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Upfront Transplant Strategies in Aplastic Anemia
- 1. Upfront Transplant Strategies in Aplastic Anemia Seiji Kojima MD. PhD. Department of Pediatrics Nagoya University Graduate School of Medicine Chairman of the Severe Aplastic Anemia Working Party Asia-Pacific Blood and Marrow Transplantation Group
- 2. Yes No Yes No Yes No #1#2 #3 APHCON Treatment Guideline for SAA
- 3. Today’s Topics 1. Use of rabbit ATG can be justified as a front-line therapy? 2. Comparable outcome can be expected between MRD and 1MMD? 3. Second course of ATG + CSA should be indicated if no alternative donor is available?
- 4. 1) Long term outcome of AA children treated with horse ATG or rabbit ATG 1) Rabbit ATG experience in Nagoya University Experience of rabbit ATG for SAA
- 5. 0 10 20 30 40 50 60 70 80 90 100 rabbitATG horse ATG horse vs rabbit ATG n= 32 n= 33 n= 22 n= 35 n= 24 n= 46 n= 105 n= 69 n= 29 n= 79n= 60 n= 60 n= 42 n= 29
- 6. Seiji Kojima MD Department of Pediatrics Nagoya University Graduate School of Medicine
- 7. Patient Characteristics Total cohort (N=455) horse ATG (n=297) rabbit ATG (n=158) P-value Median age at diagnosis (range), years 8 (0 - 17) 8 (0 - 17) 6.5 (1 - 16) 0.005 Gender, male/female 246 / 209 172 / 125 74 / 84 0.024 Etiology, n of patients (%) <0.001 Idiopathic 386 (85) 242 (81) 144 (91) Hepatitis 53 (12) 47 (16) 6 (4) Others 16 (3) 8 (3) 8 (5) Severity of AA, n of patients (%) 0.02 VSAA 272 (60) 166 (56) 106 (67) SAA 183 (40) 131 (44) 52 (33) Interval between diagnosis and IST 0.02 <18days 18days≧ 224 / 231 160 / 137 64 / 94 0.01 Median WBC count (range), x109 /L 2,100 (4 - 21,020) 1,900 (20 - 8,500) 3,100 (4 -21,020) <0.001 ≥ 2.0 x 109 /L, n of patients (%) 246 136 110 < 2.0 x 109 /L, n of patients (%) 200 160 40
- 8. Response at 6M NE CR PR NR horse ATG rabbit ATG
- 9. Covariates Univariate analysis Multivariate analysis Hazard Ratio ( 95% CI) p-value Hazard Ratio 95% CI p-value Horse ATG vs. rabbit ATG 0.995 (0.660-1.499) 0.981 - - - Gender 1.560 (1.058 - 2.300) 0.025 1.823 (1.211 - 2.744) 0.004 Severity (VSAA vs. SAA) 0.983 (0.664 - 1.454) 0.930 - - - Etiology (Hepatits vs. others 1.130 (0.620 - 2.061) 0.689 - - - Days from diagnosis to IST <30days vs. ≥30days 1.603 (1.018 - 2.525) 0.042 - - - <180days vs. ≥180days 2.362 (0.391 - 14.286) 0.349 - - - WBC count <2000 vs. ≥2000 1.163 (0.786 - 1.721) 0.449 - - - Reticulocyte count <25000 vs. ≥25000 1.465 (0.945 - 2.270) 0.088 - - - Platelet count <20000 vs. ≥20000 1.792 (1.092 - 2.943) 0.021 1.734 (0.997 - 3.015) 0.051 Predictive factor for response at 6months
