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RESEARCH

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Blood Res (2024) 59:6

Published online February 26, 2024

https://doi.org/10.1007/s44313-024-00003-z

© The Korean Society of Hematology

Comparable outcomes with low-dose and standard-dose horse anti-thymocyte globulin in the treatment of severe aplastic anemia

Arihant Jain1†, Aditya Jandial1†, Thenmozhi Mani2, Kamal Kishore3, Charanpreet Singh1, Deepesh Lad1, Gaurav Prakash1, Alka Khadwal1, Reena Das4, Neelam Varma4, Subhash Varma4 and Pankaj Malhotra1*

Author Info. +

1Department of Clinical Hematology and Medical Oncology, PGIMER, Chandigarh 160012, India
2Department of Biostatistics, CMC, Vellore, Hematology, India
3Department of Biostatistics, PGIMER, Chandigarh, India
4Department of Hematology, PGIMER, Chandigarh, India

Correspondence to : Pankaj Malhotra
hematpgi@gmail.com

Received: October 2, 2023; Accepted: January 10, 2024

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Abstract

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Background The standard dose (SD) of horse anti-thymocyte globulin (hATG) ATGAM (Pfizer, USA) or its biosimilar thymogam (Bharat Serum, India) for the treatment of Aplastic Anemia (AA) is 40 mg/kg/day for 4 days in combination with cyclosporine. Data on the impact of hATG dose on long-term outcomes are limited. Here, we describe our comparative experience using 25 mg/kg/day (low-dose [LD]) hATG for 4 days with SD for the treatment of AA.
Methods We retrospectively studied patients with AA (age > 12 years) who received two doses of hATG combined with cyclosporine. Among 93 AA patients who received hATG, 62 (66.7%) and 31 (33.3%) patients received LD and SD hATG with cyclosporine, respectively. Among these,seventeen(18.2%) patients also received eltrombopag with hATG and cyclosporine. Overall response rates [complete response (CR) and partial response (PR)] of LD and SD hATG groups at 3 months (50% vs. 48.4%; p = 0.88), 6 months (63.8% vs. 71.4%; p = 0.67), and 12 months (69.6% vs. 79.2%; p = 0.167) were comparable. The mean (Standard Deviation) 5-year Kaplan–Meier estimate of overall survival and event-free survival was 82.1 (4.6)% and 70.9 (5.5)% for the study population. The mean (standard deviation) 5-year Kaplan–Meier estimate of overall survival and event-free survival of those who received LD hATG versus SD hATG dose was 82.9 (5·3)% versus 74.8 (10·3)% (P = 0·439), and 75.2 (6.2)% versus 61.4(11.2)% (P = 0·441).
Conclusion Our study revealed that the response rates of patients with AA and LD were similar to those of patients with SD to hATG combined with cyclosporine in a real-world setting.

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Keywords: Horse anti-thymocyte globulin, Dose, Aplastic anemia, Response

Article

RESEARCH

Blood Res 2024; 59():

Published online February 26, 2024 https://doi.org/10.1007/s44313-024-00003-z

Copyright © The Korean Society of Hematology.

Comparable outcomes with low-dose and standard-dose horse anti-thymocyte globulin in the treatment of severe aplastic anemia

Arihant Jain1†, Aditya Jandial1†, Thenmozhi Mani2, Kamal Kishore3, Charanpreet Singh1, Deepesh Lad1, Gaurav Prakash1, Alka Khadwal1, Reena Das4, Neelam Varma4, Subhash Varma4 and Pankaj Malhotra1*

1Department of Clinical Hematology and Medical Oncology, PGIMER, Chandigarh 160012, India
2Department of Biostatistics, CMC, Vellore, Hematology, India
3Department of Biostatistics, PGIMER, Chandigarh, India
4Department of Hematology, PGIMER, Chandigarh, India

