1. Miguel-Angel Perales MD
Q. What is the optimal therapy for CLL patients failing to achieve PR with chemoimmunotherapy? A. Stem Cell Transplant
Miguel-Angel Perales MD
Adult Bone Marrow Transplantation Service
Memorial Sloan Kettering Cancer Center
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2. Targeting of BCR signaling
Hallek , Blood 2013;
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3. New drugs for CLL – so many choices …
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4. Byrd et al, N Engl J Med 2013;369:32-42
Goede et al, N Engl J Med 2014;370:
Furman et al, N Engl J Med 2014;370:
Cancer Discovery 2014;4:136
Souers et al, Nat Med 2013;19:
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5. Is there still a role for allogeneic HCT?

6. EBMT 2007 Transplant Consensus for CLL
Patients with CLL who meet the following criteria should be considered for Allo-HCT:
Non-response or early relapse (within 12 months) after purine analogue-containing therapy
Relapse within 24 months after purine analogue combination therapy or autologous SCT
Patients with p53 abnormalities requiring treatment
Dreger et al, Leukemia (2007) 21, 12–17
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7. Number of allo-HCT and auto-SCT for CLL in EBMT Registry
Dreger, Hematol Oncol Clin N Am 27 (2013) 355–369
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8. Prospective trials of NMA/RIC Allo-HCT in CLL
Dreger, 2010
Sorror, 2008
Brown, 2013
Khouri, 2011
Michallet, 2011 N 90 82 76 86 40
Regimen
NMA
RIC
Alternative donors (%) 59 37 63 50
Relapse (%)
40 (4 y)
38 (5 y)
40 (5 y)
n.r.
22 (3 y)
PFS (%)
42 (4 y)
39 (5 y)
43 (5 y)
36 (5 y)
46 (3 y)
OS (%)
70 (4 y)
50 (5 y)
63 (5 y)
51 (5 y)
55 (3 y)
Follow-up (y)
3.8
(0.6 – 8.5) 5
(0.9 – 7.3)
5.1
3.1
(0.9 – 10.9)
2.3
(0.3 – 5.9)
Adapted from Dreger, Hematol Oncol Clin N Am 27 (2013) 355–369
Dreger, Blood 2010;116:2438–47; Sorror, JClin Oncol 2008;26:4912–20; Brown, Leukemia 2013;27: ; Khouri, Cancer 2011;117:4679–88; Michallet, Bone Marrow Transplant 2011;46(Suppl 1):S43–4.
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9. MRD kinetics in a patient with poor-risk CLL during RIC
Dreger, Hematol Oncol Clin N Am 27 (2013) 355–369
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10. Patterns of response in CLL after allo-HCT
Ritgen et al, Leukemia (2008) 22, 1377–1386
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11. Analysis of MRD kinetics in 43 patients after RIC Allo-HCT
43 patients event-free 1 year after allo-HCT on GCLLSG CLL3X trial or pilot study
MRD status
32 MRD negative at 1 year
11 did not reach MRD till 1 year
Linked to tapering of immune suppression or donor leukocyte infusion (DLI)
Absence of MRD detection associated with decreased risk of relapse (HR (%CI , P<0.0001)
Bottcher et al, Blood Reviews 2011;25:91-96
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12. Studies on MRD kinetics after allo-HCT for CLL
GCLLSG
Milan
Barcelona
Spanish IG N 59 29 20 21
MRD assay
RQ-PCR
Flow
NestPCR
MRD pattern
Sustained neg (>12 mo)
75%
31%
65%
94%
Delayed clearance
46%
14%
50%
35%
Always positive
17%
45%
30%
n.a.
Clinical relapse by MRD pattern
Permanent neg 9%
Always pos
70%
62%
Clinical relapse in pts 12 mo 6%
11%
MRD relapse in pts 12 mo
13%
40%
Adapted from Bottcher, Blood Reviews 2011;25:91-96
Dreger, Blood 2010;116:2438–47; Ritgen, Leukemia 2008;22:1377–86; Farina, Haematologica 2009;94:654–62; Moreno, Blood 2006;107:4563–9; Caballero, Clin Cancer Res 2005;11:7757–63.
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13. Causes of Death after Transplants performed in 2008-2009
HLA-identical Sibling
Infection (12%)
Other (21%)
Primary Disease (47%)
GVHD (14%)
Organ Failure (4%)
New Malignancy (1%)
Unrelated Donor
Infection (16%)
Other (29%)
Organ Failure (6%)
Primary Disease
(33%)
New Malignancy (1%)
GVHD (15%)
Autologous
Infection (8%)
Other (16%)
Organ Failure (2%)
New Malignancy (1%)
Primary Disease (73%)
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Slide 18
SUM-WW11_17.ppt

