). Both patient with VSAA responded, 1 had PR and 1 had CR. [Table 3] shows overall response rate according to time.
Table 1: Pretreatment characteristics of study population initially included (n=18)

Click here to view
Table 2: Overall response rate of treated patients according to time (n=16)

Click here to view
Table 3: Kinetics (median time) of recovery of PB count (n=16)

Click here to view

Four out of seven (2 adults and 2 children), non responders are alive and on supportive care at present. Of remaining three, one adult patient later on develops acute myeloid leukemia (AML) and died, and remaining two were LFU. Patients who did not respond were supported by regular blood transfusion to maintain Hb >7 g/dl. Platelet transfusions were given for clinically evident bleeding and in the asymptomatic patient if platelets <10,000. Episodes of febrile neutropenia were managed with broad spectrum antibiotics.

Kinetics of Remission and Recovery of Peripheral Blood Counts

Blood counts of all 8 (5 adult: 3 children) patients, who responded showed an improvement in at least one cell line within 3 months. Median time of recovery of Hb was 153 (60-320) days, absolute neutrophil count (ANC) >500 was in 64 (30-150) days, ANC >1000 was in 110 (50-260) days and platelets recovered in 96 (50-160) days as shown in [Table 3].


One patient who had achieved PR at 150 days relapsed on the 200 th day. Due to the financial constraints, the patient was put on supportive treatment at present and he is still alive and transfusion-dependent.

Side Effects

No patient developed serum sickness. Gum hypertrophy developed in 14 out of 16 (87%) patients. Hypertension was experienced by 5 out of 16 (31%) patients, requiring short-term antihypertensives. Laboratory evidence of renal dysfunction was recognized in 2 (12%) patients, which normalized after discontinuation of CSA. Febrile neutropenia was present in 11 (68%) patients, in which 2 patients developed lobar pneumonia. One adult patient who never achieved transfusion independence developed AML after 8 months of treatment. [10] Side effects profile is described in [Table 4].
Table 4: Side effects of ATG/CSA therapy (n=16)

Click here to view

  Discussion Top

The present study cohort included consecutive patients from a single center. All patients had SAA or VSAA. Patients with mild or moderate AA were excluded.

Although the present study may be criticized for the small number of patients treated with ATG-CSA, heterogeneity of immunosuppressants used and of being from a single center, yet it illustrates clearly the real life challenges of many hematology-oncology centers in the developing world. Only 18 patients out of 102 diagnosed as AA in 2 years could receive IST, largely due to costs restraints. This also may be compounded by challenges in delivering such an important treatment at the optimal time.

There is a paucity of literature pertaining to responses of ATG and CSA in AA from developing world. The results of the present study show that an overall response within 6 months in adult patients was 60% and 16.7% in children. More rapid response to treatment may results in lower rates of early death, less need of supportive care, less use of resources, and thereby lower cost. [9]

Late presentations and referrals, difficulties in making ATG/CSA optimally available, associated comorbidities and complications, constraints in supportive care like antifungal, antibacterials, and isolation may all contribute to the relatively unsatisfactory results.

It is also important to realize that non-SAA is the major group of patients who do extremely well with ATG therapy. Once this group is excluded, there is marked variation in the results for the treatment of SAA with ATG at different centers. [11],[12] It has been seen that patient with mild/moderate AA respond to immunosuppression much better than those with SAA or VSAA.

Stanazol has been shown to be effective only in 38% of non-SAA in Indian patients with no responses in SAA and VSAA. [13] The available Indian data on the use of ATG in adults according to Agarwal et al. [11] showed 40% response rates to ATG in SAA and no response in VSAA compared to which our study demonstrated response rates 50% in adults with SAA and 100% those with VSAA (but only 1 patient had VSAA). According to pediatric data of Chandra et al. [14] response to ATG was 50%, which is similar to our study. We compared our study with different international studies as shown in [Table 5].
Table 5: Final outcome of all 16 patients in comparison to other studies

