Epidemiology, Clinico-Haematological Profile and Management of Aplastic Anaemia: AIIMS Experience

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1 30 supplement to Journal of the association of physicians of india Published on 1st of every month 1st march, 2015 Epidemiology, Clinico-Haematological Profile and Management of Aplastic Anaemia: AIIMS Experience M Mahapatra 1, PK Singh 3, M Agarwal 3, M Prabhu 3, P Mishra 2, T Seth 2, S Tyagi 1, HP Pati 1, R Saxena 1 Abstract Background: The incidence of aplastic anaemia (AA) is higher in Asia than in the West. The precise incidence of AA in India is not known due to lack of epidemiological study % of pancytopenic patients in referral centres are of aplastic anaemia. Patients and Methods: This was an analysis of 1501 patients diagnosed with aplastic anaemia over a period of seven and half years (January 2007 June 2014) attending the Aplastic clinic of department of haematology of All India Institute of Medical Sciences, New Delhi. The details regarding medical history, physical examination, complete blood count, bone marrow aspirate and biopsy, treatment received, were retrieved. Inherited bone marrow failure was screened in patients below 35 years. Treatment response was analysed for various treatment modalities. Results: 1501 patients of AA from 20 different states of India were analysed. The bulk of patients were from Uttar Pradesh (28.7%), Bihar (23.6%), Delhi/NCR (20%) and Haryana (7%). The average number of new aplastic anaemia patients enrolled per year 214 (range: ). The median age at presentation was 25 years (range 2 83), with M;F - 2.3:1. Severity of AA revealed: severe (SAA): 75%, very severe (VSAA): 15%, nonsevere (NSAA):10%. Inherited bone marrow failure syndromes constituted 5% (75 patients) of all aplastic anaemia patients. The most common clinical presentations were pallor (97%), bleeding manifestations (69.6%) and fever (54%). The haematological parameters showed: median level of haemoglobin level: 5.9 gm/dl, WBC: 2700/mm 3, ANC: 380/mm 3, platelet: 10000/mm 3. PNH clone was present in 13.5% of patients. 107 patients (7%) were lost to follow up or expired before any treatment was initiated. Only 69 patients (4.5%) received treatment with HLA-matched sibling stem cell transplantation and another 232 (15.5%) patients received ATG plus cyclosporine as immunosuppressive therapy. Seven hundred thirteen patients (47.5%) received cyclosporine. The overall response to various treatment modalities was: HLA matched sibling haematopoietic stem cell transplant: 75.3%, Anti-thymocyte globulin plus cyclosporine: 58.7%, cyclosporine plus androgen: 45.6%, cyclosporine alone: 32.2%. Conclusion: Management of AA is a real challenge in developing countries. This is one of the largest case series from a single centre from India. It is our endeavour to reduce the detrimental outcome by increasing awareness among patients and referring physicians to reduce the delay between diagnosis and treatment. 1 Professor, 2 Additional Professor, 3 Senior Resident, Department of Haematology, All India Institute of Medical Sciences, New Delhi Introduction Aplastic anaemia (AA) is a lifethreatening bone marrow failure disorder, if untreated, is associated with very high mortality. The incidence of AA is higher in Asia than in the West. It appears to be 2 to 3-fold more common in Asia than in Europe. 1 The precise incidence of AA in India is not known due to lack of epidemiological study. However, in hospital based study, it is known that 20-40% of pancytopenic patients are diagnosed as AA in referral centres. 2 In an epidemiological study in children in and around Lucknow, UP, showed the annual incidence of aplastic anaemia is around 6.8 cases per million of population per year. 3 All India Institute of medical Sciences (AIIMS) is government funded tertiary care hospital catering the northern part of India. In a previous study from AIIMS 4, it was shown that the number of new aplastic anaemia patients comprised per million (95% CI,

