Clinical, laboratory and genetic features of Erdheim-Chester disease patients: analysis of a retrospective cohort of two reference centers in Latin America

ABSTRACT Objectives and Methods: Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm with a heterogeneous clinical course, ranging from localized and asymptomatic bone lesions to a multisystem disease, causing significant morbidity and mortality. There are few cohorts published, mainly from North America and Europe. We retrospectively collected clinical data on sixteen biopsy-proven ECD patients diagnosed and treated at two Brazilian reference centres for histiocytic disorders from January 2006 to February 2020. Results: Median time from onset of symptoms to diagnosis was 13 months (0.1–142). The main organ involved in ECD was bone (75%) and also 75% of the patients presented involvement of more than one organ, characterizing a multi-organic form. BRAF status was available in 81.2% of patients and BRAF V600E mutation was detected by Sanger sequencing in only 18.8%, which can be explained by the low sensitivity of this technique. All patients were treated due to symptomatic disease and a median of two lines (range: 1–7) of therapy were needed. The most common first-line therapy used was α-interferon (75%). The median progression-free survival was 7.5 months, and the median OS was not reached. Discussion and Conclusion: In the largest Latin American cohort of patients with ECD reported to date, we observed findings which resemble demographic characteristics, sites of involvement and treatment choices reported by other groups. The outcomes may be better with target therapies such as BRAF and MEK inhibitors in patients with mutation and with the adoption of recently published consensus recommendations for the management of ECD patients.

Erdheim-Chester disease (ECD) is a rare malignancy, characterized by tissue proliferation of anomalous histiocytes CD68+/CD1a-and systemic inflammation [1,2]. Until recently, ECD was included in the non-Langerhans cell histiocytosis (nLCH) group. However, according to the World Health Organization's (WHO) most recent classification of Histiocytic Disorders, it has been assigned within the Langerhans group disease (group 'L') [3].
ECD is associated with BRAF V600E mutation and other genetic abnormalities involving the RAS-RAF-MEK-ERK pathway [4]. Moreover, it presents a heterogeneous clinical course, from localized and asymptomatic tissue infiltration to a systemic disorder with multiple organ involvement, leading to significant morbidity and mortality [2,3]. The treatment of ECD includes target agents such as BRAF and MEK inhibitors, biological agents such as α-interferon (α-IFN) and cytotoxic chemotherapy, especially 2-chloro-2'deoxyadenosina (2-CdA) and cytosine-arabinoside (ara-C) and other approaches to control 'cytokine storms' which are a pathophysiological hallmark of this disease [2].
As it is a very rare disease, there are few published series of cases involving ECD, mainly from Asia [5,6], Europe [7] and North America [8]. Owing to the lack of robust ECD data in Latin America [9], we established a registry aiming to collect clinical and laboratory data, as well as biological material from patients with ECD in Sao Paulo, Brazil. We aimed to provide data containing clinical features, outcomes of therapy and survival of Brazilian patients with ECD. Herein, we report the first data of Brazilian ECD patients captured retrospectively. These patients were diagnosed and treated in two referral centers for cancer treatment: a public healthcare service -Hospital das Clínicas at Sao Paulo University and a private service -Hospital Sírio-Libanês, from January 2006 to February 2020.
Clinical and laboratory data were captured at diagnosis, before starting the next therapy line and at the response assessment time. Categorical variables were displayed as absolute frequencies and percentages, and continuous variables as medians (range: maximum and minimum). Progression-free survival (PFS) was calculated from the diagnostic biopsy date until disease progression finding. Overall survival (OS) was defined as the interval between the date of diagnosis and death for any cause or last follow-up. OS and PFS were estimated using the Kaplan-Meier method. The SPSS software for Windows, v 25.0 was used.
Sixteen patients with biopsy-proven ECD diagnosis were included, with male predominance (75% -12/ 16), and a median age of 47.7 years (19.9-84.3). The median follow-up time was 49.9 months (6.6-162.8 months), and the median time between onset of the first symptoms and the ECD diagnosis was 13.2 months (95% CI: 7.8-61.2 months), reflecting the difficulty to establish the diagnosis due to delay in the clinical awareness of this rare disease and lack of pathognomonic histologic features.
