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CD3 : multivariate model
Variables adjusted by Age, donor, HCT-CI, DRI, CD34
HR 95CI p
PFS 0.8 [0.56-1.17] 0.272
OS 0.8 [0.54-1.24] 0.346
NRM 0.8 [0.46-1.47] 0.512
0.8CIR [0.50-1.30] 0.352
AGVHD III-IV 0.8 [0.36-1.68] 0.526
CGVHD Extensive 1.1 [0.65-1.93] 0.668
CD3
≥ median](https://image.slidesharecdn.com/1140-1200didierblaiseupdate1508-28-pbsc-bangkok-150828101041-lva1-app6892/85/Peripheral-Blood-Stem-Cell-Transplant-18-320.jpg)
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Peripheral Blood Stem Cell Transplant
- 1. PBSC revisited inpresent practice Didier Blaise, MD Bangkok August, 28th, 2015
- 2. Members of StemCell Trialists’ Collaborative Group 9 trials included (N=1,111 patients) Ben Djulbegovic Bill Bensinger Corey Cutler Iztok Hozo Claudio Annasetti Heloisa Soares Ambuj Kumar Nobert Schmitz Alois Gratwohl Jane Apperley Roy Baynes James Matcham Didier Blaise Mohamad Mothy Mathieu Kuentz Ray Powles Bhawna Sirohi Mike Clarke Sue Richards Robert Hills Keith Wheatley Dag Heldal Jan Cornelissen B Van der Holt Stephen Couban Tony Panzarella David Simpson Jeff Lipton Carmino A de Souza Afonso Vigorito Eliana CM Miranda James Morton Entezam Sahovic Ed Colcol Mahmoud Al-Jurf
- 3. Stem Cell Trialists, JCO, 2006
- 4. Stem Cell Trialists, JCO, 2006
- 5. PREVALENCE OF CGVHD Monthspost-transplantation PrevalenceofcGVHD(%) 0 18 36 54 0 25 50 75 100 BMT BCT D Blaise et al , Blood, 2002
- 6. M Mohty etal , Leukemia 2003
- 7. BM versus PBSC •Myeloablative CDT • Mainly Familial HLA-Identical Donor • GVHD prophylaxis: CSA/FK506 and MTX
- 8. M Mohty etal , Blood 2003
- 9. The increase from2.5 to 5 mg/kg of r-ATG dose in RIC is beneficial R Devillier et al , BMT 2012 9
- 10. CD34 dose afterRIC: High dose or not?
- 11. 11 Outcomes in RICregimen Mohty, Leukemia 2003 Extensive chronic GVHD MAC No ATG MRD CsA/MTX RIC ATG MRD/MUD CsA
- 12. 12 Heterogeneity of thestudies Blood (2009) BBMT (2014) BBMT (2015) Pulsipher Törlén Remberger Patients number 932 1054 544 High doses CD34 OS OS OS Diseases Myeloid AML or DMS All Donor MUD MRD or MUD MRD or MUD Conditionning R MAC/RIC/NMA RIC or NMA MAC or RIC GVHD prophylaxis Heterogeneous Heterogeneous Heterogeneous cut off cd34 4.5x10.6/kg MRD 4x10.6/kg /MUD 6x10.6/kg 8.1x10.6/kg Heterogenous population
- 13. 13 Impact of CD34/CD3 cell dose Homogenouspopulation CsA RIC PBSC
- 14. 14 1) Peripheral bloodstem cells 2) HLA identical : - Matched related - Matched unrelated donor; 3) Reduced intensity conditioning (RIC) regimen; 4) Ciclosporine A alone; Selection criteria FLU 30 mg/m² FLU 30 mg/m² FLU 30 mg/m² FLU 30 mg/m² FLU 30 mg/m² BU 130mg/m2 BU 130mg/m2 ATG 2.5mg/kg ATG 2.5mg/kg Day-2 Day 0Day-1 H S C T Day-5 Day-4 Day-3Day-6
- 15. 15 Patient characteristics N =246 % Age, years, median (range) CD3 (106 /kg), median (range) Matched related donor Lymphoid malignancies Disease Risk Index Low HCT-Comorbidity Index ≥ 3 All patients CD34 (106 /kg), median (range) 6.5 (2-14.2) 46% 59 (19-71) 279 (61-1919) 142 58% 132 54% 44 18% 110
- 16. 16 Variables adjusted byAge, donor, HCT-CI, DRI, CD3 CD34≤6.5x106 /kg CD34>6.5106 /kg N=124 (%) N=122 (%) 3-4 AGVHD 10 8 0.674 1.2 0.581 Ext CGVHD 24 21 0.539 0.7 0.243 NRM 19 23 0.638 0.9 0.841 RI 30 22 0.179 0.8 0.244 PFS 62 68 0.179 0.8 0.322 OS 52 55 0.405 0.8 0.200 pp HR Univariate model Multivariate model CD34 median CD34 : median cut off
- 17. Extensive chronic GVHD InitialStudy, Leukemia 2003 Present Study, 2015 MAC RIC
- 18. 18 CD3 : multivariatemodel Variables adjusted by Age, donor, HCT-CI, DRI, CD34 HR 95CI p PFS 0.8 [0.56-1.17] 0.272 OS 0.8 [0.54-1.24] 0.346 NRM 0.8 [0.46-1.47] 0.512 0.8CIR [0.50-1.30] 0.352 AGVHD III-IV 0.8 [0.36-1.68] 0.526 CGVHD Extensive 1.1 [0.65-1.93] 0.668 CD3 ≥ median