2 supplement to Journal of the association of physicians of india Published on 1st of every month 1st march, ) hospital OPD patients. This very high incidence of AA is possibly being due to the tertiary nature of AIIMS. With the paucity of enough available data in Indian context, we are presenting 1501 aplastic anaemia patients, one of the largest case series from a single centre from India with the aim of investigating the epidemiological, clinico-haematological profile of aplastic anaemia. Although the transplant outcome of all patients is being presented, the treatment outcome of all the patients with immunosuppressive therapy (IST) could not be analysed at the time of preparation of this manuscript. However, our experience of a sub group patients treated with immunosuppressive therapy in aplastic anaemia during the same time period is being presented. Material and Methods This was an analysis of 1501 patients diagnosed with aplastic anaemia over a period of seven and half years (January 2007 June 2014) attending the Aplastic clinic of department of haematology of All India Institute of Medical Sciences, New Delhi. The diagnosis of AA was confirmed as per criteria laid down by International Agranulocytosis and Aplastic Anaemia Study Group, To diagnose AA at least two of the following must be present: (i) haemoglobin < 10 g/dl, (ii) platelet count < 50,000/µl, (iii) neutrophil count 1,500/ µl, with a hypocellular bone marrow (BM) without infiltration or fibrosis. The details regarding medical history, physical examination, complete blood count, bone marrow aspirate and biopsy were retrieved. The inherited bone marrow failure syndromes were excluded in patients less than 35 years of age based on physical examination and chromosomal fragility studies with diepoxybutane. Paroxysmal Nocturnal Haemoglobinuria (PNH) was excluded by flow cytometry for determination of CD55 and CD59. Additional tests including liver function tests, renal function tests, and serology for hepatitis A, B, C, HIV were performed. Disease severity Patients were classified according to published severity criteria. 5 Aplastic anaemia was considered severe if the marrow cellularity was < 25%, and at least 2 of the following criteria were met: neutrophil count < /L, platelet count < /L or reticulocyte count < /L. It was considered very severe if the above criteria were fulfilled, and the neutrophil count was < /L. Treatment options Younger patients (< 45 years) with severe or very severe aplastic anaemia were counselled about stem cell transplantation (SCT) if there was a HLA identical sibling available. Otherwise, those patients received immunosuppressive therapy (IST) either antithymocyte globulin (horse-atg) plus cyclosporine or cyclosporine alone. Patients > 45 years of age were managed with IST. Those patients who could not afford IST, even cyclosporine alone, were managed with androgen therapy. The conditioning regimen used for SCT was Flu+Cy+ATG, which consisted of fludarabine 180 mg/m 2 over 6 days, Cyclophosphamide: 120 mg/kg over 2 days and antithymocyte globulin (ATG) over 4 days. GVHD prophylaxis consisted of cyclosporine (i.v. or oral) twice daily to keep trough levels between ng/ml with methotrexate on day 1 at 10 mg/ m 2 and on days 3 and 6 at 7 mg/m 2. Immunosupressive therapy (IST) consisted of equine ATG, which was administered intravenously at a dose of 40 mg/kg/ day for 4 days as continuous infusion over h. Cyclosporine was administered orally from day 14 of ATG at a dose of 5mg/kg/day and adjusted to maintain serum levels between μg/l. Oral prednisolone at a dose of 1 mg/kg/day was administered for 14 days for prevention of serum sickness. IST with cyclosporine alone or in combination with androgen therapy constituted the majority bulk of our patient population, as the cost therapy for ATG and SCT is extremely high. The dose of cyclosporine was 5 mg/kg/ day and of androgen (stanazolol) was 2 mg/kg/day. All patients were monitored for hepatic and renal toxicity. Response criteria: A complete response (CR) was defined as neutrophils > /L, platelets > /L and haemoglobin value normal for age and sex. A partial response (PR) was defined as - improvement in blood counts (haemoglobin: > 8gm/dl, ANC > /L, platelet: > /L), transfusion independence and not meeting criteria of CR. Results Demographic Parameters A total number of 1501 patients were diagnosed and followed up in the Aplastic Clinic of department of Haematology at AIIMS, New Delhi, out of which 32 (2%) patients were from outside India (Afghanistan, Nepal), the rest 1469 (98%) are from 20 different states of India. The bulk of patients were from Uttar Pradesh, Bihar, Delhi/NCR and Haryana, the distribution of patient share was 28.7%, 23.6%, 20%, 7.2% respectively (Table 1). As per the hospital record, 12% of all new haematology OPD patients are of aplastic anaemia. On an average, around 200 new cases were seen each year in aplastic clinic. The disease was most commonly seen in the patients that fall in the age group of years (Figure 1). The median age at presentation was 25 years (range 2 83), with males 1051 (70%) and females 450 (30%). History of jaundice was present in 68 (4.5%) patients and pregnancy associated aplastic anaemia was seen in 11 (0.7%) patients. Family history of aplastic anemia was observed in 7 patients.

