title: Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study.
abstract: Ibrutinib represents a therapeutic advance in chronic lymphocytic leukemia (CLL) but as monotherapy produces few complete remissions in previously treated patients. Anti-CD20 antibodies have improved response and progression-free survival (PFS) when combined with chemotherapy. We evaluated the safety and activity of adding ofatumumab to ibrutinib in 3 different administration sequences. Patients with CLL/small lymphocytic lymphoma (SLL), prolymphocytic leukemia, or Richter's transformation who failed ≥2 prior therapies were enrolled. Patients received ibrutinib 420 mg daily and 12 doses of ofatumumab 300/2000 mg in 3 schedules: ibrutinib lead-in (group 1; n = 27), concurrent start (group 2; n = 20), or ofatumumab lead-in (group 3; n = 24). Seventy-one patients were treated; most had high-risk disease including del(17)(p13.1) (44%) or del(11)(q22.3) (31%). The most frequent adverse events (any grade) were diarrhea (70%), infusion-related reaction (45%), and peripheral sensory neuropathy (44%). Overall response rates in CLL/SLL patients (n = 66) were 100%, 79%, and 71% in groups 1, 2, and 3, respectively. Estimated 12-month PFSs for all patients were 89%, 85%, and 75%, respectively. Four patients in group 3 progressed prior to receiving ibrutinib. This study demonstrates the tolerability and clinical activity of this combination with quicker time to best response than single-agent ibrutinib and with durable responses. This trial was registered at www.clinicaltrials.gov as #NCT01217749.
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Samantha M
authors.identifier: http://orcid.org/0000-0002-4335-2554
authors.initials: SM
authors.lastname: Jaglowski
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Jones
authors.affiliation: Department of Radiology, and.
authors.forename: Veena
authors.initials: V
authors.lastname: Nagar
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Flynn
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Andritsos
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Kami J
authors.initials: KJ
authors.lastname: Maddocks
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Woyach
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Kristie A
authors.initials: KA
authors.lastname: Blum
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Kelly
authors.initials: K
authors.lastname: Smucker
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Ruppert
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH; and.
authors.forename: Nyla A
authors.initials: NA
authors.lastname: Heerema
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH; and.
authors.forename: Gerard
authors.initials: G
authors.lastname: Lozanski
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Mona
authors.initials: M
authors.lastname: Stefanos
authors.affiliation: Pharmacyclics, Inc., Sunnyvale, CA.
authors.forename: Brian
authors.initials: B
authors.lastname: Munneke
authors.affiliation: Pharmacyclics, Inc., Sunnyvale, CA.
authors.forename: Jamie-Sue
authors.initials: JS
authors.lastname: West
authors.affiliation: Pharmacyclics, Inc., Sunnyvale, CA.
authors.forename: Jutta K
authors.initials: JK
authors.lastname: Neuenburg
authors.affiliation: Pharmacyclics, Inc., Sunnyvale, CA.
authors.forename: Danelle F
authors.initials: DF
authors.lastname: James
authors.affiliation: Department of Radiology, and.
authors.forename: Nathan
authors.initials: N
authors.lastname: Hall
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine; C527517:ofatumumab