Citations

Introduction: The landmark VE-BASKET trial demonstrated that Erdheim-Chester disease (ECD) patients with the BRAF-V600E mutation can be effectively treated with vemurafenib 1920 mg/day. However, all patients required dose reductions due to adverse effects. The efficacy of low dose BRAF-inhibitors is not well established in ECD. Further, as Langerhans cell histiocytosis (LCH) also harbors BRAF-V600E mutations in 50-60% of patients, BRAF-inhibitors may be effective in this disease as well. In this study, we evaluated the efficacy of low dose BRAF-inhibitors (vemurafenib and dabrafenib) in the treatment of ECD and LCH. Methods: We conducted a retrospective study of ECD and LCH patients who were seen at our institution from January 1998 to July 2018. All patients had a diagnosis of ECD and LCH determined by clinical criteria in conjunction with histopathologic findings. Based on the standard doses approved for malignant melanoma and ECD, patients were categorized into the low dose BRAF-inhibitor group if they were treated with vemurafenib < 960 mg/day or dabrafenib ≤ 150mg/day at any point in time. We used a simple response criteria that defined clinical progressive disease (PD) as worsening of symptoms attributed to ECD/LCH or radiologic PD as a progression or worsening of proven or suspected lesions due to ECD/LCH. The minimum duration for symptom improvement to be considered a response was set at 3 months. Results: A total of 89 ECD patients and 186 LCH patients were identified. Within the ECD cohort, 24 of 44 (55%) patients who were tested had the BRAF-V600E mutation. Eight patients were included in the low dose BRAF-inhibitor group. The median age at diagnosis was 57 years (range 37-74) and 5 (63%) were male. The most common areas of involvement included bone (88%), cardiovascular system (63%), kidneys (63%), and brain parenchyma (50%). The median time of follow up was 66 months (range 23-165) and the median time on low-dose BRAF-inhibitor was 10 months (range 1-27) [Table 1]. Three patients had a starting dose of vemurafenib 1920 mg/day, 4 had 960 mg/day, and 1 had 480 mg/day. All patients required dose reductions and 50% of the patients ultimately discontinued vemurafenib due to side effects. Side effects included fatigue, pruritus, nausea, facial swelling, blisters, papillomas, and/or subcutaneous nodules. Four patients were able to remain on low-dose vemurafenib for a median follow up time of 24.5 months (range 12-28) with ongoing response and no signs of clinical or radiologic PD. Within the LCH cohort, 18 of 31 tested (58%) patients had the BRAF-V600E mutation. Four patients were included in the low dose BRAF-inhibitor group. The median age at diagnosis of this cohort was 43 years (range 34-69) and 2 (50%) were male. Areas of involvement included bone (100%), brain parenchyma (hypothalamus/optic stalk and pons; 50%), and skin (25%). The median time of follow up was 31 months (range 21-46) and the median time on low-dose BRAF-inhibitor was 4 months (range 3-24) [Table 2]. Two patients had a starting dose of vemurafenib 960mg/day. The patients with brain parenchymal involvement had a starting dose of dabrafenib 150mg/day or 100mg/day. All patients taking vemurafenib 960mg/day required dose reductions and one patient discontinued treatment due to skin blistering in her feet. In the patients taking dabrafenib, no side effects have yet been reported. 3 patients had an ongoing response and did not have clinical or radiologic PD. Patient #10 however, had clinical and radiologic PD after being on vemurafenib 720mg/day for 22 months. Conclusion: Our study suggests a potential role for lower doses of BRAF-inhibitors in ECD and LCH patients harboring BRAF-V600E mutations. Dabrafenib was found to be particularly efficacious and well-tolerated in LCH involving the brain parenchyma. However, patients who undergo dose reductions should be closely monitored due to the risk of disease progression. Careful balance of toxicities and efficacy is needed for optimizing patient outcomes with targeted therapies. Disclosures Bennani: Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board. OffLabel Disclosure: Vemurafenib and dabrafenib for Langerhans cell histiocytosis. Vemurafenib dosage for Erdheim-Chester disease is less than the approved dose of 960mg every 12 hours.

Abstract Background: The incidence of multiple myeloma (MM) in the US is increasing among non-Hispanic (NH) White males and females as well as NH Black males (Costa LJ, Blood Advances 2017). However, more specific incidence studies accounting for geographic and age subgroups are limited. There is also a growing concern that incidence of many cancers is increasing in the younger population. Utilizing the Surveillance, Epidemiology, and End Results Program (SEER), we investigated the trends in MM incidence in the US according to demographic and geographic subgroups with a focus on the young adults. Methods: Incidence rates (case/100,0000) were calculated using SEER*Stat and 2000-2015 data from SEER-18 registries age-adjusted to the U.S. 2000 standard population. We calculated the annual percentage change (APC) of incidence rates according to age groups and stratified by sex, race, and registry. Age at diagnosis was analyzed in 10-year intervals starting at 20 years. All analyses used ICD-O-3 codes 9732/3 with microscopically confirmed MM. Results: There were 69,613 MM patients included in the analysis. The mean age at diagnosis was 68 years and decreased over time from 68.5 years in 2000 to 67.6 years in 2015. Men comprised 55.5% of the population. Patients <50 years constituted 7.9% of the population with 6.6% between 40-49 years. The incidence significantly (all p values <0.01) increased from 2000-2015 for the entire cohort (incidence 6.9-9.5; APC 1.1) and for males (8.6-9.5; 1.1) and females (5.7-6.3; 0.8). The highest increase in incidence among the age groups (Figure) was in 40-49 years (1.9-2.7; 2.1). When analyzing the trends for age groups stratified by sex, women ages 40-49 years had the highest increase in incidence (1.6-2.6; 2.4). The APCs of SEER-18 registries stratified by age and sex are reported in the Table. The highest APCs (>3.0) were observed in the registries of Atlanta, Greater Georgia, Hawaii, and New Jersey. When the SEER-18 registries were further stratified by race, white men ages 40-49 years in Seattle and New Jersey had APCs of 5.5 and 2.9 respectively, while Black women ages 40-49 years in Greater Georgia had an APC of 3.3. Only 3 groups of individuals had a significant decline in the incidence: Asian women ≥70 years in Los Angeles (APC -6.4), White women ≥70 years in Los Angeles (APC -1.9), and men 50-59 years in San Jose (APC -1.5). Conclusions: The overall incidence of MM is increasing in the US with the highest increment among young adults between the age groups 40-49 years. We observed geographic and demographic differences in the incidence rates, which may reflect genetic and environmental influences. Interestingly, a few geo-demographic subgroups had a decline in the incidence. Further research is needed to determine the reasons behind the observed trends. Disclosures Kapoor: Celgene: Research Funding; Takeda: Research Funding.