idelalisib and Lymphocytosis

Inhibitors of the B cell receptor (BCR) represent an attractive therapeutic option for patients with chronic lymphocytic leukemia. Recently approved inhibitors of Bruton's tyrosine kinase (ibrutinib) and phosphatidylinositol 3-kinase (idelalisib), are promising agents because they are generally well tolerated and highly effective. These agents may be particularly important in the treatment of older patients who are less able to tolerate the myelosuppression (and infections) associated with chemoimmunotherapy. As a class of medications, BCR inhibitors have some unique side effects including redistribution lymphocytosis. Ibrutinib has specific toxicities including increased risk for bleeding and atrial fibrillation. Idelalisib also has some unique toxicities consisting of transaminitis, diarrhea and pneumonitis. Ongoing clinical trials are evaluating these agents in combination with antibodies, chemotherapy and other small molecules.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Age Factors; Atrial Fibrillation; Diarrhea; Hemorrhage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Neoplasm Proteins; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Pneumonia; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell

Idelalisib is an inhibitor of the PI3Kδ isoform approved for treatment of patients with relapsed chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma. Many patients develop gastrointestinal symptoms during idelalisib therapy; however, the pathologic effects of this drug have not been characterized. We identified 50 patients who received at least 3 months of idelalisib therapy. Clinical findings and symptoms were noted for each patient, and endoscopic findings were recorded for those who underwent colonoscopic examination. Hematoxylin and eosin-stained sections from colonic biopsy samples were evaluated for histologic patterns of injury. Twenty-three (46%) patients experienced diarrhea during treatment with idelalisib, including 8 with severe symptoms (≥7 stools/d above baseline and/or requiring hospitalization). Fourteen patients underwent colonoscopic examination with mucosal biopsy. Twelve (86%) of these had colitis characterized by intraepithelial lymphocytosis, crypt cell apoptosis, and neutrophilic infiltration of crypt epithelium. Eleven patients had symptoms severe enough to warrant drug withdrawal, including 9 who were also treated with corticosteroids. Idelalisib commonly causes diarrheal symptoms in patients undergoing therapy for B-cell neoplasia, which may be severe in nearly 20% of patients. Characteristic histologic features include the combination of intraepithelial lymphocytosis and crypt cell apoptosis, often accompanied by neutrophils. Discontinuation of the drug results in symptomatic improvement and resolution of histologic changes.

Topics: Adrenal Cortex Hormones; Aged; Aged, 80 and over; Antineoplastic Agents; Apoptosis; Biomarkers; Biopsy; Class I Phosphatidylinositol 3-Kinases; Colitis; Colon; Colonoscopy; Diarrhea; Female; Humans; Immunohistochemistry; Intestinal Mucosa; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Lymphoma, Non-Hodgkin; Male; Middle Aged; Molecular Targeted Therapy; Protein Kinase Inhibitors; Purines; Quinazolinones; Recurrence; Retrospective Studies; Severity of Illness Index; Treatment Outcome