6  Clinical Features and Management of Histiocytic Neoplasms in the Era of Targeted Therapies

6.1 Session Overview

Day 1, 3:45–4:15 p.m.

Anchored to an illustrative case of a woman with long-standing osteosclerotic long-bone lesions ultimately diagnosed as Erdheim-Chester disease [slide p.4–6], Gaurav Goyal walks through the clinical phenotypes, diagnostic workup, and principles of managing histiocytic neoplasms in adults. The talk’s stated learning objectives are to recognize and differentiate ECD, LCH, and Rosai-Dorfman disease (RDD); apply appropriate diagnostic testing including molecular studies; and understand modern treatment principles in the targeted-therapy era [slide p.3]. Key 2025 ASH data featured include the ECDGA international cohort of 1,044 ECD patients, a multi-institutional adult LCH chemotherapy series, and new work on safe discontinuation of targeted therapy [slide p.11, 19, 24–27].

6.2 Speaker Spotlight

  • Gaurav Goyal, MD — University of Alabama at Birmingham. Co-led international consensus guidelines for Erdheim-Chester disease (ECD) management; principal investigator on BRAF/MEK inhibitor trials in histiocytic neoplasms; advocate for multidisciplinary care models integrating hematology, oncology, dermatology, and neurology.

6.3 What’s New in 2025–2026

6.3.1 Classification and Diverse Phenotypes

Histiocytic disorders are rare (approximately 5–6 cases per million per year), frequently misdiagnosed, and require pattern recognition across organ systems [slide p.7]. They divide into hyper-inflammatory disease (hemophagocytic lymphohistiocytosis) and neoplastic disease; the neoplastic branch is further split into chronic (slow-growing) entities — LCH, RDD, ECD, and the juvenile/adult xanthogranuloma family — and aggressive (fast-growing) histiocytic, Langerhans cell, and interdigitating dendritic cell sarcomas [slide p.8]. Each of the three chronic entities has a characteristic organ-distribution map: LCH most often affects bone (80%) and endocrine/pituitary (50–70%) sites; ECD is a multisystem disease with long-bone osteosclerosis (>80%), retroperitoneal “hairy kidney” and aortic infiltration (40–60%), cardiac involvement (40–70%), and CNS disease (~40%); RDD classically presents with cervical/generalized lymphadenopathy (30–90%) [slide p.9].

Triangulated Diagnosis

Goyal frames diagnosis as a triangulation of pathology, radiographic, clinical, and molecular information — no single modality is sufficient in these rare, multisystem diseases [slide p.14].

6.3.2 MAPK Pathway Mutations Across Histiocytoses

Activating mutations in the MAPK/ERK pathway are the unifying molecular feature. Frequencies differ by subtype (Hershkovitz-Rokah et al., Haematologica 2025) [slide p.10]:

Table 6.1: MAPK/ERK alterations in histiocytic neoplasms [slide p.10]
Alteration Notes across subtypes
BRAF V600E ~50% in ECD; also prominent in LCH and mixed histiocytic neoplasms (MHN)
MAP2K1/2 ~15–20% across ECD, LCH, RDD, and JXG
KRAS / NRAS Enriched in RDD and MHN (up to 25–40% in some entities)
ARAF, BRAF fusions, NTRK1/RET fusions Recurrent in minor subsets
CSF1R, KIT, JAK3 Seen predominantly in JXG family disorders
ETV3::NCOA2 Defining fusion in indeterminate cell histiocytosis (ICH)

6.3.3 The ECDGA International Cohort (n = 1,044)

At ASH 2025 the Erdheim-Chester Disease Global Alliance (ECDGA) presented the largest ECD dataset to date: 1,044 patients from 11 countries spanning three decades (Blood 2025;146 Suppl 1:192) [slide p.11]. Bone was the most common first manifestation (22%), followed by retroperitoneal (15%), endocrine (13%), and neurologic (12%) disease. Across the full cohort, long-bone involvement was nearly universal (80%), with retroperitoneum (63%), periaortic disease (46%), CNS (38%), facial/orbit (36%), heart (35%), skin (29%), pituitary (27%), and lung (27%) also frequent. BRAF V600E was identified in ~60%, MAP2K1 in 9%, with smaller fractions of KRAS, NRAS, and other BRAF alterations; ~24% had no detectable mutation [slide p.11].

