Erdheim-Chester Disease Global Alliance

Virtual Symposium | Tuesday, November 16, 2021

Thank you for participating in this year’s virtual symposium! Provided below is a listing for this meeting, including the agenda, a printable program, speaker bios, abstracts, and presentation slides. Following the meeting, a recording will be added here and emailed to attendees.

2021 Virtual Event Agenda

Medical Symposium Program

2021 ECD Virtual Medical Symposium Recording

Speakers:

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Kathy Brewer
President

Erdheim-Chester Disease Global Alliance Achievements and Statistics

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Masters in Engineering (1983), B.S. in Mechanical Engineering (1981). Kathy worked in the aerospace industry for 15 years, where she spent 10 years as an engineering software development manager. Since 1998 she has been involved in non-profit work and various contract work, and is currently a partner in a management consulting firm. She lost her beloved husband, F. Gary Brewer, to Erdheim-Chester Disease in 2007. He remained undiagnosed throughout his life, with the diagnosis of ECD occurring as the result of an autopsy.

Erdheim-Chester Disease Global Alliance Achievements and Statistics

ECD Global Alliance, Louisiana, USA

The ECD Global Alliance (ECDGA) has been registering Erdheim-Chester Disease patients since
the organization’s inception in 2008. Contact information for patients is captured, but little
medical information has historically been recorded. The information available provides insight
into the number of ECD patients and where they are located. The ECDGA has funded seven
research projects and an ECD dedicated patient registry, totaling over $750,000. This has aided
effective treatment and mutation discoveries that have drastically improved care for patients.
Thirty-five ECD Care Centers have been identified to more effectively provide care to patients
across the globe. Support has been provided to over 750 families from 62 countries through the
organization’s website, events, and more.
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Eli L. Diamond, MD

Report on ECD Registry and Analysis of Fatigue and Pain in ECD Registry Patients

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Eli L. Diamond, MD, is a neuro-oncologist who specializes in the care of patients with Erdheim-Chester disease (ECD) and other histiocytosis, as well as brain tumors and neurologic complications of cancer. He did his neurology residency at the Massachusetts General Hospital and Brigham and Women’s Hospital and his neuro-oncology training at Memorial Sloan Kettering Cancer Center (MSK), where he is currently a staff neuro-oncologist. He conducts and has conducted several research studies for patients with ECD including the vemurafenib trial, the cobimetinib trial, a study looking for gene mutations in ECD tumors, a study to improve ECD biopsies, and a study about ECD and the brain. At MSK, he works with a large team across many disciplines to offer the highest quality medical care and supportive care for patients with ECD, as well as to better our understanding and treatment of ECD with collaborative research.

Dr. Diamond is also the co-founder of the global ECD Patient Registry that has been supported by the ECD Global Alliance. In addition to this major contribution, he co-leads the ECD Care Center Referral Network.

Contact information
Memorial Sloan-Kettering Cancer Center
Department of Neurology
1275 York Avenue, Box 52
New York, NY 10065 USA
E-mail: diamone1@mskcc.org
Telephone: 1.212.639.5122

Report on ECD Registry and Analysis of Fatigue and Pain in ECD Registry Patients

Purpose: Erdheim-Chester disease (ECD) is a rare L-group histiocytosis in adults. Patients with ECD endure widely varying and disabling symptomatology including pain and fatigue. The frequency and severity of these symptoms, as well as associated clinical factors, have not been examined in ECD.

Methods: The Memorial Sloan Kettering (MSK) ECD Registry is a prospective longitudinal study of adult patients with ECD. Patients report demographic and treatment characteristics and complete a battery of patient-reported outcomes (PROs), including the Brief Pain Inventory (BPI) and Brief Fatigue Inventory (BFI). PROs are completed at the time of enrollment and at 6, 12, 24, and 36 months. We analyzed fatigue and pain from enrollment PROs. Clinically relevant fatigue
or pain was defined as any BPI or BFI item with a score of 4 or more. Recursive partitioning analysis was performed to identify factors associated with clinically relevant fatigue or pain. Spearman correlation was performed to analyze the correlation between pain and fatigue.

