Aplastic Anemia- A comprehensive approach 2024.pptx

Aplastic anemia- basics, pathophysiology, diagnostic work up, management.

1. Aplastic Anaemia: A Comprehensive Approach Dr Pritish Chandra Patra Associate Professor Clinical Hematology IMS and SUM Hospital, Bhubaneswar

2. Disclaimer The information contained in this presentation represents the independent evaluations and opinion of the presenter(s) and does not necessarily reflect the opinions and recommendations of Bharat Serums and Vaccines Ltd. For detailed information on any drugs discussed herein, please consult the full prescribing information issued by the manufacturer.

3. Epidemiology Issaragrisil S, Kaufman DW, Anderson T, Chansung K, Leaverton PE, Shapiro S, et al. The epidemiology of aplastic anaemia in Thailand. Blood 2006;107:1299-307. McCahon E, Tang K, Rogers PC, McBride ML, Schultz KR. The impact of Asian descent on the incidence of acquired severe aplastic anaemia in children. Br J Haematol 2003;121: 170 2. Montane E, Ibanez L, Vidal X, Ballarà­n E, Puig R, Garcà­a N, et al. Epidemiology of aplastic anaemia: a prospective multicenter study. Haematologica 2008;93:518-23. Li SS,Hsu YT,Chang C,Lee SC,Yen CC,Cheng CN,Chen JS,Lin SH,Chang KC,Chen TY, Incidence and treatment outcome of aplastic anemia in Taiwan-real-world data from single-institute experience and a nationwide population-based database. Annals of hematology . 2018 Sep 3 Vaht K,Göransson M,Carlson K,Isaksson C,Lenhoff S,Sandstedt A,Uggla B,Winiarski J,Ljungman P,Brune M,Andersson PO, Incidence and outcome of acquired aplastic anemia : real-world data from patients diagnosed in Sweden from 2000-2011. Haematologica . 2017 Oct

4. Genetic Correlation Relative mutation frequencies in AA, clonal hematopoiesis of indeterminate potential (CHIP), and MDS DNMT3A  and  ASXL1  - commonly mutated in AA, MDS, and age-associated clonal hematopoiesis  PIGA  and  BCOR/BCORL1   - commonly mutated in AA but less frequently in MDS Akiko Shimamura; Aplastic anemia and clonal evolution: germ line and somatic genetics.  Hematology Am Soc Hematol Educ Program  2016; 2016 (1): 74–82

5. Etiology Moore CA, Krishnan K. Aplastic Anemia . [Updated 2022 Jul 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022

6. Etiology: Aplastic Anemia Sultan Ayed Al Qahtani Int J Clin Exp Med 2018;11(6):5501-5512 Vincent, P.C. Drug-Induced Aplastic Anaemia and Agranulocytosis. Drugs 31, 52–63 (1986). Sameer R Melinkeri,Epidemiology , Pathogenesis and Diagnosis of Aplastic Anaemia,VOLUME:63,MARCH - 2015

7. Relation with Other Diseases PNH=paroxysmal nocturnal hemoglobinuria; LGL=large granular lymphocytosis; MDS=myelodysplastic syndromes; AML=acute myeloid leukemia; MS=multiple sclerosis; IBD=inflammatory bowel disease; DM=diabetes mellitus; ITP= immune thrombocytopenic purpura; AIHA=autoimmune hemolytic anemia; PRCA=pure red cell aplasia; PWCA=pure white cell aplasia; AMT= amegakaryocytic thrombocytopenia; HLH=hemophagocytic lymphohistiocytosis Neal S. Young,N Engl J Med. 2018 October 25; 379(17): 1643–1656.

8. Acquired Aplastic Anaemia: Look at mechanism Young NS & Maciejewski J. N Eng J Med 1997;336:1365 Proposed pathophysiology of aplastic anaemia Sameer R Melinkeri,Epidemiology , Pathogenesis and Diagnosis of Aplastic Anaemia,VOLUME:63,MARCH - 2015.