3 32 supplement to Journal of the association of physicians of india Published on 1st of every month 1st march, 2015 Table: 1 : Epidemiology, clinical and haematological parameters of Aplastic Anaemia Characteristics Demography Area wise Distribution Observation Numbers (Total : 1501) Outside India/Indian 32 (2%), 1469 (98%) Uttar Pradesh 432 (28.7%) Bihar 354 (23.6%) New Delhi 300 (20%) Haryana 108 (7.2%) Other States 275 (20.5%) Patient distribution Year wise distribution (till June) 177 Sex Male : Female 2.3 : 1 Severity Very Severe 225 (15%) Severe 1126 (75%) Non-Severe 150 (10%) Common Clinical presentations Pallor 1456 (97%) Bleeding 1044 (69.6%) manifestations Fever 810 (54%) Haematological Parameters Median (Range) Values Haemoglobin 5.9 gm/dl ( ) WBC 2700 /mm 3 ( ANC 380/ mm 3 ( ) Platelet 10000/ mm 3 ( ) Inherited Bone Total number 75 (5%) marrow failure Fanconi s Anaemia 68 Dyskeratosis 6 Congenita Shwachman-diamond 1 syndrome Treatment Received No treatment 107 (7%) Stem cell Transplant 69 (4.5%) ATG 232(15.5%) Cyclosporine 713 (47.5%) Androgen 380 (25.5%) Majority (75%) of patients were classified into severe aplastic anaemia, another 15% were of very severe and only 10% of our patients were of non-severe variety. Inherited bone marrow failure syndromes constituted 5% (75 patients) of all aplastic patients, majority (68 patients) being Fanconi anaemia (FA), 6 were Dyskeratosis congenita (DC) and one had Shwachman-diamond syndrome (SDS) Age Distribution - By Gender Male Female Total Number of patients: < > 60 Fig. 1 : Age and sex distribution of aplastic anaemia patients Clinico-Haematological Parameters The most common clinical presentations were pallor (97%), bleeding manifestations (69.6%) and fever (54%). The duration of pallor varied from 2 to 8 months with a median period of 3.6 months. Among the bleeding manifestations, gum bleeding (38%), skin (36%), epistaxis (19%) and menorrhagia (11%) were common. Eighteen (1.2%) patients presented with intracranial bleeding. Although fever was a manifestation in 810 (54%) patients, documented infections were present only in 102 (6.7%). The values of haematological parameters were summarised in Table 1. Data of presence of PNH clone at diagnosis was available in 597 (39.7%) patients. Presence of positive PNH by flow cytometry was observed in 81 (13.5%) cases. Fanconi s Anaemia Sixty eight patients were diagnosed as fanconi s anaemia with increased chromosomal breakage studies. The median age was 12 years (1-34 years) with male to female ratio 4:1. Fourteen patients (20%) were diagnosed above the age of 18 years. Fanconi patients represented 4.5% of total aplastic anaemia patients in the time period of evaluation. Only 4 families gave a history of consanguineous marriage, the patients were from 8 different states of India, no socio-economic or religious preponderance was found. Of these FA patients 29 (42%) had complete absence of any phenotypic stigmata of Fanconi anaemia. The common phenotypic features included a wide spectrum of defects, the most consistent physical finding was short stature of > 2SD (90%), hyperpigmentation (74%) and hypothenar flattening or different thumb defects (63%). There were documented renal anomalies in only 5 patients. All patients were followed for clinical course and progression of disease. All patients received standard therapy for Fanconi anaemia and were advised bone marrow transplant, supportive therapy in the form of anabolic steroids, transfusion support. None of our patients were managed with stem cell transplantation. In non transplant patients outcome depended on response to androgen therapy, this significantly influenced survival between responders

