Kanti R. Rai, MD NSLIJ-Hofstra School of Medicine Long Island Jewish Medical Center
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Transcript of Kanti R. Rai, MD NSLIJ-Hofstra School of Medicine Long Island Jewish Medical Center
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)
• Chemo-immunotherapy• Novel agents• Who should be referred for
allogeneic SCT?
Agenda in CLL
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;112:975-980FR - 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%.
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
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
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
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.
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
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)
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
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
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 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
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
Burger JA et al ASH 2012
Shorter redistributionLymphocytosis due toRituximab
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(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
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
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
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
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)