CLL - Imedex
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Transcript CLL - Imedex
Hematology Highlights 2013
Expert Reviews of the
Annual Hematology Meeting
Chronic Lymphocytic Leukemia
(CLL)
Kanti R. Rai, MD
NSLIJ-Hofstra School of Medicine
Long Island Jewish Medical Center
New Hyde Park, NY
Agenda in CLL
• Chemo-immunotherapy
• Novel agents
• Who should be referred for
allogeneic SCT?
Disclosures
Member Medical Advisory Board –
Genentech, Teva, Celgene, GSK, Sanofi
Evolution of FCR in CLL
Keating et al introduced FCR and its
dramatic results in front line CLL
Byrd et al (CALGB) introduced - FR.
FCR - Keating et al JCO 2005;23:4079-4088,
Blood 2008;112:975-980
FR - Byrd et al Blood 2003;101:6-14
FCR – Keating et al, Tam et al
Single center Phase II Trial.
N = 300
Median Age – 57 years
Over 70 year of age were 14%.
ORR 95% , CR 72 %.
MRD Negative CR – 78%
At 6 years OS 77% , FFS 51 %
6 year survival : MRD Negative vs Positive :
84% vs 65%.
FCR-300 Survival and Time to Fail
OS
1.0
0.8
Proportion
0.6
0.4
Pts.
300
300
0.2
Event
106 Survival
170 Time to Fail
0.0
0
1
2
3
4
5
6
7
8
9
10
11
12
Years
Slide courtesy Dr Michael Keating
FCR vs FC (CLL8 Trial)
Hallek et al Lancet 2010;376:1164
Phase III International Randomized study
N=817
Median Age = 61 years
Median follow up 3.5 years
FCR Arm
FC Arm
• ORR/CR - 90/44*
• ORR/CR - 80/22 #
• OS 84 %
• OS 79 % # #
* cf Keating CRs 72%
# P<0.001
## P = 0.01
FCR vs FC Phase III Trial GCLLSG
Overall Survival
At 3 years, 87 % of
patients in the
FCR group
were alive vs.
83% in
the FC group
(HR- 0·67
[95% CI 0·48–0·92],
p<0·01)
Hallek et al Lancet 2010
Bendamustine with Rituximab (BR)
by GCLLSG
Fischer et al : Multicenter Phase II (JCO 2012)
N=117
Median age 64 years
OR/CR – 88/23.1 %
CLL 10 trial comparing FCR and BR is closed
now.
FCR vs BR – an overview
Author
Number of
patients
CR
OR
Hallek et al
817
44/22 (FCR/FC)
90/80 (FCR/FC)
Keating et al
Tam et al
300
72
95
Byrd et al (FR)
104
47/28
(FCRconcurrent/
FCR Sequential)
90/77
23
88
Fischer et al (BR) 117
FCR vs BR – an overview
FCR
(German)
BR
(German)
FCR
(MDACC)
Anemia
22 (5%)
23(19.7%)
-
Thrombocytopenia
30 (7%)
26(22.2%)
5(2.2%)
Infections
103 (25%)
9(7%)
2.6% of
courses
Age >65 (n/CR%)
(54/43)
(26/3)
(30/47)
Other variants of FCR
FCR lite - Foon et al JCO 2009, Blood
March 2012.
Sequential F-C-R - Lamanna et al JCO 2009
FCR with Alemtuzumab (CFAR) –Wierda et
al Blood 2011
FCR with mitoxantrone (R-FCM) –Bosch et
al JCO-2009
Len-Rituximab
Single agent Lenalidomide is active in elderly
patients.
Phase II study – n=59 ,RR CLL
Rituximab (375 mg/m2) weekly C1 and on day 1 of
C3-C12. Lenalidomide was started on day 9 of C1 at
10 mg daily continuously in 28 day cycles.
Rituximab was administered for 12 cycles.
ORR - 66% (12%-CR). TTF (17.4 months). Median OS
(NR) estimated survival at 36 months is 71%.
