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後天再生不良性貧血之治療策略和臨床結果:單一中心之治療經驗與臨床困境
1顏志傑, 1李欣學, 1許雅婷, 1李純慧, 2陳建旭, 2鄭兆能, 1陳雅萍, 1陳彩雲
1成功大學醫學院附設醫院內科部血液腫瘤科及2小兒部
15/04/2018
中華民國血液病學會107年會報告
1
TREATMENT STRATEGIES AND OUTCOME OF
ACQUIRED APLASTIC ANEMIA: REAL-WORLD INFORMATION WITH SINGLE-CENTER EXPERIENCE
1Chih-Chieh Yen, 1Sin-Syue Li, 1Ya-Ting Hsu, 1Chun-Hui Lee, 2Chien-Hsu Chen, 2Chao-Neng Cheng, 1Ya-Ping Chen, 1Tsai-Yun Chen
1Division of Hematology/ Oncology, Departments of Internal Medicine and 2Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University
15/04/20182
Introduction• Acquired aplastic anemia (SAA):A rare but life-threatening disease1
Immune destruction of hematopoietic stem cells
Incidence: 1.5 to 7.0 cases per million person-year; 40 to 120 cases in Taiwan/ year2
• Treatment paradigm shift: from supportive care to…Allogeneic stem cell transplantation (HSCT), immunosuppressive therapy (IST) with antithymocyte globulin (ATG), cyclosporin (CsA) and erythropoietin/ thrombopoietin analogs (ESA/TSA)
1Br J Haematol 2016;172:187-207.2Haematologica 2008;93:518-23.
3
4
Treatment outcome for SAA in the year 2000 era: excellent
Our real-world experience? The elderly population ?
4Haematologica 2010;95:2119-25.5Haematologica 2016;101:884-90.
IST-treated non-transplanted SAA pts in NCKUH (n=38):
the 1991-2001 cohort
5
5-yr OS: 67%10-yr OS: 52%
responder
Non-responder
p=0.102
6International Journal of Hematology 2004;79:133-7.
Treatment response in different era ?
Introduction• Limited information about contemporary real-world practices and
treatment strategies for SAA in Taiwan
• The “real” treatment response of IST and HSCT
• Limited information about SAA in the elderly (>60 yr)
• Comparison of IST response in different treatment era
Retrospective analysis of acquired aplastic anemia patientswho received HSCT, IST or other primary treatments andcompared patients in different treatment era:
NCKUH experience6
Materials and Methods• Patients:
A total of 87 pathology (BM biopsy) and clinically-proven acquired aplastic anemia patients, as evaluated by Camittacriteria from Jan 2002 to Nov 2017 in NCKUH
• Assessment:
Baseline characteristics, severity and hematological parameters
Treatment strategies and responses in different age group
Treatment response in different era
7
Materials and Methods• Treatment modality:
HSCT: allogeneic hematopoietic stem cell transplantation includingPB or BM as stem cell source from matched-sibling, matchedunrelated or mismatched unrelated donor
IST: antithymocyte globulin (Lymphoglobuline® anti-horse orThymoglobuline® anti-rabbit) with/ without cyclosporin
Danazol: danazol 400 mg to 600 mg oral daily
Transfusion: blood component therapy when neededwith/without iron chelation therapy
8
10
* A total of 36 patients were evaluated for secondarytreatment.# 3 patients were IST-naïve and 3 patients receivedsecond IST due to non-responsiveness to first IST.
11
Objective response rate (ORR): defined as the rate of complete or partial
hematological response 6 months after primary treatment
12
Figure 1. Overall survival of all AA patients
5-yr OS: 78.8%10-yr OS: 71.2%
Median OS: not reached
13
Figure 2. Overall survival in different age group
(n=28)
(n=21)
(n=17)
(n=21)
Log-rank test, p=0.004*
14
Figure 3. Overall survival in different disease severity
(n=32)
(n=46)
(n=9)
Log-rank test, p=0.016*
15
Figure 4. Overall survival in different treatment modality
Log-rank test, p=0.15
(n=10)
(n=34)
(n=22)
(n=21)
1991-2001 cohort
2002-2017 cohort
1-year OS 98% 96%
2-year OS 90% 88%
5-year OS 67% 76%
10-year OS 52% 75%
Median OS Not reached Not reached
Table 3. Overall survival rates in different treatment era
17
Table 4. Prognostic factors for predicting OS in AA patients
18
Treatment response and disease severity predicts overall survival in AA patients
Discussion• The present study is a retrospective analysis of AA patients who
received HSCT, IST or other primary treatment; the 5-year and10-year OS were 78.8% and 71.2%, comparable to otherstudies7-8
• In the primary treatments for AA, 11.5% of patients receivedHSCT and 39.1% received IST; nearly half of the patientsreceived danazol or transfusion with supportive care; ESA/TSAeven few
20
7Haematologica 2007;92:11-8.8The New England journal of medicine 2011;365:430-8.
Discussion• Age remains the major determinant factor for primary
treatment selection
• For the elderly (>60 yr), danazol (52.4%) and transfusionwith supportive care (38.1%) are the mainstay; few received ISTor TSA/ESA (< 5%): the undertreated group (5-yr/10-yr OS63%/37%)
• A Scandinavian registry reported 52.7% of IST and 31.3% ofcyclosporin alone in the >60 yr pts. However, the no survivalimprovement in the recent decade and more early death9
219Haematologica 2017;102:1683-90.
