Is the early cyclosporine A level predictive of the outcome of immunosuppressive therapy in severe aplastic anemia? Eur J Haematol Feb. R2 이 홍 주

Introduction Acquired severe aplastic anemia (SAA) : serious hematologic disorder : pancytopenia + bone marrow hypocellularity  bone marrow transplantation (BMT) : standard therapy  Immunosuppressive therapy (IST) : older SAA patients, not suitable donor IST Ideal outcome for IST (1) high response rate (2) survival (3) low toxicity Antithymoglobulin (ATG) : single most effective drug for immunotherapy ATG + cyclosporine A (CsA) > ATG alone Goal : CsA blood levels = 150 ~ 250 ng/mL

ATG + CsA → ↑ overall response rate not survival Blood 2003;101:1236–42 Predictors of negative outcomes (1) older age (2) IST protocol other than ATG + CsA (3) > 23 d interval between diagnosis and treatment Haematologica 2007;92:11–8 Strongest predictor of survival : ANC Br J Haematol 1988;70:177–82 Object : retrospectively Higher CsA levels as well as other confirmed prognostic factors vs Outcome of IST(response rate and survival) Introduction

Patients and methods Patients Idiopathic acquired SAA January 2002 ~ February 2005 at four medical centers in Korea. Table 1 Patients’ characteristics

 IST CsA 10 mg/kg/d #2 PO D1 CSA levels : >once/3d (for 2 wks) → >once/wk (for 22wks) fluorescence polarization immunoassay aim = 150 ~ 250 ng/mL 64 patients : therapeutic doses for 6 months → tapered during 2months 2 patients : therapeutic doses for 6months → discontinued because the blood cell counts did not improve Horse ATG (h-ATG) 15 mg/kg/d IV over 12h for 5d Prednisolone : for the prevention of serum sickness 1 (D1 ~ 9) → 0.5 (D10 ~ 15) → 0.2 mg/kg/d PO (D16 ~ 21) Patients and methods Treatment protocol

Patients and methods Diagnosis and response criteria Idiopathic SAA bone marrow cellularity <25% 2/3 laboratory abnormalities ANC < 0.5 X 10 9 /L platelet count < 20 X 10 9 /L corrected reticulocyte count of <1% Complete response (CR) : Hb >11g/dL, neutrophil count >1.5 X 10 9 /L, platelet count >150 X 10 9 /L Partial response (PR) : Hb >8g/dL, neutrophil count >0.5 X 10 9 ⁄ L, platelet count >30 X 10 9 /L transfusion independence No response : Continued transfusion dependence  Exclusive criteria Fanconi anemia dyskeratosis congenita severe uncontrolled infection malignancy HAV,HBV, HCV, CMV, EB virus, parvovirus

Patients and methods Relapse and clonal evolution Relapse  ↓ <50% of the median sustained counts of any of the peripheral blood counts during remission  return of the counts to levels meeting the definition of SAA  need for transfusion support Clonal evolution  appearance of a new clonal disorder on the cytogenetics  characteristic morphological changes on bone marrow evaluation. Statistical analysis Mann–Whitney U-test Kaplan–Meier methods log-rank test. Cox’s proportional regression analysis P < 0.05 : statistical significance

Results Patient characteristics

Results The response rate according to CsA levels after initiation of IST

(A) in the response group (B) nonresponse group Figure 1 Distribution of mean CsA levels by time after IST Results The response rate according to CsA levels after initiation of IST

Figure 2 The overall response rate according to mean CsA levels during the first and second week of immunosuppressive therapy. Results The response rate according to CsA levels after initiation of IST

Results Other prognostic factors influencing the overall response rate

ATG + CsA : best therapy for severe or very severe forms of aplastic anemia ↑ response rate(about 70%) at 3 and 6 months N Engl J Med 1991;324:1297–304 ↑ response rates(70–80%), ↑ 5-yr survival of responders(80–90%) Blood 2003;101:1236–42 : guidelines for doses and length of treatment : not formally established. Discussion

Effectiveness of the IST  European Group for Blood and Marrow Transplantation (EBMT) : response rate : 74% at 6 months overall survival : 93% at 4 yr relapse rate : 35% at 5 yr  National Institute of Health (NIH, USA) on 122 patients response rate : 61% at 6 months / 58% at 12 months 7-yr survival : 55%  This retrospective study overall response of : 68.2% (45/66 patients) still alive 69.7% (46/66 patients) OS of the patients who maintained higher CsA levels : 93.5% Discussion

Overall response rate Univariate analysis - Higher CsA levels during the first and second week - previous known prognostic factors (yonger age, higher ANC, short interval between diagnosis and treatment) Multivariate Cox hazard model - higher CsA level during the first and second week - shorter interval between diagnosis and IST Overall survival - higher CsA levels during the first and second week (Multivariate analysis : independent prognostic factor) - previous known prognostic factors RFS : not associated(univariate analysis) Discussion

Relapse - requirement for additional immunosuppression and not necessarily recurrent pancytopenia : 30–40% of responding patients - renewed need for transfusions : 12% in European patients at 3 yr Blood 2000;95:1931–4  This retrospective study : 15.2% (10/66 patients) Clonal evolution - stereotypical patterns - chromosome 7 or 8  This retrospective study : lower rate of than reported in other studies because of the short duration of follow-up Discussion

limitations of this study retrospective study design small number of patients short follow-up duration Further investigation controlled prospective study design for confirmation of the results. Discussion

Early intensification of CsA levels might improve patient outcome. Conclusion