Click here to view

Our study revealed an overall response rate of 50% which is low as compared to two other studies by Marsh et al. [15] (74%) and Tichelli et al. [16] (70%). This may be due small number of patients in the study population and variation in a response rates (between 40% and 70%). [5] It could be hypothesized that the mechanism of development of AA may be different in different patients and there may be an intrinsic stem cell defect rather than an autoimmune etiology. [17]

The 6.2% mortality (1/16) in the study cohort is similar to patients using androgens and lower than stanazol (22% mortality) within 2 months of starting therapy. [13] Another Indian series reported 100% mortality in nonresponders to ATG. [11] Unhygienic living conditions led to increased morbidity in Indian patients. Because of improved supportive care, better control of infections and the use of leukocyte-depleted blood products, patients can be kept alive during prolonged periods of pancytopenia before and after treatment with IST. [18],[19] This also allows for the delayed recovery of BM function and salvage treatment with thesecond course of IST. Initial mortality can be reduced with early diagnosis, early referral, and better care. Patients being LFU is also a major issue, as in our study, 1 patient (5.5%) was LFU after getting treatment and 2 (28.7%) were lost after not getting a response. This is because of poverty, lack of education, and logistics related to long distance.

All the patients who responded revealed an improvement in at least one cell line within 3 months and continued to evolve into CR till the end of 1 st year. 3 months thus may be a reasonable checkpoint to consider salvage treatment or alternative treatment strategies as compared to the 4 months as earlier suggested. [10],[20]

Relapses were seen in SAA patients after attaining PR. It was seen in 1 patient who relapsed after a first course. Over half of such patients may respond again. Unlike most of the published series, in our study, only 1 patient (6.2%) relapsed compared to Tichelli et al.[16] where the relapse rate was 20%, possibly due to prolonged duration of CSA therapy and slow tapering.

In a study from the European Group for BMT group, 10-year cumulative risk of secondary malignancy was 18.8% in AA patients treated with IST, [21] while another study reported an incidence of 25%. The risk was particularly high in patients treated with a repeat course of IST. [21],[22] In our study, only 1 patient (6.2%) who did not respond to IST developed AML after 8 months, which is low compared to a study by Tichelli et al. (20%). Clinically, apparent adverse effects of CSA were mild, but the drug causes subclinical organ toxicity and is expensive. [10],[23] We therefore, recommend tapering and finally discontinuing CSA in patients with stable remissions for 12 months so as to avoid early relapse. Favorable early results of the treatment with ATG, methylprednisolone, and CSA have been confirmed in several small series and large trials. [2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[1]4[,1]5],[17],[18],[19],[24],[25],[26],[27] ATG and combination of CSA are more effective than CSA alone. AA may be particularly sensitive to CSA in children. [28] This report demonstrates that IST is of therapeutic benefit to half of the adult and pediatric aplastic anemia patients. Although CR was seen in 30% in adults and 33% in pediatric cases, but overall 50% cases were able to enjoy transfusion-independent life, requiring no further treatment and no treatment associated adverse effects.

  Conclusion Top

SAA is very difficult to manage without the availability of BMT and in the presence of limited resources. ATG is a hope with reasonable response ATG rates in view of the fact that BMT is not available for every patient.

Financial Support and Sponsorship


Conflicts of Interest

There are no conflicts of interest.

