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Chronic Lymphocytic Leukemia
Paolo Ghia
Complex Karyotype: a
novel predictive marker?
Thompson PA et al. Cancer 2015
Complex karyotype superseded del(17p)Anderson MA et al. Blood 2017
• ORR in patients treated with IDELA+R with CK was 80.8% (95% CI: 60.6, 93.4) vs 89.7% (95% CI: 75.8, 97.1) without CK
• OS HR for patients treated with IDELA+R with CK vs no CK was 1.97 (95% CI: 0.87, 4.48; p=0.10, unadjusted)
Kreuzer, iwCLL 2017, Presentation #410
Ibrutinib and Idela in
R/R CLL by CK status
PFS and OS by CK statusPFSa
CK IDELA+R (n=26)
CK PBO+R (n=24)
No CK IDELA+R (n=39)
No CK PBO+R (n=38)
CK, complex karyotype; NR, not reached.
Median PFSmo
Del17p + CK (n=22) 25
Del17p no CK (n=10) 52
Jones J, et al. EHA 2016 (Abstract S429; oral presentation).
3580
3179 (89%)
Non-CK
741 (23%)
1 aberration
[non-del(13q)]
406 (13%)
2 aberrations
401 (11%)
CK
2032 (64%)Normal/del(13q)
No difference in the detection rate of CK between different cell stimulation protocols
Dissecting CK in CLL
Baliakas et al, EHA 2017, oral presentation
5 abs vs 4 abs: p<0.055abs vs 3 abs: p<0.054abs vs 3abs: p=ns
Dissecting CK in CLL
52%24%
22%
Baliakas et al, EHA 2017, oral presentation
You need 5 or more
aberrations to be bad
0 5 10 15 20 25
Time (years from diagnosis)
0%
25%
50%
75%
100%%
Aliv
e non CK, n=2856 CK, >= 5 abs, n=80 CK, 4 abs, n=71 CK, 3 abs, n=167
nonCK vs CK 4abs, p=nsnonCK vs CK 3abs, p=ns
Baliakas et al, EHA 2017, oral presentation
Complex karyotype aggravates
outcomes
in IG-unmutated CLL
0 5 10 15 20
Time (years from diagnosis)
0%
25%
50%
75%
100%
% A
live
non CK, n=569 CK, >= 5 abs, n=30 CK, 4 abs, n=28 CK, 3 abs, n=60
p<0.0001
Baliakas et al, EHA 2017, oral presentation
Complex karyotype aggravates
outcomes
in CLL with TP53abs
0 5 10 15
Time (years from diagnosis)
0%
25%
50%
75%
100%%
Aliv
e non CK, n=151 CK, >= 5 abs, n=42 CK, 4 abs, n=17 CK, 3 abs, n=22
5abs vs 4abs vs 3abs: p=ns
p=0.0012
Baliakas et al, EHA 2017, oral presentation
CLL8: Phase 3 randomizedtrial of FCR vs FC in 1L CLL2
0.8
0.6
0.4
0.2
0
1.0
Months on study
PFS
(P
rob
abili
ty)
12 24 36 48 60 960 72 84
p<0.001 FC IGHV-UM (n=195)
FCR IGHV-M (n=113)
FC IGHV-M (n=117)
FCR IGHV-UM (n=197)
Long-term remissions with
FCR in first-line CLL
1. Thompson PA, et al. Blood 2016; 127:303–309;
2. Fischer K, et al. Blood 2016; 127:208–215;
3. Rossi D, et al. Blood 2015; 126:1921–1924.
IGHV-M (n=88)
IGHV-UM (n=126)
p<0.0001
FCR300: Retrospective analysis of300 CLL patients treated with 1L
FCR1
75
50
25
0
100
Time (years)
Pro
gre
ssio
n-f
ree
(%
)
2 4 6 8 10 160 12 14
Low-risk (IGHV-M) (n=90)
High-risk (del(17p)) (n=30)
Intermediate-risk (IGHV-UM and/or del(11q)) (n=197)
60
40
20
0
100
80
Time (months)
Cu
mu
lati
ve p
rob
abili
ty
of
PFS
(%
)
12 24 36 48 60 1200 72 84 96 108
Italian retrospective analysis:404 CLL patients treated with 1L
FCR3
IGHV-M, IGHV-mutated; IGHV-UM, IGHV-unmutated.
