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

Clinical, laboratory and genetic features of Erdheim-Chester disease patients: analysis of a... HEMATOLOGY 2022, VOL. 27, NO. 1, 65–69 https://doi.org/10.1080/16078454.2021.2011547 LETTER TO THE EDITOR Clinical, laboratory and genetic features of Erdheim-Chester disease patients: analysis of a retrospective cohort of two reference centers in Latin America a,b a,b Antonio Adolfo Guerra Soares Brandão , André Ramires Neder Abdo , Luís Alberto de Pádua a,b,c a,b a,b,c a,b,c,d Covas Lage , Giancarlo Fatobene , Juliana Pereira and Vanderson Rocha a b Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, Brazil; Division of Hematology, Transfusion Medicine and Cell Therapy, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, Brazil; Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in Onco-Immuno-Hematology (LIM-31), Department of Hematology, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo Brazil; Churchill Hospital, Oxford University, Oxford, UK ABSTRACT KEYWORDS Erdheim-Chester disease; Objectives and Methods: Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm with a BRAF mutation; Latin heterogeneous clinical course, ranging from localized and asymptomatic bone lesions to a America patients 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, and cytotoxic chemotherapy, especially 2-chloro-2’- characterized by tissue proliferation of anomalous his- deoxyadenosina (2-CdA) and cytosine-arabinoside (ara-C) and other approaches to control ‘cytokine tiocytes CD68+/CD1a- and systemic inflammation [1,2]. Until recently, ECD was included in the non-Langer- storms’ which are a pathophysiological hallmark of hans cell histiocytosis (nLCH) group. However, accord- this disease [2]. As it is a very rare disease, there are few published ing to the World Health Organization’s (WHO) most recent classification of Histiocytic Disorders, it has series of cases involving ECD, mainly from Asia [5,6], been assigned within the Langerhans group disease Europe [7] and North America [8]. Owing to the lack of robust ECD data in Latin America [9], we established (group ‘L’)[3]. ECD is associated with BRAF V600E mutation and a registry aiming to collect clinical and laboratory data, other genetic abnormalities involving the RAS-RAF- as well as biological material from patients with ECD in Sao Paulo, Brazil. We aimed to provide data containing MEK-ERK pathway [4]. Moreover, it presents a hetero- geneous clinical course, from localized and asympto- clinical features, outcomes of therapy and survival of matic tissue infiltration to a systemic disorder with Brazilian patients with ECD. Herein, we report the first data of Brazilian ECD patients captured retrospec- multiple organ involvement, leading to significant morbidity and mortality [2,3]. The treatment of ECD tively. These patients were diagnosed and treated in includes target agents such as BRAF and MEK inhibi- two referral centers for cancer treatment: a public healthcare service – Hospital das Clínicas at Sao tors, biological agents such as α-interferon (α-IFN) CONTACT Antonio Adolfo Guerra Soares Brandão antonio.brandao@hc.fm.usp.br © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrest- ricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 66 A. A. GUERRA SOARES BRANDÃO ET AL. Paulo University and a private service – Hospital Sírio- presented coated aortic sign, and orbital infiltration Libanês, from January 2006 to February 2020. was found in 25% (4/16), constituting the highly Clinical and laboratory data were captured at diag- specific features for the diagnosis of ECD. Table 1 sum- nosis, before starting the next therapy line and at the marizes the main clinical-molecular characteristics, response assessment time. Categorical variables were therapeutic modalities and responses of the 16 Brazilian displayed as absolute frequencies and percentages, patients with ECD included in our analysis. and continuous variables as medians (range: Absence of bone involvement is rare in ECD, as well maximum and minimum). Progression-free survival as presence of lymph node and/or spleen/liver involve- (PFS) was calculated from the diagnostic biopsy date ment [2]. In our series, 25% (4/16) of patients had no until disease progression finding. Overall survival (OS) bone involvement, as well as evidence of involvement was defined as the interval between the date of diag- of the reticuloendothelial system was observed in 25% nosis and death for any cause or last follow-up. OS and (4/16) of cases. Therefore, Table 2 summarizes the main PFS were estimated using the Kaplan–Meier method. clinical, molecular and histopathological character- The SPSS software for Windows, v 25.0 was used. istics of these ‘atypical’ cases of ECD. Sixteen patients with