9. Classification Modified Camitta Criteria ( Camitta et al, 1975; Bacigalupo et al, 1988) Killick et al. British Journal of Haematology , 2016, 172, 187–207 * This criterion has now been modified from manual percentages to absolute reticulocyte levels < 60 x 10 9 /l as assessed by automated technologies ( Rovo et al , 2013) *

10. Clinical Features of Aplastic anemia Symptoms related to the decrease in bone marrow production of hematopoietic cells Insidious o nset Initial symptoms related to anemia or bleeding or fever or infections Specific manifestations : Anemia: May manifest as pallor, headache, palpitations, dyspnea, fatigue, or foot swelling Thrombocytopenia: May result in mucosal and gingival bleeding or petechial rashes Neutropenia: May manifest as overt infections, recurrent infections, or mouth and pharyngeal ulcerations

11. Survival Based on Types: India D ifferences in survival rate of MAA and SAA patients at – 1 year: 2.01 ( P  = 0.035), 2 years: 3.75 ( P  = 0.001), and 3 years: 3.53 ( P  = 0.001) Jain D, Kumar R, Tyagi N, et al. Etiology and survival of aplastic anemia : a study based on clinical investigation.  J Clin Lab Anal . 2012;26(6):452-458. doi:10.1002/jcla.21546 Indraprastha Apollo Hospital, and Medanta —The Medicity , two of the referral centers for tertiary care diagnosis

12. Diagnosis and Evaluation Hospital Physician: Hematology/Oncology . 2019 January;14(1)

13. Bone marrow Hypocellular AML & hypocellular MDS Normocellular Aplastic Anemia

14. Diagnostic Procedures in Pancytopenia ATG, antithymocyte globulin BM, bonemarrow CsA , cyclosporine A DEB, diepoxybutane FA,Fanconi’s anemia FISH, fluorescent in situ hybridization GPI, glycosyl phosphatidyl inositol MDS, myelodysplastic syndrome Andrea Bacigalupo BLOOD, 16 MARCH 2017 x VOLUME 129, NUMBER 11

15. Approach to Diagnosis and Evaluation of AA DeZern AE, Churpek JE. Approach to the diagnosis of aplastic anemia. Blood Adv. 2021 Jun 22;5(12):2660-2671

16. Aplastic Anaemia Therapy 3 modalities of treatment- - Stem cell transplant (SCT), - Immunosuppressive therapy (IST) and Supportive care Choice of therapy depends on the severity of the disease, the age of the patient, and the degree of HLA-identity in a potential related or unrelated bone marrow donor Studies confirm that particularly in case of BMT, the interval between diagnosis and therapy has a significant influence on the prognosis A sound tentative diagnosis should be reason enough to refer patients to a Hematological Center which has experience in the therapy of aplastic anemia Hubert Schrezenmeier , Tim Henrik Brümmendorf , Hans Joachim Deeg , Britta Höchsmann , Werner Linkesch , Alexander Röth , Jörg Schubert;Aplastic Anemia - Diagnostics and Therapy of Acquired Aplastic Anemia , May 2012. Gupta V, Eapen M, Brazauskas R et al.: Impact of age on outcomes after bone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors. Haematologica 95:2119-2125, 2010

17. Br J Haematol . 2024;00:1–21

18. Survival : Classified by Age Krista Vaht et al. Haematologica 2017;102(10):1683-1690 Real-world data from patients diagnosed in Sweden from 2000–2011 5-year survival for all patients - 65.4% (Excess mortality: the difference between observed mortality and expected mortality) Relative 5-year survival – - 84.6% in <60 years - 45.3% in ≥60 years, significantly worse (After grouping all patients according to the median age at diagnosis)

19. Age Effect in Patients Receiving Firstline IST Andrea Bacigalupo BLOOD, 16 MARCH 2017 x VOLUME 129, NUMBER 11 Data from the EBMT registry

20. Strong Age Effect after Transplantation from an HLA Identical Sibling Andrea Bacigalupo BLOOD, 16 MARCH 2017 x VOLUME 129, NUMBER 11 Data from the EBMT registry

21. Age Effect in UD Transplants Andrea Bacigalupo BLOOD, 16 MARCH 2017 x VOLUME 129, NUMBER 11 B est outcome seen for very young patients, for whom first-line UD BMT may be considered Data from the EBMT registry