Results: 157 patients have enrolled in the ECD registry, 93 from Memorial Sloan Kettering and 64 from other institutions. 148 have completed enrollment PROs, 131 6-month PROs, 118 one-year PROs, and 76 two-year PROs. Clinical data about ECD diagnosis has been fully captured for 115 patients. Fatigue and pain were analyzed for 127 participants. 75 (59%) are male and 52 (41%) are female. 76 (59%) of patients had been diagnosed with ECD within the past 5 years and 51 (41%) were diagnosed more than 5 years ago. Participants had 0 (14;11%), 1 (38;30%), 2 (36; 28%), and >2 (9; 31) lines of prior therapy. Treatment at the time of PRO completion was conventional in 12 (9%), BRAF or MEK inhibition in 74 (58%) other targeted therapies in 2 (%), and no treatment in 39 (31%). 62 (49%) of participants had moderate or severe (4+) total fatigue
score, 60 (48%) had 4+ BRI interference, and 72 (57%) had 4+ fatigue severity. 40 (31%) of participants had moderate or severe (4+) total fatigue score, 41 (32%) had 4+ BRI interference, and 36 (28%) had 4+ fatigue severity. Fatigue and pain severity, interference, and total scores were correlated with one another (correlation coefficients 0.58, 0.53, 0.56; p<0.001). Clinically relevant fatigue and pain did not have any association with sites of disease, ECD treatment, or disease status. RPA demonstrated age<70, duration of ECD illness > 9.3 months, and hemoglobin <13 to be associated with clinically relevant pain (p<0.0001).

Conclusion: Clinically relevant fatigue and pain are highly frequent in ECD patients, regardless of treatment or disease status. Patients who are younger than 70, with longer duration of ECD illness, and with anemia may benefit from intensive pain evaluation.
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Giulio Cavalli, MD, Ph.D.

Oncogene-induced maladaptive activation of Trained Immunity in the pathogenesis and treatment of Erdheim-Chester disease

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Giulio Cavalli, MD PhD, is Assistant Professor of Internal Medicine at Vita-Salute San Raffaele University, Milan, Italy. He also serves as Attending Physician in the Unit of Immunology, Rheumatology, Allergy and Rare Diseases at San Raffaele Hospital, Milan, Italy, and is leading a translational research group as Principal investigator in the Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Dr. Cavalli earned his Medical Degree from Vita-Salute San Raffaele University, Milan, Italy, and later completed a PhD at Radboud University, Nijmegen, The Netherlands and a Postdoctoral fellowship at the University of Colorado Denver, Aurora, CO. His primary research interests include

Innate immunity and inflammation, Cytokines, immunometabolism, Inflammatory diseases, and Erdheim-Chester disease.

We describe a case with synchronic Systemic Aggressive Mastocytosis with Langerhans Cell Histiocytosis in a 55-year-old female, with no response to Midostaurin, Cladribine and after NGS we found a BRAF p.N486_P490del mutation (VAF 38,2%) that is intrinsically resistant to BRAF inhibitor and had a complete response after 2 months of single MEK inhibitor Trametinib.
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Jerome Razanamahery, MD

Disturbance of monocyte homeostasis in histiocytosis is close to chronic myelomonocytic leukemia and is correlated with phenotype and disease activity

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Razanamahery Jerome. MD
Internal medicine department
Dijon University Hospital
14 rue Paul Gaffarel
Dijon, France
Email address: razanamahery.jerome@hotmail.fr
Phone number: +33 3.80.29.30.31

I am graduated in internal medicine and immunology since 2017. I am a physician in the internal medicine department of Dijon university Hospital. In am particularly interested in immunology and oncology. During my residency, I could reach experience in histiocytic disorders, especially for ECD and RDD in Pitié-Salpétrière hospital with Pr Haroche. I was lucky enough to lead an internal multicentric project with Eli Diamond, Gaurav Goyal, Jean-Francois Emile and Julien Haroche describing the overlapping forms between ECD and RDD in adults patients. My current researches focus on monocytes disturbance in histiocytic disorders and the significance of their modification in the disease’s course.