- 10. OS0.000.250.500.751.00 0 50 100 150 200 analysis time treatment_ALG1_ATG2 = 1 treatment_ALG1_ATG2 = 2 Kaplan-Meier survival estimates horse ATG 92% rabbit ATG 84%
- 11. Causes of death horse ATG (n=297) rabbit ATG (n=158) TRM of SCT 7 4 MDS/AML 3 0 Infection 3 8 Hemochromatosis 1 0 Hemolysis 1 0 Accident 1 1 Bleeding 0 6
- 12. Horse ATG: 15 mg /kg/day x 5 days CSA: 6 mg/kg/day adjusted to blood level G-CSF: Only when ANC < 0.2 x 109 /L Rabbit ATG: 3.75 mg /kg/day x 5 days CSA: 6 mg/kg/day adjusted to blood level G-CSF: Only when ANC < 0.2 x 109 /L Immunosuppressive Therapy Japan AA 97 Nagoya Univ in Thymoglobulin era ( 2009 Aug ~ Now )
- 13. Neutr WBC Rabbit ATG CyA ‘Neutrophil dip’ after rabbit ATG
- 14. EBV Reactivated Patient’s Clinical Course 0 20,000 60,000 100,000 140,000 180,000 0 7 14 21 28 35 45 49 56 Rituximab 375 mg/m2 Days after administration of rabbit ATG EBVcopynumber [copies/mL(wholeblood)]
- 15. rabbit ATG + CSA (n=10) Transient decline of Neutrophil (Y/N) 10 / 0 CMV reactivation (Y/N) 5 / 5 GCV treatment (Y/N) 5 / 5 EBV reactivation (Y/N) 3 / 7 Rituximab treatment (Y/N) 2 / 8 Side effects
- 16. COLON
- 17. Patient No. Age First/Second IST ATG Onset (week) EBV-DNA (105 /ml) Outcome 1 4 First horse ATG 10 ー Dead 2 79 First rabbit ATG 5 9.1 Dead 3 69 First rabbit ATG 4 7.0 Alive 4 63 First rabbit ATG 7 5.0 Dead 5 56 First rabbit ATG 3 14.0 Dead 6 65 First rabbit ATG 1 45.0 Dead EBV –LPD after immunosuppressive therapy in Japan
- 18. Today’s Topics 1. Use of rabbit ATG can be justified as a front-line therapy? 2. Comparable outcome can be expected between MRD and 1MMD? 3. Second course of ATG + CSA should be indicated if no alternative donor is available?
- 19. PATIENTS (N = 578) 578 children (0-19 y) with AA Received BMT between 1990-2009 Available for serological HLA data (A, B, and DR) Registered to The Japan Society for Hematopoietic Cell Transplantation Matched unrelated Donor (MUD) (n=213) Matched related donor (MRD) (n=312) MMRD (n=53) 1MMRD @HLA Class I (n =32) 1MMRD @HLA class II (n=12) 2-3 MMRD (n=9) Grouped by SEROLOGICAL HLA typing data (A, B, and DR)
- 20. PATIENT CHARACTERISTICS MRD 1MMRD 2-3 MMRD MUD Class I Class II n 312 32 12 9 213 Donor, n (%) Sibling 294 (94%) 22 (69%) 4 (33%) 1 (11%) - Others Related 18 (6%) 10 (31%) 8 (67%) 8 (89%) - Unrelated donor - - - - 213 (100%) Gender, n (%) Male 176 (56%) 19 (59%) 7 (58%) 3 (33%) 120 (56%) Female 136 (44%) 13 (41%) 5 (42%) 6 (67%) 93 (44%) Age, median (range) 11.5 (0 - 19) 9 (1 - 16) 9 (1 - 19) 10 (1 - 17) 11 (1 - 19) Age, n (%) < 10 y 106 (34%) 17 (53%) 7 (58%) 4 (44%) 87 (41%) 10y - 19 y 206 (66%) 15 (47%) 5 (42%) 5 (56%) 126 (59%)
