Relapse Post AlloHSCT Symposium, 29 October 2016, Saturday

1. Prevention of relapse following allogeneic
transplantation
Poon LM
Senior consultant
Dept of Hematology Oncology
National University Cancer Institute Singapore
National University Hospital

2. Outcomes of transplant following allogeneic
transplantation
Early: CR1, Intermediate: > CR2, Advanced: Disease not in remission CIBMTR data 2015

3. Spyridonidis
(EBMT)
Leukemia
2012

4. Overall survival/Progression free survival
Transplant survival = 100 % - Disease related mortality - NRM

5. Overall survival/Progression free survival
Transplant survival = 100 % - Disease related mortality - NRM
Donor source
Supportive
Care
Experience
Good patient
selection

6. Overall survival/Progression free survival
Transplant survival = 100 % - Disease related mortality - NRM
Aim to reduce disease related mortality through reduction of relapse!

7. In the past: Currently:
Measures to prevent relapse:
Research
Novel therapies
Appropriate applications

8. Prevention of Relapse: Strategies
Pre transplant
Setting
Transplantation
aspects
Post
transplantation
ALL AML NHL

9. Disease risk Index

11. CONCEPT OF MRD

12. Prevention of Relapse: Strategies
Pre transplant
Setting
Transplantation
aspects
Post
transplantation
Improving CR rates
Reducing MRD rates
ALL:
CD20 MC antibodies
Ph+ve ALL
MRD and blinatumomab

13. (I) Pretransplant optimization (ALL): Advancements
• CD20 ALL
• Ph positive ALL
• MRD and blinatumomab

14. Prognostic significance of CD20 positivity
(>20%) in ALL
MDACC experience GRALL experience
Thomas et al: Blood 2009
HyperCVAD group
CD20- ALL: 3yr OS 60%
CD20+ ALL: 3yr OS 28% (p =0.03)
OS
Maury et al: Blood 2014

15. CD20 positive ALL:
MDACC
Addition of rituximab to
CD20+ ALL associated with
higher OS and CRD in pts
younger than 60.
Thomas et al. JCO 2010
Germans
Addition of rituximab to
CD20+ ALL associated with
There was however a faster
and higher Mol. CR rate in
the Rituximab cohort, with an
improvement in remission
duration and overall survival.
Hoelzer et al ASH 2010
Compared with historical controls:
Use of rituximab in CD20 positive ALL associated with
Improved outcomes
(CRD/ OS/ MRD)

16. Multicenter RCT
Rituximab vs no Rituximab for CD20 expressing B ALL

17. Results:

19. (I) Pretransplant optimization (ALL): Advancements
• CD20 ALL
• Ph positive ALL
• Blinatumomab

20. EBMT data Hematologica 2016

21. Available TKIs
Imatinib blocks the ATP binding center of Bcr-Abl thus
inhibiting its phosphorylation activity.

22. EBMT retrospective review
473 Ph positive adult patients transplanted between 2000 – 2010
Assessment for impact of pre transplant TKIs (n-390) and post transplant
maintenance (n=60) on outcomes

23. Reduced relapse, and Improved OS with
TKIs before HSCT

24. (I) Pretransplant optimization: Advancements
• CD20 ALL
• Ph positive ALL
• MRD and blinatumomab

25. CONCEPT OF MRD
Persistence MRD = Relapse

26. N = 21
Molecularly refractory disease (N = 15)
Molecular relapse (N = 6)

27. BiTE antibody

28. MRD vs no MRD (GMALL)
MRD status
Gokbuget et al: Blood 2012 Topp JCO 2012
OS

29. Prevention of Relapse: Strategies
Pre transplant
Setting
Transplantation
aspects
Post
transplantation
Improving CR rates
Reducing MRD rates
AML:
FLT3 AML and
FLT3 inhibitors