4 supplement to Journal of the association of physicians of india Published on 1st of every month 1st march, ± 6 months versus non-responders 14 ± 2 months (p=0.001). The cause of death in non-responders was haemorrhage or uncontrolled infections. The outcome did not depend on age of onset, or presence or absence of phenotypic features. There was no statistical significance in response to treatment or severity of haematological problems in patients with or without phenotypic characteristics of Fanconi anaemia. Treatment 107 patients (7%) were lost to follow up or expired before any treatment was initiated after diagnosis. Only 69 patients (4.5%) received treatment with HLAmatched sibling stem cell transplantation and another 232 (15.5%) patients received ATG plus cyclosporine as immunosuppressive therapy. Seven hundred thirteen patients (47.5%) received cyclosporine either alone (209 patients) or in combination with stanazolol (504 patients). Around 25.5% of total patients not received any IST, only managed with androgen therapy. Treatment outcome of all patients except SCT could not be analysed for this manuscript. So our experience of a sub-group of patients on IST during same time period is presented here. Stem cell Transplantation (SCT) Sixty nine patients (72 SCTs) of median age 22 years (range 8 45 years) received allogeneic SCT from human leucocyte antigen (HLA) matched sibling donors. Three patients received stem cell transplant two times. No patient with any inherited bone marrow failure syndromes received SCT. There were 53 males and 16 females. Source of stem cells were from peripheral blood in 64 SCTs (89%). The median time since diagnosis was 12 months (range 4 65 months) and median pre-transplant transfusions were 37 (range ). Six patients were platelet refractory and one alloimmunised for pan-red blood cell (RBC) antigens. Thirty two patients (44%) had pre-existing infections, out of which 12 (16%) had fungal infection (2: proven, 10: possible). Sixty-six patients (91.6%) received prior immunosuppressive therapy; 3 had ATG therapy before transplant. Majority (97%) of patients received empirical antibiotics and 30 (41.6%) patients received empirical antifungals for febrile neutropenia during transplant period. The median CD34 count was 5.29 x 10 6 / kg and the median neutrophil engraftment time was 10 days (range 8 17). The duration of hospital stay varied from 23 to 144 days (median: 43 days). The median follow-up period was 32 months (range 3 82). Overall incidence of acute GVHD was 25% (18 patients), with 5 had grade III-IV. Seventeen cases developed chronic GVHD, with extensive GVHD in four. There were 17 (24.6%) deaths, with three intracranial haemorrhages, five rejections with infection, four cases of refractory GVHD (acute/overlap syndrome) with cytomegalovirus reactivation, and five invasive fungal infections. 52 patients survived after a median follow up period of 32 months. So the overall survival was 75.3%. Anti-Thymocyte Globulin (ATG) and cyclosporine (CSA) Therapy One hundred three patients of aplastic anaemia on ATG therapy over a period of 4 years ( ) were evaluated. All the patients were given equine ATG (ATGAM). ATG was used in the dose of 40 mg/kg/day (total dose 160 mg/kg) for 4 consecutive days. Out of 103 patients 6 patients were died before 3 months and in consequence were excluded from the final analysis, which was made in 97 patients. There were 66 male and 31 female with a median age of 27 years (range, years). The median interval from diagnosis to treatment was 120 days (range, 30-2,160 days). The duration of hospitalisation during ATG therapy ranged from 7 to 30 days (median - 14 days). All cases required blood and platelet support, to a maximum of 7 single donor platelets (SDPs). The median SDP requirement was 2. The most common adverse event was fever related to ATG infusion. Serum sickness developed in 25 (25.9%) patients, between 6 days and 18 days after ATG infusion. At 3 months, 6 patients had CR, 35 patients PR and 56 had no response. At 6 months, 10 patients had CR, 47 patients PR and 40 had no response. The overall