A New Immunosuppressive Therapy for Very Severe Aplastic Anemia in Children with Autoantibodies

Abstract

Objective

At present, a number of very severe aplastic anemia (VSAA) patients cannot receive hematopoietic stem cell transplantation (HSCT) or standard immunosuppressive therapy (IST) due to the high cost of therapy, shortage of sibling donors, and lack of resources to support the HSCT. In addition, some VSAA patients with autoantibodies have no life-threatening infections or bleeding at the time of initial diagnosis. Considering the disease condition, economics and other factors, the present study designed a new and relatively mild treatment strategy: cyclosporine A plus pulsed high-dose prednisone (CsA+HDP).

Methods

The present study retrospectively analyzed 11 VSAA patients, who were treated with CsA+HDP in our hospital from August 2017 to August 2019.

Results

The median follow-up time for these patients was 24.9 months. The overall response rate was 54.5% (6/11) at six months after the initiation of IST and 81.8% (9/11) at deadline. Five patients achieved complete remission and four patients met the criteria for partial response at the last follow-up. The median time to response for responders was 110 days. Three patients underwent HSCT due to the poor effect of CsA+HDP or to find a suitable transplant donor. Recurrence and clonal evolution were not found in any of these patients. The estimated 3-year overall survival rate and 3-year failure-free survival rate were 100.0% and 72.7%, respectively. In addition, the results revealed that the cyclosporine-prednisone-associated toxicity was mild and well-tolerated by most patients.

Conclusion

The novel CsA+HDP regimen has good therapeutic effect and safety for VSAA patients with autoantibodies, who have no serious life-threatening infections or bleeding at the time of initial diagnosis.

Keywords

aplastic anemia / cyclosporine A / prednisone / immunosuppressive therapy / children

References

[1] MaryJY, BaumelouE, GuiguetM. Epidemiology of aplastic anemia in France: a prospective multicentric study. The French Cooperative Group for Epidemiological Study of Aplastic Anemia. Blood, 1990, 75(8): 1646-1653

[2] MontanéE, IbáñezL, VidalX, et al.. Epidemiology of aplastic anemia: a prospective multicenter study. Haematologica, 2008, 93(4): 518-523

[3] WangL, LiuH. Pathogenesis of aplastic anemia. Hematology, 2019, 24(1): 559-566

[4] ZengY, KatsanisE. The complex pathophysiology of acquired aplastic anaemia. Clin Exp Immunol, 2015, 180(3): 361-370

[5] YoungNS. Aplastic Anemia. N Engl J Med, 2018, 379(17): 1643-1656

[6] KillickSB, BownN, CavenaghJ, et al.. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol, 2016, 172(2): 187-207

[7] YoshidaN, KobayashiR, YabeH, et al.. First-line treatment for severe aplastic anemia in children:bone marrow transplantation from a matched family donor versus immunosuppressive therapy. Haematologica, 2014, 99(12): 1784-1791

[8] DufourC, PillonM, SocieG, et al.. Outcome of aplastic anaemia in children. A study by the severe aplastic anaemia and paediatric disease working parties of the European group blood and bone marrow transplant. Br J Haematol, 2015, 169(4): 565-573

[9] RogersZR, NakanoTA, OlsonTS, et al.. Immunosuppressive therapy for pediatric aplastic anemia: a North American Pediatric Aplastic Anemia Consortium study. Haematologica, 2019, 104(10): 1974-1983

[10] ZhuXF, HeHL, WangSQ, et al.. Current Treatment Patterns of Aplastic Anemia in China: A Prospective Cohort Registry Study. Acta Haematol, 2019, 142(3): 162-170

[11] MahapatraM, SinghPK, AgarwalM, et al.. Epidemiology, Clinico-Haematological Profile and Management of Aplastic Anaemia: AIIMS Experience. J Assoc Physicians India, 2015, 63: 30-353 Suppl

[12] PierriF, DufourC. Management of aplastic anemia after failure of frontline immunosuppression. Expert Rev Hematol, 2019, 12(10): 809-819

[13] KosakaY, YagasakiH, SanoK, et al.. Prospective multicenter trial comparing repeated immunosuppressive therapy with stem-cell transplantation from an alternative donor as second line treatment for children with severe and very severe aplastic anemia. Blood, 2008, 111(3): 1054-1059

[14] Peffault de LatourR, ChevretS, JubertC, et al.. Unrelated cord blood transplantation in patients with idiopathic refractory severe aplastic anemia: a nationwide phase 2 study. Blood, 2018, 132(7): 750-754

[15] ScheinbergP, NunezO, WeinsteinB, et al.. Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia. Blood, 2012, 119(2): 345-354

[16] BrodskyRA, ChenAR, DorrD, et al.. High-dose cyclophosphamide for severe aplastic anemia: long-term follow-up. Blood, 2010, 115(11): 2136-2141

[17] KookH, ChungNG, KangHJ, et al.. Acquired aplastic anemia in Korean children: treatment guidelines from the Bone Marrow Failure Committee of the Korean Society of Pediatric Hematology Oncology. Int J Hematol, 2016, 103(4): 380-386

[18] YoshidaN, KojimaS. Updated Guidelines for the Treatment of Acquired Aplastic Anemia in Children. Curr Oncol Rep, 2018, 20(9): 67

[19] AssiR, Garcia-ManeroG, RavandiF. Addition of eltrombopag to immunosuppressive therapy in patients with newly diagnosed aplastic anemia. Cancer, 2018, 124(21): 4192-4201

[20] CooperN, GhanimaW. Immune Thrombocytopenia. N Engl J Med, 2019, 381(10): 945-955

[21] AudiaS, MahévasM, SamsonM, et al.. Pathogenesis of immune thrombocytopenia. Autoimmun Rev, 2017, 16(6): 620-632

