Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation

Abstract

Key Points• Treatment with vemurafenib induced a dramatic response in 3 patients with histiocytosis harboring BRAF V600E mutations.• Tumor response was observed in both Erdheim-Chester disease and Langerhans cell histiocytosis. IntroductionErdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, characterized by the infiltration of tissues by foamy CD68 ϩ CD1a Ϫ histiocytes. 1 It is a systemic disease with diverse manifestations: the clinical course mainly depends on the extent and distribution of the disease, and ranges from asymptomatic bone lesions to life-threatening manifestations. 2 Rare cases of ECD associated with Langerhans cell histiocytosis (LCH) have been reported. 3 Unlike ECD, LCH histiocytes are CD1a ϩ and frequently infiltrate the epidermis in skin lesions. 4 Interferon ␣ (IFN) is generally the first choice for ECD therapy and improves survival. It should be prescribed at high dose if there is central nervous system and/or cardiovascular involvement. 2 However, long-term IFN treatment can lead to severe side effects and some patients are refractory to treatment. Moreover some patients with CNS and/or cardiovascular infiltrations develop secondary resistance to high-dose of IFN. Alternative treatments include recombinant human interleukin-1 receptor antagonist, cladribine, thyrosine kinase inhibitors, autologous hematopoietic stem cell transplantation. 2 However, the optimal second line therapeutic strategy remains to be defined, mostly because these treatments have been evaluated in only small numbers of patients. Despite recent therapeutic progress the overall mortality remains high (18% of the 84 ECD patients seen at our institution). BRAF V600E mutations have been observed in 38% to 69% of cases of LCH. [5][6][7] We recently reported BRAF V600E mutations in 54% of 24 patients with ECD. 8 Vemurafenib, an inhibitor of mutant BRAF, has shown some efficacy against 2 diseases (melanoma and hairy-cell leukemia) associated with the BRAF V600E mutation. 9,10

Genomically Driven Tumors and Actionability across Histologies:BRAF-Mutant Cancers as a Paradigm

“…The choice of BRAF was considered apt for the following reasons: (i) BRAF mutations as well as other BRAF anomalies (amplifications, fusions) have been described in a wide variety of tumors; (ii) two BRAF inhibitors and a MEK inhibitor have already been approved for BRAF-mutant melanoma; and (iii) there is a rich literature demonstrating responses, albeit at times in small numbers of patients, with the use of BRAF inhibitors in a variety of BRAF-mutation bearing cancers (9,10). On the other hand, BRAF-mutant colorectal cancers have proved more resistant to BRAF inhibitor monotherapy, hence striking a cautionary note.…”

Tratamiento con sirolimus y prednisona en enfermedad de Erdheim-Chester con compromiso cardiaco: Caso clínico

“…Recientemente se comunicó su eficacia en 8 casos de EEC refractaria a IFN-α, en que hubo estabilización o mejoría clínica con reducción significativa en el compromiso periaórtico y en la infiltración cardiaca. La dosis empleada fue 480-960 mg cada 12 h por vía oral 1,3,12,21 . Los efectos secundarios más frecuentes fueron rash cutáneo, xerosis y queratosis pilaris.…”

“…En ellos se han ensayado drogas antineoplásicas, biológicas e inmunosupresoras 3,7,[10][11][12][13][14][15][16][17][18][19][20][21] .…”

Writing guidelines without a net: ECD

“…6 Mice harboring Mbnl1 2/2 plus Mbnl2 1/2 alleles also recently have been shown to exhibit cardinal features of DM muscle disease. 7 In additional contexts, extended roles of MBNLs are illustrated by regulation of FOXp1 AS in a context of ES cell pluripotency, 8 and in insulin receptor transcript AS. 6 In studies by Cheng et al,…”

“…[5][6][7] This observation and the anecdotal responses reported with the BRAF600E inhibitor, vemfurafenib, have provided the rationale for clinical testing of such pathwaydirected treatments in ECD. 8 Third, the proposed clinical classification of ECD as asymptomatic and symptomatic will be helpful in tailoring therapy according to disease severity. Asymptomatic ECD patients may do very well with a watch-and-wait strategy while treatment, albeit not optimal, with interferon a, does appear to improve overall survival.…”