Grade 3/4 toxicity - neutropenia (73%). Grade 3/4
Infection or febrile episode (24%) Badoux et al JCO; Dec26th 2012
BCR Signaling pathway
Choi M et al Cancer J 2012;18: 404-410
BCR signaling inhibitors
Btk (Bruton tyrosine kinase) Inhibitor –
Ibrutinib and AVL-292
PI3Kδ-p110 isoform inhibitor- GS-1101
and IPI-145
Syk (spleen tyrosine kinase inhibitor) –
Fostamatinib, Portola compounds
Lyn – Kinase inhibitor –Dasatinib,
Bafetinib
Ibrutinib
Ibrutinib Promotes High Response Rate,
Durable Remissions, and Is Tolerable in
Treatment Naïve and Refractory CLL/SLL
Including Patients with High-Risk (HR) Disease:
Updated Results of 116 Patients in a Phase Ib/II
Study.
Abstract – 189, Byrd J. et al
Btk Inhibitor (Ibrutinib)
Bruton like tyrosine kinase (Btk) is a downstream
mediator of B-cell receptor (BCR) signaling and is
not expressed in T-cells or NK-cells.
Oral drug (420 mg qd), irreversible Btk inhibitor.
N=116, Relapsed refractory CLL(n=61) vs frontline
(n=31; all age >65 yrs).
ORR 67 % vs 71%, well tolerated.
22 months PFS – 76% and 96%.
Combination trials with Ofatumumab, FCR or BR
are ongoing.
Byrd J et al ASH 2012
Btk Inhibitor (Ibrutinib) with Rituximab
Ibrutinib 420 mg PO daily, in combination with
weekly rituximab (375 mg/m2) for weeks 1-4 (cycle
1), then daily ibrutinib plus monthly rituximab until
cycle 6, followed by daily single-agent ibrutinib.
17/20 pts – ORR 85% in high risk patients
Shorter
redistribution
Lymphocytosis
due to
Rituximab
Burger JA et al ASH 2012
Idelalisib (GS-1101)
PI3K p110 δ isoform inhibitor.
Oral drug (150 mg po bid).
N=54, relapsed refractory CLL.
ORR 33% (all PR) and LN response in 100% cases.
Pneumonia and colitis 24%
Significant effect on lymphocyte trafficking and
redistribution.
Combination trials with lenalidomide, Rituximab
and Bendamustine are ongoing.
Furman RR et al ASCO 2012
Idelalisib Combined With Ofatumumab Substantially
Increased Overall Response Rate
GS-1101 Mono
GS-1101 + O
(N=55)
100
Responsea
Rate
+95% CI
80
85%
n=17
84%
n=46
60
80%
n=16
94%
n=15
40
20
24%
n=13
CR 10%
CR 6%
LNR
OR
OR
(N=20c)
(N=20)
0
Lymph Node Overall
Responsea Responseb
(LNR)
(OR)
6 cyclesd
(N=16)
Decrease by 50% in the nodal SPD
Response as assessed by investigators based on IWCLL criteria (Hallek 2008)
C 1 Subject without follow-up assessment was excluded from analysis
d Subjects having received 6 cycles of therapy
a
b
Furman RR et al ASCO 2012
Idelalisib (GS-1101) with BR
Combinations of PI3Kδ inhibitor GS–1101 with
Rituximab (R) and/or Bendamustine (B) Are
Tolerable and Highly Active in Patients with RR
CLL: Results From a Phase I Study
Abstract – 191, Coutre SE et al
Idelalisib (GS-1101) with BR
GS-1101 with R or with B or with both BR.
GS-1101 dose of 150 mg/dose BID orally.
ORR for the GS-1101/R, GS-1101/B, and
GS-1101/BR regimens were 78%, 82% and 87%.
With a minimum follow-up of 40 weeks, 1-year PFS
rates were 74%, 88% and 87% in the GS-1101/R,
GS-1101/B, and GS-1101/BR respectively.
Adverse effects were common with GS-1101/B arm.
Abstract – 191, Coutre SE et al
# Indications of allo SCT in CLL
Young and physically fit patients with
Richter’s transformation
Refractory patients with del17p or TP53
mutations
Relapsed patients with fludarabine
refractory disease
Ultra High risk patients with CLL
#These indications may change after the approval of BCR inhibitors for the therapy of CLL
CLL Collaborations
CLL Research Consortium (CRC)
NCI- Working Group on CLL
International Workshop on CLL (iwCLL)
German CLL Study Group
CLL Global Research Foundation
Alliance for Clinical Trials in Oncology (CALGB)