ALBERT

Description: Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder. The anti–interleukin 6 (IL-6) therapy siltuximab is not available everywhere, and is not effective for over one-half of patients. Alternative treatment approaches are urgently needed. In the first iMCD clinical trial directed against a target other than IL-6 signaling, we investigated a thalidomide-cyclophosphamide-prednisone (TCP) regimen in newly diagnosed iMCD patients. This single-center, single-arm, phase 2 study enrolled 25 newly diagnosed iMCD patients between June 2015 and June 2018. The TCP regimen (thalidomide 100 mg daily for 2 years; oral cyclophosphamide 300 mg/m2 weekly for 1 year; prednisone 1 mg/kg twice a week for 1 year) was administered for 2 years or until treatment failure. The primary end point was durable tumor and symptomatic response for at least 24 weeks. Twelve patients (48%) achieved the primary end point with no relapse, 3 patients (12%) demonstrated stable disease, and 10 patients (40%) were evaluated as treatment failure. Even when considering all patients, there were significant (P 〈 .05) improvements in median symptom score, IL-6 level, hemoglobin, erythrocyte sedimentation rate, albumin, and immunoglobulin G. Among responders, the median levels of all evaluated parameters significantly improved, to the normal range, after treatment. The regimen was well tolerated. One patient died of pulmonary infection and 1 patient had a grade 3 adverse event (rash); 2 patients died following disease progression. Estimated 1-year progression-free survival and overall survival were 60% and 88%, respectively. The TCP regimen is an effective and safe treatment of newly diagnosed iMCD patients, particularly when siltuximab is unavailable. This trial was registered at www.clinicaltrials.gov as #NCT03043105.

Description: Objectives: Erdheim-Chester disease (ECD) is a rare multi-systemic form of histiocytosis. Treatment with BRAF inhibitors has markedly improved outcomes for patients with ECD; however, the estimated annual cost of BRAF inhibitors is approximately $50,000 in China. Interferon-α (IFN-α)has been used with variable efficacy as a treatment for ECD. The estimated annual cost of IFN-α is approximately $1600 in China. The aim of the current study was to describe the long-term treatment outcomes and efficacy of FDG-PET for evaluating therapeutic responses among a cohort of ECD patients who were treated with IFN-α. Methods: We retrospectively evaluated newly diagnosed ECD patients who received 600 MIU or 900 MIU of IFN-α, three times/week subcutaneous for at least 1 month at Peking Union Medical College Hospitalbetween January 2010 and May 2018. All patients were followed up every 3-6 months. We defined the most active lesion measured by standardized uptake value (SUV) on FDG-PET before treatment as target lesions. We used the ratios between most active target lesion SUV and liver SUV (SUVmax/SUVliver) for follow-up, to eliminate heterogeneity. Results: A total of 32 patients (16 male and 16 female) met the inclusion criteria. Four of them were diagnosed with mixed ECD and Langerhans cell histiocytosis. The median age at diagnosis was 48 years (range, 6-66 years). The median number of involved organs was four (range 1-8). The main sites of involvement were the bones (93.8%), retroperitoneum (40.6%), lungs (37.5%), vasculature (37.5%), central nervous system (CNS, 34.4%), pericardium (28.1%), pleura (21.9%), skin (18.8%), pituitarium (15.6%), heart (12.5%), retro-orbital involvement (12.5%), nerve root (9.4%), muscles (6.3%), thymus (6.3%), thyroid (3.1%) and breasts (3.1%). Two patients did not have an adequate amount of tissue available for genomic testing. BRAFV600Emutations were detected among 21/30 patients (70.0%). The most active target lesions at baseline detected by FDG-PET were bone (58.3%), followed by CNS (15.0%), pleura (5.0%), nerve root (5.0%) and muscle (5.0%). In all, 26 patients (81.3%) received IFN-α as the first-line treatment. Four patients (12.5%) received IFN-α after cytarabine based chemotherapy as maintenance therapy. Two patients (6.2%) received IFN-α as second-line therapy. The median duration of IFN-α therapy was 18.5 months (range, 1-51 months). One patient stopped IFN-α treatment because of intolerable adverse effects after 8 months. The overall clinical response rates were 80.0%, including 33.3% complete response, 36.7% partial response, and 10.0% stable disease. Thirty-one patients underwent a total of 81 scans by PET. A total of 17 patients underwent at least one follow-up FDG-PET scan, median of 4 (2-6). The SUVmax / SUVliver changed during treatment (Figure 1). At the last follow-up, nine (52.9%) of these patients had experienced a partial metabolic response. The median reduction in SUVmax / SUVliverfrom baseline to last PET/CT scan was 61.4% (range, 8.8%-86.6%). Thirteen (76.5%) patients experienced continuous clinical improvement during follow-up. Eight of 13 (61.5%) patients recorded at least one SUVmax / SUVliverincrease during follow-up: the median increase in this ratio was 32.0% (range, 2.6%-45.4%), which decreased in subsequent scans without changing the treatment (Figure 2). The estimated 3-year progression-free survival (PFS) and overall survival (OS) were 64.1% and 84.5%, respectively. The univariate analyses of survival showed that a significantly higher PFS was attained in patients without CNS involvement compared to those with CNS involvement (not reached vs 24 m, p=0.018).Patientswithout CNS involvement also had a significantly higher OS than those with CNS involvement (p=0.023). BRAF status was not an independent prognostic factor for PFS or OS. Conclusion: High-dose IFN-α treatment is a cost-effective option, especially for patients without CNS involvement. Single target lesion SUV elevation according to FDG-PET do not accurately demonstrate disease progression, but serial FDG-PET imaging effectively discriminate treatment response. Disclosures No relevant conflicts of interest to declare.

