Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia

Richard R. Furman et al.

R4 柯博伸 Supervisor: 劉嘉仁醫師 2014/02/24  Background . Chronic Lymphocytic Leukemia(CLL) . PI3K and B cell malignancies  Journal today . Methods . Results . Discussion  Epidemiology . Rare in East Asia . Most common adult leukemia in Western countries ▪ Incidence (United States): 6.75/100000 ♂, 3.65/100000♀ ▪ Male: female = 1.7: 1 . Median age at diagnosis: 70 year-old ▪ Younger and elderly patients: phenotypically indistinguishable, but having a signficant impact on selection of therapy

 Clonal B cell (leukemic cells) accumulation in PB, BM and lymphoid tissues.  Typical immunophenotype

Cyclin D1 -

Kokhaei et al. Ann Oncol. 2005;16(S2):ii113-i123

CLL without del(11q) or del (17p)

 ≧70y or younger with comorbidities <70y or older without significant . Obinutuzumab(O)+chlorambucil comorbidities . Rituximab(R)+chlorambucil . FCR . Bendamustine(B)+/- R . FR . Cyclophosphamide(C), . Pentostatin(P)+CR prednisolone +/- R . B+/-R . R . O+chlorambucil . Fludarabine (F)+/- rituximab . Cladribine . Chlorambucil

Type I Type II Rituximab Tositumomab Ofatumumab GA 101 CDC ++ - ADCC ++ ++ Move CD20 into lipid ++ - rafts Homotypic adhesion - ++ Induced cell death - ++ CLL with del (11q) CLL with del (17p)

 ≧70y or younger with comorbidities . Alemtuzumab +/-R . O + chlorambucil . R + chlorambucil . FCR . B +/- R . FR . C, prednisolone +/- R . HDMP + R . Reduced-FCR . O + R . R . Chlorambucil  <70y or older without significant comorbidities . FCR . B +/- R . PCR . O+chlorambucil CLL without del (17p)

 Long response . Retreat as in first-line therapy until short response CLL with del (17p)

. Alemtuzumab(A) +/- R . RCHOP . CFAR . Ibrutinib . Lenalidomide +/- R . Ofatumumab . OFAR  Phosphoinositide 3-kinase(PI3K) . In every cell type . Class I PI3K : a regulatory unit + a catalytic unit ▪ Generate lipid second messangers (PIP2 PIP3) ▪ PIP3 PLECKSTRIN-HOMOLOGY (PH domains) in numerous intracellular enzymes, such as serine/threonine kinase AKT/PKB ▪ -α: insulin signaling and angiogenesis ▪ -β: platelet function ▪ -γ: mainly in WBC, esp T cells ▪ -δ: mainly in WBC, signaling, development and survival of B cells . Class II PI3K . Class III PI3K

 CAL-101 . A potent and selective inhibitor of PI3K-δ isoform . On CLL cells ▪ Direct therapeutic effect (Apoptosis)

 Independent of IgVH mutational status or cytogenetic difference ▪ Disrupt external survival stimuli from microenvironment

Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals BLOOD, 23 SEPTEMBER 2010 VOLUME 116, NUMBER 12  CAL-101

. Block constitutive PI3K signaling ▪ ↓ phosphorylation of AKT and other downstream effectors ▪ ↑caspase cleavage ▪ Induction of apoptosis

CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability BLOOD, 13 JANUARY 2011 VOLUME 117, NUMBER 2 Eligibility (n = 52) Relapsed/refractory CLL requiring treat by 2008 International Workshop on CLL criteria

R, 375 mg/m2 weekly x 8

Idelalisib, 100 or 150 mg BID, 48 weeks continuously

B, 70 or 90 mg/m2 D1 + D2, C1-6 Extension Study Idelalisib, 100 or 150 mg BID, 48 weeks continuously Idelalisib, 150 mg BID, continuously

B, 70 mg/m2 D1 + D2, C1-6 Patients with R, 375 mg/m2 C1-6 continued benefit

Idelalisib, 150 mg BID, 48 weeks continuously

Coutre SE et al. Proc ASH 2012;Abstract 191. Combination Idelalisib + R Idelalisib + B Idelalisib + BR All (N = 19) (N = 18) (N = 15) (N = 52)