22. Survival Rate : Therapy Comparison According to primary treatment For patients treated with IST (n=161) divided into different age groups Krista Vaht , Magnus Göransson , Kristina Carlson, Cecilia Isaksson, Stig Lenhoff , Anna Sandstedt , Bertil Uggla, Jacek Winiarski , Per Ljungman , Mats Brune , Per-Ola Andersson. Incidence and outcome of acquired aplastic anemia : real-world data from patients diagnosed in Sweden from 2000–2011. Haematologica 2017;102(10):1683-1690 Real-world data from patients diagnosed in Sweden from 2000–2011 IST Treatment No survival difference 0–18 years: 86.2% 19–39 years: 90% 40– 59 years: 69.7% ( P =0.67, P =0.12, and P =0.056, respectively) Significantly worse survival rate of 52.2% in ≥60 years compared with patients aged 0–18 years (P=0.003) and 19–39 years (P=0.001), but not with patients aged 40–59 years (P=0.15) 96.0% 68.9 % 29.6% 68.9 % 5-year survival rate No significant difference in survival in younger patients (0–18 and 19–39 years), whether primarily treated with IST or underwent SCT; 88.1% vs. 100% (P=0.113)

23. H orse ATG/ CsA and Rabbit ATG/ CsA as First Therapy in SAA Phillip Scheinberg , Neal S. Young; How I treat acquired aplastic anemia.  Blood  2012; 120 (6): 1185–1196 Study (year) Horse ATG, N Rabbit ATG, N Horse ATG, response, % Rabbit ATG, response, % Design Outcome comparison between ATGs Zheng (2006) 47  32  79  53  Prospective, randomized  Comparative statistics not reported  Garg (2009)     —  13  —  92  Prospective  No comparative statistics, comparison with reported results with horse ATG in the literature  Atta (2010)  42  29  60  35  Retrospective  Difference at statistical significance (historical comparison)  Afable (2011) 67  20  58  45  Retrospective  Difference not statistically significant (historical comparison)  Scheinberg (2011)  60  60  68  37  Prospective, randomized  Statistically significant difference (direct comparison) 

24. Response to horse ATG and rabbit ATG Increase in Blood Counts in Patients with Hematologic Improvement better with hATG vs rATG (41 patients in the horse-ATG group and 22 patients in the rabbit-ATG group) Survival on patients were censored at the time of stem-cell transplantation S urvival when stem-cell transplantation events were ignored Overall Survival 96% in the horse-ATG group Vs 76% in the rabbit-ATG group Phillip Scheinberg et al. .Horse versus Rabbit Antithymocyte Globulin in Acquired Aplastic Anemia,N Engl J Med 2011; 365:430-438

25. Maschan MA et al., Bone Marrow Transplant, 2004, vol. 33 pg. S27 Marsh JC et al, Blood (ASH Annual Meeting Abstracts), 2011, vol. 117 pg. 2408 Salamonowicz M et al. Blood (ASH Annual Meeting Abstracts)2011;117:3435 Jeong D et al. Blood (ASH Annual Meeting Abstracts) 2011;117:1346 Shin S et al. Blood (ASH Annual Meeting Abstracts), 2011, vol. 117 pg. 3430 Hochsmann B et al. Blood (ASH Annual Meeting Abstracts), 2011, vol. 117 pg. 3434 hATG vs rATG : Outcomes Studies Confirmed Better Response With hATG

26. Durability of Response after horse ATG 95% s urvival in 10 years without late event; 65% otherwise High-risk evolution to monosomy 7, complex karyotype, high-grade myelodysplasia, or leukemia occurs in approximately 10% of responders long term A pprox. 50%. probability of a first late event (relapse or clonal evolution) among responders (N = 243) S urvival was worse in those with a high-risk clonal event Phillip Scheinberg , Neal S. Young; How I treat acquired aplastic anemia.  Blood  2012; 120 (6): 1185–1196 Improved life expectancy and a durable hematologic response that avoids relapse and clonal evolution

27. IST and hATG: C omparison of Responses Shah, S., Jain, P., Shah, K.  et al.  Immunosuppressive therapy for aplastic anemia : a single- center experience from western India.  Ann Hematol   98,  41–46 (2019 Shah_2018

