Treatment Strategies and Outcomes of the Rare Histiocytic Disorders: Long-Term Results of the International Rare Histiocytic Disorders Registry (IRHDR)

Background: Rare histiocytic disorders (RHDs) are diverse myeloid neoplasms that include Juvenile xanthogranuloma (JXG), Erdheim-Chester Disease (ECD), Rosai-Dorfman disease (RDD), Malignant histiocytoses (MH), ALK+ histiocytosis, indeterminate cell histiocytosis (ICH) and mixed histiocytosis (MXH). Methods: IRHDR data were collected retrospectively and prospectively including clinical features, diagnosis with central pathology (CP) review, treatments and outcomes. Descriptive statistics of data registered during the first 9 years are presented. Results: From April 2015 - June 2024, 214 patients were enrolled, 133 completed CP review; 111 confirmed RHD and 22 excluded. We present 192 RHD patients; median age at diagnosis was 11 years (0.11-77 years), 112 (58.3%) were males. JXG family patients (n=66): 2 KRAS+, 1 BRAF-other+, 1 MAP2K1+, 1 CSFR1+. Thirty-six were cutaneous (2 had JMML): 11 (31%) did well with observation, and 13 (36%) severe cases responded well to surgery +/- steroids. One progressive nodular had partial response (PR) to MEK-inhibitor (MEK-I). Five had reticulohistiocytoma: 2 had observation (complete response - CR), and 2 oral chemotherapy (1 PR; 1 resistant had PR after everolimus). Sixteen were systemic: 3 (19%) had vinblastine/steroids - LCH-III (CR), 1 surgery (CR), and 2 observation (1 CR; 1 stable disease - SD); 7 (44%) had relapsed/refractory (R/R) disease: 2 had cladribine or surgery (PR), and 5 others were refractory to cladribine or clofarabine (1 PR after MEK-I). Two systemic JXG were post-ALL, 1 died from toxicity and 1 is alive (SD). Three had adult JXG: 2 musculoskeletal had surgery/observation (CR), and 1 cutaneous had RET-kinase inhibitor (CR). Five intraocular: 3 had surgery (CR/PR), 2 resistant to oral chemotherapy had MEK-I (1 CR; 1 SD after intrarterial melphalan). ECD patients (n=41): 16 BRAF-V600E+, 3 MAP2K1+, 1 KRAS+. Five were localized, 19 systemic, and 15 CNS. BRAF/MEK-I induced more responses (81% overall response rate - ORR) than conventional therapies (interferon-α, chemotherapy, anakinra, radiation; 55% ORR) as first-line or salvage therapy. RDD patients (n=51): 2 BRAF-V600E+, 2 KRAS+, 1 MAP2K1+. Twenty-four were nodal: 7 (29%) had observation (SD), 12 (50%) had surgery +/- steroids (variable responses), 1 had clofarabine (PR), and 1 had chemotherapy followed by MEK-I (died from progressive disease - PD). Twenty-seven were systemic: 11 (41%) had oral chemotherapy (73% ORR), 3 (27%) R/R had cladribine (all PR); 2 had surgery (75% ORR), 5 observation (40% ORR); 2 had indomethacin or radiotherapy (SD); 5 (19%) R/R received BRAF/MEK-I (60% ORR); 1 refractory to surgery and cladribine (died from PD). MH patients (n=16): 3 KRAS+, 1 BRAF-V600E+. Twelve histiocytic subtype, 2 Langerhans cell, 1 interdigitating cell and 1 indeterminate cell tumour. Eight MH were localized: 3 had surgery +/- chemotherapy (2 CR, 1 relapse had PDL-1 inhibitor), 3 steroids +/- chemotherapy (1 CR, 1 SD, 1 PD with CR after cladribine). One R/R to cladribine/radiotherapy (SD), and 1 post-ALL MH was refractory to cladribine (died from PD). Seven MH were systemic: 3 had ALL-like therapy (2 CR, 1 SD), 2 chemotherapy + steroids (1 SD, 1 died from PD), and 1 had MEK-I (PR then relapsed). One with CNS+ MH had surgery followed by BRAF/MEK-I (CR). ALK+ histiocytosis patients (n=7): 5 localized: 2 musculoskeletal had observation (1 CR, 1 SD), 1 ocular had crizotinib (PR), 1 localized to the trachea had surgery (CR). Two CNS+ had LCH-III +/- surgery (1 CR; 1 R/R had PR to lorlatinib then relapsed). ICH patients (n=6): 1 BRAF-V600E+, 1 BRAF-other+, 1 MAP2K1+. 100% ORR was seen in 4 localized with observation or steroids, and 2 systemic/CNS with LCH-III. MXH patients (n=5): 2 BRAF-V600E+, 1 BRAF-other+, 1 MAP2K1+. One had localized RDD/LCH, 4 were systemic: 3 ECD/LCH, 1 ECD/RDD. Most MXH were refractory to conventional therapies, with durable responses to BRAF/MEK-I. After a median follow-up of 29.6 months, 94.8% of patients (n=182) are alive in CR/SD. Event-free survival is 84%; 28 (15%) relapsed. Five patients died, 4 from PD, and 1 from toxicity. Conclusions:RHDs are characterized by pathological, clinical and molecular diversity, with variable responses to conventional therapies. Most refractory systemic cases respond to ALK/BRAF/MEK-I. Further mutational analysis may identify novel targeted therapies, which could be helpful for resistant RHDs.