Disturbance of monocyte homeostasis in histiocytosis is close to chronic myelomonocytic leukemia and is correlated with phenotype and disease activity

Purpose: Monocytes have a significant role in histiocytosis pathogenesis. Little is known about their phenotype in histiocytosis and the difference with other myeloproliferative or inflammatory conditions.
Methods: The phenotype of monocytes from patients with histiocytosis was compared to one of the patients with chronic myelocytic monocytic leukemia (CMML), essential thrombocythemia (ET), giant cell arteritis (GCA), and healthy donors (HD). Monocytes were defined as classical (CD14++CD16-), intermediate (CD14+CD16+) and non-classical (CD14+CD16++) by flow cytometry analysis.
Results: Seventy-two patients were included (16 histiocytoses, 7 ET, 7 CMML, 21 GCA, and 21 HD).
Among histiocytosis patients, eight had ECD among whom five (62.5%) had BRAF^V600E gene mutation; four patients suffered from LCH among whom one (25%) was BRAF^V600E mutated. Four patients had RDD among whom two (50%) had MAP2K1 gene mutation. Three patients with histiocytosis had concomitant myeloid neoplasms (2 CMML, 1 ET), and six had concomitant CHIP.
The frequency of classical monocytes was higher in histiocytosis compared to ET (median with IQR: 92% [83.5-96.0] vs 76% [71.0-84.0] for ET. The frequency of intermediate monocytes was lower in histiocytosis compared to ET (4.5% [3.00-7.75] vs 13% [9.00-18.00]) and GCA (4.5% [3.00-7.75] vs 7.91% [6.01-20.75]). The frequencies of classical (87.50% [78.50-92.50] vs 97% [96.0-98.0]), intermediate (5% [4.0-12.25] vs 2.5% [1.250-2.750]), and non-classical monocytes (4% [3.250-11.0] vs 0.5% [0.500-1.500]) differed between CMML patients and patients with both histiocytosis and clonal hematopoiesis. Monocyte subsets were similar between CMML patients and patients with histiocytosis harboring MAP-kinase pathway gene mutation. Monocyte distribution did not differ depending on the type of histiocytosis, molecular status, association
with myeloid neoplasms/clonal hematopoiesis, or targeted therapy treatment. The frequency of non-classical monocytes was lower in patients with vascular involvement ([0.775-2.500] vs 4.00% [1.750-9.500]). Intermediate monocytes were less frequent in responder patients (3.5% [2.00-5.00] vs 7.5% [4.00-16.00])

Conclusion: The distribution of monocyte subsets is homogenous between the different types of histiocytosis. It’s close to CMML, a myeloproliferative disorder sometimes involving the MAPkinase pathway, but different from ET and GCA. Monocyte subset distribution analysis in histiocytosis could be helpful for the diagnosis and be a surrogate marker of disease activity.
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Yu Oyama, MD

Novel recurrent mutations in Erdheim-Chester Disease patients identified by whole exome sequencing and whole genome sequencing.

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Yu Oyama, MD
Department of Hematology and Oncology
The University of Tokyo Hospital
Education and Professional experience
2010-2016 The Jikei University: School of Medicine
2016-2018 The University of Tokyo Hospital, junior resident
2018 – Department of Hematology and Oncology, The University of Tokyo Hospital, senior resident
Currently – Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo

Somatic mutations associated with hyperactivation of MAPK pathway are frequent alterations in patients with Erdheim-Chester disease (ECD), but no known driver mutations are detected in some patients. So far, there is no specific target of treatment for them. To uncover novel driver mutations and establish new treatment strategies in these patients, we performed a nationwide survey and whole-exome sequencing (WES) and whole-genome sequencing (WGS) analysis.
We collected 22 samples of ECD lesions from 15 adult patients. All cases were pathologically proved. A mean of 188 nonsynonymous mutations per patient was identified in tumor-only analysis (range, 17-3598) of WES, and 3134 in tumor-normal analysis (range, 2588-3680) of WGS. We detected known driver mutations in seven of 15 cases (47%). Among them, BRAFV600E was detected in 5 cases, MAP2K1 C121S in 1 case, and NRAS Q61R in 1 case by WES and WGS. The
median variant allele frequency (VAF) for these known activating kinase mutations was 14.4% (range, 6.3-34.7). We could not detect known driver mutations in the other 8 cases (53%).