28. Other Agents Added to h orse ATG/ CsA Regimens Vs Standard horse ATG/ CsA Study (year) N Agent(s) added to horse ATG/ CsA Design Outcome compared with standard horse ATG/ CsA Kojima (2000) 119  G-CSF, danazol  Prospective, randomized  No difference in response, relapse, clonal evolution, or survival  Gluckman (2002)  102  G-CSF  Prospective, randomized  No difference in response, relapse, clonal evolution, or survival  Zheng (2006) 77  GM-CSF, EPO  Prospective, randomized  No difference in response or survival  Scheinberg (2006)     104  Mycophenolate mofetil  Prospective  No difference in response, relapse, clonal evolution, or survival compared with historical control  Teramura (2007)  101  G-CSF  Prospective, randomized  No difference in response, clonal evolution, and survival; fewer relapses in G-CSF arm  Scheinberg (2009)     77  Sirolimus  Prospective, randomized  No difference in response, relapse, clonal evolution, or survival  Tichelli (2011) 192  G-CSF  Prospective, randomized  No difference in response, relapse, event-free survival, and overall survival  Phillip Scheinberg , Neal S. Young; How I treat acquired aplastic anemia.  Blood  2012; 120 (6): 1185–1196

29. Relapse after prolonged Cyclosporine treatment after ATG. M edian time to relapse for the taper cohort was approximately 2 years, which contrasts to about 1 year when CsA was discontinued at 6 months. 40-50% of the relapses occurred within the first year when CsA was discontinued after 6 months Phillip Scheinberg et al Prolonged Cyclosporine Administration After Antithymocyte Globulin Delays But Does Not Prevent Relapse in Severe Aplastic Anemia,Am J Hematol . 2014 June ; 89(6): 571–574.

30. Combination treatment for severe aplastic anemia improves responses by preventing cytotoxic T-lymphocyte–mediated attack on hematopoietic stem cells and boosting stem cell function through thrombopoietin growth factor signaling. ATG+EPAG Nirija Ranjit Anderson etal,Eltrombopag in Frontline Therapy for Severe Aplastic Anemia : A RACE Against Time,The Hematologist (2022) 19 (3). Peffault de Latour R, Kulasekararaj A, Iacobelli S, et al. Eltrombopag added to immunosuppression in severe aplastic anemia . N Engl J Med. 2022;386(1):11–23.

31. EPAG: Mechanism and Evidences Scheinberg , P. Activity of eltrombopag in severe aplastic anemia. Blood Adv 2018; 2: 3054–3062.

32. Hematologic Responses : Epag O RR 88% with EPAG + IST 47% with EPAG alone Hong Y, Li X, Wan B, Li N, Chen Y. Efficacy and Safety of Eltrombopag for Aplastic Anemia : A Systematic Review and Meta-analysis. Clin Drug Investig . 2019 Feb;39(2):141-156.

33. Hematologic and Trilineage responses: EPAG Response was observed in at least one lineage in 64% and 74% of cohorts A and B, respectively, including trilineage responses in 27% and 34% of cohorts A and B, respectively Nationwide survey on the use of eltrombopag in patients with severe aplastic anemia: a report on behalf of the French Reference Center for Aplastic Anemia Lengline E, Drenou B, Peterlin P, Tournilhac O, Abraham J, Berceanu A, Dupriez B, Guillerm G, Raffoux E, de Fontbrune FS, Ades L, Balsat M, Chaoui D, Coppo P, Corm S, Leblanc T, Maillard N, Terriou L, Socié G, de Latour RP. Nationwide survey on the use of eltrombopag in patients with severe aplastic anemia : a report on behalf of the French Reference Center for Aplastic Anemia . Haematologica . 2018 Feb;103(2):212-220. PMID: 29170252; P

34. Eltrombopag added to IST

35. Eltrombopag Response Rates After IST R esponse rate was also higher than expected with standard immunosuppression : R ate was 87% in the current study , as compared with 66% in our historical cohort . The overall response rate (94%) and complete response rate (58%) were notably higher in cohort 3, in which patients had the longest exposure to eltrombopag Townsley , Danielle M. and Scheinberg , Phillip and Winkler, Thomas and Desmond, Ronan and Dumitriu , Bogdan and Rios, Olga and Weinstein, Barbara and Valdez, Janet and Lotter, Jennifer and Feng, Xingmin and Desierto , Marie and Leuva , Harshraj and Bevans, Margaret and Wu, Colin and Larochelle, Andre and Calvo, Katherine R. and Dunbar, Cynthia E. and Young, Neal S,Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia , N Engl J Med 2017; 376:1540-1550  

36. EATG+CsA in ATG intolerable Patients SOAR Concluded Eltrombopag + CsA therapy may be beneficial as 1L treatment for patients with SAA who cannot receive treatment with ATG Carlos Vallejo, Jun Ho Jang, Carlo Finelli , Efreen Montaño Figueroa, Lalita Norasetthada , Rodrigo T. Calado , Mehmet Turgut, Regis Peffault De Latour, Ulrike Kriemler-Krahn , Jens Haenig , Joan Maier, Phillip Scheinberg,Efficacy and Safety of Eltrombopag Combined with Cyclosporine As First-Line Therapy in Adults with Severe Acquired Aplastic Anemia : Results of the Interventional Phase 2 Single-Arm Soar Study,Blood,Volume 138, Supplement 1,2021,Page 2174.

37. EPAG addition responses Treatment Naïve SAA: Paediatric Olga Goronkova,Galina Novichkova,Tatiana Salimova,Irina Kalinina,Dina Baidildina,Ulyana Petrova,Kristina Antonova,Maria Sadovskaya,Elena Suntsova,Dmitry Evseev,Victor Matveev,Dmitry Venyov,Lili Khachatryan,Dmitry Litvinov,Alexey Pshonkin,Galina Ovsyannikova,Natalia Kotskaya,Darina Gobadze,Yulia Olshanskaya,Alexander Popov,Elena Raykina,Olga Mironenko,Kirill Voronin,Bazarma Purbueva,Elmira Boichenko,Yulia Dinikina,Evgeniya Guseynova,Dmitry Sherstnev,Elena Kalinina,Sergey Mezentsev,Olga Streneva,Natalia Yudina,Olga Plaksina,Elena Erega,Michael Maschan,Alexey Maschan , Efficacy of combined immunosuppression with or without eltrombopag in children with newly diagnosed aplastic anemia, Blood Adv, 2023, Adding ELTR to standard IST was well tolerated and increased the CR rate Characteristics ELTR + IST (n = 49), n (%) IST (n = 49), n (%) Age (yr), median (range) 10.5 (2-17.7) 8.7 (2.1-16.8)

38. Eltrombopag Added to IST: Children Addition of EPAG added to standard IST did not improve outcomes in children with treatment-naïve SAA. EPAG in the paediatric population should not automatically be considered standard of care Groarke , E.M., Patel, B.A., Gutierrez-Rodrigues, F., Rios, O., Lotter, J., Baldoni, D., St. Pierre, A., Shalhoub , R., Wu, C.O., Townsley , D.M. and Young, N.S. (2021), Eltrombopag added to immunosuppression for children with treatment-naïve severe aplastic anaemia. Br J Haematol , 192: 605-614.

