Long-term Outcome After Vemurafenib / BRAF Inhibitors Interruption in Erdheim-chester Disease

Study Overview
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Brief Summary
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Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis. Diagnosis of ECD is based on clinical symptoms, imaging and histology with infiltration of tissues by foamy CD68 positive CD1a negative histiocytes. Because half of the ECD patients carry a BRAFV600E mutation, we recently proposed vemurafenib, an inhibitor of mutant BRAF, as a possible targeted therapy. We have treated more than10 patients with refractory ECD with life-threatening manifestations associated with the BRAFV600E mutation and observed a short and long term efficacy. However, vemurafenib may have several side effects and long term administration of this drug has not been evaluated. In other diseases such as melanoma, duration of administration is usually shorter, due to bad prognosis of the disease and progression despite treatment. As in long-term follow-up, ECD patients with vemurafenib seem to have a stable disease, we want to evaluate the possibility of treatment interruption as this is what we do in our current practice. Other BRAF inhibitors, such as dabrafenib, have recently been proposed for treating BRAF mutated histiocytoses. Other BRAF inhibitor interruption treatment should also be prospectively evaluated.

Detailed Description
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Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis. Diagnosis of ECD is based on clinical symptoms, imaging and histology with infiltration of tissues by foamy CD68 positive+ CD1a negative histiocytes. The clinical course mainly depends on the extent and distribution of the disease, and ranges from asymptomatic bone lesions to life-threatening manifestations. The overall mortality remains high (22% of the 100 ECD patients seen at our institution in August 2013). Due to the rare nature of the disease (500 cases worldwide have been reported since 1930) no prospective therapeutic trial has been performed. Interferon alpha (IFN alpha), in its standard or pegylated forms, is the first line therapy for ECD. However, long-term IFN alpha treatment can lead to severe side effects. Moreover, some patients with CNS and/or cardiovascular infiltrations, the two lethal organ involvement, develop secondary resistance to high doses of IFN alpha. For refractory patients, anakinra, cladribine, tyrosine kinase inhibitors, or infliximab have been proposed as second line treatments. The optimal second line therapeutic strategy remains however to be defined, mostly because these treatments have been evaluated in only small numbers of patients. Because half of the ECD patients carry a BRAFV600E mutation, we recently proposed vemurafenib, an inhibitor of mutant BRAF, as a possible targeted therapy. We have treated 10 patients with refractory ECD with life-threatening manifestations associated with the BRAFV600E mutation and observed a short and long term efficacy (median follow-up 9 months). However, vemurafenib may have several side effects and long term administration of this drug has not been evaluated. In other diseases such as melanoma, duration of administration is usually shorter, due to bad prognosis of the disease and progression despite treatment. As in long-term follow-up, ECD patients with vemurafenib seem to have a stable disease, we want to evaluate the possibility of treatment interruption as this is what we do in our current practice. Other BRAF inhibitors, such as dabrafenib, have recently been proposed for treating BRAF mutated histiocytoses.

Official Title
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Long-term Outcome After Vemurafenib / BRAF Inhibitors Interruption in Erdheim-chester Disease

Conditions
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Erdheim-Chester Disease

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age superior or equal to 18 years Clinical and radiological presentation concordant with ECD Presence of histological proof of ECD Treatment with vemurafenib or other BRAF inhibitor Agreement to participate Exclusion Criteria: Pregnancy Patients who exceed the safe weight limit of the PET/CT bed (220 kg) or who cannot fit through the PET/CT bore (diameter 70 cm).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| vemurafenib/other BRAF inhibitors<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PET scan response | Modification of SUVmax between M0 and M6 will be used as the main evaluation criteria for each lesion. As assessed by PERCIST criteria, patients will be classified as complete metabolic responders (CMR; complete resolution of pathologic 18F-FDG uptake), partial metabolic responders (PMR; reduction of a minimum of 30% in activity of target lesions), stable metabolic disease (SMD; not CMR, PMR, or progressive metabolic disease (PMD; increase of a minimum of 30% in activity of target lesions or presentation of a new lesion). In contrast to the PERCIST suggestions, tumor SUVmax rather than peak SUV will be measured. Target lesion will be defined by the most active lesion on FDG-PET/CT study before treatment and, for each patient, one or two secondary target lesions among the most active lesions will also be studied. Side-by-side image review and analysis will be performed to ascertain that the SUVmax is derived from the same lesions on baseline and follow-up scans | 6 months (M6) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Specific organ assessment (cardiac, retroperitoneal, neurological) |  | Months 6 and Months 12 | 
| PET scan |  | Months 12 | 
| CRp value (mg/liter) |  | Months 6 and Months 12 |