  References Top

Frickhofen N, Kaltwasser JP, Schrezenmeier H, Raghavachar A, Vogt HG, Herrmann F, et al.Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. The German aplastic anemia study group. N Engl J Med 1991;324:1297-304.  Back to cited text no. 1
Rosenfeld SJ, Kimball J, Vining D, Young NS. Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia. Blood 1995;85:3058-65.  Back to cited text no. 2
Champlin R, Ho W, Bayever E, Winston DJ, Lenarsky C, Feig SA, et al. Treatment of aplastic anemia: results with bone marrow transplantation, antithymocyte globulin, and a monoclonal anti-T cell antibody. Prog Clin Biol Res 1984;148:227-38.  Back to cited text no. 3
Camitta B, O′Reilly RJ, Sensenbrenner L, Rappeport J, Champlin R, Doney K, et al. Antithoracic duct lymphocyte globulin therapy of severe aplastic anemia. Blood 1983;62:883-8.  Back to cited text no. 4
Bacigalupo A, Brand R, Oneto R, Bruno B, Socié G, Passweg J, et al. Treatment of acquired severe aplastic anemia: Bone marrow transplantation compared with immunosuppressive therapy - The European Group for Blood and Marrow Transplantation experience. Semin Hematol 2000;37:69-80.  Back to cited text no. 5
Frickhofen N, Kaltwasser JP, Schrezenmeier H, Raghavachar A, Vogt HG, Herrmann F, et al. Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. The German Aplastic Anemia Study Group. N Engl J Med 1991;324:1297-304.  Back to cited text no. 6
Camitta BM, Thomas ED, Nathan DG, Santos G, Gordon-Smith EC, Gale RP, et al. Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality. Blood 1976;48:63-70.  Back to cited text no. 7
Frickhofen N, Heimpel H, Kaltwasser JP, Schrezenmeier H, German Aplastic Anemia Study Group. Antithymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia. Blood 2003;101:1236-42.  Back to cited text no. 8
Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207-14.  Back to cited text no. 9
Naithani R, Chandra J, Sharma S. Acute myeloid leukemia after intensive immunosuppressive therapy in aplastic anemia. Indian Pediatr 2005;42:939-42.  Back to cited text no. 10
Agarwal MB, Agarwal UM, Bhave AB, Vishwanathan C. Anti-lymphocyte globulin therapy in acquired aplastic anaemia. J Assoc Physicians India 1993;41:371-3.  Back to cited text no. 11
Bacigalupo A, Hows J, Gluckman E, Nissen C, Marsh J, Van Lint MT, et al. Bone marrow transplantation (BMT) versus immunosuppression for the treatment of severe aplastic anaemia (SAA): a report of the EBMT SAA working party. Br J Haematol 1988;70:177-82.  Back to cited text no. 12
Marwaha RK, Bansal D, Trehan A, Varma N. Androgens in childhood acquired aplastic anaemia in Chandigarh, India. Trop Doct 2004;34:149-52.  Back to cited text no. 13
Chandra J, Naithani R, Ravi R, Singh V, Narayan S, Sharma S, et al. Antithymocyte globulin and cyclosporin in children with acquired aplastic anemia. Indian J Pediatr 2008;75:229-33.  Back to cited text no. 14
Saracco P, Quarello P, Iori AP, Zecca M, Longoni D, Svahn J, et al. Cyclosporin A response and dependence in children with acquired aplastic anaemia: a multicentre retrospective study with long-term observation follow-up. Br J Haematol 2008;140:197-205.  Back to cited text no. 15
Schrezenmeier H. Treatment of Aplasticanemia with Immunosuppressin and Hematopoient Growth Factors: 25 th Annual EBMT Meeting Eductional Book. Hamburg, Germany; 1998. p. 123-31.  Back to cited text no. 16
Tichelli A. Immunosuppressive therapy in aplasticanemia. Blood 2011;117:4433.  Back to cited text no. 17
Bacigalupo A, Bruno B, Saracco P, Di Bona E, Locasciulli A, Locatelli F, et al. Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia: An update of the GITMO/EBMT study on 100 patients. European Group for Blood and Marrow Transplantation (EBMT) Working Party on Severe Aplastic Anemia and the Gruppo Italiano Trapianti di Midolio Osseo (GITMO). Blood 2000;95:1931-4.  Back to cited text no. 18
Gluckman E, Esperou-Bourdeau H, Baruchel A, Boogaerts M, Briere J, Donadio D, et al. Multicenter randomized study comparing cyclosporine-A alone and antithymocyte globulin with prednisone for treatment of severe aplastic anemia. Blood 1992;79:2540-6.  Back to cited text no. 19
Gupta V, Gordon-Smith EC, Cook G, Parker A, Duguid JK, Wilson KM, et al. A third course of anti-thymocyte globulin in aplastic anaemia is only beneficial in previous responders. Br J Haematol 2005;129:110-7.  Back to cited text no. 20
Tichelli A, Passweg J, Nissen C, Bargetzi M, Hoffmann T, Wodnar-Filipowicz A, et al. Repeated treatment with horse antilymphocyte globulin for severe aplastic anaemia. Br J Haematol 1998;100:393-400.  Back to cited text no. 21
Di Bona E, Rodeghiero F, Bruno B, Gabbas A, Foa P, Locasciulli A, et al. Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. Gruppo Italiano Trapianto di Midollo Osseo (GITMO) Br J Haematol 1999;107:330-4.  Back to cited text no. 22
Schrezenmeier H, Hinterberger W, Hows J, Ljungman P, Locasciulli A, Marin P, et al. For the EBMT SAAWorking party second immunosuppressive treatment of patients with aplastic anemia not responding to the first course of immunosuppression: A report from the working party on severe aplastic anemia of the EBMT. Bone Marrow Transplantation 1995;15 Suppl. 1: S10.  Back to cited text no. 23
Socié G, Henry-Amar M, Bacigalupo A, Hows J, Tichelli A, Ljungman P, et al. Malignant tumors occurring after treatment of aplastic anemia. European Bone Marrow Transplantation-Severe Aplastic Anaemia Working Party. N Engl J Med 1993;329:1152-7.  Back to cited text no. 24
Marsh J, Schrezenmeier H, Marin P, Ilhan O, Ljungman P, McCann S, et al. Prospective randomized multicenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia: a report from the European Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia Working Party. Blood 1999;93:2191-5.  Back to cited text no. 25
Reghavachar A, Kolbe K, Hoffken K. Standard immunosuppression is superior to cyclosporine/filgrastim in severe aplasticanemia: the German Multicemter Study [abstract]. Bone Marrow Transplant 1999;23 Suppl 1:S31.  Back to cited text no. 26
Kojima S, Hibi S, Kosaka Y, Yamamoto M, Tsuchida M, Mugishima H, et al. Immunosuppressive therapy using antithymocyte globulin, cyclosporine, and danazol with or without human granulocyte colony-stimulating factor in children with acquired aplastic anemia. Blood 2000;96:2049-54.  Back to cited text no. 27
Fogarty PF, Yamaguchi H, Wiestner A, Baerlocher GM, Sloand E, Zeng WS, et al. Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet 2003;362:1628-30.  Back to cited text no. 28