30. The Multi- Kinase Inhibitor Midostaurin (M) Prolongs Survival
Compared with Placebo (P) in Combination with Daunorubicin
(D)/ Cytarabine (C) Induction (ind), High- Dose C
Consolidation (consol), and As Maintenance (maint) Therapy
in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients
(pts) Age 18- 60 with FLT3 Mutations (muts): An International
Prospective Randomized (rand) P- Controlled Double- Blind
Trial (CALGB 10603/ RATIFY [Alliance])
Richard M. Stone, Sumithra Mandrekar, Ben L Sanford, Susan Geyer, Clara D. Bloomfield, Konstanze
Dohner, Christian Thiede, Guido Marcucci, Francesco Lo- Coco, Rebecca B. Klisovic, Andrew Wei, Jorge
Sierra, Miguel A. Sanz, Joseph M. Brandwein, Theo de Witte, Dietger Niederwieser, Frederick R.
Appelbaum, Bruno C. Medeiros, Martin S Tallman, Jurgen Krauter, Richard F. Schlenk, Arnold Ganser,
Hubert Serve, Gerhard Ehninger, Sergio Amadori, Richard A. Larson and Hartmut Dohner
Blood 2015 126:6;
Art icleArt icle Info & Metrics e- Letters
ASH plenary session 2015

31. • Addition of midosurin to standard induction associated with improved
OS and EFS, both censored and uncensored at time of SCT.

32. Prevention of Relapse: Strategies
Pre transplant
Setting
Transplantation
aspects
Post
transplantation
Improving CR rates
Reducing MRD rates
ALL:
CD20 MC antibodies
Ph+ve ALL
MRD and blinatumomab
AML:
FLT3 AML and
FLT3 inhibitors
Optimization of
conditioning
Regimens
MRD directed
Strategies?

33. Options
Novel Chemotherapy
Agents
• Zevalin
• Thiotepa
• Clofarabine
• Rituximab
Better Combinations
• Gem Bu Mel
• Flu Bu Clo
• Flu Bu Thiotepa
• Flu Mel Thiotepa

34. MRD
Conditioning intensity

35. Conditioning intensity…
Question asked: In pts with AML undergoing transplantation, does a
Myeloablative conditioning overcome the adverse impact of MRD
Positivity?
• Retrospective analysis From FHCC
• 359 consecutive adults with AML who underwent myeloablative allo HCT
from a peripheral blood or bone marrow donor between 2006 and 2014.
• MRD tested by 10 color flow.

36. OS Relapse

37. • Patients undergoing HCT while in
morphologic remission with MFC-detectable
MRD have a substantially increased relapse
risk, approaching 65% to 70% after 3 years,
and 3-year OS estimates of only
approximately 25%, with MRD being the
dominant risk factor for adverse outcome.
• MA conditioning may not be enough to
overcome the poor prognostic outcomes of
residual MRD.

38. Leung et al Blood 2012
Review of pts on paediatric trials in St Judes
N = 122 (AML N = 58, ALL N= 64)
Looked at MRD pretransplant and impact of outcomes

41. • MRD is associated with poorer outcomes.
• Myeloablative conditioning alone may not be able to
negate the poorer outcomes of MRD positivity.
Questions that remain controversial:
• Is there a level of MRD beyond which transplant is
not useful?
• Should we aim to achieve MRD negativity before
transplant if donor available.
• Does post transplantation manipulations help?

42. Prevention of Relapse: Strategies
Pre transplant
Setting
Transplantation
aspects
Post
transplantation
Improving CR rates
Reducing MRD rates
ALL:
CD20 MC antibodies
Ph+ve ALL
MRD and blinatumomab
AML:
FLT3 AML and
FLT3 inhibitors
Optimization of
conditioning
Regimens
MRD directed
strategies
Maintenance therapy:
- TKIs (Ph ALL)
-Azacitidine
-FLT3 inhibitors
DLI: Preemptive/
prophylactic

43. Ongoing maintenance trials in AML (I)

44. Ongoing maintenance trials in AML (II)

45. Consensus Statement EBMT

46. Both prophylactic and preemptive options are valid. If
monitoring facilities not ideal: Consider prophylactic
measures

47. Italian data: Dominietto et al Blood 2007
Italian group data using preemptive DLI in pts with AML undergoing alloHCT

48. SUMMARY

49. P Tsirigotis BMT 2016

50. Pretreatment: Try to get best responses (pref MRD –ve)
Consider
Maintenance
therapy

51. Prevention of Relapse: Strategies
Pre transplant
Setting
Transplantation
aspects
Post
transplantation
Improving CR rates
Reducing MRD rates
ALL:
CD20 MC antibodies
Ph+ve ALL
MRD and blinatumomab
AML:
FLT3 AML and
FLT3 inhibitors
Optimization of
conditioning
Regimens
MRD directed
strategies
Maintenance therapy:
- TKIs (Ph ALL)
-Azacitidine
-FLT3 inhibitors
DLI: Preemptive/
prophylactic

52. Thank you for your
attention !