1 / 47

Haploidentical Stem cell Transplantation

Haploidentical Stem cell Transplantation. Tsila Zuckerman Rambam Health Campus ISH 5/2009. Topics for discussion. Principles of haplo transplants Update data on haplo SCT( OS,DFS,TRM) Future directions (Improving results) in haplo (CTLs, T replete , NIMA) Pro & cons.

gray-maddox
Download Presentation

Haploidentical Stem cell Transplantation

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Haploidentical Stem cell Transplantation Tsila Zuckerman Rambam Health Campus ISH 5/2009

  2. Topics for discussion Principles of haplo transplants Update data on haplo SCT( OS,DFS,TRM) Future directions (Improving results) in haplo (CTLs, T replete , NIMA) Pro & cons

  3. Principles of Haplo SCT • Virtually every patient has a potential haplo donor. • Major historical obstacles in 3 loci mismatched transplant: Lethal GVHD Graft rejection

  4. The veto effect Veto activity is the capacity of the donor CD34 + cells to specifically suppress host CTL-p directed against antigens of the veto cells themselves Reich-Zeliger et al. 2004 J. Immunol. 173:6660

  5. Principles of Haplo Transplants • High intensity conditioning for maximal anti tumor effect & immunosupression • “Megadose” of stem cells to insure engraftment • Extensive T cell depletion to prevent GVHD • No post transplant immunosupression to facilitate immune reconstitution

  6. Update Data on Haplo SCT Perugia experience: Use of automated clinimacs device with increased yield of CD34 cells collection, median reduction of T cells of 4.5 logs and B cells of 3.2 log. 104 patients . 67 AML, 30% in relapse. 37 ALL, 35% in relapse. engraftment :primary 94%,secondary 100%. a GVHD II-IV 2%,cGVHD ext. 4%. TRM 36.5%. 70% due to infections (>50% viral) 1104 patients . Aversa F. JCO 2005

  7. Probability of EFS according to disease status at transplantation Primary engraftment 94% Secondary engraftment 100% aGVHD II-IV 2% cGVHD 4% TRM 36.5%( 70% infection related) Aversa F. et al. J Clin Oncol; 2005

  8. Cumulative incidence of leukemia relapse at 2 years for patients with ALL & AML according to disease status at transplantation Aversa F. et al. J Clin Oncol, 2005

  9. EBMT Survey on Haplo BMT Leukemia free survival according to disease status 173 AML 93 ALL Ciceri F et al, Blood 2008

  10. EBMT Survey on Haplo BMT Relapse rate according to disease status Ciceri F et al, Blood 2008

  11. Can we separate GVL from GVHD?

  12. NK cells alloreactivity • Lack of expression of self MHC molecules on mismatched allogeneic targets results in NK cell mediated lysis (“missing self” recognition)

  13. Balance between activating and inhibitory receptors Regulation of NK cell response by activating and inhibitory receptors

  14. Relapse rate according to the presence of NK alloreactivity & disease status at transplantation 112 high risk AML 61 CR 51 relapse Ruggeri, L. et al. Blood 2007

  15. OS according to NK alloreactivity status Ruggeri, L. et al. Blood 2007

  16. Susceptible T- ALL AML CML NHL MM Resistant common phenotype ALL Susceptibility to NK alloreactivity

  17. New modalities in Haplo transplants • Reduced intensity transplants • T replete transplants • Choosing the right donor (feto- maternal microchimerisem) • Enhancing GVL effect (DLI / NK infusion) • Immune reconstitution

  18. New modalities in Haplo transplants • Reduced intensity transplants • T replete transplants • Choosing the right donor (feto- maternal microchimerisem) • Enhancing GVL effect (DLI / NK infusion) • Immune reconstitution

  19. Reduced intensity transplants

  20. New modalities in Haplo transplants • Reduced intensity transplants • T replete transplants • Choosing the right donor (feto- maternal microchimerisem) • Enhancing GVL effect (DLI / NK infusion) • Immune reconstitution

  21. T replete transplants Luznik L Biol Blood Marrow Transpl. June , 2008

  22. T replete transplants N=68 Luznik L Biol Blood Marrow Transpl. , 2008

  23. Transplant outcome Luznik L Biol Blood Marrow Transpl., 2008

  24. New modalities in Haplo transplants Reduced intensity transplants T replete transplants Choosing the right donor (feto- maternal microchimerisem) Enhancing GVL effect (DLI / NK infusion) Immune reconstitution

  25. Haplo SCT from Tolerized Donor Tolerance induced from in uterore exposure to maternal Ags and results in long lasting feto-maternal microchimerism. Tolerized donor: mother or NIMA mismatched sibling.