39. Eltrombopag Key Features : Pediatric population EPAG added to Standard IST portrayed mixed results in Pediatric Population and requires Careful consideration. Positive Studies Eltrombopag added to the IST has shown a good safety profile , without manifestations of excessive toxic effects. A ddition of eltrombopag to standard IST was well tolerated and resulted in satisfactory hematological response at 6 and 12 months in this single-institution experience  Escalate (II Dose escalation study )overall response rate to ETB in pediatric refractory/relapsed SAA pts was encouraging. ETB exposure was higher in pts aged 1 to <6 y than in those aged 6 to <18 y because of the age-related increase in ETB clearance. Despite the higher exposure in the younger pts, the daily dose achieved was generally 150 mg in both the 1 to <6 y and 6 to <18 y groups. Eltrombopag combined with standard IST increased the complete response rate in treatment-naïve children with severe aplastic anemia and increased the overall response rate in pediatric patients with SAA but not in those with vSAA . Negative Studies The trend towards relapse was higher and EFS significantly lower in children who received EPAG compared to IST alone. Addition of EPAG added to standard IST did not improve outcomes in children with treatment-naïve SAA. EPAG in the paediatric population should not automatically be considered standard of care. Marrapodi Maria Maddalena, Mascolo Annamaria, Roberti Domenico, Martino Martina Di, Rafaniello Concetta, Riccardi Consiglia , Rossi Francesca,The efficacy and the safety of eltrombopag in pediatric patients with severe aplastic anemia : a systematic review,Frontiers in Pediatrics ,Vol 11,2023. Lesmana H, Jacobs T, Boals M, Gray N, Lewis S, Ding J, Kang G, Hale M, Weiss M, Reiss U, Wang W, Wlodarski M. Eltrombopag in children with severe aplastic anemia . Pediatr Blood Cancer. 2021 Aug;68(8):e29066 Akiko Shimamura, Alexey Maschan , Carolyn Bennett, Jason E Farrar, Sujith Samarasinghe, Brigitte Strahm , Winfred C. Wang, Adrianna Vlachos, Charlotte M. Niemeyer, Timothy S. Olson, Denise D'Alessio , Elise Burmeister Getz, Tomasz Lawniczek , Yunnan Xu, David A. Williams; Eltrombopag in Pediatric Patients with Previously Untreated or Refractory/Relapsed Severe Aplastic Anemia : The Phase II Escalate Trial. Blood 2022; 140 (Supplement 1): 705–707. Groarke EM, Patel BA, Gutierrez-Rodrigues F, Rios O, Lotter J, Baldoni D, St Pierre A, Shalhoub R, Wu CO, Townsley DM, Young NS. Eltrombopag added to immunosuppression for children with treatment-naïve severe aplastic anaemia. Br J Haematol . 2021 Feb;192(3):605-614.

40. Pediatric Amendment of BSH management of AA Treatment consists of hematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST) Samarasinghe, S., Veys , P., Vora, A. and Wynn, R. (2018), Paediatric amendment to adult BSH Guidelines for aplastic anaemia. Br J Haematol , 180: 201-205. 

41. Indian experience - IST with hATG

42. EQUINE ATG IN INDIA : AN OVERVIEW Sno Studies Type Population N ATG type Outcome 1 Ramzan et al Retrospective Children 20 Thymo 65%(0%,65%) 2 Gupta et al Retrospective children 27 Thymo 29.7%(11.1%,18.6%) 3 Agarwal et al Prospective Adults 30 Thymo 50%(6.6%,43.4%) 4 Shah et al Retrospective Children and Adults 91 (23&68) Thymo 48.4%(8.8%,39.6%)(Child:60.9%(8.7%,52.2%),Adult(44.1%(8.8%,35.3%) 5 Mahapatra et al Retrospective Not mentioned 26 Thymo 50%(3.8%,46.2%) 6 Amalnath et al Retrospective Adults 60 Thymo 68.3%(3.3%,65%) 7 Mahapatra et al Retrospective Median age 27 years 97 Atgam 58.7%(10.3%,48.4%) 8 George et al Retrospective Adults and Chidren 530( 410& 120) Atgam/ Lymphoglobuline 58.4%(23.3%,35.1%) 9 Nair et al Retrospective Children 33 Atgam 87.9%(24.2%,63.6%) 10 Nair et al Retrospective Adults 120 Atgam 5.8%(9.2%,76.6%) 11 Malhotra et al Retrospective Adults 30 Low dose Atgam(20) and Thymogam (10) 77%(3%,74%) 12 Patel et al Retrospective Adults and Chidren 18 Not Mentioned 43.7%(6.2%,37.5%) 13 Sharma et al Retrospective Children 28 Atgam/Thymogam/Lymphoglobuline 50%(14,3%,35.7%) RRstudiedat1year Agarwal MB, Jijina F, Shah S, Malhotra P, Damodar S, Ross C (2015) Safety and efficacy of indigenous equine antithymocyte globulin along with cyclosporine in subjects with acquired aplastic anemia . Indian J Hematol Blood Transfus 31:174–9 Nair V, Sondhi V, Sharma A, Das S, Sharma S (2012) Survival after immunosuppressive therapy in children with aplastic anemia . Indian Pediatr 49:371–376 6. Nair V, Sharma A, Das S, Sondhi V, Sharma S (2013) Immunosuppressive therapy in adults with aplastic anaemia: single-institution experience from India. Postgrad Med J 89:508–515 7. Gupta V, Kumar A, Tilak V, Saini I, Bhatia B (2012) Immunosuppressive therapy in aplastic anemia . Indian J Pediatr 79(12):1587–91 8. Ramzan M, Yadav SP, Zafar MSH, Dinand V, Sachdeva A (2014) Outcome of pediatric acquired aplastic anemia : a developing world experience. Pediatr Hematol Oncol 31(1):29–38 9. Shah S, Jain P, Shah K, Patel K, Parikh S, Patel A et al (2019) Immunosuppressive therapy for aplastic anemia : a single- center experience from western India. Ann Hematol 98(1):41–6 10. Mahapatra M, Singh PK, Agarwal M, Prabhu M, Mishra P, Seth T et al (2015) Epidemiology, clinico -haematological profile and management of aplastic anaemia: AIIMS experience. J Assoc Physicians India 63(3 Suppl ):30–5 11. George B, Mathews V, Viswabandya A, Abraham A, Ganapule A, Fouzia NA et al (2015) Immunosuppressive therapy and bone marrow transplantation for aplastic anaemia—the CMC experience. J Assoc Physicians India 63(3 Suppl ):36–40 Malhotra P, Bodh V, Gurumurthy GS, Datta AK, Varma N, Varma S (2015) Outcomes of immunosuppressant therapy with lower dose of antithymocyte globulin and cyclosporine in aplastic anemia . Hematology 20(4):239–44 13. a Patel AB, Panchal HP, Anand AS, Patel AA, Parikh SP, Shah SA (2015) Acquired severe aplastic anemia treated with antithymocyte globulin and cyclosporine: an experience of regional cancer center , western India. J Appl Hematol 6:53–57 Sharma R, Chandra J, Sharma S, Pemde H, Singh V (2012) Antithymocyte globulin and cyclosporine in children with aplastic anemia : a developing country experience. J Pediatr Hematol Oncol. 34:93–9 Amalnath DS. 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. Indian J Hematol Blood Transfus . 2020 Jul;36(3):473-476 RR of Thymogam in adults is similar to that of ATGAM from India and elsewhere. With ATGAM being three times costlier Thymogam seems to be a viable alternative.