- 21. 0.000.250.500.751.00 probabilityofsurivival 0 2000 4000 6000 8000 days after transplantation 5-year OVERALL SURVIVAL Class-I 1MMRD (n=32) 91.7 +/- 4.6% Class-II 1MMRD (n=12) 91.7 +/- 8.0% 2-3 MMRD (n=9) 66.7 +/- 12.2% MUD (n=213) 79.0 +/- 2.9% MRD (n=312) 91.4 +/- 1.5%
- 22. MULTIVARIATE ANALYSIS OF OS HR (95% CI) P-value Age <10 1 0.002 >=10 2.647 (1.515-4.622) Period of SCT 1990-1999 2.210 (1.515-4.622) 0.001 2000-2009 1 Donor MRD 1 1MMRD (Class I) 0.847 (0.199-3.605) NS 1MMRD (Class II) 1.930 (0.257-14.504) NS 2-3 MMRD 6.238 (1.866-20.856) 0.003 MUD 4.308 (2.588-7.170) <0.001
- 23. 0.000.250.500.751.00 0 20 40 60 80 100 Days after transplantation ACUTE GVHD (grade III – IV) MRD 5.2 +/- 1.4 % 1MMRD (class I) 32.9 +/- 10.1% p < .001 1MMRD (class II) 18.5 +/- 11.9% p = .03 2-3 MMRD 0.0% p = NS MUD 16.2 +/- 2.9% p < .001 MRD 2-3 MMRD 1MMRD (Class I) 1MMRD (Class II) MUD
- 24. 0.000.250.500.751.00 0 2000 4000 6000 8000 Days after transplantation CHRONIC GVHD (Extensive) MRD 9.0 +/- 1.7 % 1MMRD (class I) 10.0 +/- 5.5% 1MMRD (class II) 0.0 % 2-3 MMRD 12.5 +/- 11% MUD 14.3 +/- 2.8% P= Not significant
- 25. TREATMENT ALGORISM FOR CHILDREN WITH AA Newly diagnosed AA MRD/1MMRD(+) BMT from MRD/1MMRD IST CR/PR NR MUD(+) MUD(-) BMT from MUD 2nd IST or HAPLO / CBT MRD/1MMRD(-) FIRST LINE THERAPY SECOND LINE THERAPY
- 26. Today’s Topics 1. Use of rabbit ATG can be justified as a front-line therapy? 2. Comparable outcome can be expected between MRD and 1MMD? 3. Second course of ATG + CSA should be indicated if no alternative donor is available?
- 30. Preconditioning Regimen from Haploidentical Donor day–7 – 6 – 5 – 4 – 3 – 2 – 1 0 +1 +2 +3 +4 +5 +6 BMT PBSCT •GVHD Prophylaxis ： FK506+sMTX Flu(30mg/ m2 × ４ ) ○ ○ ○ ○ ATG (2.5mg/kg × ４ ) ○ ○ ○ ○ (5mg/kg × １ ) ○ L-PAM(70mg/m2 × ２ ) ○ ○ TBI(2.5Gy × ２ ) ○ Nagoya University
- 31. Patient Characteristics Pt. Patient Donor HLA disparity NCC (×108 /kg) CD34+cell s (×106 /kg)Age / Sex Age / Sex 1 9 / F 36 / F 4 / 6 11.0 4.2 2 4 / F 35 / M 4 / 6 30.3 35.0 3 12 / F 15 / M 4 / 6 5.4 6.0 4 15 / F 47 / M 4 / 9 5.8 3.3
- 32. Outcome Pt. Neutr >500/μl(day) acute GVHD chronic GVHD other complication Survival (mo) 1 29 −（ ） −（ ） −（ ） > 105 2 15 III −（ ） CMV, EBV, TMA > 71 3 20 −（ ） −（ ） CMV, EBV > 42 4 20 −（ ） （ + ） CMV, EBV > 8
- 33. Conclusion 1. Use of rabbit ATG as a front-line therapy is justified when horse ATG is not available. 2. When 1MMD donor is available, bone marrow transplantation is the first choice of treatment for SAA children. 3. Haploidentical transplantation can be indicated if HLA-mached unrelated donor is not found for non- responder to immunosuppressive therapy.
