1. Hematopoietic Stem Cell Transplantation for Patients with AML
Amir Abbas Hedayati-Asl
Ped. Hematologist Oncologist /BMT
Tehran University of Medical Sciences, HORC-SCT
Royan Institute
Hematology & Oncology Department
Cancer Personalized Medicine Program
Stem Cell Biology and Technology Department

2. Simplified Classification of AML
• AML sensitive to conventional chemotherapy • CBF leukemia (without c-KIT mutation) • Diploid AML with NPM1 and CEBPA mutation (without FLT3 mutation) • Dose intensification of chemotherapy may be helpful • Chemo-resistant and high risk AML • New agents are needed • Allo-SCT in the mainstay of therapy

9. Role of Allo HSCT
Allogeneic hematopoietic stem cell transplantation (allo HSCT) from an HLA-matched related donor provides the most potent anti-leukemic effect of any post-remission therapy in AML, as demonstrated by the lowest rates of relapse.
Graft vs leukemia plays and important role here.
Provides the best chance of long-term survival

10. Disadvantages :
◦ Graft failure ◦ GVHD ◦ Peri-transplant mortality rate The current recommendations for the performance of allo HSCT for patients in CR1 are limited to those whose risk of relapse significantly exceeds the incremental mortality from allo HSCT over standard chemotherapy.

11. FAQs Which patients should be offered this in CR1?
How much, if any, additional post-remission therapy should be administered prior to allo HSCT?

14. Indications
The decision to undergo an allo HSCT will depend on the prognostic factors at diagnosis and, no less importantly, at the point of achieving CR1 Thus, allo HSCT in CR1 should be considered in patients with unfavorable cytogenetics and those with intermediate-risk cytogenetics, except possibly those with the NPM1+/Flt3-ITD– subgroup

18. Post-remission therapy in patients with AML may consist of continuing chemotherapy or transplantation using either autologous or allogeneic stem cells.
Patients with favorable subtypes of AML generally receive chemotherapeutic consolidation, although recent studies have also suggested favorable outcome after
HSCT.

19. Although allo-HSCT is considered the preferred type of post-remission therapy in poor- and very-poor-risk AML.
The place of allo-HSCT in intermediate-risk AML is being debated.
Autologous HSCT is considered a valuable alternative that may be preferred in patients without minimal residual disease after induction chemotherapy.

20. Recent developments in the field of alternative donors:
cord blood
haploidentical donors
are highlighted, and we discuss reduced-intensity alloHSCT who represent the predominant category of patients with AML who have a high risk of relapse in first remission.

21. Survival of pediatric AML has improved considerably over the past decades. Since 1985, allo-SCT is widely recommended for patients who have a matched sibling donor.
However, it remains controversial whether allo-SCT is superior to chemotherapy for children with newly diagnosed AML.

22. Prognosis

24. Because allo-SCT also gives more severe side effects and results more often in secondary malignancies than chemotherapy, we do not recommend allo-SCT in first remission for pediatric AML in general???

25. Further research should focus on the possibility that subgroups might benefit from allo- SCT, aiming at further improvements in the prognosis of pediatric AML.

26. Allo-SCT is a procedure in which a person receives stem cells from a donor.
Currently, patients and donors are typed by molecular techniques for HLA class I and II antigens.
A well-matched donor matches for at least 9 of 10 alleles at HLA-A, -B, -C, -DRB1, and -DQB1.

27. Donor
The donor can be a matched related donor (MRD), most often a matched sibling donor (MSD).
If no MRD is available, a matched unrelated donor (MUD) may be available.
MUD is sometimes used in high-risk patients in first complete remission or after relapse, and more studies suggest that MUD–allo-SCT provides similar outcome as MSD–allo-SCT.
For children who lack both a MSD and a MUD, a haploidentical related donor or an unrelated cord blood donor can be used.

28. In auto-SCT, the patients’ own stem cells are used for rescue after myeloablative therapy. GVHD does not occur, so usually, treatment-related mortality is low.
However, the relapse rate is higher compared with allo-SCT because a potential graft-versus-leukemia effect is lacking.
It is generally accepted that auto-SCT in first remission is not different from chemotherapy in terms of survival.

