The Role of Allogeneic Transplantation
for High-Risk CLL
(in the age of targeted therapy)
David G. Maloney, MD, PhD
Member, Fred Hutchinson Cancer Research Center
Professor of Medicine, University of Washington,
Seattle, WA
Allogeneic HCT has been Considered Standard
Rx for Patients with High-Risk CLL
•
•
•
Patients refractory to purine analogues
Short response to aggressive chemoimmunotherapy
(FCR) < 24 mo
Presence of 17p-/TP53 mutations
•
Early trials with myeloablative regimens have given way
to reduced intensity regimens with decreased NRM
•
Is this still the case in the era of ibrutinib, idelalisib and
ABT-199?
EBMT position paper: Dreger et al, Leukemia;21; 2007,
Blood, 2014 on line
Survival for Fludarabine-Refractory CLL
• 147 pts
• Treated by different salvage therapies
• Overall response rate (RR) 22%
• CR 1%
Keating MJ; Leu & Lym; 2002
Myeloablative Allogeneic
Transplantation for CLL
N
Age
Med(range)
NRM
Survival
PFS
Reference
54
41 (21-28)
46% @ 3y
46% @ 3y
na
EBMT, Michallet 1996
38
45 (26-57)
38% @ 5y
33% @ 5y
30% @ 5y
CIBMTR, Pavletic 2005
25
47 (29-55)
24% @ 6y
55% @ 6y
24% @ 6y
DFIC, Gribben 2005
30
48 (32-59)
47% @ 5y
39% @ 5y
39% @ 5y
Canada, Toze 2005
12
39 (29-53)
25%
65%
65%
Spain, Esteve 2001
28
43 (26-58)
32% @ 6y
45% @ 5y
42% @ 5y
MDACC, Khouri 2002
Adapted from Delgado, Blood 2009
Adjusted Incidence Rate
0
Age
85+
80-84
75-79
70-74
65-69
60-64
55-59
15
50-54
20
45-49
25
40-44
35-39
30-34
25-29
20-24
15-19
10-14
5-9
1-4
<1
Aging and Hematopoietic Malignancies
30
AML
NHL
Myeloma
CLL
ALL
CML
10
5
Conditioning Regimens
Reduced Intensity
Myeloablative
Cy120/TBI 12 Gy
Cy200/ATG
HLA-matched
unrelated
HLA-identical
sibling
Immunosuppression
Genetic Disparity
HLA-haploid.-related/
T-cell depleted/
Cord blood
F/Cy/TBI 2 Gy
Ale/F/M 140
Cy120/TBI 5.5 Gy
Bu16/Cy120
F/M 180
F/TBI 2 Gy
F/M 140
Bu8/F/ATG
F/Cy
TLI ATG
Flag-Ida
TBI 2 Gy
TT-Cy
Myelosuppression
Aggressiveness of Malignancy
(Adapted from R. Champlin)
F/Bu16
Seattle Protocol: Nonmyeloablative Conditioning
FLU
2 Gy TBI
HCT
Chimerism Analyses
30 mg/m2/d
Days -4 -3 -2 -1 0
28
35 40
56
84
100
180
CSP/TAC BID
MMF BID
CSP/TAC BID
MMF BID / TID
McSweeney et al., Blood 97: 3390, 2001.
Niederwieser et al., Blood 101: 1620, 2003.
Maris et al., Blood 102: 2021, 2003.
Sandmaier et al., ASH 2005, 2009.
Observations using 2 Gy TBI +/- Flu
• G-CSF mobilized peripheral blood source
– Two days PBSC harvest
– No restriction on CD34 or CD3 numbers
• Out-patient treatment.
– Minimal hematologic toxicity using MRD, greater with MURD
• Reliable engraftment with full donor chimerism in >95%
patients
• Graft makes it’s own space and replaces marrow function
• Anti-tumor activity due to immunologic graft-vs-tumor activity
Experience with Flu/TBI for Fludarabine
Refractory, Advanced CLL
• 128 patients with CLL, SLL, or PLL
• Transplanted between 12/1997-12/2009
• Median follow up of survivors: 64 (12-138) months
Overall responses and outcomes at 5-years
Percent
n = 128
CR: 52%
OS: 43%
Relapse: 34%
PFS: 36%
NRM: 31%
Years after HCT
Outcomes by donor type (at 5-years)
Overall survival
Alive and on IS
URD
Percent
MRD
Years after HCT
Risk factors: Disease status at HCT
Refractory = 69
Responsive = 51
Progression = 8
P = 0.3
Percent
Progression/relapse
Years after HCT
NRM
Risk factors: Chromosomal abnormalities
PFS
Percent
P = 0.22
Years after HCT
del17q
Normal
del 11q
Tri12
del 13q
Others
Risk factors: lymph node size
≥5 cm = 33
<5 cm = 95
PFS
Percent
P = 0.01
43%
14%
Progression/relapse
NRM
P = 0.003
54%
27%
Years after HCT
Risk factors: OS by lymph node size < 5 cm vs > 5 cm
Risk factors: Prior Alemtuzumab within 12 ms
Yes = 30
No = 98
Percent
PFS
Progression/relapse
NRM
P = 0.01
Years after HCT
Multivariate analyses
Relapse/
Progression
HR
Cytogenetics
LN size
Disease status at
HCT
Prior Campath within
12 ms
p
PFS
HR
p
Normal/13q
1.0
1.0
Trisomy 12
0.93
0.91
0.86
0.76
Del17q/11q/Other
1.47
0.25
1.40