Treatment analysis within the same cohort demonstrated that targeted inhibitors — BRAFi, MEKi, and combined BRAFi+MEKi — produced higher response rates than non-targeted options (IFNα, chemotherapy, steroids, anti-cytokine agents), with BRAFi+MEKi yielding the highest response (~74% any response). Five-year overall survival was approximately 83%. On multivariate analysis, neurodegenerative disease (HR 4.16), associated hematologic malignancy pre-ECD (HR 2.97), elevated CRP at diagnosis (HR 3.83), and no response to any treatment line (HR 2.83) independently predicted worse survival [slide p.19].

6.3.4 Workup and Histopathology

A suspected or confirmed histiocytic neoplasm should trigger four parallel work-streams [slide p.12]:

  • Biopsy — needle or surgical, with expert pathology review, BRAF V600E testing, and NGS for MAPK/ERK mutations and fusion assays.
  • Imaging — “head-to-toes” PET-CT is the backbone; add brain and cardiac MRI for ECD and chest CT for pulmonary LCH.
  • Laboratory — CBC, chemistries, liver/kidney tests, inflammatory markers, and blood-based BRAF/MAPK testing.
  • Situational endocrine/immunologic testing — urine and serum osmolality for diabetes insipidus; pituitary, gonadal, and adrenal hormones; IgG4 and autoimmune panels (especially for RDD).

Immunohistochemistry remains central to distinguishing the three chronic entities: LCH expresses CD1a and langerin; ECD is Factor XIIIa–positive with xanthomatous features and fibrosis; RDD is S100- and OCT2-positive with the hallmark emperipolesis (lymphocytes within histiocyte cytoplasm) [slide p.13].

6.3.5 Treatment Landscape and Targeted Therapy

The therapeutic armamentarium spans targeted inhibitors, immunotherapy, chemotherapy, anti-cytokine agents, and supportive measures such as bisphosphonates, corticosteroids, and radiation — notably, vemurafenib and cobimetinib are the only on-label agents; everything else is used off-label [slide p.16].

6.3.5.1 BRAF and MEK Inhibitors

  • Vemurafenib received US FDA approval for ECD in November 2017 based on 26 patients (22 ECD, 4 LCH) with BRAF V600E disease and a 100% FDG-PET overall response rate (Diamond et al., JAMA Oncol 2018) [slide p.17].
  • Cobimetinib received US FDA approval in November 2022 for all histiocytic neoplasms based on 18 patients (12 ECD, 2 RDD, 2 mixed ECD/RDD, 2 LCH; 8 BRAF-wild-type) with an 89% overall response rate across ARAF, BRAF, RAF1, MEK1/2, KRAS, and NRAS alterations (Diamond et al., Nature 2019) [slide p.17].
Start Low, Go Slow with BRAF/MEK Inhibitors

Adverse effects range from nuisance to incapacitating and include rash (with increased risk of cutaneous malignancies, mandating dermatologic surveillance), arthralgias, fatigue, diarrhea, leg swelling, and lab abnormalities. Rare but serious toxicities include retinopathy and LVEF reduction, requiring baseline retinal exams and echocardiography. Goyal advises starting at ≤50% of the FDA-approved dose and points out that personalized dosing schedules and drug holidays are feasible [slide p.22].

6.3.5.2 Chemotherapy Still Matters in Adult LCH

At ASH 2025, Borre and colleagues (including Goyal) reported a multi-institutional retrospective study of 63 adults with MAPK-pathway altered LCH treated with frontline fixed-duration chemotherapy — most commonly cytarabine (Blood 2025;146 Suppl 1:2999) [slide p.20]. The overall response rate was 88.9% (complete response 25.4%, partial response 63.5%). Median progression-free survival was 2.61 years, and was substantially worse in multisystem compared with single-system disease (3-year PFS ~42% vs. higher for unifocal disease). The take-home: chemotherapy remains highly efficacious in adult LCH and is a reasonable alternative to targeted therapy.