Therefore, to reveal novel driver mutations, we focused on these 8 cases. Notably, EPHA2 P786L, MYBPC3 D798N, TDRD5 P115L, and TCEAL4 F17L mutations are recurrently found in 2 out of the 8 cases, and these are not found in the cases with known driver mutations. The VAFs of EPHA2 P786L were 9.1% and 9.3%, MYBPC3 D798N 5.5% and 11.9%, TDRD5 P115L 10.2% and 18.7%, and TCEAL4 F17L 7.5% and 9.0% in each case. In conclusion, we identified EPHA2 P786L, MYBPC3 D798N, TDRD5 P115L, and TCEAL4 F17L mutations as candidates of novel driver mutations in ECD. To elucidate the role of these mutations in the pathogenesis of ECD, further functional analyses are warranted.
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Oshrat Rokah, Ph.D.

The Contribution of MicroRNAs to the Inflammatory and Neoplastic Characteristics of Erdheim–Chester Disease

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Oshrat Rokah, PhD
Head, Molecular Research Lab, Assuta Medical Center, Tel-Aviv, Israel.

Dr. Oshrat Rokah is the head of the Molecular Research Lab at Assuta Medical Center located in Tel-Aviv, Israel. Dr. Rokah holds a PhD and MSc from the Department of Genetics in the Faculty of Medicine at Tel Aviv University.

During her studies, Dr. Rokah received several honorable awards and scholarships, among them, the David and Paulina Trotsky Award for Outstanding Students. Dr. Rokah was one of the pioneers in studying microRNA expression in chronic myeloid leukemia, this contributed to better understand the molecular mechanism underlying the development of the disease, and new avenues for therapeutic treatment.
Dr. Rokah has extensive knowledge in complex, advanced, and diverse molecular research methods and today she is the mentor of five PhD students from Ariel University. She works in full and intensive cooperation with the clinical field, physicians and scientists, in order to target real clinical needs and deficiencies. The research in the lab focuses on the role of non-coding RNAs in hematological malignancies and the aberrant molecular mechanisms associated with deregulated expression of these molecules.

As a part of the dedicated clinic at Assuta Medical center for histiocytoses neoplasms, her lab is investigating the functional roles of these non-coding molecules in Erdheim-Chester Disease.

The pathogenesis of histiocytic neoplasms is driven by mutations activating the MAPK/ERK pathway, but little is known about the transcriptional and post-transcriptional alterations involved in these neoplasms. We analyzed microRNA (miRNA) expression in plasma samples and tissue biopsies of Erdheim–Chester disease (ECD) patients. In silico analysis revealed a potential role of miRNAs in regulating gene expression in these neoplasms as compared with healthy controls (HC). NanoString analysis revealed 101 differentially expressed plasma miRNAs in 16 ECD patients as compared with 11 HC, 95% of which were downregulated. MiRNAs-15a-5p, -15b-5p, -21-5p, -107, -221-3p, -320e, -630, and let-7 family miRNAs were further evaluated by qRT-PCR in an extended cohort of 32 ECD patients, seven LCH and 15 HC. Six miRNAs (let-7a, let-7c, miR-15a-5p, miR-15b-5p, miR-107, and miR-630) were highly expressed in LCH plasma and tissue samples as compared with ECD. Pathway enrichment analysis indicated the miRNA contribution to inflammatory and pro-survival signaling pathways. As miR-15a-5p was the most prominently downregulated miRNA in ECD patients compared to healthy individuals we further elucidated its role in ECD pathogenesis. Bioinformatics analysis followed by a luciferase assay showed that chemokine ligand 10 (CXCL10) is a target gene regulated by miRNA-15a-5p. This was confirmed in 24/34 ECD patients that had low expression of miR-15a-5p concurrent with upregulated CXCL10. Overexpression of miR-15a-5p in cell lines harboring BRAF or RAS mutations (Ba/F3, KG-1a, and OCI-AML3) resulted in CXCL10 downregulation, followed by LIN28a and p-ERK signaling
downregulation and let-7 family upregulation. Overexpression of miR-15a-5p inhibited cell growth and induced apoptosis by decreasing Bcl-2 and Bcl-xl levels. Finally, treatment of ECD patients with MAPK/ERK signaling inhibitors for 16 weeks resulted in let-7 family members and miR-15a-5p upregulation, which was in parallel with the radiologic response seen by PET-CT. Our study highlights the potential contribution of miRNAs to the inflammatory and neoplastic characteristics of ECD and suggests that miR-15a-5p is a tumor suppressor in ECD through the CXCL10-ERK-LIN28a-let7 axis, highlighting another layer of post-transcriptional regulation in this disease. Also, it suggests that upregulation of miR-15a-5p in ECD patients may have a potential therapeutic role.
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Jerome Razanamahery, MD

