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3909 Treatment Strategies and Outcomes of the Rare Histiocytic Disorders: Long-Term Results of the International Rare Histiocytic Disorders Registry (IRHDR)

Program: Oral and Poster Abstracts
Session: 201. Granulocytes, Monocytes, and Macrophages: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical Research, Diseases, Treatment Considerations, Registries, Myeloid Malignancies
Monday, December 9, 2024, 6:00 PM-8:00 PM

Oussama Abla1, Jennifer Picarsic2*, Jean-Francois Emile3,4*, Laura Galluzzo5*, Arnelle Lardizabal6*, Faten Abla6*, Jorge Braier7*, Guido Felizzia7*, Elena Sieni, MD8*, Francesco Pegoraro8*, Cor van den Bos9*, Barbara Degar, MD10, Faisal Razzaqi, MD11*, David Samuel11*, Zdenka Krenova12*, Olga Gryniewicz-Kwiatowska13*, Steven W. Allen14*, Rima Jubran15*, Itziar Astigarraga16*, Maria Kondyli17*, Michael Girschikofsky18*, Carl Friedrich Classen19*, Sheila Weitzman20*, Eli L. Diamond21* and James A. Whitlock20

1Division of Haematology/Oncology, The Hospital for Sick Children/University of Toronto, Toronto, ON, Canada
2Department of Pathology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA
3Paris-Saclay University, Versailles SQY University, EA4340-BECCOH, Versailles, France
4Assistance Publique–Hôpitaux de Paris (AP-HP), Ambroise-Paré Hospital, Pathology Department, Boulogne, France
5Hospital Nacional de Pediatria Garrahan, Beunos Aires, Argentina
6Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada
7Hospital Nacional de Pediatria Garrahan, Buenos Aires, Argentina
8Department of Hematology and Oncology, Meyer Children’s Hospital IRCCS, Florence, Italy
9Department of Hemato-Oncology Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands
10Dana Farber Cancer Institute and Boston Children’s Hospital, Boston, MA
11Valley Children’s Hospital, Madera, CA
12Department of Pediatric Oncology, University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
13Department of Pediatric Oncology, Children’s Memorial Health Institute, Warsaw, Poland
14UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
15Children’s Hospital Los Angeles, Los Angeles, CA
16Department of Pediatrics, Hospital Universitario Cruces, Osakidetza, IIS, Bizkaia, UPV/EHU, Barakaldo, Spain
17CHU Saint-Justine, Montreal, QC, Canada
18Ordensklinikum, Linz Elisabethinen, Austria
19University Children's Hospital, Rostock, Germany
20Division of Haematology/Oncology, The Hospital for Sick Children/University of Toronto, Toronto, Canada
21Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY

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.

Disclosures: Emile: Recordati: Honoraria; Deciphera: Honoraria; Servier: Honoraria; Oseus: Honoraria. Razzaqi: Jazz Pharmaceutical: Speakers Bureau; Sobi, Inc: Speakers Bureau. Gryniewicz-Kwiatowska: Recordati Rare Diseases: Other: Registration fee; Bayer: Other: Travel and accommodation costs refundation; Guerbet: Other: Clinical trial. Whitlock: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH