https://orcid.org/0000-0003-0725-6263
In this issue of Blood Advances, Pegoraro et al1 suggest that treatment holidays may be an appropriate option for patients with Erdheim-Chester disease (ECD) and those who are in remission with BRAF inhibitors (BRAFi).
ECD is a clonal myeloid cell inflammatory disorder that is characterized by histiocytes that harbor MAPK pathway activating mutations, which can potentially lead to multiorgan damage.2 Patients with life-threatening manifestations can now be treated with BRAFi or MEK inhibitors (MEKi), often with remarkable efficiency.2-4
The pathogenesis of ECD was unclear until the mutation was found in bone marrow hematopoietic stem cells and myeloid progenitors, similar to several myeloid neoplasms.5,6 Evaluation of the BRAFV600E mutation in early mouse and human multipotent hematopoietic progenitors showed that the mutation induced a senescence program, which led to myeloid progenitor growth arrest, apoptosis resistance, and inflammatory cytokine secretion from mutated histiocytes.7 Tissue damage in ECD therefore seems to be secondary to inflammation induced by the mutated histiocytes rather than by a proliferative mechanism that can be seen in other cancers. Consequently, kinase inhibitors (Ki) seem to act more like anti-inflammatory rather than antiproliferative agents. This may also explain why BRAFi and MEKi are used at lower doses in ECD than in solid cancers. Unfortunately, treatment with Ki seems to suspend the damaging effects of the mutated cells rather than being curative. The LOVE (Long-term Outcomes after Vemurafenib/BRAF inhibitors interruption in ECD) study described BRAFi withdrawal after a median treatment time of 20 months in 20 patients with ECD and demonstrated a relapse rate of 75% with a median time to relapse of 6 months.8 BRAFi treatment was resumed in 10 patients, which led to remission in all cases.8 Many hypotheses can be advanced to explain this phenomenon, which can also be seen in other clonal hematologic diseases. For example, in chronic myeloid leukemia, Ki may not eliminate the dormant mutated stem cells in the bone marrow, which may lead to disease relapse after treatment discontinuation.9
It is therefore difficult to consider stopping Ki in ECD. Thus, logically, 3 options are on the table to prevent side effects (which are not negligible) in patients in prolonged remission with Ki, namely dose reduction, spacing out of doses, and treatment holidays.
Pegoraro et al have chosen the third option in their study based on what has been proposed in solid cancers.10-12 They offered treatment holidays to 11 patients with BRAFV600E mutated ECD in remission under BRAFi, which led to a 25% dose reduction (3 weeks off in a 12-week period). Monitoring of disease activity was regularly conducted. After a median follow-up of 23 months, no patients showed clinical, biologic or morphologic disease activation. Moreover, patients described an improvement in constitutional symptoms (nausea, fatigue) and BRAFi-induced skin toxicities.
To prevent immediate and long-term BRAFi and MEKi side effects while maintaining disease remission, treatment holidays seem to be a safe and suitable option for patients with ECD. Obviously, long-term follow-up in a larger cohort as part of a clinical trial is needed to establish the wisdom of treatment holidays.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