30. Risk Group Stratification
However, most groups agree that patients with t(8;21), inv(16), t(16;16), and t(15;17) belong to the low-risk group,
Patients with monosomy 5, monosomy 7, deletions of 5q, or greater than 15% blasts in the marrow after the first course of chemotherapy belong to the HR group.
Most groups agree that children who have acute APL, myeloid leukemia of Down syndrome (ML DS), t(8,21) or inv(16)/t(16,16) should not receive allo-SCT during first remission.

34. The safety and efficacy of reduced-intensity conditioning (RIC) regimens for the treatment of pediatric acute myeloid leukemia is unknown.

36. Results of uni-variate and multivariate analysis showed no significant differences in the rates of :
Acute and chronic graft-versus-host disease
Leukemia-free
Overall survival between treatment groups.

39. The 5-year probabilities of overall survival with RIC and MAC regimens were 45% and 48%, respectively .
Moreover, relapse rates were not higher with RIC compared with MAC regimens (39% vs 39%).
Recipients of MAC regimens were not at higher risk for transplant-related mortality compared with recipients of RIC regimens (16% vs 16%)

46. Place of Auto HSCT
Most of the major prospective studies published over the past decade have described a lower relapse rate for patients undergoing an auto HSCT in comparison with chemotherapy and a meta-analysis of six trials, including 4410 patients, also indicated that auto HSCT is associated with a modest improvement in DFS.
In most prospective studies of auto HSCT the OS was not significantly improved

47. Place of unrelated transplants
The German AML01/99 study : addressed the value of unrelated HSCT for AML in CR1.
In this study patients with unfavorable cytogenetics, or those with residual leukemia on the day 15 post-induction marrow, were assigned to receive an allo HSCT from a matched sibling, if such a donor were available.
Otherwise, patients were to receive a matched unrelated donor transplant, if a suitable donor could be found, or an auto HSCT.
The 4-year OS was 68% with sibling allo HSCT and 56% with an unrelated allo HSCT; both significantly better than an auto HSCT or chemotherapy

48. Conclusions
The value of allo-SCT in pediatric AML remains controversial and depends on the results obtained with chemotherapy alone.
During the past 10 to 20 years not only the efficacy of intensive chemotherapy and salvage therapy after relapse has improved, but also methodical problems comparing treatment groups are better taken in account.

51. Cell Therapy for AML

52. AML- Sensitivity to immunotherapy
Allogeneic hematopoietic transplantation is curative through the immune graft-vs leukemia effect – T-cells – NK cells • Major cause of treatment failure is relapse • Can we develop more effective cellular immune therapy with T- and NK- cells

54. Problems Cancer cells are poorly immunogenic
• Cancer cells induce hyporesponsiveness/tolerance
• Allogeneic transplantation can provide Non-tolerized effector cells reactive against allo-antigens as well as leukemia related targets.

57. Lessons from Anti CD19 CAR T-cells
Effective against B-cell malignancies, ALL, lymphoma, CLL
• Responders also eradicate normal B-cells
• Patients can survive without B cells - IVIG
• Cross reactivity and destruction of normal hematopoiesis is a major problem with CARs against AML
– May ablate cells with suicide gene
– Can give prior to hematopoietic transplantation

58. Targeting AML with CAR- T cells
Myeloid cell surface antigens
– CD123 (IL-3 receptor)
– CD33 (may be absent on leukemia stem cells)
• Leukemia related antigens
– WT1
– PR1 (derived from Proteinase 3)

62. Conclusions
Cellular immunotherapy is a highly promising approach to treatment of AML
• Leukemia antigens have been identified
• Challenge is to avoid damage to normal hematopoiesis; may be overcome with suicide switch or use prior to HSCT
• NK cells naturally target AML; NK CARs further increase cytotoxicity
• Clinical trials using CAR T-cells, other antigen specific T-cells and NK cells are in progress