Hematology/Oncology Case Conference · 2018-04-19 · 1Division of Hematology/ Oncology,...

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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 2 小兒部 15/04/2018 中華民國血液病學會107年會報告 1

Transcript of Hematology/Oncology Case Conference · 2018-04-19 · 1Division of Hematology/ Oncology,...

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

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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.

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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

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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

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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

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Results

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* 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.

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Objective response rate (ORR): defined as the rate of complete or partial

hematological response 6 months after primary treatment

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Figure 1. Overall survival of all AA patients

5-yr OS: 78.8%10-yr OS: 71.2%

Median OS: not reached

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Figure 2. Overall survival in different age group

(n=28)

(n=21)

(n=17)

(n=21)

Log-rank test, p=0.004*

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Figure 3. Overall survival in different disease severity

(n=32)

(n=46)

(n=9)

Log-rank test, p=0.016*

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Figure 4. Overall survival in different treatment modality

Log-rank test, p=0.15

(n=10)

(n=34)

(n=22)

(n=21)

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Table 3: Patient characteristics and responses to IST in different treatment era

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

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Table 4. Prognostic factors for predicting OS in AA patients

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Treatment response and disease severity predicts overall survival in AA patients

Discussion

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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

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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

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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

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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

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Thanks for your listening

Division of Hematology/Oncology, National Cheng Kung University Hospital, Tainan, TaiwanYen Chih-Chieh 顏志傑

[email protected]

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.

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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.

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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.

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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.

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Appendices

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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.