Discussion• Only VSAA had significant poor OS; NSAA had a slightly better but
not significant OS than SAA: comparable to literature10
• Patients who received HSCT had the best OS (10-yr OS >95% );IST and danazol were similar in OS and transfusion withsupportive care the worse
• Disease severity and treatment response predict the OS inmultivariate analysis; age not significant: due to interactions withtreatment response
2210Haematologica 2008;93:518-23.
Discussion• Response to IST in different treatment era: similar adjusted for
patient age
• Response rate: 53.6% in all patient age (ORR 20% in ATG alone and 72% in ATG + cyclosporin)
• EBMT reported ORR of cyclosporin alone 46% and ATG + cyclosporin 74%11
• Response to IST independent of age ?12
2311Annals of internal medicine 1999;130:193-201.12Blood 1999;93:2191-5.
Discussion: anti-horse vs anti-rabbit ATG
24
Anti-horse ATG:13-14
Better response rateBetter 3-year overall survivalComparable infection/ toxicityBenefit in non-Asian ethnic group
Anti-rabbit ATG:Better CD4(+) T cell depletionLess CD8(+) T cell depletionLonger lymphopenia
In our study
1991-2001 cohort: anti-horse 100%; ORR= 39.5%2002-2017 cohort: anti-horse 22%; ORR= 33.3%(age-adjusted; p>0.1)
13Annals of hematology 2017;96:2031-43.14The New England journal of medicine 2011;365:430-8.
Conclusion•Age remained the most prevalent factor for treatment
strategy selection in aplastic anemia patients
• Poor treatment response and more severe diseasecorrelate with poor overall survival
• The elderly population is the potential groupundertreated by current optimal management.
• The response to IST is similar in different treatment eradespite the differences in the source of anti-thymocyteglobulin
26
Thanks for your listening
Division of Hematology/Oncology, National Cheng Kung University Hospital, Tainan, TaiwanYen Chih-Chieh 顏志傑
References
1. Killick SB, Bown N, Cavenagh J, et al. Guidelines for the diagnosisand management of adult aplastic anaemia. Br J Haematol2016;172:187-207.
2. Montane E, Ibanez L, Vidal X, et al. Epidemiology of aplastic anemia:a prospective multicenter study. Haematologica 2008;93:518-23.
3. Camitta BM, Thomas ED, Nathan DG, et al. Severe aplastic anemia:a prospective study of the effect of early marrow transplantation onacute mortality. Blood 1976;48:63-70.
4. Gupta V, Eapen M, Brazauskas R, et al. Impact of age on outcomesafter bone marrow transplantation for acquired aplastic anemiausing HLA-matched sibling donors. Haematologica 2010;95:2119-25.
28
References
5. Devillier R, Dalle JH, Kulasekararaj A, et al. Unrelated alternative donortransplantation for severe acquired aplastic anemia: a study from the FrenchSociety of Bone Marrow Transplantation and Cell Therapies and the EBMTSevere Aplastic Anemia Working Party. Haematologica 2016;101:884-90.6. Feng Y-H, Yen C-J, Huang W-T, Su W-C, Chen T-Y, Tsao C-J. Clinical Responseof Antilymphocyte Globulin-Based Treatment in Patients in Taiwan withAplastic Anemia: Positive Hepatitis C Antibody May Represent a ResponsePredictor. International Journal of Hematology 2004;79:133-7.7. Locasciulli A, Oneto R, Bacigalupo A, et al. Outcome of patients withacquired aplastic anemia given first line bone marrow transplantation orimmunosuppressive treatment in the last decade: a report from theEuropean Group for Blood and Marrow Transplantation (EBMT).Haematologica 2007;92:11-8.
29
References8. Scheinberg P, Nunez O, Weinstein B, et al. Horse versus rabbitantithymocyte globulin in acquired aplastic anemia. The New Englandjournal of medicine 2011;365:430-8.
9. Vaht K, Göransson M, Carlson K, et al. Incidence and outcome of acquiredaplastic anemia: real-world data from patients diagnosed in Sweden from2000–2011. Haematologica 2017;102:1683-90.
10. Gupta V, Eapen M, Brazauskas R, et al. Impact of age on outcomes afterbone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors. Haematologica 2010;95:2119-25.
11. Tichelli A, Socie G, Henry-Amar M, et al. Effectiveness ofimmunosuppressive therapy in older patients with aplastic anemia.European Group for Blood and Marrow Transplantation Severe AplasticAnaemia Working Party. Annals of internal medicine 1999;130:193-201.
30
References
12. Marsh J, Schrezenmeier H, Marin P, et al. Prospective randomizedmulticenter study comparing cyclosporin alone versus the combinationof antithymocyte globulin and cyclosporin for treatment of patientswith nonsevere aplastic anemia: a report from the European Blood andMarrow Transplant (EBMT) Severe Aplastic Anaemia Working Party.Blood 1999;93:2191-5.
13. Yang N, Chen J, Zhang H, et al. Horse versus rabbit antithymocyteglobulin in immunosuppressive therapy of treatment-naive aplasticanemia: a systematic review and meta-analysis. Annals of hematology2017;96:2031-43.
14. Scheinberg P, Nunez O, Weinstein B, et al. Horse versus rabbitantithymocyte globulin in acquired aplastic anemia. The New Englandjournal of medicine 2011;365:430-8.
31
Hypocellular marrow Pancytopenia (2/3)
+
Severity 3 BM PB
Severe (SAA) BM cellularity < 25% At least two: ANC <500/μL, PLT <20K/μL,
reticulocyte <1%
Very severe (VSAA) As above ANC <200/μL
Non-severe (NSAA) Not fulfilled Not fulfilled33
<10g/dL
<50K/μL
ANC<1500/μL
3Camitta BM. et al. Blood 1976;48:63-70.