- 19. 19 CONCLUSION Impact of invivo T cell depletion? Myeloablative conditionning Reduced intensity conditionning No rational for limiting the maximal amount of CD3 or CD34 cell dose in the setting of RIC with ATG. CD34 : No impact CD3 : No impact
- 20. BM or PBSCfor haplo HSCT
- 22. PBSC for Haplo MarseilleExperience on 102 patients Characteristics • Age: 59 (22 – 73) • Follow-up: 15 months (1 – 31) • CD 34+ (mediane) 5.1 x 106/Kg • CD3+ (mediane) 262 x 106/Kg • DRI: Intermediate 59%; High 30%; V.High 7% • HCT-CI ≥ 3: 63% • CDT: 68% Baltimore; 32% RTC
- 23. Hematologic Recovery ANC >0,5x109/L mediane 21 (14 – 47) jours PLT > 20x109/L mediane 35 (10- 134) jours Chimerism J+90 (séquençage CD3+) 98% Graft Failure 2%
- 24.
- 25. 2-y RI and2-y NRM 0.0 0.5 1.0 1.5 2.0 0.00.20.40.60.81.0 2-y RI = 24% Years from transplant Cumulativeincidence Time to Relapse (median, range): 3.3 months (0.5 – 14) 0.0 0.5 1.0 1.5 2.0 0.00.20.40.60.81.0 2-y NRM = 23 % Cumulativeincidence Years from transplant 100-day NRM 12%
- 26. 2-y OS andPFS
- 27. BM PBSC Pvalue N° pts 46 23 Age 44 (19-68) 54 (25-65) .06 Follow-up (jours) 721 (365-728) 332 (135-498) <.0001 PNN > 0,5 x 109/L (jours) 20 21 .18 PLT >20 x 109/L (jours) 29 29 .13 GVH aigue 2-4 25% 33% .43 GVH chronique 13% 13% .21 NRM 22% 12% .96 Probabilité de OS et PFS à 2 ans = 68 et 62% non statistiquement différente L. Castagna et al. BBMT 2015
- 28. BMT CTN (BM) IPC/UK/AUS/FHCRC (PBSC) p value Patients(N°) 43 43 Follow-up (mos) 36 16 100 d aGVHD grade 3-4 0% 5% 0.410 2 y cGVHD 28% 18% 0.214 2 y OS 58% 56% 0.735
- 29. Conclusions • No increasefor acute or chronic GVHD • NRM, OS or PFS similar • No benefit for hematologic recovery • Ease for large program
Editor's Notes
- #12 Given these changes, the purpose of the current studies is to evaluate if the results found in the setting of MAC regimen could be applied in the setting of RIC;
- #13 Actually, the heterogeneity in terms of disease, donor, conditioning regimen and gvhd prophylaxies could explain in part these discordant results. Moreover the optimal cut off for high doses of cd34 is not well defined.
- #14 The objectif of our study was to evaluate the impact of cd34 and cd3 cell dose on the outcomes after RIC allotransplantation in a population as homogeneous as possible, in order to overcome the effects of the transplatation procedure.
- #15 To answer this question we conducted a retrospective study between 2005 and 2013; Our selection criteria were All Hematological malignancies indicated for Allo-HSCT with peripheral blood stem cell. HLA identical donor that is to say : matched related or unrelated donors 3) Reduced intensity conditioning (RIC) regimen, with 5days of fludarabine, 2 days of busilvex, and 2 days of rabbit ATG thymoglobuline r; 4) Ciclosporine A alone as GVHD prophylaxis
- #16 We can notice that Only 18% of these patients had a low Disease Risk Index and 46% had an Comorbidity index more than 3.
- #17 When adjusted by the confounding factors, the multivariate model confirms the absence of impact of high doses cd34 cells.
- #18 As exemple in picture, you can see that in contrast with the previous results in MAC, there was no significant difference in terms of extensive chronic GVHD;
- #19 Also, we use the multivariate cox model and we didn’t find any difference.
- #20 To conclude, we found no impact of the CD34 and CD3 cell dose on the outcomes after allotransplantation in the contexte of RIC with ATG, HLA identical donor and Csa as GVHD prophylaxis. This absence of impact may be due to the use of ATG which could explain the differences between MAC and RIC regimen. Thus, we supposed that, in the latter situation, there is no rational for limiting the maximal amount of CD34+ or CD3+ cell dose in PBSC graft. Although our study consisted of a large and homeneous cohort, it was a retrospective analysis. So, This results deserve to be validated on prospective well conducted trial.