Kanti R. Rai, MD

NSLIJ-Hofstra School of Medicine

Long Island Jewish Medical Center

New Hyde Park, NY

Kanti R. Rai, MD

NSLIJ-Hofstra School of Medicine

Long 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 CLLAgenda in CLL

DisclosuresDisclosures

Member Medical Advisory Board –

Genentech, Teva, Celgene, GSK, Sanofi

Member Medical Advisory Board –

Genentech, Teva, Celgene, GSK, Sanofi

Evolution of FCR in CLLEvolution 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

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 alFCR – 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%.

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 FailFCR-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

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

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 GCLLSGFCR vs FC Phase III Trial GCLLSG

Overall 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

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.

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 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

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%)

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 Len-Rituximab

Badoux et al JCO; Dec26th 2012

BCR Signaling pathwayBCR Signaling pathway

Choi M et al Cancer J 2012;18: 404-410

BCR signaling inhibitorsBCR 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

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.

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 alAbstract – 189, Byrd J. et al

IbrutinibIbrutinib

Btk Inhibitor (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.

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 RituximabBtk 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

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)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.

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

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

es

po

ns

ea

Ra

te+

95%

CI

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 therapy

Furman 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

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 BRIdelalisib (GS-1101) with BR

Abstract – 191, Coutre SE et alAbstract – 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.

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 BRIdelalisib (GS-1101) with BR

Abstract – 191, Coutre SE et alAbstract – 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

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# Indications of allo SCT in CLL

#These indications may change after the approval of BCR inhibitors for the therapy of CLL#These indications may change after the approval of BCR inhibitors for the therapy of CLL

CLL CollaborationsCLL CollaborationsCLL 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)

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)