[22] ZuffereyA, KapurR, SempleJW. Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP). J Clin Med, 2017, 6(2): 16

[23] LiuQ, XuH, GuanX, et al.. Clinical Significance of Antinuclear and Antiextractable Nuclear Antigen Antibody in Childhood Immune Thrombocytopenia. Semin Thromb Hemost, 2017, 43(6): 629-634

[24] BidotCJ, JyW, HorstmanLL, et al.. Antiphospholipid antibodies (APLA) in immune thrombocytopenic purpura (ITP) and antiphospholipid syndrome (APS). Am J Hematol, 2006, 81(6): 391-396

[25] GiordanoP, UrbanoF, LassandroG, et al.. Role of antithyroid autoimmunity as a predictive biomarker of chronic immune thrombocytopenia. Pediatr Blood Cancer, 2019, 66(1): e27452

[26] CarcaoMD, ZipurskyA, ButchartS, et al.. Short-course oral prednisone therapy in children presenting with acute immune thrombocytopenic purpura (ITP). Acta Paediatr Suppl, 1998, 424: 71-74

[27] O’BrienSH, RitcheyAK, SmithKJ. A cost-utility analysis of treatment for acute childhood idiopathic thrombocytopenic purpura(ITP). Pediatr Blood Cancer, 2007, 48(2): 173-180

[28] MazzucconiMG, FaziP, BernasconiS, et al.. Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience. Blood, 2007, 109(4): 1401-1407

[29] OvedJH, LeeCSY, BusselJB. Treatment of Children with Persistent and Chronic Idiopathic Thrombocytopenic Purpura: 4 Infusions of Rituximab and Three 4-Day Cycles of Dexamethasone. J Pediatr, 2017, 191: 225-231

[30] BusselJB, LeeCS, SeeryC, et al.. Rituximab and three dexamethasone cycles provide responses similar to splenectomy in women and those with immune thrombocytopenia of less than two years duration. Haematologica, 2014, 99(7): 1264-1271

[31] TakamatsuH, FengX, ChuhjoT, et al.. Specific antibodies to moesin, a membrane-cytoskeleton linker protein, are frequently detected in patients with acquired aplastic anemia. Blood, 2007, 109(6): 2514-2520

[32] HiranoN, ButlerMO, Von Bergwelt-BaildonMS, et al.. Autoantibodies frequently detected in patients with aplastic anemia. Blood, 2003, 102(13): 4567-4575

[33] GotoM, KuribayashiK, TakahashiY, et al.. Identification of autoantibodies expressed in acquired aplastic anaemia. Br J Haematol, 2013, 160(3): 359-362

[34] FerraraG, PetrilloMG, GianiT, et al.. Clinical Use and Molecular Action of Corticosteroids in the Pediatric Age. Int J Mol Sci, 2019, 20(2): 444

[35] GalonJ, FranchimontD, HiroiN, et al.. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J, 2002, 16(1): 61-71

[36] CainDW, CidlowskiJA. Immune regulation by glucocorticoids. Nat Rev Immunol, 2017, 17(4): 233-247

[37] CariL, De RosaF, NocentiniG, et al.. Context-Dependent Effect of Glucocorticoids on the Proliferation, Differentiation, and Apoptosis of Regulatory T Cells: A Review of the Empirical Evidence and Clinical Applications. Int J Mol Sci, 2019, 20(5): 1142

[38] SzatmariI, NagyL. Nuclear receptor signalling in dendritic cells connects lipids, the genome and immune function. EMBO J, 2008, 27(18): 2353-2362

[39] KojimaS, HibiS, KosakaY, 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(6): 2049-2054

[40] NaritaA, ZhuX, MuramatsuH, et al.. Prospective randomized trial comparing two doses of rabbit antithymocyte globulin in patients with severe aplastic anaemia. Br J Haematol, 2019, 187(2): 227-237

[41] ShallisRM, AhmadR, ZeidanAM. Aplastic anemia: Etiology, molecular pathogenesis, and emerging concepts. Eur J Haematol, 2018, 101(6): 711-720

[42] SabatinoJJJr, PröbstelAK, ZamvilSS. B cells in autoimmune and neurodegenerative central nervous system diseases. Nat Rev Neurosci, 2019, 20(12): 728-745

[43] ScheinbergP, NunezO, WeinsteinB, et al.. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med, 2011, 365(5): 430-438

[44] Cabannes-HamyA, BoisselN, Peffault De LatourR, et al.. The effect of age in patients with acquired aplastic anaemia treated with immunosuppressive therapy: comparison of Adolescents and Young Adults with children and older adults. Br J Haematol, 2018, 183(5): 766-774

[45] DolbergOJ, LevyY. Idiopathic aplastic anemia: diagnosis and classification. Autoimmun Rev, 2014, 13(4–5): 569-573

[46] CaiB, SaidQ, LiX, et al.. Healthcare costs and resource utilization in patients with severe aplastic anemia in the US. J Med Econ, 2019, 22(10): 1055-1062

[47] HossainMJ, XieS. Patient features and survival of pediatric aplastic anemia in the USA: a large institution experience. J Public Health (Oxf), 2019, 41(2): 329-337

[48] MaciejewskiJP, SelleriC. Evolution of clonal cytogenetic abnormalities in aplastic anemia. Leuk Lymphoma, 2004, 45: 433-440

[49] ScheinbergP, YoungNS. How I treat aplastic anemia. Blood, 2012, 120: 1185-1196

[50] KikuchiA, YabeH, KatoK, et al.. Long-term outcome of childhood aplastic anemia patients who underwent allogeneic hematopoietic SCT from an HLA-matched sibling donor in Japan. Bone Marrow Transplant, 2013, 48(5): 657-660