Use of rituximab for refractory cytopenias associated with autoimmune lymphoproliferative syndrome (ALPS).

BACKGROUND: ALPS is a disorder of apoptosis resulting in accumulation of autoreactive lymphocytes, leading to marked lymphadenopathy, hepatosplenomegaly, and multilineage cytopenias due to splenic sequestration and/or autoimmune destruction often presenting in childhood. We summarize our experience of rituximab use during the last 8 years in 12 patients, 9 children, and 3 adults, out of 259 individuals with ALPS, belonging to 166 families currently enrolled in studies at the National Institutes of Health. METHODS: Refractory immune thrombocytopenia (platelet count <20,000) in nine patients and autoimmune hemolytic anemia (AIHA) in three patients led to treatment with rituximab. Among them, seven patients had undergone prior surgical splenectomy; three had significant splenomegaly; and two had no palpable spleen. RESULTS: In seven out of nine patients with ALPS and thrombocytopenia, rituximab therapy led to median response duration of 21 months (range 14-36 months). In contrast, none of the three children treated with rituximab for AIHA responded. Noted toxicities included profound and prolonged hypogammaglobulinemia in three patients requiring replacement IVIG, total absence of antibody response to polysaccharide vaccines lasting up to 4 years after rituximab infusions in one patient and prolonged neutropenia in one patient. CONCLUSION: Toxicities including hypogammaglobulinemia and neutropenia constitute an additional infection risk burden, especially in asplenic individuals, and may warrant avoidance of rituximab until other immunosuppressive medication options are exhausted. Long-term follow-up of ALPS patients with cytopenias after any treatment is necessary to determine relative risks and benefits.

Virtual bronchoscopy for evaluation of malignant tumors of the thorax.

OBJECTIVE: Virtual bronchoscopy is a novel technique making use of 3-dimensional reconstruction of 2-dimensional helical computed tomographic images for noninvasive evaluation of the tracheobronchial tree. This study was undertaken to evaluate the diagnostic potential of virtual bronchoscopy by comparing virtual bronchoscopic images with fiberoptic bronchoscopic findings in patients with thoracic malignant disease. METHODS: Thirty-two consecutive patients with thoracic malignant tumors underwent virtual bronchoscopy for evaluation of suspected tracheobronchial lesions. For each virtual bronchoscopic examination, 200 to 300 contiguous 1.25-mm images of the thorax were obtained in only one or two 17-second breath holds by using a multislice computed tomographic scanner. Virtual bronchoscopy images were reconstructed and interpreted blind to the actual endoscopic findings. Results of virtual bronchoscopy were compared with fiberoptic bronchoscopic findings in 20 patients. RESULTS: Anatomic computer simulation of the bronchial tree was successfully created in all patients. In 7 (35%) of 20 patients, results of fiberoptic bronchoscopy were found to be within normal limits. In all patients with normal anatomy, virtual bronchoscopy accurately correlated with the fiberoptic findings. Thirteen (65%) patients had a total of 22 abnormal findings on fiberoptic bronchoscopy. Virtual bronchoscopy detected 18 of 22 abnormal fiberoptic bronchoscopic findings: 13 of 13 obstructive lesions, 5 of 6 endoluminal lesions, and 0 of 3 mucosal lesions. The sensitivity of virtual bronchoscopy was 100% for obstructive lesions, 83% for endoluminal lesions, 0% for mucosal lesions, and 82% for all abnormalities; the specificity of virtual bronchoscopy was 100%. CONCLUSIONS: Preliminary evaluation indicates that virtual bronchoscopy may be a promising and noninvasive modality for identifying bronchial obstructions and endoluminal lesions, as well as for assessing the tracheobronchial tree beyond stenoses. However, at present, virtual bronchoscopy does not enable the detection of subtle mucosal lesions, and as such, this modality may not be appropriate for identifying premalignant lesions in the respiratory tract. Although fiberoptic bronchoscopy remains the standard modality for evaluating airway patency and mucosal lesions, virtual bronchoscopy may provide additional information that may be useful in the management of pulmonary malignant tumors.

Fluorodeoxyglucose positron emission tomography (FDG-PET) for monitoring lymphadenopathy in the autoimmune lymphoproliferative syndrome (ALPS).

Autoimmune lymphoproliferative syndrome (ALPS) is associated with mutations that impair the activity of lymphocyte apoptosis proteins, leading to chronic lymphadenopathy, hepatosplenomegaly, autoimmunity, and an increased risk of lymphoma. We investigated the utility of fluorodeoxyglucose positron emission tomography (FDG-PET) in discriminating benign from malignant lymphadenopathy in ALPS. We report that FDG avidity of benign lymph nodes in ALPS can be high and, hence, by itself does not imply presence of lymphoma; but FDG-PET can help guide the decision for selecting which of many enlarged nodes in ALPS patients to biopsy when lymphoma is suspected.

Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome.

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of apoptosis associated most often with heritable FAS mutations leading to lymphadenopathy, hypersplenism and chronic refractory autoimmune cytopenias. Mycophenolate mofetil (MMF) was used to treat cytopenias in 13 ALPS patients aged 9 months to 17 years from a cohort of 118 children (aged < 18 years) and 82 adults. Twelve responded for a median follow-up of 49 weeks (range 38-240 weeks), defined by maintenance of adequate blood counts and reduction in dosage or cessation of other immunosuppressive agents. This preliminary experience suggests that MMF may spare steroid usage in patients with ALPS-associated cytopenias.