6.3.6 A Risk-Stratified Treatment Algorithm

Goyal’s working algorithm pairs disease extent with molecular findings [slide p.21]:

  • Asymptomatic single-system, non-critical organ → observe with close follow-up; smoking cessation is essential for pulmonary LCH.
  • Symptomatic unifocal disease → limited surgery or local therapy (particularly for RDD and unifocal LCH).
  • Multifocal, multisystem, or critical-organ disease → confirm diagnosis and stage (path review + PET/CT ± brain MRI + molecular testing), then:
    • ECD → targeted therapy preferred; BRAF V600E → BRAFi; RAS/RAF/MEK mutations → MEKi or matched inhibitor; if targeted therapy unavailable → interferon, cladribine, etc.
    • LCH → systemic chemotherapy (cladribine or cytarabine) or targeted therapies.
    • RDD → immunosuppressants (lenalidomide, sirolimus) or MEK inhibitor, especially if RAS/MEK mutation identified.
  • Clinical trial participation should be considered at every decision point; specific kinase inhibitors (crizotinib, selpercatinib, larotrectinib, pexidartinib) apply when ALK, RET, NTRK, or CSF1R alterations are identified [slide p.16, 21].

6.3.7 Discontinuing Targeted Therapy: Can We Stop?

Illustrating the central management dilemma, the case patient had a dramatic response to vemurafenib (ataxia resolved, no longer wheelchair-bound) but — four years in — developed fatigue, falls, reduced cognition, and atrial fibrillation, prompting treatment cessation and subsequent disease recurrence in the lower extremities, managed successfully by resuming vemurafenib [slide p.18, 23, 28].

At ASH 2025 Yang and colleagues reported a 5-center retrospective study (n = 32) of patients with LCH, ECD, RDD, or mixed histiocytosis who had achieved a CR/PR on targeted therapy for ≥12 months before stopping (Blood 2025;146 Suppl 1:726) [slide p.24–26]:

  • 59% were on a MEK inhibitor (cobimetinib or trametinib), 28% on a BRAF inhibitor, and 13% on dual BRAF+MEK therapy.
  • Best responses: 65% CR, 36% PR; median treatment duration 35 months; median time from best response to discontinuation 23 months.
  • Reasons for stopping: patient preference (50%), toxicities (30%), other medical conditions (16%), cost (4%).
  • After a median 37-month follow-up, median PFS was 42 months and 2-year PFS 59%; 47% progressed, and 19% progressed within 6 months.
  • MEKi-containing regimens had substantially longer post-discontinuation PFS than BRAFi alone (51 vs. 10 months; HR 0.27, p = 0.022), and BRAF V600E disease relapsed faster than BRAF-wild-type disease (median 13.3 months vs. not reached; HR 4.04, p = 0.018).
  • Of the 15 progressors, 13 were re-challenged with targeted therapy (7 switched class) and all recaptured a response (2 CR, 5 PR).
BRAF V600E Is the High-Risk Phenotype for Stopping

BRAF V600E–mutant disease and other high-risk features may not be suitable candidates for discontinuation. Non-BRAF V600E (particularly MAP2K1-mutant) disease on a MEK inhibitor has the most durable off-treatment remissions [slide p.26].

6.3.8 Clonal Persistence Explains the Relapse Risk

Complementing the clinical data, Nashvi et al. (Blood 2025;146 Suppl 1:1495) used ddPCR on CD34+ marrow cells and single-cell sequencing to show that targeted therapy induces clinical responses but does not clear BRAF V600E hematopoietic clones — the BRAF V600E variant allele fraction in CD34+ cells was essentially identical in treatment-naive and MEK/BRAFi-treated patients [slide p.27]. This provides a biological rationale for why patients with BRAF V600E disease are prone to relapse when treatment is withdrawn.