Correspondence to:Pankaj Malhotra
hematpgi@gmail.com

Received: October 2, 2023; Accepted: January 10, 2024

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Abstract

Background The standard dose (SD) of horse anti-thymocyte globulin (hATG) ATGAM (Pfizer, USA) or its biosimilar thymogam (Bharat Serum, India) for the treatment of Aplastic Anemia (AA) is 40 mg/kg/day for 4 days in combination with cyclosporine. Data on the impact of hATG dose on long-term outcomes are limited. Here, we describe our comparative experience using 25 mg/kg/day (low-dose [LD]) hATG for 4 days with SD for the treatment of AA.
Methods We retrospectively studied patients with AA (age > 12 years) who received two doses of hATG combined with cyclosporine. Among 93 AA patients who received hATG, 62 (66.7%) and 31 (33.3%) patients received LD and SD hATG with cyclosporine, respectively. Among these,seventeen(18.2%) patients also received eltrombopag with hATG and cyclosporine. Overall response rates [complete response (CR) and partial response (PR)] of LD and SD hATG groups at 3 months (50% vs. 48.4%; p = 0.88), 6 months (63.8% vs. 71.4%; p = 0.67), and 12 months (69.6% vs. 79.2%; p = 0.167) were comparable. The mean (Standard Deviation) 5-year Kaplan–Meier estimate of overall survival and event-free survival was 82.1 (4.6)% and 70.9 (5.5)% for the study population. The mean (standard deviation) 5-year Kaplan–Meier estimate of overall survival and event-free survival of those who received LD hATG versus SD hATG dose was 82.9 (5·3)% versus 74.8 (10·3)% (P = 0·439), and 75.2 (6.2)% versus 61.4(11.2)% (P = 0·441).
Conclusion Our study revealed that the response rates of patients with AA and LD were similar to those of patients with SD to hATG combined with cyclosporine in a real-world setting.

Keywords: Horse anti-thymocyte globulin, Dose, Aplastic anemia, Response

Fig 1.

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Figure 1.Response rate over a time across the group
Blood Research 2024; 59: https://doi.org/10.1007/s44313-024-00003-z

Fig 2.

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Figure 2.Kaplan–Meier analysis comparing overall survival (OS) between with low-dose and standard-dose hATG groups
Blood Research 2024; 59: https://doi.org/10.1007/s44313-024-00003-z

Fig 3.

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Figure 3.Kaplan–Meier analysis comparing event free survival (EFS) between with low-dose and standard-dose hATG groups
Blood Research 2024; 59: https://doi.org/10.1007/s44313-024-00003-z

Baseline characteristics of the study population.


VariableTotal patients (n = 93)Low dose hATG (n = 62)Standard dose hATG (n = 31)P value
Age, mean ± SD33.4 ± 15.335.2 ± 15.529.7 ± 14.2
Age ≤ 40 years n(%)62 (66.7)37 (59.7)25 (80.6)0.043
Age > 40 years n(%)31 (33.3)25 (40.3)6 (19.4)
Sex
Male n(%)60 (64.5)40 (64.5)20 (64.5)1.000
Female n(%)33 (35.5)22 (35.5)11 (35.5)
Symptom to diagnosis interval in months, median (IQR)3 (2,5)3 (2,5)3 (1.75, 5.25)0.713
Severity of AA
Severe AA n(%)87 (93.5)58 (93.5)29 (93.5)1.000
Very severe AA n(%)6 (6.5)4 (6.5)2 (6.5)
PNH clone
Positive n(%)33 (35.5)24 (38.7)9 (29.0)0.133
Negative n(%)41 (44.1)29 (46.8)12 (38.7)
Not available n(%)19 (20.4)9 (14.5)10 (32.3)
Prior red blood cell transfusion n(%)74 (79.6)48 (77.4)26 (83.9)0.467
Prior platelet transfusion requirement n(%)63 (67.7)41 (66.1)22 (71.0)0.638
Hematologic parameters
Hemoglobin (g/L), mean ± SD6.4 ± 1.96.4 ± 1.96.3 ± 1.90.909
TLC (× 109/L), mean ± SD2.6 ± 1.22.5 ± 1.22.8 ± 0.90.268
ANC (× 109/L), median (range)0.6 (0.3–1.1)0.6 (0.3–1.1)0.7 (0.3–1.3)0.481
ALC (× 109/L), median (range)1.5 ± 0.671.5 ± 0.641.8 ± 0.70.173
Platelet count (× 109/L), median (range)14 (8–2.2)13 (9–20)14 (7.8–23)0.671