response rate of 58.7% was achieved. There was no statistical difference in response rate between paediatric (< 18 years) and adult (>18 years) group (p; 0.08). The patients with severe aplastic anaemia (SAA) responded better than very severe AA (p: 0.02). Fifteen patients relapsed at a median interval of 360 days from treatment (range, 225-1,050 days). The actuarial survival at 4 years in those who responded was 89.58% versus 61.29% in those who did not respond. Our Experience with indigenous ATG preparation Thirty one patients received the indigenous equine ATG (THYMOGAM) over a period of 4 years. Most of those patients could not afford ATGAM, so preferred to receive the indigenous product. The dose of ATG was 40 mg/kg/day (total dose 160 mg/ kg) for 4 consecutive days. Out of 31 patients, 5 died (3: intracranial bleeding, 1: sepsis, 1: transformed to AML) before 6 months (3 before 3 months) and in consequence were excluded from the final 6 th month analysis, which was made in 26 patients. The median interval from diagnosis to treatment was 9 months (range, 3-68 months). At the time of treatment, the median haemoglobin level was 5.2 g/dl (range, g/dl) and the median neutrophil count was 0.4 x 10 9 /l (range, x 10 9 /l) and the median platelet count was 11 x 10 9 /l (range, x 10 9 /l). At 3 months the overall response rate of 28.5% (PR: 8) was achieved. At 6 months 1 patient had CR, 12 patients PR and 13 had no response. The overall response rate of 50% was achieved. Mild reaction in the form of chill and rigor was seen in majority of

5 34 supplement to Journal of the association of physicians of india Published on 1st of every month 1st march, 2015 patients. Serum sickness was seen in 7 (22.5%) patients. Median duration of development of serum sickness was 9 days (range, 6-15). Seven patients (22.58%) develop infection within 1 month of post ATG, out of that 5 patients had no aetiology was found and 2 patients had definite aetiology; 1 bacterial pneumonia, 1 pseudomonas sepsis. Majority of infected patients are in the non-response group. Four patients relapsed at a median interval of 320 days from treatment (range, days). Cyclosporine alone or cyclosporine combination with stanazolol To study and compare the safety and efficacy of cyclosporine and stanazolol with cyclosporine alone in acquired aplastic anaemia, 158 patients were enrolled to a randomised controlled study over a period of two years. Patients of newly diagnosed acquired aplastic anaemia without HLA matched donor or who can t afford ATG were included. Oral cyclosporine was used in dose of 5 mg/kg/day in two divided doses in both arm and oral androgen (stanazolol) in dose of 2 mg/kg/ day in three divided doses was added in combination arm. The primary end point was haematological response at 6 months. Cyclosporine levels were not done routinely, only done in selected patients with side effects. Out of total 158 patients were randomised in two groups, 121 patients completed the 6 months of planned follow up. At the end of 6 months, in combination arm (n= 59), 5 (8.4%) showed CR and 22 (37.2%) had PR, whereas cyclosporine alone arm (n=62), showed 4 (6.4%) CR and 16 (25.8%) PR. Although the overall response to combination arm is 45.6%, as compared to 32.2% of cyclosporine alone arm, it was not statistically significant (p: 0.501). Except for G.I. upset, which was higher in combination arm (p=0.006), there was no statistically significant difference in side effects in two groups. The blood transfusion requirement and use of antibiotic and antifungal were same in both groups. There was more days of cyclosporine interruption in combination arm (mean days, S.D ) than in cyclosporine alone arm (mean 7.71 days S D 16.04) (p=0.04). Discussion Aplastic anaemia is being considered as a rare disease with varied incidence worldwide. The precise incidence in India is not known due to lack of epidemiological data. Study conducted by Ahmed et al 3 showed disease incidence 6.8% in Lucknow, India but this had limitations of age groups and the numbers of patient s included. In referral hospitals, aplastic anaemia accounts for 20-40% all pancytopenic patients. 