6.3.9 Resources: Histio-Care Network and Partnerships

Goyal highlighted the Histio-Care Network (curehistio.org) linking Mayo Clinic (Rochester and Phoenix), University of Michigan, Moffitt, and UAB’s O’Neal Comprehensive Cancer Center for referral, education, and research collaboration [slide p.30]. He also outlined the broader ecosystem — the Histiocyte Society with its LCH, non-LCH, and HLH steering committees; NACHO (North American Consortium for Histiocytosis); ECHO (European Consortium for Histiocytosis); and the Histiocytosis Association and ECD Global Alliance patient-advocacy groups [slide p.31]. The Histiocytic Disorder Survivor Study (funded by Blood Cancer United and the American Cancer Society) is actively enrolling adults and children with ECD, LCH, RDD, or JXG to define long-term outcomes [slide p.32].

6.4 Clinical Pearls

Goyal closed with five take-home messages [slide p.29]:

  1. Histiocytic neoplasms are phenotypically diverse — ECD, LCH, RDD, and malignant histiocytic neoplasms each have distinctive organ predilections and require pattern recognition.
  2. Adequate staging and molecular assessment are vital — PET-CT “head-to-toes,” targeted imaging of brain/heart/lungs by subtype, and NGS for MAPK/ERK alterations and fusions are the foundation of modern care.
  3. Targeted therapies are promising but challenges remain — prolonged (often indefinite) treatment, cumulative toxicities, and access/cost issues limit their utility; starting at ≤50% of FDA-approved doses is a pragmatic strategy.
  4. Discontinuation may be feasible for selected low-risk patients (e.g., non-BRAF V600E disease on a MEK inhibitor with a durable ≥12-month response), but BRAF V600E disease is at high risk for rapid relapse and generally warrants continued therapy; nearly all relapsers recapture response on re-challenge.
  5. Multidisciplinary collaboration is key — through networks such as Histio-Care, NACHO, ECHO, and the Histiocyte Society — to advance both patient care and research in these rare diseases.
Vemurafenib and Cobimetinib Are the Only On-Label Agents

Every other drug used in histiocytic neoplasms — including dabrafenib, trametinib, cladribine, cytarabine, methotrexate, interferon, sirolimus, anakinra, and tocilizumab — is used off-label [slide p.16]. Clinicians, payors, and patients should be counseled accordingly.

6.5 Key References

  1. Hershkovitz-Rokah O, et al. Molecular landscape and therapeutic targets in histiocytic neoplasms. Haematologica. 2025;110(11):2603–2619. [slide p.10, 13]
  2. Goyal G, et al. Erdheim-Chester disease: consensus recommendations for evaluation, diagnosis, and treatment in the molecular era. Blood. 2020;135(22):1929–1945. [slide p.9, 12]
  3. Diamond EL, et al. Vemurafenib for BRAF V600–mutant Erdheim-Chester disease and Langerhans cell histiocytosis. JAMA Oncol. 2018;4(3):384–388. [slide p.17]
  4. Diamond EL, et al. Efficacy of MEK inhibition in patients with histiocytic neoplasms. Nature. 2019;567(7749):521–524. [slide p.17]
  5. Pegoraro F, et al. Clinical presentation and prognosis in Erdheim-Chester disease: analysis of an international cohort of 1,044 patients within the ECDGA network. Blood. 2025;146(Suppl 1):192. [slide p.11, 19]
  6. Borre CI, et al. Efficacy of frontline fixed-duration chemotherapy in MAPK-pathway altered adult Langerhans cell histiocytosis: a multi-institutional international retrospective study. Blood. 2025;146(Suppl 1):2999. [slide p.20]
  7. Yang X, et al. Discontinuation of targeted therapy in histiocytic neoplasms with durable response: a multicenter retrospective study. Blood. 2025;146(Suppl 1):726. [slide p.24–26]
  8. Nashvi M, et al. Clonal persistence of BRAF V600E under MEK inhibition in histiocytosis. Blood. 2025;146(Suppl 1):1495. [slide p.27]
  9. Goyal G, et al. Adult disseminated Langerhans cell histiocytosis: incidence, racial disparities, and long-term outcomes. Mayo Clin Proc. 2019;94(10):2054–2071. [slide p.9, 12]