biopsy-proven ECD diagnosis In our cohort, biopsies from the involved organ were included, with male predominance (75% – 12/ showed that no case was positive for CD1a, 94% (15/ 16), and a median age of 47.7 years (19.9–84.3). The 16) were positive for CD68 and 18.7% (3/16) for S-100 median follow-up time was 49.9 months (6.6–162.8 protein. At the baseline, the median hemoglobin was months), and the median time between onset of the 118 g/L (79–147 g/L), the median leukocyte count was 9 9 first symptoms and the ECD diagnosis was 13.2 8.36 × 10 /L (4.63–16.06 × 10 /L) and the median plate- 9 9 months (95% CI: 7.8–61.2 months), reflecting the let count was 354 × 10 /L (186–558 × 10 /L). Additional difficulty to establish the diagnosis due to delay in laboratory features such as albumin, total bilirubin and the clinical awareness of this rare disease and lack of creatinine were mostly unremarkable. Positron emission pathognomonic histologic features. tomographies with 18-fluorodeoxiglucose (18-FDG-PET- In our cohort, the main ECD involved organ was CT) were performed for all patients and 81.3% (13/16) bone (75% – 12/16), followed by skin (43.8% – 7/16), presented avid lesions. BRAF status was available in 13 central nervous system (CNS) (43.8% – 7/16), lymph of 16 (81.3%) patients and BRAF V600E mutation was node (25% – 4/16), lung (12.5% – 2/16), liver (6.3% – detected by Sanger sequencing in 18.8% (3/13), lower 1/16), spleen (6.3% – 1/16), muscle (6.3% – 1/16) and than reported in developed country cohorts (57–70%) gastrointestinal tract (6.3% – 1/16). The majority of [4]. CNS lesions occurred in the pituitary gland (86% – 6/ Unexpectedly, we showed lower frequency of BRAF 7). Twelve patients (75%) presented involvement of V600E mutation in our cases of ECD than previously more than one organ, characterizing a multi-organic described by others authors (18.8% versus 50–60%). form. Xanthelasma and xanthomas were the most However, we were not able to perform molecular common skin lesions. The most frequent clinical tests searching for this mutation in 3 of 16 (18.8%) manifestations were bone pain (43.8% – 7/16) and neu- patients. Thereafter, this could have collaborated to rogenic diabetes insipidus (37.5% – 6/16). Osteosclerotic underestimate the real frequency of this mutation in lesions occurred in 75% (12/16) of cases, retroperitoneal our cohort. Moreover, according to Melloul et al. [10], fibrosis and thickening of the renal fascia (‘hairy kidney’ the BRAF V600E mutation in histiocytic malignancies or ‘perinephric straining’) in 37.5% (6/16), 25% (4/16) shows low allelic fraction (< 5%) which impairs its Table 1. Clinical–molecular characteristics and therapeutic responses in 16 Brazilian patients with Erdheim-Chester disease. N = 16 Age Gender Sites of involvement BRAF status Primary therapy Response Patient 1 84 Male Skin, bone, lung, serous membranes Wild-type Vemurafenib Partial response Patient 2 24 Male Skin, muscles Wild-type Surgery Partial response Patient 3 28 Male Bone, liver, spleen, lymph nodes, CNS Wild-type Steroids Partial response Patient 4 47 Female Kidney ‘hairy kidney’ Wild-type Interferon Stable disease Patient 5 64 Female Skin, bone Not acessed Interferon Stable disease Patient 6 54 Male Bone Wild-type Interferon Partial response Patient 7 52 Female Skin, bone, CNS and ‘coated aorta’ Wild-type Steroids and thalidomide Progressive disease Patient 8 33 Male Skin, bone, CNS Wild-type Interferon Partial response Patient 9 29 Male Bone, lymph nodes, lung and GIT Not acessed Interferon Partial response Patient 10 42 Male CNS, ‘coated aorta’, ‘hairy kidney’ Not accessed Interferon Partial response Patient 11 55 Male Bone, CNS, ‘hairy kidney’ Wild-type Interferon Partial response Patient 12 55 Female Bone, lymph nodes, ‘coated aorta’‘hairy kidney’ Mutated Interferon Partial response Patient 13 53 Male Bone, ‘coated aorta’, ‘hairy kidney’ Wild-type Interferon Progressive disease Patient 14 63 Male Skin, bone, CNS, ‘hairy kidney’ Mutated Interferon No response Patient 15 19 Male CNS Wild-type Interferon Partial response Patient 16 55 Male Skin, bone, lymph nodes Mutated Interferon No response CNS, central nervous system; GIT, gastrointestinal tract. HEMATOLOGY 67 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 diag- nosis 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 cor- ticosteroids (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. Cytotoxic chemotherapy was the most common second-line treatment used; 2-CdA monotherapy was indicated for 4/16 (25%) patients and LCH-like polyche- motherapy regimens containing etoposide, vimblas- tine, methotrexate and 6-mercaptopurine in 2 of 16 (12.5%) patients. Other therapeutic modalities admi- nistered during the follow-up included radiotherapy (4/16 – 25% of patients), and