Dramatic efficacy of Vemurafenib on psychiatric symptoms revealing BRAF^V600E Erdheim-Chester Disease

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Razanamahery Jerome. MD
Internal medicine department
Dijon University Hospital
14 rue Paul Gaffarel
Dijon, France
Email address: razanamahery.jerome@hotmail.fr
Phone number: +33 3.80.29.30.31

I am graduated in internal medicine and immunology since 2017. I am a physician in the internal medicine department of Dijon university Hospital. In am particularly interested in immunology and oncology. During my residency, I could reach experience in histiocytic disorders, especially for ECD and RDD in Pitié-Salpétrière hospital with Pr Haroche. I was lucky enough to lead an internal multicentric project with Eli Diamond, Gaurav Goyal, Jean-Francois Emile and Julien Haroche describing the overlapping forms between ECD and RDD in adults patients. My current researches focus on monocytes disturbance in histiocytic disorders and the significance of their modification in the disease’s course.

Purpose: Psychiatric manifestations in Erdheim-Chester Disease (ECD) is not described in the spectrum of neurological manifestations, particularly as the initial onset of the disease, making the diagnostic challenging.

Methods: We present the first case of neuro-histiocytosis, presenting as a psychiatric delirium with hallucinations, recovering upon targeted therapy with BRAF V600E inhibitor.

Results: An 81-year-old Caucasian woman suffered from delirium with hallucination. Her medical history included Grave’s disease, deep venous thrombosis, retinal vein occlusion, and macular degeneration. She had auditory hallucinations for 7 months for the current condition, followed by a two-month history of visual hallucinations and logorrhea. She also had persecutory delusion and hallucinations without an underlying psychiatric disorder. The neurological examination showed a cerebellar syndrome (Scale for the assessment and rating of ataxia (SARA) score: 13/40). The patient also had acute heart failure. The echography showed a pericardial effusion requiring drainage. Brain magnetic resonance imaging (MRI) showed confluent FLAIR hyperintensity lesions in the pons and superior cerebellum peduncles. Lumbar puncture was unremarkable except for elevated neopterin. Body computed tomography showed a “hairy kidney” and adventitia vessels thickening. The 18 fluorodeoxyglucose PET showed bilateral symmetric osteosclerosis of long bone suggestive of ECD. The diagnostic was confirmed with a perirenal biopsy showing diffuse infiltration of CD68+, CD1a- histiocytes with BRAF V600E gene mutation on pyrosequencing. The patient received interferon-alpha (180 micrograms/week) twice then specific BRAF inhibitor Vemurafenib. Rapid regression of the psychiatric symptoms and neurological improvement (SARA Score: 12/40) occurred within days of treatment. After 8 weeks, the patient had clinical improvement. The brain MRI showed partial regression of the lesions. 18FDG-PET shows a reduction in radiotracer uptake on all ECD sites compatible with a partial metabolic response.

