gdc-0973 and Histiocytosis--Sinus

Rosai-Dorfman disease (RDD) is a rare histiocytic neoplasm with recent studies showing alterations in the MAPK pathway, most commonly in the KRAS and MEK genes in about 40% of patients. Reports on the use of MEK-inhibitor therapy in RDD have been limited to small case studies. There are no approved treatments for this neoplasm, and therefore patients with RDD need efficacious treatments.. To study the outcomes after treatment with cobimetinib based on MAPK pathway alterations in patients with RDD.. This retrospective cohort study conducted at 2 tertiary care centers included patients with RDD who underwent treatment with cobimetinib between January 1, 2013, and December 1, 2021. Cobimetinib was administered at a dosage of 20 to 60 mg orally once daily as a single agent for 21 days in a 28-day cycle. Pathology was centrally reviewed. Response assessment was centrally conducted and was based on the established positron emission radiography response criteria used for clinical trials of targeted therapies in histiocytosis.. Main outcomes were overall response rate (ORR), progression-free survival (PFS), adverse events (AEs) of cobimetinib in the entire cohort, and ORRs and PFS based on MAPK pathway alterations in patients with RDD.. A total of 16 patients (median [range] age at cobimetinib initiation, 57 [31-74] years; 11 [69%] women) were included in the study. The median follow-up duration was 19.0 months (95% CI, 8.4-27.8 months). The ORR was 63% (n = 10), including 5 complete responses and 5 partial responses. Somatic alterations in the KRAS or MEK genes were detected in 8 (50%) patients. Patients with KRAS or MEK alterations had significantly higher ORR (88% vs 38%; P = .03), deeper responses (complete responses among responders: 71% vs 0%; P = .002), and better PFS (at 1 year, 100% vs 29% were free from progression or death, respectively; P < .001) compared with those without such alterations. Grade 2 or higher AEs occurred in 12 (75%) patients, and 9 (56%) required dose reduction or temporary/permanent treatment discontinuation due to AEs.. In this cohort study, treatment with cobimetinib was associated with positive outcomes in KRAS- or MEK-variant RDD. However, AEs requiring dose modifications were common.

Topics: Adult; Aged; Cohort Studies; Female; Histiocytosis, Sinus; Humans; Male; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Neoplasms; Proto-Oncogene Proteins p21(ras); Retrospective Studies

Destombes-Rosai-Dorfman disease (RDD) is a rare multisystemic histiocytosis. Pulmonary involvement during RDD has been poorly described. The goal of this study was to examine the clinical presentations, radiological features, and outcomes of 15 patients with RDD and lung involvement.. The cases of RDD with lung involvement were extracted from the French National Histiocytosis registry. Efficacy of the MEK inhibitor cobimetinib in treating lung disease was evaluated with an. Fifteen patients (six women; median age, 40 years at RDD diagnosis) were included. All patients had evidence of systemic disease with extrapulmonary localizations of the disease (lymphadenopathy [n = 12], skin [n = 9], bones [n = 6], retroperitoneal involvement [n = 3], sinuses [n = 3], parotid gland [n = 2], submandibular gland [n = 1], and breast [n = 1]). Presenting symptoms were dominated by dyspnea and dry cough in seven patients. Restrictive physiology was observed in two of five patients. BAL showed lymphocytosis in one of five cases. Eight patients received corticosteroids, all but one with variable immunosuppressive or immunomodulatory therapies. Two patients received cobimetinib for severe lung disease, with dramatic pulmonary metabolic and tumoral responses. Two patients died during follow-up: one of hemoptysis, and the other of an unrelated cerebral tumor.. Pulmonary involvement in RDD is rare, proteiform, and sometimes severe. The MEK inhibitor cobimetinib can lead to dramatic responses.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Azetidines; Bronchoalveolar Lavage Fluid; Cough; Dyspnea; Female; Fluorodeoxyglucose F18; France; Histiocytosis, Sinus; Humans; Immunosuppressive Agents; Lung; Lung Diseases; Lymphocytosis; Male; Middle Aged; Piperidines; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Radiopharmaceuticals; Registries; Retrospective Studies; Young Adult

Rosai- Dorfman disease (RDD) is a rare systemic pseudo-lymphomatous disorder with unknown etiology. No guidelines exist regarding its management and treatment when the disease is progressing. Choroidal involvement in RDD has rarely been reported and has often been misdiagnosed. We describe a case of a 64-year-old male diagnosed with RDD by means of choroidal biopsy, successfully treated with a MEK inhibitor, namely Cobimetinib, and its follow-up over 5 years, with good final anatomical and functional results. This is the first reported case of RDD diagnosed with an intraocular biopsy performed on a non-enucleated globe, thus preserving the integrity and function of the eye. This case emphasizes the need for a choroidal biopsy when the diagnosis is not straightforward and the starting of targeted therapy to retain a good visual function.

Topics: Azetidines; Biopsy; Histiocytosis, Sinus; Humans; Male; Middle Aged; Piperidines