European Journal of Haematology 92 (172–176)
CASE REPORT
Salvage therapy of refractory severe aplastic anemia by decreasing cyclosporine dose regimen Amandine Bertrand1, Mickael Philippe2, Yves Bertrand1, Dominique Plantaz3, Nathalie Bleyzac1,2 trie et Biologie Evolutive, UMR CNRS 5558, Universite Lyon 1, Pediatric Hematology and Oncology Unit, IHOP, Lyon; 2Laboratoire de Biome ^pital La Tronche, University of Grenoble, Grenoble, France Villeurbanne; 3Pediatric Hematology and Oncology Unit, Ho
1
Abstract Optimal modalities for immunosuppressive therapy (IST) for severe aplastic anemia (SAA) have to be determined, and especially cyclosporine (CyA) dosing to promote regulatory T cells (Treg) which are lacking and which account for physiopathological mechanisms. We are reporting on three cases of pediatric patients suffering from SAA, initially without hematological response between 4 and 7 months after IST, and who have responded 2 months after the decrease in CyA target trough blood levels to 100 ng/mL, and one case which has early responded by applying low trough blood levels from the beginning. As it has been demonstrated that Treg increase in IST responders and that Treg are stimulated only by low CyA concentrations, these case series suggest that lower CyA doses than actually recommended could be more efficient to enhance the proportion of responders. This report highlights a new field of perspectives for the treatment for SAA. Key words aplastic anemia; regulatory T lymphocytes; cyclosporine matologie et d’Oncologie Pe diatrique 1 place J.Renault, 69008 Lyon, France. Correspondence Amandine Bertrand, MD, Institut d’He Tel: (+33) 4 69 16 65 60; Fax: (+33) 4 69 16 65 51; e-mail:
[email protected] Accepted for publication 17 October 2013
Severe aplastic anemia (SAA) is a rare hematological disease, for which bone marrow transplantation remains the best treatment provided that a genoidentical donor is available. Immunosuppressive therapy (IST) with a combination of anti-thymocyte globulin (ATG) and cyclosporine (CyA) is the alternative treatment for patients non-eligible for bone marrow transplantation (1–4). However, there are still uncertainties about optimal modalities for IST as well as on the physiopathological mechanisms, which might explain the efficiency. Hematological response after IST suggests that SAA triggering may be related to an immune mechanism (5), even if it remains unclear. However, a potential link with regulatory T cells (Treg) has recently been highlighted: it has been shown that Treg are reduced at diagnosis (6–10). Furthermore, they have been suggested as a prognostic factor for hematological response to IST (10). In vivo, CyA stimulates the proliferation of regulatory T cells at low doses, but inhibit their development at upper doses (11). Decreasing trough blood levels for CyA seems to be an interesting option to raise the chance of
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response: recovery of Treg function could theoretically be favored. This report summarizes three cases of pediatric patients affected by SAA, who initially have not responded to conventional IST, and for whom response has been obtained after decreasing target trough blood levels for CyA at 100 ng/mL. Another case with early response by applying low target trough blood levels for CyA from the beginning of IST is also presented. Case report no 1
A 20-month-old girl presented at the emergency care unit with a hemorrhagic syndrome. Blood cell count revealed a pancytopenia, with leukocytes 4.7 9 109/L, absolute neutrophils count (ANC) 0.14 9109/L, hemoglobin 84 g/L, reticulocyte counts 2 9 109/L, and platelets 2 9 109/L (Table 1). No malformative syndrome was found during clinical exam, except growth retardation. Bone marrow biopsy confirmed SAA’s diagnosis. Medullar karyotype was
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Bertrand et al.