  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]

This article has been cited by
1 Idiopathic Aplastic anemia: Indian Perspective
Tuphan Kanti Dolai, Manisha Jain, Manoranjan Mahapatra
Indian Journal of Hematology and Blood Transfusion. 2022;
[Pubmed] | [DOI]
2 Response to Horse ATG (Thymogam, Bharat Serums and Vaccine, India) and Cyclosporine in Aplastic Anemia: A Single Centre, Retrospective Study of 60 Patients from Southern India
Deepak S Amalnath
Indian Journal of Hematology and Blood Transfusion. 2019;
[Pubmed] | [DOI]
3 Response to Immunosuppressive Therapy in Acquired Aplastic Anaemia: Experience of a Tertiary Care Centre from Eastern India
Bijita Dutta,Tuphan Kanti Dolai,Prakas Kumar Mandal,ShuvraNeel Baul,Rajib De,Karthika Senthil,Prantar Chakrabarti
Indian Journal of Hematology and Blood Transfusion. 2019;
[Pubmed] | [DOI]
4 Immunosuppressive therapy for aplastic anemia: a single-center experience from western India
Sandip Shah,Preetam Jain,Kamlesh Shah,Kinnari Patel,Sonia Parikh,Apurva Patel,Harsha Panchal,Asha Anand
Annals of Hematology. 2018;
[Pubmed] | [DOI]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Subjects and methods
Article Tables

 Article Access Statistics
    PDF Downloaded460    
    Comments [Add]    
    Cited by others 4    

Recommend this journal