Treatment characteristics of study population.


VariableTotal patients (n = 93)Low dose ATG (n = 62)Standard dose ATG (n = 31)P value
Diagnosis to ATG interval (months, range)2 (1,5)2 (1,5)3 (1,6)0.957
Timing of hATG
As first-line, n(%)58 (62.4)37 (59.7)21 (67.7)0.449
As second-line, n(%)35 (37.6)25 (40.3)10 (32.3)
Eltromobpag with ATG
Yes, n(%)17 (18.3)12 (19.4)5 (16.1)0.704
No, n(%)76 (81.7)50 (80.6)26 (83.9)
Formulation of ATG
ATGAM51 (54.8)39 (62.9)12 (38.7)0.027
Thymogam42 (45.2)23 (37.1)19 (61.3)
Duration of IST after ATG (months), median (range)25 (12,47)25.5 (14.75,51.25)25 (9,34)0.072

Hematologic responses of the study population based on hATG dose.


VariableTotal patients (n = 93), n(%)Low-dose ATG (n = 62), n(%)Standard-dose ATG (n = 31), n(%)P value
Overall response ( PR + CR)
At 3 months46/93 (49.5)31/62 (50)15/31 (48.4)0.883
At 6 months57/86 (66.3)37/58 (63.8)20/28 (71.4)0.483
At 12 months58/80 (72.5)39/56 (69.6)19/24 (79.2)0.382
Response at 3 months
CR5/93 (5.4)4/62 (6.5)1/31 (3.2)0.809
PR41/93 (44.1)27/62 (43.5)14/31 (45.2)
NR47/93 (50.5)31/62 (50.0)16/31 (51.6)
Response at 6 months
CR12/86 (14.0)8/58 (13.8)4/28 (14.3)0.813
PR45/86 (52.3)29/58 (50.0)16/28 (57.1)
NR29/86 (33.7)21/58 (36.2)8/28 (28.6)
Response at 12 months
CR16/80 (20.0)10/56 (17.9)6/24 (25.0)0.614
PR42/80 (52.5)29/56 (51.8)13/24 (54.2)
NR22/80 (27.5)17/56 (30.3)5/24 (20.8)
Best response
CR44/93 (47.3)28/62 (45.2)16/31 (51.6)0.813
PR28/93 (30.1)19/62 (30.6)9/31 (29.0)
NR21/93 (22.6)15/62 (24.2)6/31 (19.4)
CR after 12 months23/93 (24.7)15/62 (24.2)8/31 (25.8)0.865
Time to best response (months), median(IQR)10 (3–18)12 (3–18)6 (3–18)0.635
Relapse on IST11 (11.8)7 (11.3)4 (12.9)1.000
Time to relapse (months), median (IQR)44 (20–94.5)51.56 (24.75–88.75)35.0 (10–98)0.330
Clonal evolution2 (2.2)0 (0)2 (6.5)0.109

Generalized estimating equation analysis for respone to hATG over time.


VariablesOR(95%CI)P value
Treatment arm
Standard dose ATG1.28 (0.43–3.86)0.659
Low dose ATG1.00
Time1.89 (1.26–2.84)0.002
Standard dose ATG x time0.81 (0.50–1.30)0.377
Low dose ATG x time1.00
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