Description: Objectives Erdheim-Chester disease (ECD) is a rare form of histiocytosis with a broad, non-specific clinical spectrum. Here, we retrospectively evaluated the clinical and pathologic characteristics, presence of the BRAF V600E mutation, treatment options and outcomes of Chinese patients diagnosed with ECD at our center. Methods Patients diagnosed with ECD between January 2010 and April 2015 at Peking Union Medical College Hospital were included for study. We evaluated baseline characteristics, reviewed histological material, and tested for the presence of the BRAF V600E mutation using immunohistochemistry and polymerase chain reaction (PCR). Results Sixteen patients were diagnosed with ECD. Median age at diagnosis was 47 years (range, 22-61 years). Median disease duration (from the first symptom to diagnosis) was 22.5 months (range, 3-100 months). The main sites of involvement included bone (93.8%), cardiovascular region (43.8%), skin (31.3%), central nervous system (25.0%), and ¡°hairy kidney¡± (25%). Thirteen patients displayed characteristic histological features, including foamy histiocyte infiltration of polymorphic granuloma and fibrosis or xanthogranulomatosis, with CD68-positive and CD1-¦Á- negative immunostaining. Three patients (designated 3, 5 and 10) displayed CD68-positive and CD1¦Á- negative histiocyte infiltration, but not the above histological characteristics, and were thus initially misdiagnosed as Rosai-Dorfman disease. All three cases were BRAFV600E mutation-positive, leading to revision of diagnosis as ECD. Diagnosis of ECD in each case was additionally supported by typical radiographic findings. The BRAF V600E mutation was detected in 68.8% patients using PCR and 50.0% patients with immunohistochemistry. Ten patients (62.5%) received IFN-¦Á as first-line treatment, 3 patients showed improvement, 3 remained stable, 3 were too early for evaluation and 1 died. Three patients (5, 10 and 11) underwent transsphenoidal pituitary lesion surgery but were not subjected to systemic treatment, owing to the absence of symptoms and disease activity post-surgery and remained stable after a median of 16 months (range, 6-30 months) from diagnosis. Thirteen patients (81.3%) were still alive at median follow-up of 14.5 months. Conclusion ECD remains a largely overlooked disease, and increased recognition by clinicians and pathologists is necessary for effective diagnosis and treatment. The presence of the BRAF V600E mutation may facilitate discrimination of ECD from other non-Langerhans cell histiocytoses. Table 1. Characteristics and treatment of 16 patients with ECD Patient Sex/ age, years Disease duration, mo Main sites of involvement BRAF IH BRAF V600E Therapy Vital Status OS£¬mo 1 M/33 5 B N/A - IFN-6 MIU 3/wk Alive 15 2 M/22 43 S, B - - IFN-3 MIU 3/wk Alive 11 3 M/25 18 B, LN, CNS - + Pred Dead 13 4 F/28 3 S, B + + None Alive 16 5 M/60 27 B, PIT + + Surgery Alive 15 6 F/61 5 B, H, LV, R£¬CNS, MS, S N/A + IFN-6 MIU 3/wk Dead 25 7 F/23 67 S, B, H, LV - - IFN-3 MIU 3/wk Alive 19 8 M/60 43 B, P, LV, R N/A + IFN-6 MIU 3/wk Alive 14 9 M/46 84 CNS, B + + IFN-6 MIU 3/wk Alive 22 10 F/51 7 PIT + + Surgery Alive 6 11 F/36 72 PIT, B + + Surgery Alive 30 12 M/55 100 B, S, CNS, PIT - + IFN-6 MIU 3/wk Alive 3 13 F/50 11 B, H N/A + IFN-6 MIU 3/wk Alive 5 14 F/46 8 B, LV, P + + IFN-6 MIU 3/wk Alive 1 15 M/52 30 B, LV, R, P£¬E - - IFN-6 MIU 3/wk Alive 1 16 M/47 4 B, LV, R, LN - - None Dead 36 Age is at diagnosis£»disease duration is from the first symptom to diagnosis IH, immunohisochemistry; B, long bones; LN, lymph nodes; LV, large vessels; H, heart; S, skin; CNS, central nervous system; MS, maxillary sinus; PIT, pituitary gland; R, retroperitoneal; P, pericardial effusion; E, Exophthalmos; MIU, million international units; N/A, not available Disclosures No relevant conflicts of interest to declare.