cobimetinib, imatinib and infliximab, in 1/16 (6%) patient each. The therapeutic management of Brazilian patients was heterogeneous, although most of them received α-IFN as first-line therapy. Since 2020, international rec- ommendations for management of patients with ECD have been published [2], and their applications will allow more homogeneous strategies for the ECD thera- peutic approach and a reliable comparison between results obtained in different treatment centers worlwide. The median PFS was 7.5 months (95% CI: 5.1–10.0 months) and the median OS was not reached. PFS at 4 years was 27.3% (95% CI: 3.8–50.8%) and OS at 4 years was 92.9% (95% CI: 79.2–100%). One patient died of infectious complication at 50 months, after a single cycle of rescue chemotherapy with 2-CdA. The overall response rate (ORR) at first-line therapy was 62.5% (10/16), with no one reaching complete response, and 12.5% (2/16) were refractory. In the sub- group treated with α-IFN in the first line, ORR was observed in 58.3% (7/12), with median PFS of 8.6 months (95% CI: 5.3–12.0 months) and 7.2 months (95% CI: 0–15.4 months) for those who did not receive α-IFN. To our knowledge, this is the largest Latin Ameri- can cohort of patients with ECD reported to date. Our findings resemble demographic characteristics, sites of involvement and treatment choices reported by other groups [5–9], 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. N = 16 Sites of involvement BRAF status Biopsy site Histology and IHC RE involvement Diagnostic criteria Patient 2 Skin, muscles Wild-type Skin Foamy histiocytes, Touton giant cells No Classic histopathologic and IHC findings CD1a-, S100-, CD68+ Patient 3 Bone, liver, spleen, lymph nodes, Wild-type Bone, lymph Foamy histiocytes and fibrosis CD1a-, Yes Classic histopathologic and IHC findings plus typical CNS node S100-, CD68+ Lymph node biopsy with classic findings; Spleen/ symmetric bone involvement liver presumed by PET-CT Patient 4 Kidney ‘hairy kidney’ Wild-type Kidney Foamy histiocytes CD1a-, S100+, CD68+, No Classic histopathologic and IHC findings plus perinephric XIIIa+ stranding Patient 9 Bone, lymph nodes, lung and GIT Not Bone Histiocytic proliferation, CD1a-, S100- CD68 Yes, Lymph node involvement presumed by PET-CT Histopathologic and IHC plus symmetric bone involvement acessed + of lower extremities Patient CNS, ‘coated aorta’, ‘hairy kidney’ Not CNS Foamy histiocytes, CD1a-, S100-, CD68+ No Classic histopathology plus periaortic infiltrates and 10 accessed perinephric stranding Patient Bone, lymph nodes, ‘coated aorta’, Mutated Bone Histiocytic proliferation, fibrosis, CD1a-, Yes, Lymph node involvement presumed by PET-CT Classic histopathology, molecular criteria plus classic 12 ‘hairy kidney’ S100-, CD68+ clinical findings Patient CNS Wild-type CNS Histiocytic proliferation, Touton cells, No Classic histopathologic and IHC findings plus atrophic 15 CD1a-, S100-, CD68+ cerebellum involvement Patient Skin, bone, lymph nodes Mutated Skin, bone Foamy histiocytes, CD1a-, S100-, CD68+, Yes, lymph node involvement presumed by PET-CT Classic histopathology, molecular criteria plus symmetric 16 XIIIa+ bone involvement IHC: immunohistochemistry, RE: reticuloendothelial involvement (lymph nodes, spleen, liver or bone marrow), CNS: central nervous system. 68 A. A. GUERRA SOARES BRANDÃO ET AL. the use of α-IFN on survival as it has been shown in Disclosure statement other larger series [11]. Our α-IFN ORR was lower No potential conflict of interest was reported by the author(s). than that described by another study (58.3% vs. 80%) [12]. A small proportion of patients had access to target therapies, a treatment modality Funding known to be associated with better PFS [13]. The The author(s) reported there is no funding associated with high cost of these medications justifies the low avail- the work featured in this article. ability in resource middle-income countries, such as Brazil. Although the Brazilian cohort is small and shares ORCID many characteristics similar to other ECD case series, Antonio Adolfo Guerra Soares Brandão http://orcid.org/ the main difference observed is highlighted compared 0000-0002-1826-611X to Estrada-Veras et al. [8] and Cohen-Aubart et al. [14] since we found higher frequency of cases without bone involvement (25% vs. 5-10%). Similarly, we References showed higher rate of reticuloendothelial system [1] Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revi- involvement (25% vs. 8–10%), no cases with ECD/LCH sion of the World Health Organization classification of overlapping (0% vs. ∼10%) and lower frequency of lymphoid neoplasms. Blood. 