  26. Proposed scheme for choosing the appropriate donor PARENTSHAPLOIDENTICAL Sib Mother NIMA / IMA c b (1) NIMA / IPA a d Patient IMA / IPA b d Father NIPA / IPA c d (2) NIPA / IMA c b

  27. Haploidentical SCT T-cell-replete NIMA-complementary SCT (n=35) aGVHD II-IV aGVHD III-IV OS OS Ichinohe T et al: Blood 2004

  28. aGVHD grade II-IV following mismatched related transplant according to donor type IBMTR registry study 269 patients with acute leukemia Family donor 1-2 Ag mismatch P<0.02 Jon j. van Rood ,Blood 2002

  29. Stern M, Blood 2008

  30. Stern M, Blood 2008

  31. New modalities in Haplo transplants Reduced intensity transplants T replete transplants Choosing the right donor (feto- maternal microchimerisem) Enhancing GVL effect (DLI / NK infusion) Immune reconstitution

  32. Enhancing GVL effect (DLI / NK infusion) • G-CSF mobilized DLI (1x106/ kg) with short course immunosupressionHuang XJ ,JCI,2008,28(4):390-7 • CD8 depleted DLI . Soiffer RJ, Biol Blood Marrow Transplant,2002,8(11) 625-32. • NK- DLI ( ≥ 1.0 x 10(7)/kg CD56+/CD3- NK cells)Passweg JR, Leukemia,2004,18: 1835-1838

  33. New modalities in Haplo transplants Reduced intensity transplants T replete transplants Choosing the right donor (feto- maternal microchimerisem) Enhancing GVL effect (DLI / NK infusion) Immune reconstitution

  34. Immune reconstitution • Suicide gene engineered DLI . Ciceri F , lancet oncol,2009,10(5);489-500 • Adoptive transfer of virus specific (CMV,EBV) cytotoxic T lymphocytes Peggs K, lancet,2003,362,1375-1377 • Selective depletion of alloreactive T cells using immunotoxins, immunomagnetic beads, FACs sorting, photodynemic purgingPerruccio K , Blood Cells Mol Dis. 2008 Jan-Feb;40(1):76-83.

  35. Dey BR, BJH, 2006

  36. EUROCORD Comparison of outcomes after Unrelated Cord Blood or Haploidentical T-cell depleted Peripheral Blood Stem Cells in Adults with High Risk Acute Leukemia V Rocha, F Aversa, M Labopin, G Sanz, F Ciceri, W Arcese, D Bunjes, J Rowe, P Di Bartolomeo, F Frassoni, M Martelli and E Gluckman on behalf of the Eurocord-Netcord and Acute Leukemia Working Party EBMT

  37. Patients From 1998-2002 229 haplo and 139 UCBT were performed for adults with high risk acute leukemia (AML and ALL) Two different analysis were performed: AML patients Haplo= 154 UCBT= 66 ALL patients Haplo= 75 UCBT= 73

  38. AML Patients and Disease characteristics Haplo UCBT P N 154 66 Status at transplant 0.9 CR1 33 (21%) 15 (23%) CR2 32 (21%) 12 (18%) More advanced 89 (58%) 39 (59%) Previous autologous transplant 21% 25% 0.61 Intervalfromdiag-transplant 333 d 384 d 0.16 Medianyear of transplantation 2000 2000 0.21

  39. 1.0 Haplo versus UCBT for adult patients with AML LFS .8 .6 UCBT (n=66) 30±6% .4 .2 Haplo (n=154) 24±4% P=0.39 years 0.0 3 0 1 2

  40. 1.0 Haplo versus UCBT for adult patients with ALL LFS .8 .6 CB (n=73) 36±6% .4 .2 Haplo (n=75) 13±4% P=0.01 years 0.0 0 1 2 3

  41. Overall survival of MRD , Haplo and MUD according to disease status (early vs late) Early Δ= MRD ●=MUD =haplo Late ◊=MRD ▼=MUD ▲=haplo Ottinger HD, Blood 2003

  42. □ - MRD Δ – haplo ▼ - MUD Ottinger HD et al, Blood 2003

  43. Relapse risk Adv MRD Adv MUD Early MRD Adv Haplo Early Haplo Early MUD Ottinger HD et al, Blood 2003

  44. Pro Donor for every patient Immediate availability Ability to select the best of many potential donors Easy access to repeat donation/DLI Cons Delayed immune reconstitution Pro & cons

  45. THANK YOU

More Related