- 34. Acknowledgement • Asian Pacific Blood and Marrow Transplantation Group : Childhood Aplastic Anemia Study Group Dao Chul Jeong, Xiao Fan Zhu • The Japan Society for Hematopoietic Cell Transplantation Childhood Aplastic Anemia Working Group Hideki Muramatsu, Hiromasa Yabe, Akira Kikuchi, Ryoji Kobayashi • Japan Childhood Aplastic Anemia Study Group Nao Yoshida, Yoshiyuki Takahashi, Akira Ohara
Notas do Editor
- 小児再生不良性貧血においては、 HLA 一致血縁者間骨髄移植が治療の第 1 選択であり、 HLA 一致血縁ドナーが得られない場合には、免疫抑制療法を選択することが過去 30 年間にわたって標準的な治療方針とされてきた。 このような治療選択の指針は、主に 1980 年代における両治療法の治療成績の比較に基づいている。しかし、骨髄移植と同様に免疫抑制療法の治療成績の向上も著しい。 今日の治療選択の指針を作成するために、エビデンスのアップデートが必要である。
- Immunosuppressive therapy consisted of horse ATG (Lymphoglobulin from Genzyme) at a dose of 15 mg/kg/day and CSA. In the Japanese study the ATG had been given for 5 days, in the German study for 8 days. G-CSF was administered to patients with less than 200 neutrophils/µl in the Japanese group and less than 500/µL in the German cohort.
- To supply a gap of evidence for transplantation from HLA mismatched family donor, We planned and analyzed 578 pediatric AA patients received Bone marrow transplantation between 1990 and 2009, and get registered in the database of the Japan Society for Hematopoietic Cell transplantation. Of course, majority of patients are transplanted from HLA matched related donor or matched unrelated donor, but A substantial number of patients are transplanted from serologically HLA mismatched related donor, MMRD. Among 53 mismatched related transplantation, 32 patients transplanted from donor who is 1locus mismatched in HLA Class I, and 12 patients from 1 locus mismatched in class II. 9 patients are transplanted from 2-3 loci mismatched donor, that is to say, Haploidentical transplantation donor.
- This slide shows the patient characteristics. Patients’ gender and age are equally distributed among each group. But, as expected, sibling donor percentage is unsymmetrical.
- This slide shows the 5 year overall survival of each patient group. Compared to matched related donor, matched unrelated donor and 2-3 loci mismatched related donor were significantly worse outcomes, while class I and class II 1 locus mismatched donor groups showed perfectly superimposed survival curves to matched related donor group.
- In multivariate analysis, age over 10 years, and transplanted before 2000 and 2-3 loci mismatched related donor and unrelated donor are identified independent risk factors for poor survival.
- Compared to HLA matched related donor, the incidence of Acute GVHD grade III – IV is significantly higher in 1 locus HLA mismatched related donor and matched unrelated donor. Unexpectedly, none of the patients transplanted from haploidentical donor developed severe acute GVHD, despite patient number is very small, only 9.
- This slide shows the cumulative incidence of extensive chronic GVHD. In any donor group, severe chronic GVHD is occurred in very small percentage of patients, and there is no statistical significance.
- If the newly diagnosed aplastic anemia patient have matched related donor OR 1 LOCUS MISMATCHED RELATED DONOR, first line therapy would be BMT. And IST indication should be narrowed.
- BU (1mg/kg×4/day)×2days day –7 , -6 L-PAM (60mg/m 2 /day)×3days day –5 ~ -3 ATG (2.5mg/kg/day)×2days day –3 , -2 ATG (5mg/kg/day) day +4 TBI (12Gy,4 分割 ) 眼球半遮蔽 day –2 , -1 2/2 BMT 総細胞数： 3.6×10^8/kg CD34(+) 細胞数 0.7% ： 2.55×10^6/kg 2/7 PBSCT 1 日目 総細胞数： 1.67×10^9/kg CD34(+)45(+) 細胞数： 5.0×10^6/kg 2/8 PBSCT 2 日目 総細胞数： 6.5×10^8/kg CD34(+)45(+) 細胞数 0.4% ： 2.6×10^6/kg