2016;127(20):2375–2390. doi:10.1182/blood-2016-01-643569. BRAF V600E mutation (18.8% vs. ∼50-60%). In addition, [2] Goyal G, Heaney ML, Collin M, et al. Erdheim-Chester we found lower response to α-IFN (58.3% vs. ∼70–80%) disease: consensus recommendations for evaluation, and higher OS (92.9% at 4 years vs. ∼80% at 5 years). diagnosis, and treatment in the molecular era. Blood. Our study has several limitations, including a small 2020;135(22):1929–1945. doi:10.1182/blood.201900 sample and those intrinsic to a retrospective analysis, but we believe that it can contribute to the clinical [3] Emile JF, Abla O, Fraitag S, et al. Revised classification of histiocytoses and neoplasms of the macrophage-den- and laboratorial knowledge of Latin American patients dritic cell lineages. Blood. 2016;127(22):2672–2681. with this rare histiocytic neoplasm. We described doi:10.1182/blood-2016-01-690636. difficulties inherent to ECD diagnosis, particularly in [4] Haroche J, Charlotte F, Arnaud L, et al. High prevalence the scenario of low and middle-income countries, of BRAF V600E mutations in Erdheim-Chester disease where molecular diagnostic techniques are not univer- but not in other non-Langerhans cell histiocytoses. Blood. 2012;120(13):2700–2703. doi:10.1182/blood- sally accessible. We thus demonstrate that although 2012-05-430140. ECD causes significant morbidity, the mortality was [5] Toya T, Ogura M, Toyama K, et al. Prognostic factors of low and satisfactory clinical control was obtained in Erdheim-Chester disease: a nationwide survey in Japan. more than half of patients with α-IFN. These outcomes Haematologica. 2018;103(11):1815–1824. doi:10.3324/ may be better with target therapies use as BRAF and haematol.2018.190728. MEK inhibitors in patients with mutation. [6] Cao XX, Sun J, Li J, et al. Evaluation of clinicopathologic characteristics and the BRAF V600E mutation in In conclusion, ECD is a rare disease with non-specific Erdheim-Chester disease among Chinese adults. Ann signs and symptoms and consequently not promptly Hematol. 2016;95(5):745–750. doi:10.1007/s00277-016- recognized by many physicians, which contribute to 2606-1. keeping this disease sub-diagnosed. Our data high- [7] Haroche J, Cohen-Aubart F, Amoura Z. Erdheim-Chester lights the need of continuous medical education on disease. Blood. 2020;135(16):1311–1318. doi:10.1182/ blood.2019002766. ECD and the establishment of reference centers with [8] Estrada-Veras JI, O’Brien KJ, Boyd LC, et al. The clinical availability of diagnostic tools. Importantly, the estab- spectrum of Erdheim-Chester disease: an observational lishment of local and national registries of rare diseases cohort study. Blood Adv. 2017;1(6):357–366. doi:10. is essential to enlarge the cohort and to confirm this 1182/bloodadvances.2016001784. preliminary data. Only cooperative groups will [9] Roverano S, Gallo J, Ortiz A, et al. Erdheim-Chester provide reliable information and guide recommen- disease: description of eight cases. Clin Rheumatol. 2016;35(6):1625–1629. doi:10.1007/s10067-016-3269-y. dations for therapies for this entity which has just [10] Melloul S, Helias-Rodzewicz Z, Cohen-Aubart F, et al. over 2000 cases cataloged in different registries Highly sensitive methods are required to detect worldwide. mutations in histiocytosis. Haematologica. 2019;104 (3):e97–e99. doi:10.3324/haematol.2018.201194. [11] Arnaud L, Hervier B, Neel A, et al. CNS involvement Acknowledgements and treatment with interferon are independent We thank Dr Sheila Aparecida Coelho de Siqueira (Hospital prognostic factors in Erdheim-Chester disease: a das Clínicas da Faculdade de Medicina da USP, São Paulo, multicenter survival analysis of 53 patients. Blood. Brazil) for performing tissue biopsies analysis. We thank 2011;117(10):2778–2782. doi:10.1182/blood-2010-06- Prof. Dr Israel Bendit (Hospital das Clínicas da Faculdade de 294108. Medicina da USP, São Paulo, Brazil) for analyzing the BRAF [12] Cao XX, Niu N, Sun J, et al. Clinical and positron emis- V600E mutation in tissues samples. sion tomography responses to long-term high-dose HEMATOLOGY 69 interferon-α treatment among patients with Erdheim- BASKET. Study [published correction appears in JAMA Chester disease. Orphanet J Rare Dis. 2019;14(1):11), Oncol. 2019 Jan 1;5(1):122]. JAMA Oncol 2018;4 Published 2019 Jan 10. doi:10.1186/s13023-018-0988-y. (3):384–388. doi:10.1001/jamaoncol.2017.5029. [13] Diamond EL, Subbiah V, Lockhart AC, et al. Vemurafenib [14] Cohen-Aubart F, Emile JF, Carrat F, et al. Phenothypes for BRAF V600-mutant Erdheim-Chester disease and and survival in Erdheim-Chester disease: results from Langerhans cell histiocytosis: analysis of data from the a 165-patient cohort. Am J Hematol. 2018;93(5):E114– histology-independent, phase; 2, open-label VE- E117. doi:10.1002/ajh.25055. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Hematology Online Taylor & Francis

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