43. S ummary Choice of AA therapy depends on the severity of the disease, the age of the patient, and the degree of HLA-identity in a potential related or unrelated bone marrow donor C urrent standard first line IST - horse ATG combined with ciclosporin Eltrombopag is new addition to IST in management of AA with improved response IST or IST+EPAG recommended first line therapy for non-severe AA patients requiring treatment, severe or very severe AA if lack a matched sibling donor (MSD), and severe or very severe AA patients aged >35-50 years U se of high/moderate dose cyclophosphamide (without stem cell support) not recommended in AA A ddition of a third drug to h-ATG/ CsA , such as G-CSF, mycophenolate mofetil, or sirolimus - not improve outcomes S ubstitution of h-ATG by r-ATG, cyclophosphamide, or alemtuzumab - equally ineffective because of inferior response rates or excessive toxicities or both Strategy of stem cell stimulation with eltrombopag in SAA - more successful than other approaches of intensifying immunosuppression or stimulation of more committed marrow progenitor cells Longer-term follow-up and different combinations and doses needed to better define the role and optimal delivery of the Tpo -RAs in AA in the future ATG only be administered in centers familiar with its use and be given to in-patients

44. Key Take Away Horse antithymocyte globulin plus cyclosporine Still remains the current standard immunosuppressive regimen despite many efforts to improve beyond it. Eltrombopag has shown significant activity as a single agent in treatment of refractory patients with hematologic response rates of 40% to 50%. Eltrombopag when combined with horse antithymocyte globulin plus cyclosporine in first line (3-drug regimen), overall and complete hematologic response rates were higher. Late events of relapse and clonal evolution are in accordance with a vast long-term experience with horse antithymocyte globulin plus cyclosporine alone. Longer follow-up will be important to determine durability of response and possible cure rates following the novel regimen i.e., standard immunosuppression with eltrombopag combination.

45. CONCLUSION hATG + CyA is still considered the standard IST for AA patients EPAG addition further Improves long term survival in AA at standard recommended doses Patient can have transfusion free life The treatment is well tolerated & requires only a brief hospitalization

46. Thank You