14. Toxicity of NMA/RIC Allo-HCT in CLL
Dreger, 2010
Sorror, 2008
Brown, 2013
Khouri, 2011
Michallet, 2011 N 90 82 76 86 40
Regimen
NMA
RIC
Mucositis gr 3-4 (%) 6 12
n.r.
< 5
Infection gr 3-4 (%) 55 60 48
Day 100 NRM (%) 2
< 10
< 3 3
NRM (%)
23 (4 y)
23 (5 y)
16 (5 y)
17 (1 y)
27 (3 y)
aGVHD 2-4 (3-4) (%)
45 (14)
n.r. (16-23)
30 (17)
37 (7)
44 (23)
Extensive cGVHD (%)
49-53 56 29
Follow-up (y)
3.8
(0.6 – 8.5) 5
(0.9 – 7.3)
5.1
3.1
(0.9 – 10.9)
2.3
(0.3 – 5.9)
Adapted from Dreger, Hematol Oncol Clin N Am 27 (2013) 355–369
Dreger, Blood 2010;116:2438–47; Sorror, JClin Oncol 2008;26:4912–20; Brown, Leukemia 2013;27: ; Khouri, Cancer 2011;117:4679–88; Michallet, Bone Marrow Transplant 2011;46(Suppl 1):S43–4.
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15. NRM after allo-HCT for lymphoma (EBMT 2006 – 2010)
Dreger, Hematol Oncol Clin N Am 27 (2013) 355–369
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16. Changing landscape in CLL
Multiple new drugs recently approved or expected to be approved for CLL
Changes in front-line and salvage therapy now and in the future with potential combinations of drugs + monoclonal antibodies and use of maintenance therapy
Targeting of CD19 with ADC or CAR T cells
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17. New drugs for CLL – so many choices …
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18. Open questions in the new era of CLL
Will new drugs or drug combinations redefine prognosis for “poor-risk” CLL?
Will more patients achieve MRD-neg status with new drug combinations?
Is a cure possible in CLL with new drug combinations?
What about the emergence of resistance?
What is long-term safety of novel agents?
What will be the cost of long-term therapy with new drugs in patients with CLL?
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19. Results of ibrutinib in patients with 17p deletion
Byrd et al, N Engl J Med 2013;369:32-42
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20. Outcome after allo-HCT in patients with 17p–chronic CLL
Schetelig et al, J Clin Oncol 2008; 26:
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21. Prognostic factors for PFS after NMA/RIC Allo-HCT in CLL
Dreger, 2010
Sorror, 2008
Brown, 2013
Khouri, 2011
Michallet, 2011 N 90 82 76 86 40
Higher age
++ (>55) -
++ (>65)
Comorbidity score
n.r. ++
++ (>0)
Alternative donors
Prior therapy
Purine-analog Refract
HCT
17p-
Adapted from Dreger, Hematol Oncol Clin N Am 27 (2013) 355–369
Dreger, Blood 2010;116:2438–47; Sorror, JClin Oncol 2008;26:4912–20; Brown, Leukemia 2013;27: ; Khouri, Cancer 2011;117:4679–88; Michallet, Bone Marrow Transplant 2011;46(Suppl 1):S43–4.
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22. Integration of new approaches in allo-HCT for CLL
Kochenderfer et al, Blood. 2013;122(25):
Cruz et al , Blood :
Burkhardt et al, J Clin Invest. 2013;123(9):3756–3765
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23. How do we identify CLL patients who benefit from allo-HCT?
Summary
Allogeneic HCT remains a curative option for patients with CLL, with long-term PFS 40-45% and OS 50-70%
The benefit is derived from clearly demonstrated graft-versus-leukemia effects and is associated with achieving MRD negative status
How do we identify CLL patients who benefit from allo-HCT?
Can we use novel agents after allo-HCT to further improve outcomes?
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24. Treatment algorithm for CLL patients in frontline indications
Hallek M Blood 2013;122:
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©2013 by American Society of Hematology

25. Treatment algorithm for CLL patients in second-line indications
Hallek M Blood 2013;122:
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©2013 by American Society of Hematology