IgG4-related disease and B-cell malignancy due to an IKZF1 gain-of-function variant.

BACKGROUND: Monoallelic loss-of-function IKZF1 (IKAROS) variants cause B-cell deficiency or combined immunodeficiency, whereas monoallelic gain-of-function (GOF) IKZF1 variants have recently been reported to cause hypergammaglobulinemia, abnormal plasma cell differentiation, autoimmune and allergic manifestations, and infections. OBJECTIVE: We studied 7 relatives with autoimmune/inflammatory and lymphoproliferative manifestations to identify the immunologic disturbances and the genetic cause of their disease. METHODS: We analyzed biopsy results and performed whole-exome sequencing and immunologic studies. RESULTS: Disease onset occurred at a mean age of 25.2 years (range, 10-64, years). Six patients suffered from autoimmune/inflammatory diseases, 4 had confirmed IG4-related disease (IgG4-RD), and 5 developed B-cell malignancies: lymphoma in 4 and multiple myeloma in the remaining patient. Patients without immunosuppression were not particularly prone to infectious diseases. Three patients suffered from life-threatening coronavirus disease 2019 pneumonia, of whom 1 had autoantibodies neutralizing IFN-α. The recently described IKZF1 GOF p.R183H variant was found in the 5 affected relatives tested and in a 6-year-old asymptomatic girl. Immunologic analysis revealed hypergammaglobulinemia and high frequencies of certain lymphocyte subsets (exhausted B cells, effector memory CD4 T cells, effector memory CD4 T cells that have regained surface expression of CD45RA and CD28-CD57+ CD4+ and CD8+ T cells, TH2, and Tfh2 cells) attesting to immune dysregulation. Partial clinical responses to rituximab and corticosteroids were observed, and treatment with lenalidomide, which promotes IKAROS degradation, was initiated in 3 patients. CONCLUSIONS: Heterozygosity for GOF IKZF1 variants underlies autoimmunity/inflammatory diseases, IgG4-RD, and B-cell malignancies, the onset of which may occur in adulthood. Clinical and immunologic data are similar to those for patients with unexplained IgG4-RD. Patients may therefore benefit from treatments inhibiting pathways displaying IKAROS-mediated overactivity.

The Cardiovascular Event Risk Associated with Tyrosine Kinase Inhibitors and the Lipid Profile in Patients with Chronic Myeloid Leukemia.

BACKGROUND: Second- and third-generation tyrosine kinase inhibitors (TKIs) are now available to treat chronic-phase chronic myeloid leukemia (CP-CML) in the first and second line. However, vascular adverse events (VAEs) have been reported for patients with CML treated with some TKIs. METHODS: We retrospectively evaluated the cumulative incidence (CI) and cardiovascular risk for 210 patients included in the Canarian Registry of CML. RESULT: With a mean follow up of 6 years, 19/210 (9.1%) patients developed VAEs, all of whom presented at least one cardiovascular risk factor at diagnosis. The mean time to VAE presentation was 54 months from the start of TKI treatment. We found a statistically significant difference between the CI for nilotinib-naïve vs. nilotinib-treated patients (p = 0.005), between dasatinib-naïve and dasatinib-treated patients (p = 0.039), and for patients who received three lines of treatment with first-line imatinib vs. first-line imatinib (p < 0.001). From the multivariable logistic regression analyses, the Framingham risk score (FRS) and patients with three lines of TKI with first-line imatinib were the only variables with statistically significant hazard ratios for VAE development. Significant increases in HDL-C and total cholesterol may also be predictive for VAE. CONCLUSIONS: In conclusion, it is important to estimate the cardiovascular risk at the diagnosis of CML as it can help determine whether a patient is likely to develop a VAE during TKI treatment.

[Osteonecrosis of the jaw in patients with multiple myeloma during and after treatment with zoledronic acid]. / Osteonecrosis del maxilar en pacientes con mieloma múltiple durante y después del tratamiento con ácido zoledrónico.

BACKGROUND AND OBJECTIVE: To analyze the incidence, the clinical features, and the factors associated with the development of osteonecrosis of the jaw (ONJ) in patients with multiple myeloma (MM) treated with zoledronic acid. PATIENTS AND METHODS: Sixty-four patients diagnosed with MM and treated with zoledronic acid between August 1996 and March 2006 were included. Demographic data, predisposing factors, the type of antineoplastic therapy received and the infusions of biophosphonate were recorded. The main characteristics of the seven patients with ONJ, including clinical and physical examinations data, diagnostic methods and treatment established were reported. RESULTS: The overall incidence of ONJ was 7 out of 64 patients (10.93%). A recent oral surgical procedure has been associated with the ONJ (p < 0.0001). The mean of infusions of zoledronic acid before onset of osteonecrosis (standard deviation) was 30 (7.04) in contrast to 19.5 (11.8) cycles (p = 0.03) in the patients who did not present this complication. The cumulative risk increased from 6.7% after 20 treatments with zoledronic acid up to 31.7% at 36 infusions. Three patients exhibited ONJ after discounting zoledronic acid. CONCLUSIONS: The ONJ in patients with MM who underwent dental or oral surgery appears to be associated with long term exposure to zoledronic acid. The long-lasting bone effect of biophosphonate could explain the appearance of osteonecrotic lesions after discontinuing treatment with biphosphonate.