Objectives
To evaluate the outcome of M-CLL patients without
poor FISH cytogenetics in relation to the type of
therapy
• 834 CLL patients from 3 European Institutions (Italy,Spain, Sweden)
• M-CLL: n= 493 (165 patients required therapy)
• U-CLL: n= 341 (272 patients required therapy)
Cuellar-García et al, EHA 2017 oral presentation
TFS and OS:mutated vs unmutated CLL
5yr-TFS was 73% (CI, 71-75) for M-CLLand 28% (CI, 26-30) for U-CLL
5-yr OS was 92% (CI, 90-93) for M-CLLand 77% (CI, 75-79) for U-CLL
The median duration of response to first therapy was 28 months (95% CI 24-32 months) in M-CLL vs 18 months (95% CI 16-20) in U-CLL (p<0.001)
n=493 M-CLLMedian 249 (Not evaluable)
n=341 U-CLLMedian 103 (89-117)
P<0.001
Months
OS
Months
n=493 M-CLLMedian 180 (144-217)
n=341 U-CLLMedian 25 (20-29)
P<0.001
TFS
Cuellar-García et al, EHA 2017 oral presentation
Outcome according to type of therapy in unmutated CLL
n=44 FCR/BR Median 24 (21-33)
n=77 Others Median 21 (14-28)
P=0.811
n=44 FCR/BR median 137 m(117-153)
n=77 Others Median 84 m(75-93)
OS
P=0.003
Months
Patients treated with small molecules and allogeneic SCT were excluded from this analysis
TFS
Months
Cuellar-García et al, EHA 2017 oral presentation
Outcome according to type of therapy in mutated CLL without
poor cytogenetics
n=21 FCR/BR Median 42 (24-60)
n=53 Others Median 57 (44-69)
P=0.697
TFS OS
n=21 FCR/BR Median 176 (166-185)
Months Months
P=0.468
n=53 Others Median 186(142-217)
Patients treated with small molecules and allogeneic SCT were excluded from this analysis
Cuellar-García et al, EHA 2017 oral presentation
Phase 2 Study of Ibrutinib, FC, and
Obinutuzumab (iFCG) for Previously Untreated
Patients With CLL With Mutated IGVH and Non-
Del(17p)
Jain et al EHA 2017 oral presentation
Jain et al EHA 2017 oral presentation
Phase 2 Study of Ibrutinib, FC, and
Obinutuzumab (iFCG) for Previously Untreated
Patients With CLL With Mutated IGVH and Non-
Del(17p)
Phase 2 Study of Ibrutinib, FC, and
Obinutuzumab (iFCG) for Previously Untreated
Patients With CLL With Mutated IGVH and Non-
Del(17p)
iFCG induces high rate of MRD- remission in BM (83% after 3
cycles)
All patients (n=9) who reached the 1-year time point were BM
MRD- and have discontinued ibrutinib per study design
Common AEs during iFCG therapy were neutropenia and
thrombocytopenia
Jain et al EHA 2017 oral presentation
Cramer et al EHA 2017 oral presentation
Phase 2 CLL2-Bag Trial of Sequential
Bendamustine (B), Obinutuzumab (G),
and Venetoclax (A) in CLL
Phase 2 CLL2-Bag Trial of Sequential
Bendamustine (B), Obinutuzumab (G),
and Venetoclax (A) in CLL
Cramer et al EHA 2017 oral presentation
Phase 2 CLL2-Bag Trial of Sequential
Bendamustine (B), Obinutuzumab (G),
and Venetoclax (A) in CLL
Cramer et al EHA 2017 oral presentation
Phase 2 CLL2-Bag Trial of Sequential
Bendamustine (B), Obinutuzumab (G),
and Venetoclax (A) in CLL
Cramer et al EHA 2017 oral presentation
Authors’ conclusions
Cramer et al EHA 2017 oral presentation
Novel drugs
Abstract First author Title
S772 Nastoupil Phase 1 Study of Ublituximab, TGR-1202, and
Ibrutinib in R/R CLL and NHL
S773 Hamlin Phase 2 Study of Cerdulatinib in R/R B Cell
Malignancies
Phase 1 Study of Ublituximab, TGR-
1202, and Ibrutinib in R/R CLL and NHL
Nastoupil et al, EHA 2017 Poster presentation
Phase 1 Study of Ublituximab, TGR-
1202, and Ibrutinib in R/R CLL and NHL
Nastoupil et al, EHA 2017 Poster presentation
Phase 2 Study of Cerdulatinib in
R/R B Cell Malignancies:
3 patients at 35 mg BID dose had SAEs
– 2 grade 5 infections, 1 grade 3 pancreatitis
• Starting dose reduced to 30 mg BID and a PK
monitoring and dose reduction strategy was
implemented
Hamlin et al, EHA 2017 Poster presentation
Terminated Phase 2 Study of
Idelalisib and Rituximab in TN CLL
With Del(17p)
Hillmen et al, EHA 2017 oral presentation
Terminated Phase 2 Study of
Idelalisib and Rituximab in TN CLL
With Del(17p)
Hillmen et al, EHA 2017 oral presentation
Terminated Phase 2 Study of
Idelalisib and Rituximab in TN CLL
With Del(17p)
Hillmen et al, EHA 2017 oral presentation
Terminated Phase 2 Study of
Idelalisib and Rituximab in TN CLL
With Del(17p)
Hillmen et al, EHA 2017 oral presentation
• In front-line CLL, IDELA plus rituximab treatment resulted in a similar pattern of AEs to that seen in relapsed CLL studies with similar duration of therapy
– However, the frequency of Grade ≥3 ALT/AST was increased compared to the relapsed setting
• There was no significant effect of age on the risk of either ALT/AST elevations or diarrhoea/colitis
• There was a trend toward higher risk of Grade ≥3 ALT/AST elevation in patients with IGHV mutation
• The occurrence of CMV and PJP infections is consistent with current IDELA labelling and speaks to the potential benefit of risk mitigation through PJP prophylaxis and CMV monitoring during treatment
Authors’ conclusions
Hillmen et al, EHA 2017 oral presentation
THE END
THANK YOU FOR THE ATTENTION