Post on 21-Dec-2015
transcript
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 AgeMed(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
0
5
10
15
20
25
30
<1
1-4
5-9
10-1
4
15-1
9
20-2
4
25-2
9
30-3
4
35-3
9
40-4
4
45-4
9
50-5
4
55-5
9
60-6
4
65-6
9
70-7
4
75-7
9
80-8
4
85+
AMLNHLMyelomaCLLALLCML
Age
Ad
just
ed I
nci
den
ce R
ate
Aging and Hematopoietic Malignancies
Myelosuppression
Imm
uno
sup
pre
ssio
n
Reduced Intensity Myeloablative
TBI 2 Gy
F/TBI 2 Gy
F/Cy
F/M 140
Flag-Ida
F/M 180
Bu8/F/ATG
Cy120/TBI 5.5 Gy
Cy120/TBI 12 Gy
Bu16/Cy120
TT-Cy
F/Cy/TBI 2 Gy
F/Bu16
Cy200/ATG
Ale/F/M 140
TLI ATG
Conditioning Regimens
Aggressiveness of Malignancy
Gen
etic
Dis
parit
y
HLA-haploid.-related/T-cell depleted/Cord blood
HLA-matched unrelated
HLA-identical sibling
(Adapted from R. Champlin)
McSweeney et al., Blood 97: 3390, 2001. Maris et al., Blood 102: 2021, 2003.Niederwieser et al., Blood 101: 1620, 2003. Sandmaier et al., ASH 2005, 2009.
Seattle Protocol: Nonmyeloablative Conditioning
MMF BID
2 Gy TBIHCT
Chimerism Analyses
-3 560 28 35 84-4 -2
FLU30 mg/m2/d
-1 180
CSP/TAC BID
MR
D
MMF BID / TID
CSP/TAC BID
100
UR
D
40Days
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
Years after HCT
CR: 52%
Per
cent
Relapse: 34%
NRM: 31%
OS: 43%
PFS: 36%
n = 128
Risk factors: Disease status at HCT
Progression = 8Responsive = 51Refractory = 69
Years after HCT
Per
cent
NRMProgression/relapse
P = 0.3
Risk factors: Chromosomal abnormalities
Years after HCT
Per
cent
P = 0.22 del 11qNormal
del17q
Othersdel 13q
Tri12PFS
Risk factors: lymph node size
<5 cm = 95≥5 cm = 33
Years after HCT
Per
cent
NRMProgression/relapse
PFS
P = 0.003
P = 0.01 43%
14%
54%
27%
Risk factors: Prior Alemtuzumab within 12 ms
No = 98Yes = 30
Years after HCT
Per
cent
NRMProgression/relapse
PFS
P = 0.01
Relapse/ Progression
PFS
HR p HR p
Cytogenetics 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
LN size < 5 cm 1.0 1.0
≥ 5 cm 2.26 0.02 1.86 0.02
Disease status at HCT
Responsive 1.0 1.0
Refractory 1.12 0.74 1.11 0.69
Progression 0.98 0.97 1.08 0.88
Prior Campath within 12 ms
No 1.0 1.0
Yes 1.78 0.02 2.54 0.005
Multivariate analyses
Sorror JCO 2008
CLL: Risk-Stratification Model
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
3 year OS 78% (n=28) 60% (n=34) 43% (n=7) 27% (n=13)
Selected Trials of Reduced Intensity Conditioning Allogeneic HCT for CLL
NAge Years
(range)
RegimenDonor NRM
aGVHD 2-4
cGVHD Extensive
OS/PFS%
Reference
82 56 (42-72)
Flu/TBI 63% RD37% URD
25% 5y 55% 49% RD53% URD
50/455 yr
Sorror et al 2008
90 53 (27-65)
Fly/Cy +/- ATG
40% RD 23% 6y 45% 55% 58/38 6 yr
Dreger et al 2010, 2013
76 55 (36-73)
Flu/Mel 33% RD67% URD
16% 30% 62% 63/435 yr
Brown et al 2006, 2013
40 54 (35-65)
Flu/TBI/R 100% RD 27% 3y 44% 29% 55/463 yr
Michallet et al2013
86 58 (36-70)
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% 72/672 yr
Schetelig et al2003
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 vs Ofatumumab for relapsed CLL (n=391)
Byrd JC et al. N Engl J Med 2014;371:213-223
PFS
OS
Median age: 67Bulky disease: 50-60%17p del: 33%Median prior Rx: 2-3FLU refractory: 45%
PFS (6 Mo) 17p- patients
Ibrutinib: 83%Ofatumumab: 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
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