2 The present study was conducted on 1501 patients, largest case series from a single institute in India. AIIMS, New Delhi, being tertiary care centre, a lot of patients referred mostly from the northen and eastern part of India, The demographic picture of aplastic anaemia showed the patients from 20 different states of India. However, the majority of patients were from UP, Bihar, Delhi/NCR region. In the present study, the average number of new aplastic anaemia patients enrolled per year 214 (range: ), which is very high, because of referral nature of AIIMS. The disease was common in the age group of years old patients, which is similar to previous observation by Jain et al 6, whereas the study conducted by Varma et al 7 showed a median age of 8 years. The incidence inherited disease like Fanconi s Anaemia in the present study was seen in 5% of all the patients, where as if we analyse with patients below 35 years, then it was around 6.6%. Other studies,6-8 from India showed the incidence of inherited bone marrow failure varied from 9.2% 13.8% of all aplastic anaemia patients. Haematopoietic stem cell transplant and immunosuppressive therapy (IST) are the primary modalities of treatment of aplastic anaemia. Present study showed around 30% of patients, either received no treatment or managed with only androgen therapy, as they could not afford any form of IST or SCT. Two major challenges in management of aplastic anaemia in India are the duration from diagnosis to treatment, which is too long and the cost of therapy. There is no universal state-funded health-care system in India, and only a minority of people is covered by insurance or their employers. Majority of patients are heavily pre-transfused, usually with leuco-depleted blood products. 9,10 In our study, around 40% of patients are infected before initiation of any treatment and more than 90% receive immunosuppressive therapy before stem cell transplantation. Stem cell transplant for SAA is a challenge in the developing world. From economic constraints to highly unfavourable clinic-haematological profiles, BMT is not accessible to all our patients. Peripheral blood as stem cell source and better conditioning regimen with more immunosuppression serves as a practical solution due to faster engraftment, less need for transfusions, and consequently earlier resolution of established infections Engraftment time in our patients ranged from a median 10 days (range 8 17) for neutrophils and median 15 days (range 6 42) for platelets and is similar to reports from different centres. In our experience, increased risk of GVHD with PBSCT was not observed in our patients with 26% acute GVHD, 7% grade III-IV acute GVHD, 25% chronic GVHD, and 9% extensive chronic GVHD, which was similar to other centres. IST in aplastic anaemia is well established since 1970s, with several large prospective trials showing consistent results An effective IST regimen is equine ATG in combination with cyclosporine which produces haematologic response in 60-75% cases. Various Indian studies, showed variable results,