Conclusion: This case highlights the first description of delirium as a manifestation of neuro-ECD with dramatic improvement with targeted therapy.
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André Neder Ramires Abdo, MD

Synchronic Systemic Aggressive Mastocytosis and Langerhans Cell Histiocytosis with BRAF p.N486_P490del

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Dr. Abdo leads the ECD Care Center location in Brazil. He is a hematology oncologist at the Hospital das Clinicas – Instituto do Cancer do Estado de Sao Paulo – Universidade de São Paulo. Appointments: Assistant of Hematology at the Cancer Institute of the State of São Paulo – ICESP. Assistant Physician, Discipline of Hematology and Hemotherapy, Hospital das Clínicas, Faculty of Medicine of São Paulo. Coordinator of Postgraduate Studies in Lymphomas at Hospital Alemão Oswaldo Cruz. Manager of the Lymphoma and Myeloma Center at Hospital Alemão Oswaldo Cruz.

Contact information

E-mail: andre.abdo@hc.fm.usp.br

We describe a case with synchronic Systemic Aggressive Mastocytosis with Langerhans Cell Histiocytosis in a 55-year-old female, with no response to Midostaurin, Cladribine and after NGS we found a BRAF p.N486_P490del mutation (VAF 38,2%) that is intrinsically resistant to BRAF inhibitor and had a complete response after 2 months of single MEK inhibitor Trametinib.
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Anaïs Roeser, MD

Role of vascular endothelial growth factor in Erdheim-Chester Disease

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Anaïs ROESER, MD, Resident in Internal Medicine, Université de Paris, Assistance Publique-Hôpitaux de Paris (Paris, France). Master of Science in Immunology, Institut Necker Enfants Malades, Institut Pasteur and Université de Paris.

Erdheim-Chester disease (ECD) is a rare histiocytosis characterized by tissue infiltration of CD68+, CD1a- histiocytes, derived from cells of the mononuclear phagocyte system harboring recurrent mutations in the MAPK-signaling pathway. Vascular endothelial growth factor-A (VEGFA), also referred to as VEGF, is a major regulator of angiogenesis. In Mycobacterial-associated granulomas, macrophages produce VEGF that induces the recruitment of monocytes. VEGF is expressed by histiocytes in Langerhans cell histiocytosis. We hypothesized that VEGF could play a role in ECD pathophysiology. The first aim of our study was to determine if VEGF was expressed by histiocytes in ECD lesions. The second aim was to assess levels of serum VEGF (sVEGF) in ECD patients, and determine if they were associated with the patient’s characteristics.

We conducted a retrospective study, screening all ECD patients seen in the French National Reference Center for Histiocytoses of the Pitié-Salpêtrière Hospital from 2009 to 2019. Patients were included if they had at least one sVEGF determination. Biopsies of patients with extreme sVEGF were centrally reviewed and stained for VEGF with 2 different antibodies.

We included 248 patients in the analysis. sVEGF were high (> 500pg/mL) at first determination in 53%. Median sVEGF was 843pg/mL in the high sVEGF group, 288pg/mL in the low sVEGF group. Sex, age, and BRAF status were not significantly different between the 2 groups. We analyzed 26 histological samples of ECD. Histiocytes had moderate to high VEGF staining in all samples analyzed. Control included 4 biopsies of reactional sinusal histiocytoses, in which no VEGF staining was observed on histiocytes. Patients with high sVEGF had more frequently a vascular involvement (71% vs 48%, p=0.0004), especially a “coated aorta” (50% vs 34%, p=0.009), and a cardiac involvement (58% vs 41%, p=0.008). Consecutive measurements of sVEGF were available for 183 patients (median interval: 24 months). sVEGF significantly decreased during follow-up (p<0.0001), with a median variation (∆sVEGF) of -153pg/mL. Consecutive cardiac MRIs were available for 45 patients (median interval: 48 months). Thoracic aorta coating was present in 31 patients (69%) and persisted in all cases. All patients had cardiac involvement: 6 achieved complete response, 25 partial response, 12 were stable, and 2 progressed. Mean ∆sVEGF of patients with complete response, partial response, stable disease were respectively – 591.3, – 163.9, – 239.6pg/mL and were significantly different from patients who progressed (mean ∆sVEGF
+ 555.5pg/mL).

