Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma.
Marginal zone lymphoma (MZL) is a heterogeneous B-cell malignancy for which no standard treatment exists. MZL is frequently linked to chronic infection, which may induce B-cell receptor (BCR) signaling, resulting in aberrant B-cell survival and proliferation. We conducted a multicenter, open-label, phase 2 study to evaluate the efficacy and safety of ibrutinib in previously treated MZL. Patients with histologically confirmed MZL of all subtypes who received ≥1 prior therapy with an anti-CD20 antibody-containing regimen were treated with 560 mg ibrutinib orally once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed overall response rate (ORR) by 2007 International Working Group criteria. Among 63 enrolled patients, median age was 66 years (range, 30-92). Median number of prior systemic therapies was 2 (range, 1-9), and 63% received ≥1 prior chemoimmunotherapy. In 60 evaluable patients, ORR was 48% (95% confidence interval [CI], 35-62). With median follow-up of 19.4 months, median duration of response was not reached (95% CI, 16.7 to not estimable), and median progression-free survival was 14.2 months (95% CI, 8.3 to not estimable). Grade ≥3 adverse events (AEs; >5%) included anemia, pneumonia, and fatigue. Serious AEs of any grade occurred in 44%, with grade 3-4 pneumonia being the most common (8%). Rates of discontinuation and dose reductions due to AEs were 17% and 10%, respectively. Single-agent ibrutinib induced durable responses with a favorable benefit-risk profile in patients with previously treated MZL, confirming the role of BCR signaling in this malignancy. As the only approved therapy, ibrutinib provides a treatment option without chemotherapy for MZL. This study is registered at www.clinicaltrials.gov as #NCT01980628.
Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.|Weill Department of Medicine, Weill Cornell Medical College, New York, NY.
Ariela
A
Noy
David Geffen School of Medicine at UCLA, Los Angeles, CA.
Sven
S
de Vos
Hemato-oncology Department, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris Diderot University, Sorbonne Paris-Cité, Paris, France.
Catherine
C
Thieblemont
Weill Department of Medicine, Weill Cornell Medical College, New York, NY.
Peter
P
Martin
Winship Cancer Institute of Emory University, Atlanta, GA.
Christopher R
CR
Flowers
Hematologie, Centre Hospitalier Universitaire, Université de Lille, Lille, France.
Franck
F
Morschhauser
Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.
Graham P
GP
Collins
Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
Shuo
S
Ma
Clinical Research Alliance, Center for Lymphoma and Myeloma, Weill Cornell Medical College, New York, NY.
Morton
M
Coleman
Florida Cancer Specialists, Atlantis, FL.
Shachar
S
Peles
Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA.|Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
Stephen
S
Smith
Division of Hematology and Medical Oncology, Department of Medicine, Hofstra Northwell School of Medicine, Hempstead, NY.
Jacqueline C
JC
Barrientos
Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA; and.
Alina
A
Smith
Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA; and.
Brian
B
Munneke
Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA; and.
Isaiah
I
Dimery
Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA; and.
Darrin M
DM
Beaupre
City of Hope National Medical Center, Duarte, CA.
Robert
R
Chen
D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced / Q000473:pathology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced / Q000473:pathology; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D018442:Lymphoma, B-Cell, Marginal Zone / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D011014:Pneumonia / Q000139:chemically induced / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D012008:Recurrence
D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000225:Adenine