Salvage therapy of aplastic anemia
Table 1 Patients demographics, biology at diagnosis and treatment
Case Case Case Case
1 2 3 4
Sex/age
Leuko (9 109/L)
ANC (9 109/L)
Hb (g/L)
Retic (9 109/L)
Pt (9 109/L)
Treatment
F/20 m M/8y M/8y M/10y
4.7 2.3 4.7 2.6
0.14 0.3 0.62 0.52
84 30 40 77
12 9 25.7
2 3 26 20
hATG 160 rATG 17.5 hATG 160 hATG 160
mg/kg, CyA 15 mg/kg/d, corticoids mg/kg/d, CyA 15 mg/kg/d, corticoids mg/kg, CyA 10 mg/kg/d, corticoids mg/kg, CyA 15 mg/kg/d, corticoids
Leuko, leukocytes; ANC, absolute neutrophils count; Hb, hemoglobin; retic, reticulocytes; pt, platelets; TBC, target through blood level; F, female; M, male; m, months; y, years; hATG, horse anti-thymocyte globulin; rATG, rabbit anti-thymocyte globulin; CyA, cyclosporine A; d, day.
normal, without 7-monosomia. The abdominal ultrasonography found horseshoe kidneys and heterogeneous spleen. Hemoglobin electrophoresis and afetoprotein were normal. Research for Fanconi anemia was negative. As there was no genoidentical donor, IST has been introduced 3 months after the diagnosis, with horse ATG (ATGAM) 40 mg/kg/d for 4 d, cyclosporine (CyA) 15 mg/kg/d, and corticoids. The initial CyA target trough blood level was 150 ng/mL. The patient showed a serum illness on day 9. Blood cell count has remained low during 5 months, without major complications (four septicemias with blood cultures positive for staphylococcus). Taking into account the difficult issue in finding a donor, we decided to decrease the target trough blood level for CyA to 100 ng/mL 3 months (day 97) after starting IST. Blood cell count increased progressively, and the patient became transfusion independent at day 193 for red cells and day 160 for platelets. ANC became superior to 0.5 9 109/L on day 160 (Table 2). Criteria for complete response met at 9 months after immunosuppressive therapy
and 6 months after decreasing target trough blood level for CyA. Case report no 2
A 8-yr-old boy presented at emergency care unit with anemic and hemorrhagic syndrome. Blood cells count revealed a pancytopenia, with leukocytes count at 2.3 9 109/L, ANC at 0.3 9 109/L, platelets count at 3 9 109/L, hemoglobin level at 30 g/L with normal MCV at 88 fl, and reticulocyte counts 3 9 109/L (Table 1). Bone marrow biopsy confirmed SAA, without 7-monosomia. Clinical history revealed nondocumented hepatitis 2 yr ago. Clinical exam and abdominal ultrasonography were normal, as hemoglobin electrophoresis and a-fetoprotein. Viral serologies came out negative. Research for Fanconi anemia was negative. As there was no genoidentical donor, IST has been introduced 1 month after diagnosis, with rabbit ATG (Thymoglobuline) 3.75 mg/kg/d for 5 d, CyA 15 mg/kg/d, and corticoids. The initial CyA
Table 2 Response to IST before and after decreasing cyclosporine TBC (mean, SD)
Case 1
Case 2
Case 3
Hb (g/L) Transfusion Reticulocytes (9 109/L) Platelet (9 109/L) Transfusion Leukocytes (9 109/L) ANC (9 109/L) Hb (g/L) Transfusion Reticulocytes (9 109/L) Platelet (9 109/L) Transfusion Leukocytes (9 109/L) ANC (9 109/L) Hb (g/L) Transfusion Reticulocytes (9 109/L) Platelet (9 109/L) Transfusion Leukocytes (9 109/L) ANC (9 109/L)
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Before
After
94.4 (13.7) 15 9.2 (12.6) 14.5 (14.0) 28 4.4 (1.8) 0.0 (0.0) 97.3 (19.3) 21 9.6 (6.6) 20.1 (18.8) 28 0.9 (0.4) 0.0 (0.0) 96.6 (17.7) 17 / 34.7 (17.9) 34 4.3 (1.1) 0.84 (0.62)
92.1 (15.8) 5 until d95 26.3 (28.3) 40.8 (38.0) 7 until d62 3.9 (0.8) 0.79 (0.49) 85.7 (11.9) 13 until d120 47.7 (31.8) 22.5 (19.1) 18 until d138 3.0 (0.7) 1.5 (0.6) 90.8 (9.1) 2 until d64 / 32.2 (13.3) 6 until d59 3.7 (0.5) 0.84 (0.25)
P (Mann–Whitney)
0.261
0.580
