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AML and Cell Therapy
- 1. Acute Myeloid Leukemia Allo HSCT after Low Toxicity CDT A step toward individualized allogeneic immunotherapy? Didier Blaise, MD Institut Paoli Calmettes, CRCM and Aix Marseille University Marseille, France
- 2. What do we know about allo HSCT? 2 Koreth J, Jama, 2009 Are these data reflecting present time? – 1982 to 2006 – Median age: 35-39 years – HLA –ID siblings – CYTBI / BUCY Evidence based medicine = Not always real life
- 3. Donor T Cell Donor mononuclear cell Host cells Conditioning regimen Disease Endotoxin IL2 IFN G IL1 TNF@ IL1 TNF@ CDT is a major factor for Mortality
- 4. Reduced Toxicity Strategies and challenges • Young: Lower NRM? – Similar GVL • Older: HSCT access? – Acceptable NRM – Efficient GVL
- 5. The less intensive, the less toxic? Flu-Bu-ATG N=69 Flu-TBI N=70 Age 54 (21-65) 52 (34-65) - AML/HMY - HLY 37% 63% 27% 73% - Advanced 63% 65% Blaise, D , cancer 2012 Flu-Bu- ATG Flu-TBI NRM 38% 22% Relapse 27% 54% 5 HLA-Matched, Related Allo PBSCT
- 6. The less intensive, the less toxic? Flu-Bu-ATG N=69 Flu-TBI N=70 Age 54 (21-65) 52 (34-65) - AML/HMY - HLY 37% 63% 27% 73% - Advanced 63% 65% Blaise, D , cancer 2012 Flu-Bu- ATG Flu-TBI NRM 38% 22% Relapse 27% 54% 2-4 aGVHD 47% 28% Ext cGVHD 61% 46% 6 HLA-Matched, Related Allo PBSCT
- 7. GVHD remains a major cause of death after RIC NonRelapseMortality 7 p=0.003 17% 31% 41% 12% Saillard C, Leuk & Lymphoma, 2014
- 8. Dose Intensity and Toxicity • DI is not the only cause of toxicity
- 9. The increase from 2.5 to 5 mg/kg of r-ATG dose in RIC is beneficial Devillier, R , BMT 2012 9
- 10. Study NMAC1 N 274 Age 60 (5-74) AML 100% CR1 / CR>1 /adv 58% / 36% / 6% CDT TBI2 BU2 BU4 100% R-ATG 0% MRD / UD 43% / 57% 10 Feasibility of Dose Intensity in older pts 1. Gyurkockza B, J Clin Oncol 2010
- 11. Study NMAC1 RIC2 MA-LTC3 N 274 102 79 Age 60 (5-74) 58 (20-70) 58 (55-76) AML 100% 100% 80% CR1 / CR>1 /adv 58% / 36% / 6% 76% /20% / 4% 32% / 23% / 47% CDT TBI2 BU2 BU4 100% 100% 100% R-ATG 0% 100% 1 AG mm / UD MRD / UD 43% / 57% 56% / 44% 52% / 48% 11 Feasibility of Dose Intensity in older pts 1. Gyurkockza B, J Clin Oncol 2010 2. Oudin C, haematologica 2014 3. Alatrash G, BBMT 2011
- 12. Study NMAC1 RIC2 MA-LTC3 N 274 102 79 Graft Failure 12 0 0 100 days NRM 4% 5% 5% Overall NRM 26% 24% 26% 12 Feasibility of Dose Intensity in older pts 1. Gyurkockza B, J Clin Oncol 2010 2. Oudin C, haematologica 2014 3. Alatrash G, BBMT 2011
- 13. Dose Intensity and Toxicity • DI is not the only cause of toxicity • DI is not always associated with toxicity
- 14. CR1 AML NMAC N=160 RIC N=78 MA-RTC N= 25 14 Importance of Dose Intensity in Disease Control?
- 15. The less intensive, the less toxic? Flu-Bu-ATG N=69 Flu-TBI N=70 Age 54 (21-65) 52 (34-65) - AML/HMY - HLY 37% 63% 27% 73% - Advanced 63% 65% Blaise, D , cancer 2012 Flu-Bu- ATG Flu-TBI NRM 38% 22% Relapse 27% 54% 2-4 aGVHD 47% 28% Ext cGVHD 61% 46% 15 HLA-Matched, Related Allo PBSCT
- 16. Dose Intensity and Toxicity • DI is not the only cause of toxicity • DI is not always associated with toxicity • DI may contribute controlling disease
- 17. 17 • Eligibility • Poor prognosis AML/MDS • HLA identical RD or UD • Primary endpoint : 2 year PFS • Sample size: 177 patients • Quality of life study • Economics • Non interventional PK • BX Pharmacogenomics Dose Intensity study NCT: 01985061
- 18. Conclusions • Toxicity was (is) a major issue – Low post-transplant toxicity is achievable • It is critical for some populations: Older/unfit patients • CDT is an important adjustment variable – Low toxicity does not mean only reduced intensity • Disease control is the major issue – Low toxicity is not NO toxicity • Still some work to do... – Intensive CDT with low toxicity is achievable • Individualized CDT may be critical for better disease control – Optimized CDT may not be sufficient to cure some diseases • Post transplant therapy?
