CLL - Imedex

Report
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)

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