Abstract

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (FL) represent indolent malignancies characterized by multiple episodes of relapse. Therapy has centered on agents that largely target the B-cell receptor pathway. Duvelisib is a second-generation oral inhibitor of phosphoinositide-3 kinase, downstream of the B-cell receptor pathway, approved in the United States for relapsed CLL/SLL and FL. Duvelisib represents a highly active agent, and ongoing investigations, including fixed-duration drug combinations and alternative dosing schedules, are aimed at reducing immune-mediated toxicities.

REFERENCES

REFERENCES
1.
Fruman
DA
,
Chiu
H
,
Hopkins
BD
,
Bagrodia
S
,
Cantley
LC
,
Abraham
RT
.
The PI3K pathway in human disease
.
Cell
.
2017
;
170
(
4
):
605
-
635
.
2.
Winkler
DG
,
Faia
KL
,
DiNitto
JP
, et al
.
PI3K-δ and PI3K-γ inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models
.
Chem Biol
.
2013
;
20
(
11
):
1364
-
1374
.
3.
Paul
J
,
Soujon
M
,
Wengner
AM
, et al
.
Simultaneous inhibition of PI3Kδ and PI3Kα induces ABC-DLBCL regression by blocking BCR-dependent and -independent activation of NF-κB and AKT
.
Cancer Cell
.
2017
;
31
(
1
):
64
-
78
.
4.
Balakrishnan
K
,
Peluso
M
,
Fu
M
, et al
.
The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (Duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL
.
Leukemia
.
2015
;
29
(
9
):
1811
-
1822
.
5.
Dong
S
,
Guinn
D
,
Dubovsky
JA
, et al
.
IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells
.
Blood
.
2014
;
124
(
24
):
3583
-
3586
.
6.
Faia
K
,
White
K
,
Murphy
E
, et al
.
The phosphoinositide-3 kinase (PI3K)-δ,γ inhibitor, duvelisib shows preclinical synergy with multiple targeted therapies in hematologic malignancies
.
PLoS One
.
2018
;
13
(
8
):
e0200725
.
7.
Hoellenriegel
J
,
Meadows
SA
,
Sivina
M
, et al
.
The phosphoinositide 3′-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia
.
Blood
.
2011
;
118
(
13
):
3603
-
3612
.
8.
Ali
AY
,
Wu
X
,
Eissa
N
, et al
.
Distinct roles for phosphoinositide 3-kinases γ and δ in malignant B cell migration
.
Leukemia
.
2018
;
32
(
9
):
1958
-
1969
.
9.
O’Brien
S
,
Patel
M
,
Kahl
BS
, et al
.
Duvelisib, an oral dual PI3K-δ,γ inhibitor, shows clinical and pharmacodynamic activity in chronic lymphocytic leukemia and small lymphocytic lymphoma in a phase 1 study
.
Am J Hematol
.
2018
;
93
(
11
):
1318
-
1326
.
10.
Flinn
IW
,
Hillmen
P
,
Montillo
M
, et al
.
The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL
.
Blood
.
2018
;
132
(
23
):
2446
-
2455
.
11.
Sharman
JP
,
Coutre
SE
,
Furman
RR
, et al
.
Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia
.
J Clin Oncol
.
2019
;
37
(
16
):
1391
-
1402
.
12.
Gopal
AK
,
Schuster
SJ
,
Fowler
NH
, et al
.
Ibrutinib as treatment for patients with relapsed/refractory follicular lymphoma: results from the open-label, multicenter, phase II DAWN study
.
J Clin Oncol
.
2018
;
36
(
23
):
2405
-
2412
.
13.
Flinn
IW
,
Miller
CB
,
Ardeshna
KM
, et al
.
DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma
.
J Clin Oncol
.
2019
;
37
(
11
):
912
-
922
.
14.
Gopal
AK
,
Kahl
BS
,
de Vos
S
, et al
.
PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma
.
N Engl J Med
.
2014
;
370
(
11
):
1008
-
1018
.
15.
Dreyling
M
,
Santoro
A
,
Mollica
L
, et al
.
Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma
.
J Clin Oncol
.
2017
;
35
(
35
):
3898
-
3905
.
16.
Casulo
C
,
Sancho
J-M
,
Van Eygen
K
, et al
.
Contempo: preliminary results in first-line treatment of follicular lymphoma with the oral dual PI3K-δ,γ inhibitor, duvelisib, in combination with rituximab or obinutuzumab
.
Blood
.
2016
;
128
(
22
):
2979
.
17.
Casulo
C
,
Day
B
,
Dawson
KL
, et al
.
Disease characteristics, treatment patterns, and outcomes of follicular lymphoma in patients 40 years of age and younger: an analysis from the National Lymphocare Study
.
Ann Oncol
.
2015
;
26
(
11
):
2311
-
2317
.
18.
Gopal
AK
,
Kahl
BS
,
Flowers
CR
, et al
.
Idelalisib is effective in patients with high-risk follicular lymphoma and early relapse after initial chemoimmunotherapy
.
Blood
.
2017
;
129
(
22
):
3037
-
3039
.
19.
Chellappa
S
,
Kushekhar
K
,
Munthe
LA
, et al
.
The PI3K p110δ isoform inhibitor idelalisib preferentially inhibits human regulatory T cell function
.
J Immunol
.
2019
;
202
(
5
):
1397
-
1405
.
20.
Leonard
JP
,
Trneny
M
,
Izutsu
K
, et al;
AUGMENT Trial Investigators
.
AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma
.
J Clin Oncol
.
2019
;
37
(
14
):
1188
-
1199
.
21.
Geyer
MB
,
Rivière
I
,
Sénéchal
B
, et al
.
Autologous CD19-targeted CAR T cells in patients with residual CLL following initial purine analog-based therapy
.
Mol Ther
.
2018
;
26
(
8
):
1896
-
1905
.
22.
Burris
HA
III
,
Flinn
IW
,
Patel
MR
, et al
.
Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study
.
Lancet Oncol
.
2018
;
19
(
4
):
486
-
496
.
You do not currently have access to this content.