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Abstract

HEMATOLOGY 2022, VOL. 27, NO. 1, 65–69 https://doi.org/10.1080/16078454.2021.2011547 LETTER TO THE EDITOR Clinical, laboratory and genetic features of Erdheim-Chester disease patients: analysis of a retrospective cohort of two reference centers in Latin America a,b a,b Antonio Adolfo Guerra Soares Brandão , André Ramires Neder Abdo , Luís Alberto de Pádua a,b,c a,b a,b,c a,b,c,d Covas Lage , Giancarlo Fatobene , Juliana Pereira and Vanderson Rocha a b Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, Brazil; Division of Hematology, Transfusion Medicine and Cell Therapy, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, Brazil; Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in Onco-Immuno-Hematology (LIM-31), Department of Hematology, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo Brazil; Churchill Hospital, Oxford University, Oxford, UK ABSTRACT KEYWORDS Erdheim-Chester disease; Objectives and Methods: Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm with a BRAF mutation; Latin heterogeneous clinical course, ranging from localized and asymptomatic bone lesions to a America patients 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, and cytotoxic chemotherapy, especially 2-chloro-2’- characterized by tissue proliferation of anomalous his- deoxyadenosina (2-CdA) and cytosine-arabinoside (ara-C) and other approaches to control ‘cytokine tiocytes CD68+/CD1a- and systemic inflammation [1,2]. Until recently, ECD was included in the non-Langer- storms’ which are a pathophysiological hallmark of hans cell histiocytosis (nLCH) group. However, accord- this disease [2]. As it is a very rare disease, there are few published ing to the World Health Organization’s (WHO) most recent classification of Histiocytic Disorders, it has series of cases involving ECD, mainly from Asia [5,6], been assigned within the Langerhans group disease Europe [7] and North America [8]. Owing to the lack of robust ECD data in Latin America [9], we established (group ‘L’)[3]. ECD is associated with BRAF V600E mutation and a registry aiming to collect clinical and laboratory data, other genetic abnormalities involving the RAS-RAF- as well as biological material from patients with ECD in Sao Paulo, Brazil. We aimed to provide data containing MEK-ERK pathway [4]. Moreover, it presents a hetero- geneous clinical course, from localized and asympto- clinical features, outcomes of therapy and survival of matic tissue infiltration to a systemic disorder with Brazilian patients with ECD. Herein, we report the first data of Brazilian ECD patients captured retrospec- multiple organ involvement, leading to significant morbidity and mortality [2,3]. The treatment of ECD tively. These patients were diagnosed and treated in includes target agents such as BRAF and MEK inhibi- two referral centers for cancer treatment: a public healthcare service – Hospital das Clínicas at Sao tors, biological agents such as α-interferon (α-IFN) CONTACT Antonio Adolfo Guerra Soares Brandão antonio.brandao@hc.fm.usp.br © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrest- ricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 66 A. A. GUERRA SOARES BRANDÃO ET AL. Paulo University and a private service – Hospital Sírio- presented coated aortic sign, and orbital infiltration Libanês, from January 2006 to February 2020. was found in 25% (4/16), constituting the highly Clinical and laboratory data were captured at diag- specific features for the diagnosis of ECD. Table 1 sum- nosis, before starting the next therapy line and at the marizes the main clinical-molecular characteristics, response assessment time. Categorical variables were therapeutic modalities and responses of the 16 Brazilian displayed as absolute frequencies and percentages, patients with ECD included in our analysis. and continuous variables as medians (range: Absence of bone involvement is rare in ECD, as well maximum and minimum). Progression-free survival as presence of lymph node and/or spleen/liver involve- (PFS) was calculated from the diagnostic biopsy date ment [2]. In our series, 25% (4/16) of patients had no until disease progression finding. Overall survival (OS) bone involvement, as well as evidence of involvement was defined as the interval between the date of diag- of the reticuloendothelial system was observed in 25% nosis and death for any cause or last follow-up. OS and (4/16) of cases. Therefore, Table 2 summarizes the main PFS were estimated using the Kaplan–Meier method. clinical, molecular and histopathological character- The SPSS software for Windows, v 25.0 was used. istics of these ‘atypical’ cases of ECD. Sixteen patients with biopsy-proven ECD diagnosis In our cohort, biopsies from the involved organ were included, with male predominance (75% – 12/ showed that no case was positive for CD1a, 94% (15/ 16), and a median age of 47.7 years (19.9–84.3). The 16) were positive for CD68 and 18.7% (3/16) for S-100 median follow-up time was 49.9 months (6.6–162.8 protein. At the baseline, the median hemoglobin was months), and the median time between onset of the 118 g/L (79–147 g/L), the median leukocyte count was 9 9 first symptoms and the ECD diagnosis was 13.2 8.36 × 10 /L (4.63–16.06 × 10 /L) and the median plate- 9 9 months (95% CI: 7.8–61.2 months), reflecting the let count was 354 × 10 /L (186–558 × 10 /L). Additional difficulty to establish the diagnosis due to delay in laboratory features such as albumin, total bilirubin and the clinical awareness of this rare disease and lack of creatinine were mostly unremarkable. Positron emission pathognomonic histologic features. tomographies with 18-fluorodeoxiglucose (18-FDG-PET- In our cohort, the main ECD involved organ was CT) were performed for all patients and 81.3% (13/16) bone (75% – 12/16), followed by skin (43.8% – 7/16), presented avid lesions. BRAF status was available in 13 central nervous system (CNS) (43.8% – 7/16), lymph of 16 (81.3%) patients and BRAF V600E mutation was node (25% – 4/16), lung (12.5% – 2/16), liver (6.3% – detected by Sanger sequencing in 18.8% (3/13), lower 1/16), spleen (6.3% – 1/16), muscle (6.3% – 1/16) and than reported in developed country cohorts (57–70%) gastrointestinal tract (6.3% – 1/16). The majority of [4]. CNS lesions occurred in the pituitary gland (86% – 6/ Unexpectedly, we showed lower frequency of BRAF 7). Twelve patients (75%) presented involvement of V600E mutation in our cases of ECD than previously more than one organ, characterizing a multi-organic described by others authors (18.8% versus 50–60%). form. Xanthelasma and xanthomas were the most However, we were not able to perform molecular common skin lesions. The most frequent clinical tests searching for this mutation in 3 of 16 (18.8%) manifestations were bone pain (43.8% – 7/16) and neu- patients. Thereafter, this could have collaborated to rogenic diabetes insipidus (37.5% – 6/16). Osteosclerotic underestimate the real frequency of this mutation in lesions occurred in 75% (12/16) of cases, retroperitoneal our cohort. Moreover, according to Melloul et al. [10], fibrosis and thickening of the renal fascia (‘hairy kidney’ the BRAF V600E mutation in histiocytic malignancies or ‘perinephric straining’) in 37.5% (6/16), 25% (4/16) shows low allelic fraction (< 5%) which impairs its Table 1. Clinical–molecular characteristics and therapeutic responses in 16 Brazilian patients with Erdheim-Chester disease. N = 16 Age Gender Sites of involvement BRAF status Primary therapy Response Patient 1 84 Male Skin, bone, lung, serous membranes Wild-type Vemurafenib Partial response Patient 2 24 Male Skin, muscles Wild-type Surgery Partial response Patient 3 28 Male Bone, liver, spleen, lymph nodes, CNS Wild-type Steroids Partial response Patient 4 47 Female Kidney ‘hairy kidney’ Wild-type Interferon Stable disease Patient 5 64 Female Skin, bone Not acessed Interferon Stable disease Patient 6 54 Male Bone Wild-type Interferon Partial response Patient 7 52 Female Skin, bone, CNS and ‘coated aorta’ Wild-type Steroids and thalidomide Progressive disease Patient 8 33 Male Skin, bone, CNS Wild-type Interferon Partial response Patient 9 29 Male Bone, lymph nodes, lung and GIT Not acessed Interferon Partial response Patient 10 42 Male CNS, ‘coated aorta’, ‘hairy kidney’ Not accessed Interferon Partial response Patient 11 55 Male Bone, CNS, ‘hairy kidney’ Wild-type Interferon Partial response Patient 12 55 Female Bone, lymph nodes, ‘coated aorta’‘hairy kidney’ Mutated Interferon Partial response Patient 13 53 Male Bone, ‘coated aorta’, ‘hairy kidney’ Wild-type Interferon Progressive disease Patient 14 63 Male Skin, bone, CNS, ‘hairy kidney’ Mutated Interferon No response Patient 15 19 Male CNS Wild-type Interferon Partial response Patient 16 55 Male Skin, bone, lymph nodes Mutated Interferon No response CNS, central nervous system; GIT, gastrointestinal tract. HEMATOLOGY 67 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 diag- nosis 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 cor- ticosteroids (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. Cytotoxic chemotherapy was the most common second-line treatment used; 2-CdA monotherapy was indicated for 4/16 (25%) patients and LCH-like polyche- motherapy regimens containing etoposide, vimblas- tine, methotrexate and 6-mercaptopurine in 2 of 16 (12.5%) patients. Other therapeutic modalities admi- nistered during the follow-up included radiotherapy (4/16 – 25% of patients), and cobimetinib, imatinib and infliximab, in 1/16 (6%) patient each. The