In our study, VEGF was expressed by ECD histiocytes. sVEGF was high in 53% of ECD patients, and its elevation was associated with cardiac and vascular involvements. Variations of sVEGF were associated with responses of cardiac involvement under therapy.
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Francesco Pegoraro, MD

Kidney involvement in Erdheim-Chester disease: a multicenter cohort study on 195 patients

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Francesco Pegoraro
pegoraro.fr@gmail.com
francesco.pegoraro@unif.it
Address: via Giuseppe Mazzoni 27, 50134, Firenze, Italy
Mobile: +39 3492457769
Place and date of birth: Torino (Italy), 13/08/1993

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Background: Erdheim-Chester disease (ECD), a non-Langerhans cell histiocytosis, infiltrates the peri-renal retroperitoneum in around 60% of cases and often causes obstructive uropathy. Little is known about kidney function and prognosis in ECD. Herein, we investigated kidney involvement and outcome in a large cohort of ECD patients.

Methods: Consecutive patients with histologically confirmed ECD followed at four referral centers in France, Italy, and Israel between 2000-2020 were included. Data on kidney function were assessed at diagnosis and last visit; where available, data collected at one, two, and five years, were also included. Imaging studies and information on medications and responses to treatment were collected.

Results: One hundred and ninety-five patients (72% of whom were men) were included (mean age at onset 52±15.5 years; mean age at diagnosis 56.5±14.3 years). Perirenal involvement was found in 142 patients (73%). Of them, 81 (42%) also had ureteral involvement, 74 (38%) hydronephrosis, 16 (8%) kidney atrophy, 60 (31%) vascular peduncle, and 37 (19%) adrenal gland involvement. Perirenal involvement was significantly associated with older age (p=0.001), male
sex (p=0.004), hypertension (p=0.001), large vessel (p25% and ESKD/death at last visit were an age at onset >50y, hypertension, the BRAFV600E mutation, and a low eGFR at baseline. At multivariate analysis, the presence of cardiovascular risk factors was significantly associated with CKD 4-5 or eGFR decrease >25% (p=0.005), whereas age >50y was associated with ESKD or death (p=0.005). Interestingly, conventional therapies (e.g., interferon- α, anti-cytokine drugs) had a protective effect on the risk of ESKD or death (p=0.029).

Conclusions: Perirenal infiltration is frequent in ECD and is associated with worse renal function at the time of diagnosis; however, cardiovascular risk factors and age are the main independent predictors of kidney outcome.
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Ashley Aaroe, MD

Treatment of Non-Langerhans Cell Histiocytosis with the MEK Inhibitor Trametinib

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Dr. Aaroe earned her medical degree from the Northwestern University Feinberg School of Medicine in 2015. She subsequently completed a residency in neurology at the New York-Presbyterian Hospital, Weill Cornell Medical Center. Prior to her recruitment to the Department of Neuro-Oncology at MD Anderson, in the renowned Texas Medical Center, she completed fellowship training also at MD Anderson. She is board certified in Neurology by the American Board of Psychiatry and Neurology, and in Neuro-Oncology by the United Council for Neurologic Subspecialties.

Her clinical interests include the management of primary and metastatic brain tumors, and neurological complications of cancer and cancer therapy. She has served on the editorial board of Continuum and as a reviewer for Neurology. She is member of several professional societies including the Society for Neuro-Oncology (SNO) where she serves on the public policy committee, and the American Academy of Neurology (AAN) where she is active in medical education. In addition to her clinical and research activities she is passionate about physician advocacy, and regularly participates in events with policymakers on behalf of the AAN and the National Brain Tumor Society. Dr. Aaroe will serve as faculty liaison for the patient reported outcomes (PRO) program at the Brain and Spine Center facilitating collection and interpretation of data regarding patient symptom burden and overall quality of life.

Erdheim-Chester disease (ECD) and Rosai-Dorfman disease (RDD) are rare non-Langerhans cell histiocytoses with limited therapeutic options. Recent studies suggested that activation of the MAPK pathway through BRAFV600E mutation or other alterations is a hallmark of histiocytosis and can be associated with a favorable response to BRAF inhibitors or the MEK inhibitor cobimetinib. To assess efficacy and safety, we analyzed 26 real-world patients (17 ECD, 5 ECD/RDD, 3 RDD, 1 ECD/LCH) treated with the oral MEK inhibitor trametinib at four major US care centers. Most
patients were effectively managed at reduced doses of 0.5mg to 1 mg of oral trametinib daily. The most common treatment-related toxicity was rash (27% of patients). The response rate in evaluable patients was 71%. At the median follow-up of 23 months, treatment effects were durable with a median time-to-treatment failure of 37 months while median progression-free and overall survival have not been reached.
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Eli L. Diamond, MD

Outcomes after discontinuing targeted therapy in ECD and other histiocytoses

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Eli L. Diamond, MD, is a neuro-oncologist who specializes in the care of patients with Erdheim-Chester disease (ECD) and other histiocytosis, as well as brain tumors and neurologic complications of cancer. He did his neurology residency at the Massachusetts General Hospital and Brigham and Women’s Hospital and his neuro-oncology training at Memorial Sloan Kettering Cancer Center (MSK), where he is currently a staff neuro-oncologist. He conducts and has conducted several research studies for patients with ECD including the vemurafenib trial, the cobimetinib trial, a study looking for gene mutations in ECD tumors, a study to improve ECD biopsies, and a study about ECD and the brain. At MSK, he works with a large team across many disciplines to offer the highest quality medical care and supportive care for patients with ECD, as well as to better our understanding and treatment of ECD with collaborative research.

Dr. Diamond is also the co-founder of the global ECD Patient Registry that has been supported by the ECD Global Alliance. In addition to this major contribution, he co-leads the ECD Care Center Referral Network.

Contact information
Memorial Sloan-Kettering Cancer Center
Department of Neurology
1275 York Avenue, Box 52
New York, NY 10065 USA
E-mail: diamone1@mskcc.org
Telephone: 1.212.639.5122

Purpose: There is data to suggest that interruption of BRAF inhibition in patients with ErdheimChester Disease frequently leads to disease relapse. In this study, we present outcomes in diverse histiocytosis patients treated with BRAF, MEK, or dual BRAF/MEK inhibition, with subsequent treatment interruption. Methods: Patients with Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), Rosai-Dorfman disease (RDD), Juvenile Xanthogranuloma
(JXG), or mixed histiocytosis (ECD/LCH or ECD/RDD) whose targeted therapy was interrupted in favor of observation or chemotherapy were analyzed for subsequent relapse and recaptured response after rechallenge with targeted therapy. Relapse-free survival (RFS) was calculated from the date of treatment interruption until relapse (n=14) for those with an event or until last followup for those who were censored (n=6). There were no patients who died without relapse. Histiocytosis subtypes, duration of treatment and disease status prior to treatment interruption,
tumor mutation, and class of targeted therapy were associated with RFS using Cox proportional hazards modeling. Results: 20 patients were analyzed. 13 (65%) were male, and diagnoses were ECD (8; 40%), ECD/LCH (4;20%), LCH (2;10%), RDD (2;10%), ECD/RDD (2;10%), and JXG (2;10%). Patients were initially treated with BRAF inhibition (9; 45%), MEK inhibition (9;45%), or dual therapy (2; 10%), and at the time of treatment interruption 13 (65%) had a complete response (CR) and 7 (35%) had a partial response (PR). Following treatment interruption, 14 (70%) of
patients had subsequent relapse at a mean time of 9.7 months; 13 of these were rechallenged, and 9 (of 10 evaluable) recaptured a CR or PR. The 6 patients who did not relapse had ECD or mixed disease (3), JXG (2), and RDD (1); 5 of these 6 were treated with MEK inhibition prior to interruption, and the 6th with dual therapy. Patients with BRAFV600E mutation (HR: 6.1; 95%CI: 1.3-27.9) or BRAF inhibitor monotherapy (HR: 3.3; 95%CI: 1.0-10.0) were more likely to relapse. Conclusion: Relapse following interruption of targeted therapy is frequent in histiocytosis.
Further study may demonstrate patients with less frequent relapse, such as those with non-ECD disease treated with MEK inhibition.