Absence of bone involvement is rare in ECD, as well as presence of lymph node and/or spleen/liver involvement [2]. In our series, 25% (4/16) of patients had no bone involvement, as well as evidence of involvement of the reticuloendothelial system was observed in 25% (4/16) of cases. Therefore, Table 2 summarizes the main clinical, molecular and histopathological characteristics of these 'atypical' cases of ECD.
Unexpectedly, we showed lower frequency of BRAF V600E mutation in our cases of ECD than previously described by others authors (18.8% versus 50-60%). However, we were not able to perform molecular tests searching for this mutation in 3 of 16 (18.8%) patients. Thereafter, this could have collaborated to underestimate the real frequency of this mutation in our cohort. Moreover, according to Melloul et al. [10], the BRAF V600E mutation in histiocytic malignancies shows low allelic fraction (< 5%) which impairs its identification in less sensitive techniques such as Sanger sequencing. In addition, in our cohort we did not use more sensitive techniques such as PCR (dd PCR) or next-generation sequencing. All patients were treated due to symptomatic disease and a median of two lines (range: 1-7) of therapy were needed. The median time between diagnosis and first line of therapy was 1.1 months (95% CI: 0.4-5.2 months). The most common first-line therapy used was αα-interferon (75% -12/16), followed by corticosteroids (31% -5/16), thalidomide (12.5% -2/16), anti-BRAF/vemurafenib (6% -1/16) and tumor excision (6% -1/16). First-line treatment was discontinued in 18.8% (3/16) of patients due to toxicity, particularly fever, myalgia and flu-like symptoms associated with α-INF.
The therapeutic management of Brazilian patients was heterogeneous, although most of them received α-IFN as first-line therapy. Since 2020, international recommendations for management of patients with ECD have been published [2], and their applications will allow more homogeneous strategies for the ECD therapeutic approach and a reliable comparison between results obtained in different treatment centers worlwide.
To our knowledge, this is the largest Latin American cohort of patients with ECD reported to date. Our findings resemble demographic characteristics, sites of involvement and treatment choices reported by other groups [5][6][7][8][9], although it is clear that the proportion of ECD patients showing BRAF mutation (18.8%) seemed to be lower than previously reported (50%) [4]. Owing to the small sample size of our cohort, it was not possible to look at the impact of Table 2. Diagnosis and characteristics of Brazilian Erdheim-Chester disease patients without bone involvement and/or with involvement of the reticuloendothelial system. the use of α-IFN on survival as it has been shown in other larger series [11]. Our α-IFN ORR was lower than that described by another study (58.3% vs. 80%) [12]. A small proportion of patients had access to target therapies, a treatment modality known to be associated with better PFS [13]. The high cost of these medications justifies the low availability in resource middle-income countries, such as Brazil.
Our study has several limitations, including a small sample and those intrinsic to a retrospective analysis, but we believe that it can contribute to the clinical and laboratorial knowledge of Latin American patients with this rare histiocytic neoplasm. We described difficulties inherent to ECD diagnosis, particularly in the scenario of low and middle-income countries, where molecular diagnostic techniques are not universally accessible. We thus demonstrate that although ECD causes significant morbidity, the mortality was low and satisfactory clinical control was obtained in more than half of patients with α-IFN. These outcomes may be better with target therapies use as BRAF and MEK inhibitors in patients with mutation.
In conclusion, ECD is a rare disease with non-specific signs and symptoms and consequently not promptly recognized by many physicians, which contribute to keeping this disease sub-diagnosed. Our data highlights the need of continuous medical education on ECD and the establishment of reference centers with availability of diagnostic tools. Importantly, the establishment of local and national registries of rare diseases is essential to enlarge the cohort and to confirm this preliminary data. Only cooperative groups will provide reliable information and guide recommendations for therapies for this entity which has just over 2000 cases cataloged in different registries worldwide.