therapeutic management of Brazilian patients was heterogeneous, although most of them received α-IFN as first-line therapy. Since 2020, international rec- ommendations for management of patients with ECD have been published [2], and their applications will allow more homogeneous strategies for the ECD thera- peutic approach and a reliable comparison between results obtained in different treatment centers worlwide. The median PFS was 7.5 months (95% CI: 5.1–10.0 months) and the median OS was not reached. PFS at 4 years was 27.3% (95% CI: 3.8–50.8%) and OS at 4 years was 92.9% (95% CI: 79.2–100%). One patient died of infectious complication at 50 months, after a single cycle of rescue chemotherapy with 2-CdA. The overall response rate (ORR) at first-line therapy was 62.5% (10/16), with no one reaching complete response, and 12.5% (2/16) were refractory. In the sub- group treated with α-IFN in the first line, ORR was observed in 58.3% (7/12), with median PFS of 8.6 months (95% CI: 5.3–12.0 months) and 7.2 months (95% CI: 0–15.4 months) for those who did not receive α-IFN. To our knowledge, this is the largest Latin Ameri- can cohort of patients with ECD reported to date. Our findings resemble demographic characteristics, sites of involvement and treatment choices reported by other groups [5–9], 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. N = 16 Sites of involvement BRAF status Biopsy site Histology and IHC RE involvement Diagnostic criteria Patient 2 Skin, muscles Wild-type Skin Foamy histiocytes, Touton giant cells No Classic histopathologic and IHC findings CD1a-, S100-, CD68+ Patient 3 Bone, liver, spleen, lymph nodes, Wild-type Bone, lymph Foamy histiocytes and fibrosis CD1a-, Yes Classic histopathologic and IHC findings plus typical CNS node S100-, CD68+ Lymph node biopsy with classic findings; Spleen/ symmetric bone involvement liver presumed by PET-CT Patient 4 Kidney ‘hairy kidney’ Wild-type Kidney Foamy histiocytes CD1a-, S100+, CD68+, No Classic histopathologic and IHC findings plus perinephric XIIIa+ stranding Patient 9 Bone, lymph nodes, lung and GIT Not Bone Histiocytic proliferation, CD1a-, S100- CD68 Yes, Lymph node involvement presumed by PET-CT Histopathologic and IHC plus symmetric bone involvement acessed + of lower extremities Patient CNS, ‘coated aorta’, ‘hairy kidney’ Not CNS Foamy histiocytes, CD1a-, S100-, CD68+ No Classic histopathology plus periaortic infiltrates and 10 accessed perinephric stranding Patient Bone, lymph nodes, ‘coated aorta’, Mutated Bone Histiocytic proliferation, fibrosis, CD1a-, Yes, Lymph node involvement presumed by PET-CT Classic histopathology, molecular criteria plus classic 12 ‘hairy kidney’ S100-, CD68+ clinical findings Patient CNS Wild-type CNS Histiocytic proliferation, Touton cells, No Classic histopathologic and IHC findings plus atrophic 15 CD1a-, S100-, CD68+ cerebellum involvement Patient Skin, bone, lymph nodes Mutated Skin, bone Foamy histiocytes, CD1a-, S100-, CD68+, Yes, lymph node involvement presumed by PET-CT Classic histopathology, molecular criteria plus symmetric 16 XIIIa+ bone involvement IHC: immunohistochemistry, RE: reticuloendothelial involvement (lymph nodes, spleen, liver or bone marrow), CNS: central nervous system. 68 A. A. GUERRA SOARES BRANDÃO ET AL. the use of α-IFN on survival as it has been shown in Disclosure statement other larger series [11]. Our α-IFN ORR was lower No potential conflict of interest was reported by the author(s). than that described by another study (58.3% vs. 80%) [12]. A small proportion of patients had access to target therapies, a treatment modality Funding known to be associated with better PFS [13]. The The author(s) reported there is no funding associated with high cost of these medications justifies the low avail- the work featured in this article. ability in resource middle-income countries, such as Brazil. Although the Brazilian cohort is small and shares ORCID many characteristics similar to other ECD case series, Antonio Adolfo Guerra Soares Brandão http://orcid.org/ the main difference observed is highlighted compared 0000-0002-1826-611X to Estrada-Veras et al. [8] and Cohen-Aubart et al. [14] since we found higher frequency of cases without bone involvement (25% vs. 5-10%). Similarly, we References showed higher rate of reticuloendothelial system [1] Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revi- involvement (25% vs. 8–10%), no cases with ECD/LCH sion of the World Health Organization classification of overlapping (0% vs. ∼10%) and lower frequency of lymphoid neoplasms. Blood. 