- 19. Why are individualized trt needed? Patel JP, NEJM, 2012 • Cytogenetics • Molecular Biology • Disease Status • MRD(?) • Age • Comorbidities Not AML… but AMLs!
- 20. Risk changes with accurate assessment Intermediate Risk? Patel JP, NEJM, 2012
- 21. Risk changes with accurate assessment E Jourdan, Blood, 2013 21 MRD CBF AML Good Risk?
- 22. 5-year relative survival rates with respect to age in patients with AML1 5-yearsurvivalrate 0 10 20 30 40 50 60 Age, years <45 45–54 65+55–64 1. Howlader N, et al (eds). SEER Cancer Statistics Review, 2010 2. Appelbaum FR et al, Hematology Am Soc Hematol Educ,2001 OS in patients aged >55 years (ECOG data from 1973–1997)2 Outcome of AML in the elderly
- 23. Older patients with CBF AML 5-years LFS: 26% CR rate: 88% Prebet et al JCO 2010
- 24. Not AML… but AMLs… and different patients…
- 25. Patient -3 -2 -1-4-6 -5 0 Immunotherapy: Allo HSCT + recent developments 25 Disease High Risk Allo-HSCT Bridge to Allo Disease High Risk Refractory • MoABs ? Bi-specifics • Car-T cells? • Checkpoint inhibitors?
- 26. DonorIndividualized Conditioning Patient Age Comorbidities -3 -2 -1-4-6 -5 0 26 GVHD prophylaxis Disease Stage Prognostic Factors MRD Allo-HSCT HLA match vs Alternative D NMAC/RIC vs. MA-RTC No Post-Graft IS Long vs. short term In-vivo T-cell deplet Bridge to Allo Immunotherapy: Allo HSCT + recent developments
- 27. DonorIndividualized Conditioning Patient Age Comorbidities -3 -2 -1-4-6 -5 0 27 GVHD prophylaxis Allo-HSCT Chimerism Disease Stage Prognostic Factors MRD Relapse Immunotherapy: Allo HSCT + recent developments Bridge to Allo
- 28. Donor Conditioning Patient Age Comorbidities -3 -2 -1-4-6 -5 0 28 GVHD prophylaxis Allo-HSCT Chimerism MRD Disease Stage Prognostic Factors MRD Immunotherapy: Allo HSCT + recent developments Bridge to Allo Individualized Conditioning
- 29. Donor Conditioning Patient Age Comorbidities -3 -2 -1-4-6 -5 0 29 GVHD prophylaxis Chimerism Individualized Immunotherapy • Cellular therapy: DLI, NK-DLI , Treg • Tumor Antigen vaccination: WT1… • Post graft drugs: Aza, Lenalidomide, anti-Kir moab… • Car? Checkpoint inhibitors? MRD Allo-HSCT Disease Stage Prognostic Factors MRD Immunotherapy: Allo HSCT + recent developments Bridge to Allo Individualized Conditioning
- 31. Tomorrow allogeneic immunotherapy? Immunotherapy bridge CDT MAC/MA-RTC vs. RIC Donor HLA id vs. alternative GVHD Prophylaxis No ATG vs. ATG short vs. long term CSA Post Graft immunotherapy No vs. Yes 31
- 32. SR CR1 Immunotherapy bridge CDT MAC/MA-RTC vs. RIC +++ Donor HLA id vs. alternative + GVHD Prophylaxis No ATG vs. ATG short vs. long term CSA ++++ Post Graft immunotherapy No vs. Yes + 32 Tomorrow allogeneic immunotherapy?
- 33. Tomorrow allogeneic immunotherapy? SR CR1 HR CR1 Advanced Immunotherapy bridge + +++ CDT MAC/MA-RTC vs. RIC +++ ++ + Donor HLA id vs. alternative + +++ ++++ GVHD Prophylaxis No ATG vs. ATG short vs. long term CSA ++++ ++ + Post Graft immunotherapy No vs. Yes + +++ ++++ 33
- 34. Conclusions • Allogeneic Immunotherapy is an effective therapy for AL • What is essential ? – Not what has been done so far… –But what we yet have to do! 34 Ollie, So much to do… Keep going! Stan
- 35. 35