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Kanti R. Rai, MDNSLIJ-Hofstra School of MedicineLong Island Jewish Medical Center
New Hyde Park, NY
Hematology Highlights 2013 Expert Reviews of the
Annual Hematology MeetingChronic Lymphocytic Leukemia
(CLL)
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• Chemo-immunotherapy• Novel agents• Who should be referred for
allogeneic SCT?
Agenda in CLL
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Disclosures
Member Medical Advisory Board –
Genentech, Teva, Celgene, GSK, Sanofi
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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;112:975-980FR - Byrd et al Blood 2003;101:6-14
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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%.
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OS
Slide courtesy Dr Michael Keating
FCR-300 Survival and Time to Fail
0 1 2 3 4 5 6 7 8 9 10 11 12
Years
0.0
0.2
0.4
0.6
0.8
1.0
Pts. Event 300 106 Survival 300 170 Time to Fail
Prop
ortio
n
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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• ORR/CR - 90/44*• OS 84 %
FC Arm• ORR/CR - 80/22 #
• OS 79 % # #* cf Keating CRs 72%# P<0.001## P = 0.01
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FCR vs FC Phase III Trial GCLLSGOverall Survival
At 3 years, 87 % of patients in the
FCR group were alive vs.
83% inthe FC group
(HR- 0·67 [95% CI 0·48–0·92],
p<0·01)
Hallek et al Lancet 2010
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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.
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Author Number of patients
CR OR
Hallek et al 817 44/22 (FCR/FC) 90/80 (FCR/FC)
Keating et alTam et al
300 72 95
Byrd et al (FR) 104 47/28 (FCRconcurrent/FCR Sequential)
90/77
Fischer et al (BR)
117 23 88
FCR vs BR – an overview
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FCR(German)
BR(German)
Anemia 22 (5%) 23(19.7%)
Thrombocytopenia 30 (7%) 26(22.2%)
Infections 103 (25%) 9(7%)
Age >65 (n/CR%) (54/43) (26/3)
FCR vs BR – an overviewFCR
(MDACC)
-
5(2.2%)
2.6% of courses
(30/47)
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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
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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%)
Len-Rituximab
Badoux et al JCO; Dec26th 2012
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BCR Signaling pathway
Choi M et al Cancer J 2012;18: 404-410
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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
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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
Ibrutinib
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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
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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
Burger JA et al ASH 2012
Shorter redistributionLymphocytosis due toRituximab
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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
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Idelalisib Combined With Ofatumumab Substantially Increased Overall Response Rate
GS-1101 Mono(N=55)
OverallResponseb
(OR)
Lymph NodeResponsea
(LNR)
LNR(N=20c)
OR(N=20)
OR 6 cyclesd
(N=16)
GS-1101 + O R
espo
nsea
Rat
e+9
5% C
I
a Decrease by 50% in the nodal SPDb Response as assessed by investigators based on IWCLL criteria (Hallek 2008)C 1 Subject without follow-up assessment was excluded from analysis
0
20
40
60
80
100
84%n=46
CR 10%
24%n=13
85%n=17 80%
n=16
94%n=15
CR 6%
d Subjects having received 6 cycles of therapyFurman RR et al ASCO 2012
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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
Idelalisib (GS-1101) with BR
Abstract – 191, Coutre SE et al
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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.
Idelalisib (GS-1101) with BR
Abstract – 191, Coutre SE et al
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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
# Indications of allo SCT in CLL
#These indications may change after the approval of BCR inhibitors for the therapy of CLL
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CLL CollaborationsCLL Research Consortium (CRC)NCI- Working Group on CLL
International Workshop on CLL (iwCLL)German CLL Study Group
CLL Global Research FoundationAlliance for Clinical Trials in Oncology (CALGB)