2016;127(20):2375–2390. doi:10.1182/blood-2016-01-643569. BRAF V600E mutation (18.8% vs. ∼50-60%). In addition, [2] Goyal G, Heaney ML, Collin M, et al. Erdheim-Chester we found lower response to α-IFN (58.3% vs. ∼70–80%) disease: consensus recommendations for evaluation, and higher OS (92.9% at 4 years vs. ∼80% at 5 years). diagnosis, and treatment in the molecular era. Blood. Our study has several limitations, including a small 2020;135(22):1929–1945. doi:10.1182/blood.201900 sample and those intrinsic to a retrospective analysis, but we believe that it can contribute to the clinical [3] Emile JF, Abla O, Fraitag S, et al. Revised classification of histiocytoses and neoplasms of the macrophage-den- and laboratorial knowledge of Latin American patients dritic cell lineages. Blood. 2016;127(22):2672–2681. with this rare histiocytic neoplasm. We described doi:10.1182/blood-2016-01-690636. difficulties inherent to ECD diagnosis, particularly in [4] Haroche J, Charlotte F, Arnaud L, et al. High prevalence the scenario of low and middle-income countries, of BRAF V600E mutations in Erdheim-Chester disease where molecular diagnostic techniques are not univer- but not in other non-Langerhans cell histiocytoses. Blood. 2012;120(13):2700–2703. doi:10.1182/blood- sally accessible. We thus demonstrate that although 2012-05-430140. ECD causes significant morbidity, the mortality was [5] Toya T, Ogura M, Toyama K, et al. Prognostic factors of low and satisfactory clinical control was obtained in Erdheim-Chester disease: a nationwide survey in Japan. more than half of patients with α-IFN. These outcomes Haematologica. 2018;103(11):1815–1824. doi:10.3324/ may be better with target therapies use as BRAF and haematol.2018.190728. MEK inhibitors in patients with mutation. [6] Cao XX, Sun J, Li J, et al. Evaluation of clinicopathologic characteristics and the BRAF V600E mutation in In conclusion, ECD is a rare disease with non-specific Erdheim-Chester disease among Chinese adults. Ann signs and symptoms and consequently not promptly Hematol. 2016;95(5):745–750. doi:10.1007/s00277-016- recognized by many physicians, which contribute to 2606-1. keeping this disease sub-diagnosed. Our data high- [7] Haroche J, Cohen-Aubart F, Amoura Z. Erdheim-Chester lights the need of continuous medical education on disease. Blood. 2020;135(16):1311–1318. doi:10.1182/ blood.2019002766. ECD and the establishment of reference centers with [8] Estrada-Veras JI, O’Brien KJ, Boyd LC, et al. The clinical availability of diagnostic tools. Importantly, the estab- spectrum of Erdheim-Chester disease: an observational lishment of local and national registries of rare diseases cohort study. Blood Adv. 2017;1(6):357–366. doi:10. is essential to enlarge the cohort and to confirm this 1182/bloodadvances.2016001784. preliminary data. Only cooperative groups will [9] Roverano S, Gallo J, Ortiz A, et al. Erdheim-Chester provide reliable information and guide recommen- disease: description of eight cases. Clin Rheumatol. 2016;35(6):1625–1629. doi:10.1007/s10067-016-3269-y. dations for therapies for this entity which has just [10] Melloul S, Helias-Rodzewicz Z, Cohen-Aubart F, et al. over 2000 cases cataloged in different registries Highly sensitive methods are required to detect worldwide. mutations in histiocytosis. Haematologica. 2019;104 (3):e97–e99. doi:10.3324/haematol.2018.201194. [11] Arnaud L, Hervier B, Neel A, et al. CNS involvement Acknowledgements and treatment with interferon are independent We thank Dr Sheila Aparecida Coelho de Siqueira (Hospital prognostic factors in Erdheim-Chester disease: a das Clínicas da Faculdade de Medicina da USP, São Paulo, multicenter survival analysis of 53 patients. Blood. Brazil) for performing tissue biopsies analysis. We thank 2011;117(10):2778–2782. doi:10.1182/blood-2010-06- Prof. Dr Israel Bendit (Hospital das Clínicas da Faculdade de 294108. Medicina da USP, São Paulo, Brazil) for analyzing the BRAF [12] Cao XX, Niu N, Sun J, et al. Clinical and positron emis- V600E mutation in tissues samples. sion tomography responses to long-term high-dose HEMATOLOGY 69 interferon-α treatment among patients with Erdheim- BASKET. Study [published correction appears in JAMA Chester disease. Orphanet J Rare Dis. 2019;14(1):11), Oncol. 2019 Jan 1;5(1):122]. JAMA Oncol 2018;4 Published 2019 Jan 10. doi:10.1186/s13023-018-0988-y. (3):384–388. doi:10.1001/jamaoncol.2017.5029. [13] Diamond EL, Subbiah V, Lockhart AC, et al. Vemurafenib [14] Cohen-Aubart F, Emile JF, Carrat F, et al. Phenothypes for BRAF V600-mutant Erdheim-Chester disease and and survival in Erdheim-Chester disease: results from Langerhans cell histiocytosis: analysis of data from the a 165-patient cohort. Am J Hematol. 2018;93(5):E114– histology-independent, phase; 2, open-label VE- E117. doi:10.1002/ajh.25055.

Journal

Hematology Online – Taylor & Francis

Published: Dec 31, 2022

Keywords: Erdheim-Chester disease; BRAF mutation; Latin America patients

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