0.16
< 5 cm
1.0
≥ 5 cm
2.26
Responsive
1.0
Refractory
1.12
0.74
1.11
0.69
Progression
0.98
0.97
1.08
0.88
No
1.0
Yes
1.78
1.0
0.02
1.86
0.02
1.0
1.0
0.02
2.54
0.005
CLL: Risk-Stratification Model
3 year OS
Group 1: No HCT-CI/ LN <5 cm
Group 2: HCT-CI > 0
Group 3: LN > 5 cm
Group 4: HCT-CI >0 and LN >5 cm
78% (n=28)
60% (n=34)
43% (n=7)
27% (n=13)
Sorror JCO 2008
Selected Trials of Reduced Intensity
Conditioning Allogeneic HCT for CLL
Age
Years
(range)
Regimen
82
56 (4272)
90
N
Donor
NRM
aGVHD
2-4
cGVHD
Extensive
OS/PFS
%
Reference
Flu/TBI
63% RD
37% URD
25% 5y
55%
49% RD
53% URD
50/45
5 yr
Sorror et al
2008
53 (2765)
Fly/Cy +/ATG
40% RD
23% 6y
45%
55%
58/38
6 yr
Dreger et al
2010, 2013
76
55 (3673)
Flu/Mel
33% RD
67% URD
16%
30%
62%
63/43
5 yr
Brown et al
2006, 2013
40
54 (3565)
Flu/TBI/R
100% RD
27% 3y
44%
29%
55/46
3 yr
Michallet et al
2013
86
58 (3670)
Flu/Cy/R
50% RD
17% 4y
37%
56%
51/36*
5 yr
Khouri et al
2011
30
50
(12-63)
Flu/Bu +
ATG
50% RD
16% 2y
56%
21%
72/67
2 yr
Schetelig et al
2003
Allogeneic Transplantation for CLL
• Major risks are GVHD and infection
– Low day 100 NRM < 5%, but 15-30% NRM at 1 year
– ~25% risk of cGVHD effecting QOL
• Graft vs CLL effect is active in CLL
– Lower risk of relapse in the setting of cGVHD
– Higher risk of relapse with T cell depletion
– Clearance of MRD
• May provide curative potential
• Effective in high-risk disease
– Fludarabine refractory
– Adverse cytogenetics
– unmutated Ig genes
• May provides a better functioning hematopoietic and immune
system post HCT
Nonmyeloablative Allogeneic Transplantation
for CLL
• Effective therapy for fludarabine refractory CLL
• Appears superior to available treatment options
• Risk factors for poor outcome include
– Lymph node size > 5 cm
– The presence of comorbidities
– Alemtuzumab within 12 months
• Other factors (cytogenetics, age, CD38) did not have a significant
effect on outcome
• The challenge is to determine the optimal time to consider
transplant
– Prior to the development of bulky disease
– Earlier for patients with high risk disease?
B-Cell Receptor Signaling and Inhibition in B-Cell Malignancies.
Stevenson F K et al. Blood 2011;118:4313-4320
Ibrutinib for Relapsed Refractory CLL
Byrd J NEJM 369(1):32, 2013
Ibrutinib vs Ofatumumab for relapsed CLL (n=391)
PFS
Median age:
Bulky disease:
17p del:
Median prior Rx:
FLU refractory:
67
50-60%
33%
2-3
45%
PFS (6 Mo) 17p- patients
OS
Byrd JC et al. N Engl J Med 2014;371:213-223
Ibrutinib:
Ofatumumab:
83%
49%
Treatment of Refractory CLL: Idelalisib
• Rituximab and Idelalisib
active in relapsed/ref
CLL
• Improved PFS and OS
compared with
rituximab alone
• Use in
relapsed/refractory CLL
warranted
Furman RR et al NEJM 370(11):997, 2014
Dreger, P et al Blood Online 10/9/2014
Points to Discuss With Patients
• HCT has been considered as the treatment of
choice for high-risk CLL
• Only documented curative potential for CLL
• B cell TKI/BCL-2 inhibitors are major advances
– Best option available to date
– responders have 2 yr OS 70-90% (60-80% HCT)
– long term uncertain, resistance possible, cure unlikely
• Outcome of HCT post novel agents uncertain
• HCT has early NRM (15-30%) in first 2 years with
risk of cGVHD (25%)
Dreger, P et al Blood Pre pub 10/2014
Conclusions: Role of Allogeneic HCT for
High-Risk CLL
• BCR inhibitors best available treatment
– cure (or CR) seems unlikely
– resistance can arise (uncertain timing)
• Allogeneic HCT is still the ONLY curative option
• Timing remains controversial (and patient specific)
– prior to bulky disease
• Randomized trials unlikely, requires close contact with
HCT team
• At minimum discuss options, HLA type, determine options
• Targeted therapy with CAR-T cells will also impact HCT

Colleagues at FHCRC / UW
Mohamed Sorror

Postdoctoral Fellows

Transplant + Research Nurses

Clinical Support Staff

Collaborating Investigators
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