Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib.
Chronic lymphocytic leukemia (CLL) is characterized by immune dysregulation, often including hypogammaglobulinemia, which contributes to a high rate of infections and morbidity. Ibrutinib, a covalent inhibitor of Bruton tyrosine kinase (BTK), inhibits B-cell receptor signaling and is an effective, US Food and Drug Administration (FDA)-approved treatment of CLL. Inactivating germline mutations in BTK cause a severe B-cell defect and agammaglobulinemia. Therefore, we assessed the impact of ibrutinib on immunoglobulin levels, normal B cells, and infection rate in patients with CLL treated with single-agent ibrutinib on a phase 2 investigator-initiated trial. Consistent with previous reports, immunoglobulin G (IgG) levels remained stable during the first 6 months on treatment, but decreased thereafter. In contrast, there were a transient increase in IgM and a sustained increase in IgA (median increase 45% at 12 months, P < .0001). To distinguish the effects on clonal B cells from normal B cells, we measured serum free light chains (FLCs). In κ-clonal CLL cases, clonal (κ) FLCs were elevated at baseline and normalized by 6 months. Nonclonal (λ) FLCs, which were often depressed at baseline, increased, suggesting the recovery of normal B cells. Consistently, we observed normal B-cell precursors in the bone marrow and an increase in normal B-cell numbers in the peripheral blood. Patients with superior immune reconstitution, as defined by an increase in serum IgA of ≥50% from baseline to 12 months, had a significantly lower rate of infections (P = .03). These data indicate that ibrutinib allows for a clinically meaningful recovery of humoral immune function in patients with CLL. This trial was registered at www.clinicaltrials.gov as #NCT015007330.
Hematology Branch and.
Clare
0000-0001-8498-4729
C
Sun
Office of Biostatistics Research, National Heart, Lung, and Blood Institute.
Xin
X
Tian
Hematology Branch and.
Yuh Shan
YS
Lee
Experimental Medicine Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research.
Sreenivasulu
S
Gunti
Hematology Branch and.
Andrew
A
Lipsky
Hematology Branch and.
Sarah E M
SE
Herman
Laboratory of Pathology, National Cancer Institute.
Dalia
D
Salem
Laboratory of Pathology, National Cancer Institute.
Maryalice
M
Stetler-Stevenson
Laboratory of Pathology, National Cancer Institute.
Constance
C
Yuan
Laboratories of Immunoregulation, National Institute of Allergy and Infectious Diseases, and.
Lela
L
Kardava
Laboratories of Immunoregulation, National Institute of Allergy and Infectious Diseases, and.
Susan
S
Moir
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD; and.
Irina
I
Maric
Hematology Branch and.
Janet
J
Valdez
Hematology Branch and.
Susan
S
Soto
Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD.
Gerald E
GE
Marti
Hematology Branch and.
Mohammed Z
MZ
Farooqui
Experimental Medicine Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research.
Abner L
AL
Notkins
Hematology Branch and.
Adrian
A
Wiestner
Hematology Branch and.
Georg
G
Aue
D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D056724:Immunity, Humoral / Q000187:drug effects*; D007136:Immunoglobulins / Q000097:blood / Q000276:immunology; D007239:Infections / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D008297:Male; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D020127:Recovery of Function / Q000187:drug effects / Q000276:immunology; D013997:Time Factors
D007136:Immunoglobulins; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine