Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience.
B-cell receptor kinase inhibitor (KI) therapy represents a paradigm shift in chronic lymphocytic leukemia (CLL) management, but data on practice patterns after KI discontinuation and optimal sequencing are limited. We conducted a multicenter, retrospective, comprehensive analysis on 178 patients with CLL (ibrutinib = 143; idelalisib = 35) who discontinued KI therapy. We examined responses, toxicity, post-KI therapies, and overall survival (OS). Patients had a median of 3 prior therapies (range 0-11); del17p (34%), p53 mutation (27%), del11q (33%), and complex karyotype (29%). Overall response rate (ORR) to first KI was 62% (complete response 14%). The most common reasons for KI discontinuation were toxicity (51%), CLL progression (29%), and Richter transformation (RT) (8%). Median progression-free survival (PFS) and OS from KI initiation were 10.5 and 29 months, respectively. Notably, initial KI choice did not impact PFS or OS; however, RT portended significantly inferior OS (P = .0007). One hundred fourteen patients received subsequent salvage therapy following KI discontinuation with an ORR to subsequent KI at 50% and a median PFS of 11.9 months. Median PFS in KI-intolerant patients treated with an alternate KI was not reached vs 7 months for patients with CLL progression. In summary, these data demonstrate that toxicity was the most common reason for KI discontinuation, that patients who discontinue KI due to toxicity can respond to an alternate KI, and that these responses may be durable. This trial was registered at www.clinicaltrials.gov as #NCT02717611 and #NCT02742090.
Center for Chronic Lymphocytic Leukemia, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.
Anthony R
AR
Mato
University of Chicago Comprehensive Cancer Center, Chicago, IL.
Chadi
C
Nabhan
Wilmot Cancer Institute, University of Rochester, Rochester, NY.
Paul M
PM
Barr
Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
Chaitra S
CS
Ujjani
Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
Brian T
BT
Hill
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY.
Nicole
N
Lamanna
John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ.
Alan P
AP
Skarbnik
John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ.
Christina
C
Howlett
Penn State Cancer Institute, Penn State University, Hershey, PA.
Jeffrey J
JJ
Pu
University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA.
Alison R
AR
Sehgal
Center for Chronic Lymphocytic Leukemia, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.
Lauren E
LE
Strelec
Center for Chronic Lymphocytic Leukemia, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.
Alexandra
A
Vandegrift
Center for Chronic Lymphocytic Leukemia, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.
Danielle M
DM
Fitzpatrick
Wilmot Cancer Institute, University of Rochester, Rochester, NY.
Clive S
CS
Zent
John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ.
Tatyana
T
Feldman
John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ.
Andre
A
Goy
Penn State Cancer Institute, Penn State University, Hershey, PA.
David F
DF
Claxton
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY.
Spencer Henick
SH
Bachow
Tufts University Medical Center, Boston, MA; and.
Gurbakhash
G
Kaur
Center for Chronic Lymphocytic Leukemia, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.
Jakub
J
Svoboda
Center for Chronic Lymphocytic Leukemia, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.
Sunita Dwivedy
SD
Nasta
Center for Chronic Lymphocytic Leukemia, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.
David
D
Porter
Center for Chronic Lymphocytic Leukemia, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.
Daniel J
DJ
Landsburg
Center for Chronic Lymphocytic Leukemia, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.
Stephen J
SJ
Schuster
Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
Bruce D
BD
Cheson
Celgene Corporation, Summit, NJ.
Pavel
P
Kiselev
Tufts University Medical Center, Boston, MA; and.
Andrew M
AM
Evens
D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D015331:Cohort Studies; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D016016:Proportional Hazards Models; D011687:Purines / Q000008:administration & dosage* / Q000009:adverse effects; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D052999:Quinazolinones / Q000008:administration & dosage* / Q000009:adverse effects; D012189:Retrospective Studies; D016879:Salvage Therapy / Q000379:methods / Q000401:mortality; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D010880:Piperidines; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D052999:Quinazolinones; C551803:ibrutinib; D000225:Adenine; C552946:idelalisib