Age, median (range), years 66 (54-87) 64 (41-86) 61 (45-72) 64 (41-87)

Gender, males, % 68 44 60 58

Bulky adenopathy,a % 58 61 67 62

Refractory disease,b % 37 72 47 52

Prior therapies, median (range), n 2 (1-8) 3 (1-9) 4 (1-9) 3 (1-9) a Presence of ≥1 node with diameter ≥5 cm b Progression within 6 months of last therapy

Coutre SE et al. Proc ASH 2012;Abstract 191. Idelalisib +R +B +BR

(N=19) (N=18) (N=15)

95% CI 95%

± Response Rate Rate Response

Lymph Node Overall LNR OR LNR OR Response Response (LNR)a (OR)b a Decrease by ≥50% in the nodal SPD b Response by 2008 IWCLL criteria

Coutre SE et al. Proc ASH 2012;Abstract 191. Primary study Primary + Extension study Idelalisib Idelalisib +R/+B/+BR +R/+B/+BR

(N = 52) (N = 52)

free Survival free

- % Progression % Months Progression % Months Median PFS: not reached Median PFS: not reached 1-year PFS: 67.1% 1-year PFS: 68.7%; 2-year PFS: 63.4%

Coutre SE et al. Proc ASH 2012;Abstract 191. Primary + Extension study Idelalisib +R/+B/+BR

(N = 52) % Survival %

Months Median OS: not reached 1-year OS: 87.5%; 2-year OS: 84.0%

Coutre SE et al. Proc ASH 2012;Abstract 191. Grade ≥3 AEs* (n = 52) Febrile neutropenia 15% Pneumonia 12% Transaminase elevation 10% Diarrhea 6% Dyspnea 4% Pyrexia 6%

*Analysis of primary study

• AEs leading to drug discontinuation: abdominal pain (n = 1), autoimmune hemolytic anemia (n = 1), febrile neutropenia (n = 1), neutropenia (n = 1), pneumonia (n = 1), pneumonitis (n = 1), rash erythematous (n = 1), sepsis (n = 1)

Coutre SE et al. Proc ASH 2012;Abstract 191. January 22, 2014 R R* 8cycles + Placebo Treated CLL in PD A ≦ N ( 24 months after last tx) PD D Not able to receive O cytotoxic agents M R* 8cycles + I • Tx-related myelotoxicity I • eGFR< 60 ml/min Z PD • CIRS>6 (not CLL related) E N=220 1:1 R* 8cycles + Double-I

• Idelalisib(I):150mg BID • Rituxmab(R): 375/m2*1, 500mg/m2 Q2W*4, 500mg/m2 Q4W*3 ASSESSMENTS

 Clinical visit + lab test  Lymphocytosis was . Q2W for 12 weeks exclude for PD while . Q4W for 12 weeks receiving B-cell receptor . Q6W for 24 weeks inhibitor . Then Q12W-  Determine RR and PD  Serial computed . by who are unaware of study tomography design . Q8w for 6 months . Then Q12W- 78% ≧ 65 y/o

35% poor marrow function

40% CCR< 60ml/min

>80% unmutated IGHV 40 % 17p- or TP53 mutation

85% CIRS>6

93%

Median PFS Not been reached 46% 5.5 months

HR (for PD or death) =0.15; 95% [CI] = 0.08-0.28; p<0.001

92%

Median OS Not been reached 80% Not been reached

HR(for death)= 0.28; 95% [CI] = 0.09-0.86; p=0.02  81% in R+I group vs. 13 % in Placebo+I group . Odds ratio: 20.02; p<0.001 . All were partial response 93% vs. 4%, Odds ratio 264, p<0.001

 Idelalisib + R vs. Ibrutinib . Basic characteristics were similar  Including previous treatment . PFS seemed not better . But overcome 17p deletion

Ibrutinib phase 1b-2 trail In relapsed/refractory CLL N=85

Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia NEJM 369;1 july 4, 2013  Adverse effects should be monitored for a longer time, esp. for some late-onset event such as diarrhea, immune suppression…  For relapsed/refractory CLL patients . Idelalisib and rituximab combination  Idelalisib +/- other chemo-immunotherapy combination is worth of expectation  Growing lists of agents with activity . Ibrutinib . Obinutuzumab(GA-101) . ABT-199 . CART19… Thanks for your attention!!!