PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma.
BACKGROUND
Phosphatidylinositol-3-kinase delta (PI3Kδ) mediates B-cell receptor signaling and microenvironmental support signals that promote the growth and survival of malignant B lymphocytes. In a phase 1 study, idelalisib, an orally active selective PI3Kδ inhibitor, showed antitumor activity in patients with previously treated indolent non-Hodgkin's lymphomas.


METHODS
In this single-group, open-label, phase 2 study, 125 patients with indolent non-Hodgkin's lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered idelalisib, 150 mg twice daily, until the disease progressed or the patient withdrew from the study. The primary end point was the overall rate of response; secondary end points included the duration of response, progression-free survival, and safety.


RESULTS
The median age of the patients was 64 years (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). Subtypes of indolent non-Hodgkin's lymphoma included follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenström's macroglobulinemia (10). The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin's lymphoma, though the numbers were small for some categories. The most common adverse events of grade 3 or higher were neutropenia (in 27% of the patients), elevations in aminotransferase levels (in 13%), diarrhea (in 13%), and pneumonia (in 7%).


CONCLUSIONS
In this single-group study, idelalisib showed antitumor activity with an acceptable safety profile in patients with indolent non-Hodgkin's lymphoma who had received extensive prior treatment. (Funded by Gilead Sciences and others; ClinicalTrials.gov number, NCT01282424.).
The authors' affiliations are listed in the Appendix.
Ajay K
AK
Gopal
Brad S
BS
Kahl
Sven
S
de Vos
Nina D
ND
Wagner-Johnston
Stephen J
SJ
Schuster
Wojciech J
WJ
Jurczak
Ian W
IW
Flinn
Christopher R
CR
Flowers
Peter
P
Martin
Andreas
A
Viardot
Kristie A
KA
Blum
Andre H
AH
Goy
Andrew J
AJ
Davies
Pier Luigi
PL
Zinzani
Martin
M
Dreyling
Dave
D
Johnson
Langdon L
LL
Miller
Leanne
L
Holes
Daniel
D
Li
Roger D
RD
Dansey
Wayne R
WR
Godfrey
Gilles A
GA
Salles
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008198:Lymph Nodes / Q000473:pathology; D018655:Lymphocyte Count; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines / Q000009:adverse effects / Q000627:therapeutic use*; D052999:Quinazolinones / Q000009:adverse effects / Q000627:therapeutic use*; D012008:Recurrence
D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; C552946:idelalisib