6 supplement to Journal of the association of physicians of india Published on 1st of every month 1st march, with response rate 33.3% to 87.9%. In the present study, response rate was 50% to 58.7% with two different preparations of ATG. Most of our patients tolerated ATG well with very few major side effects It was difficult to compare the response rates of the different preparations due to different clinical profile and insufficient number of cases, and follow up period but there was no difference in toxicity profile. However, we have observed more complete response (CR) with Atgam as compared to indigenous ATG (Thymogam). Majority (47.5%) of our patients received cyclosporine alone or in combination with androgen. This is mostly because of increased cost of therapy with SCT or ATG. There was no significant difference in response rate between cyclosporine alone and in combination with androgen. Conclusion Aplastic anaemia management is a real challenge in a country like India. It is our endeavour to reduce this detrimental outcome by increasing awareness among patients and referring physicians to reduce the delay between diagnosis and treatment. Curtailing such delays will help reduce multiple transfusions and pre-treatment infections, thus improving the overall survival rates in our SAA patients. Acknowledgement We are grateful to Dr. Avinash kumar Singh and Dr. Tufan Kumar Dolai for their contribution in analysing a part of the data during their senior residency at AIIMS, New Delhi. References 1. Young NS, Kaufman DW. The epidemiology of acquired aplastic anemia. Haematologica 2008;93: Mahapatra M. Pancytopenia: aplastic Anemia. degruchy s Clinical Hematology in Medical Practice. Wiley India edition. (6 th Edition).2013; Chapter 6: Ahmed M, Anand M, Kumar A, Siddiqui MKJ. Childhood aplastic anaemia in Lucknow, India: Incidence, organochlorines in the blood and review of case reports following exposure to pesticides. Clinical Biochemistry 2006;39: Kumar Rajat, Choudhary DR, Mahapatra M, Kotwal A, Mathur Alka, Gopal Krishan, Chatterjee T, Saxena R,Choudhry VP. A retrospective hospital based study of 440 patients of aplastic anemia from India: Epidemiology; response to therapy; and possible significance of jaundice during therapy. [abstr 5299] Blood; 2004;104:410b. 5. 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: Jain D, Raina V, Fauzdar A et al. Chromosomal breakage study in aplastic anemia patients in india. Asian Journal of Medical Sciences 2010;2: Varma N,Varma S,. Marwaha RK, Malhotra P et al. Multiple constitutional aetiological factors in bone marrow failure syndrome (BMFS) patients from north India. Indian J Med Res 2006;124: Gupta V, Kumar A, Tilak V, Saini I, Bhatia B. Immunosuppressive therapy in aplastic anemia. Indian J Pediatr 2012;79: Mahapatra M, Mishra P, Seth T, Rathod N, Rathi S, Saxena R. Short and long term outcomes of allogenic hematopoietic stem cell transplant performed in non-hepa filtered single rooms: A single center experience from India. Bone Marrow Transplantation 2010;45:S Mishra P, Rathod N, Mahapatra M, Seth T, Rathi S, Kapoor R,Gupta N, Sharma S, Aggarwal N, Singh AK, Dayama A, Dhingra B. Peripheral blood stem cell transplant is safe in heavily pre-transfused aplastic anemia patients without increased morbidity from chronic graftversus-host disease. Bone Marrow Transplantation 2010;45:S Seth T, Kanga U, Sood P, Sharma V, Mishra P, Mahapatra M. Audit of peripheral stem cell transplantation for aplastic anemia in multitransfused infected patients. Transplant Proc 2012;44: Kumar R, Prem S, Mahapatra M, Seth T, Choudhary DR, Mishra P, Pillai L, Narendra AM, Mehera NK, Saxena R, Choudhry VP. 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Safety and efficacy of indigenous equine antithymocyte globulin along with cyclosporine in subjects with acquired aplastic anemia. Indian J Hematol Blood Transfus Online published on 16 th July. DOI /s z. 22. Sharma SK, Singh PK, Seth T, Mishra P, Mahapatra M. Antithymocyte globulin induced recurrent seizures in a case of severe aplastic anemia. Indian J Hematol Blood Transfus 2014;30: Dayama A, Seth T, Mishra P, Mahapatra M. Antithymocyte globulin induced posterior reversible encephalopathy in aplastic anemia. Neurol India 2013;61: Gupta N, Mahapatra M, Rathi S, Kapoor R, Singh A, Seth T, Mishra P. Acute renal failure following antithymocyte globulin therapy for aplastic anaemia-report of two cases and review of literature. Ann Hematol 2011;90: