Histiocytic Disorder Research Articles

Failure of crizotinib based systemic treatment in ALK positive histiocytosis involving the central nervous system: a case report and literature review

BackgroundAmong the histiocytic disorders, anaplastic lymphoma kinase (ALK)-positive histiocytosis emerged in 2008. As more and more cases of the novel entity are reported, our understanding of it is deepened. However, only a few cases with central nervous system (CNS) involvement have been reported. Furthermore, the lesion in the suprasellar region has not been documented. Case presentationWe presented a case of ALK-positive histiocytosis involving the suprasellar region of a one-year-and-four-month-old boy. Through clinical, neuropathological, and genomic analyses, the patient was diagnosed with ALK-positive histiocytosis. After lesions were resected he started treatment with a combination of the three compounds vincristine, prednisolone, and crizotinib, but they did not work. Cytarabine was then added as an additional chemotherapy drug for him, and the lesions in the brain and lungs were shrunk by combining treatment of crizotinib, dexamethasone, vincristine, and cytarabine according to the RECIST (esponse Evaluation Criteria In Solid Tumours).ConclusionsAdditional adjuvant chemotherapy drugs are needed when ALK-inhibitor treatment is ineffective.

Cutaneous Rosai-Dorfman Disease – A Case Report and Review of Literature

Rosai–Dorfman disease (RDD), or Sinus Histiocytosis with Massive Lymphadenopathy (SHML) is a self-limiting, rare benign proliferative disorder of histiocytes in the lymph nodes with occasional extra-nodal involvement of the skin. Isolated Cutaneous Rosai-Dorfman disease(C-RDD) without node involvement is an exceedingly rare occurrence. Despite its unique characteristics, the diagnosis of Cutaneous Rosai Dorfman disease is hampered by its variable clinical presentation, misleading histopathological patterns, and the absence of lymphadenopathy. Herein we present a case report of Cutaneous Rosai-Dorfman disease without any lymph node involvement.

Juvenile and adult xanthogranuloma: A 30-year single-center experience and review of the disorder and its relationship to other histiocytoses

BackgroundJuvenile xanthogranuloma (JXG) is the most common type of non-Langerhans cell histiocytosis whose cell of origin, etiology and pathogenesis are not fully understood. We aimed to provide an update on histopathologic and immunophenotypic profile of this well-characterized entity whose relationship to the other histiocytoses has received renewed attention in light of recent molecular genetic studies. Materials and methodsA retrospective review of all the cases with the pathologic diagnosis of “xanthogranuloma” was performed on our archives from 1989 to 2019. ResultsA total of 525 patients with 547 lesions diagnosed as JXG were identified with the median age of 4.5 years, a male predominance (M:F ratio 1.3:1) and a predilection for the head and neck region (40.8%). Cutaneous lesions comprised 76.8% cases and another 15.7% presented within soft tissues. The most common non-soft tissue, extracutaneous lesions included the brain (2.6%), and lungs (1.8%). Three basic histopathologic patterns were identified: early classic (EJXG) (14.2%), classic (CJXG) (45.3%), and transitional JXG (TJXG) (40.5%). Multinucleated giant cells, either Touton or non-Touton, were most frequently present in CJXG followed by TJXG. Mitosis was rare (<1/10 high-power field) among different patterns. There was an association among the patterns and lymphocytic infiltrates (P = 0.036), and presence of Touton or non-Touton giant cells (P < 0.001 for both) but not for mitotic count (P = 0.105) or eosinophilic infiltrates (P = 0.465). Additionally, there was a correlation between age groups and presence of non-Touton giant cells (P = 0.012) but not for Touton cells (P = 0.127). We have demonstrated that immunophenotypic expression of the lesion was not associated with age at diagnosis nor morphologic pattern: factor XIIIa 192/204 (94.1%), CD11c 75/77 (97.4%), CD4 82/84 (97.6%), CD68 200/201 (99.5%), CD163 15/15 (100%), CD1a 1/110 (0.9%), S-100 48/152 (31.6%), CD31 15/21 (71.4%), and vimentin 104/105 (99.0%). ConclusionWe have documented in a substantial series of cases of JXG that there is a correlation between one of the three basic histopathologic patterns with age at diagnosis, but with a consistent immunophenotype among the three patterns. Considering sensitivity and specificity rates, we suggest that a combination of CD11c, CD4, CD1a and either CD163 (preferred) or CD68 stains provides more specific diagnostic yield in the differentiation of JXG from other histiocytic disorders. JXG is also discussed in terms of its relationship and distinction from other similar histiocytic disorders in the context of MAPK/ERK pathway mutations.

MRNA sequencing analysis and growth inhibitory effects of palbociclib on cell lines from canine histiocytic proliferative disorders.

Canine histiocytic proliferative disorders include aggressive and fatal diseases, such as histiocytic sarcoma (HS) and histiocytosis (SyH). The molecular mechanisms underlying cell proliferation need to be elucidated for the development of effective treatments. In the present study, mRNA expression levels were comprehensively analysed in cell lines derived from localized HS, disseminated HS, SyH and Langerhans cell histiocytosis (LCH) in dogs. Based on the results obtained, the growth inhibitory effects of palbociclib, a CDK4/6 inhibitor, were verified with the cell lines in vitro and in xenograft mouse model. Hierarchical clustering and principal component analysis plots of mRNA expression profiles divided the cell lines into three groups: a localized HS group, disseminated HS/SyH group, and LCH. The results of an ingenuity pathway analysis suggested that the MAPK signalling pathway was activated in the localized HS and LCH cell lines, and the PI3K signalling pathway in the disseminated and localized HS cell lines. In all cell lines, the expression of the tumour suppressor genes TP53, CDKN2A and CDKN1A was down-regulated, whereas that of Rb was preserved. In vitro assessments revealed the growth inhibitory effects of palbociclib in all cell lines examined. In a xenograft mouse model using a cell line from disseminated HS, palbociclib exerted significant growth inhibitory effects. These results suggest the potential of palbociclib as a therapeutic drug candidate for the treatment of malignant histiocytic proliferative disorders of the dog.

Rosai\u2013Dorfman\u2013Destombes disease of the nervous system: a systematic literature review

BackgroundRosai–Dorfman–Destombes disease (RDD) is a rare histiocytic disorder with heterogeneous clinical manifestations and rare neurologic involvement. The existing clinical literature about neurologic RDD has yet to be critically examined.MethodsWe performed a four-database English-language systematic literature search for cases of RDD neurohistiocytosis, excluding secondary literature. Individual patient data for neurologic symptoms, disease sites, treatments, and responses were captured. Responses to first-line and second-line surgical interventions, post-surgical radiotherapy, and systemic therapies were analyzed.ResultsAmong 4769 articles yielded by literature search, 154 articles were fully reviewed, containing data on 224 patients with neurologic RDD. 128 (83.1%) articles were single case reports. 149 (66.5%) patients were male, 74 (33.5%) female, with a median age of 37.6 years (range 2–79). Presenting neurologic symptoms included headache (45.1%), focal neurological deficits (32.6%), visual symptoms (32.1%), and seizures (24.6%). RDD involvement was multifocal in 32 (14.3%) cases. First-line treatment involved resection in 200 (89.6%) patients, with subsequent progression in 52 (26%), including 41 (78.8%) with unifocal disease. No difference was observed in progression-free survival comparing post-operative radiotherapy to no radiotherapy following partial resection. Chemotherapy given alone as first-line treatment led to complete or partial response in 3/7(43%) patients. Second-line treatments led to complete or partial response in 18/37(37.5%) patients. Mutational data were reported on 10 patients (4.46%).ConclusionsThis review highlights the limited published data about neurologic RDD, which presents with varied symptomatology and outcome. Further study is needed about its mutational landscape, and more effective therapies are needed for recurrent and refractory disease.

Coexistent Rosai Dorfman disease and Langerhans cell histiocytosis in an Orbital mass: A Case Report.

Rosai Dorfman disease (RDD) is a rare benign histiocytic proliferative disorder of lymph node sinuses. Langerhans cell histiocytosis (LCH) is a solitary or multisystem clonal proliferation of abnormal dendritic cells (Langerhans cells) with varied presentations. The co-occurrence of these two entities is quite rare. A six-year-old boy presented with multiple mass lesions in the neck since two years and a nodular lesion in right upper eyelid for the past 4 months. He was diagnosed with tubercular lymphadenitis 2 years back, and was given a course of anti-tubercular therapy (ATT) elsewhere. No improvement was seen. Fine needle aspiration cytology (FNAC) of the cervical lymph nodes revealed reactive lymphadenitis while lymph node biopsy showed features of RDD. Excision biopsy of the orbital mass showed features of both RDD and LCH. The patient was started on tablet prednisolone. Six months later, complete resolution of lymph node enlargement and remaining orbital mass was noted. Post operative contrast enhanced Magnetic Resonance Imaging of head and neck was normal. The coexistence of RDD and LCH may be a result of divergent differentiation from a common lineage or a de novo phenotypic evolution.

Extranodal Rosai-Dorfman-Destombes disease mimicking renal cell carcinoma: a case report and review of literature

Rosai-Dorfman-Destombes disease (RDD) is an uncommon histiocytic disorder of unknown aetiology. Extranodal involvement occurs in a significant proportion of patients but involvement of the kidney is rare. Here we present a case report of extranodal RDD of the kidney. Imaging revealed a heterogeneously enhancing solid mass lesion in left renal hilum infiltrating renal medulla and deeper layers of renal cortex. With the clinical diagnosis of suspected left renal cell cancer, laparoscopic left radical nephrectomy was performed. Macroscopic examination showed specimen covered with Gerota’s fascia and perinephric pad of fat. Renal capsule could be easily split off. On cut section, ill circumscribed solid lesion having variegated appearance with areas of necrosis and haemorrhage, involving middle and lower pole, was noted. Renal sinus appeared to be involved. Microscopic examination showed sheets of histiocytes with abundant eosinophilic to vacuolated cytoplasm. There was emperipolesis of intact lymphocytes. Also, seen were sheets of plasma cells, lymphocytes with intervening dense hyalinised stroma. Retro peritoneal lymph nodes and para-aortic lymph nodes also showed similar histological picture. Immunohistochemistry showed that the histiocytes were positive for S100 and CD68. IgG4-positive plasma cells were not seen. These findings showed that the lesion represented and extranodal RDD of the kidney. Although rare, extranodal RDD should also be included in the differential diagnosis of a renal mass and frozen section be advised whenever feasible.

A258 ROSAI-DORFMAN0-DESTOMBES DISEASE: A RARE CAUSE OF OBSTRUCTIVE JAUNDICE

BackgroundRosai-Dorfman-Destombes Disease (RDD) is rare histiocytic disorder that is most frequently seen in children and young adults. Gastrointestinal involvement is reported in <1% of cases and typically involves the small bowel and colon. Pancreatic and hepatic involvement has been previously reported but is extremely rare.AimsTo describe a case of obstructive jaundice in the setting of a very rare histiocytic disorder known as RDD.MethodsCase ReportResultsA 59-year old previously healthy male of Asian descent presented with obstructive jaundice. Initial imaging demonstrated intra and extrahepatic biliary duct dilation with concurrent diffuse enlargement of the pancreas compatible with autoimmune pancreatitis. Endoscopic retrograde cholangiopancreatography (ERCP) was performed with stenting and biopsy. ERCP demonstrated a distal common bile duct stricture with biopsies suggestive of low grade reactive changes and inflammation. Subsequent endoscopic ultrasound (EUS) guided biopsy of the pancreas showed active and chronic inflammation, necrosis, and atrophic pancreatic tissue, with no definitive evidence of autoimmune pancreatitis (Figure 1). Ca-19-9 and IgG4 were normal. He was treated with a course of prednisone and responded well, with repeat CT imaging showing almost complete resolution of the previously demonstrated pancreatic changes. A diagnosis of autoimmune pancreatitis was made. He re-presented 6-months later, however, with fatigue and repeat imaging now displayed lymphadenopathy in the neck, chest, and abdomen, and a bulky pancreatic head with associated hepatomegaly. Lymph node excisional biopsy confirmed the diagnosis of RDD with the presence of scattered histiocytic cells showing emperipolesis with a low number of IgG4 positive cells (Figure 1). The patient was promptly initiated on prednisone and rituximab and has since then had excellent clinical response.ConclusionsRDD is a rare non-Langerhans cell histiocytosis of unknown etiology that has a prevalence of 1:200 000. RDD clinically presents with painless bilateral cervical lymphadenopathy and can manifest with both nodal and extra nodal involvement. The most common sites of extra nodal disease are the skin and central nervous system, but rarely, can also present with pancreatic involvement. The use of fine needle guided biopsy in diagnosing RDD with extra nodal disease can be limited by low yield, sclerotic tissue, or non-diagnostic findings. For this reason, RDD with pancreatic involvement can masquerade as autoimmune pancreatitis, pancreatic malignancy and IgG4-related disease.This case report raises awareness about RDD with pancreatic and biliary involvement, a rare entity, that can present with obstructive jaundice. Figure 1: Histological sections of lymph node(left) with hystiocytic cells showing emperipolesis(arrow) and pancreas(right) showing active and chronic inflamation, necrosis and atrophyFunding AgenciesNone

Establishment and characterisation of cell lines and xenograft mouse models of canine systemic histiocytosis and disseminated histiocytic sarcoma.

Canine histiocytic proliferative disorders include reactive diseases (histiocytosis) and neoplastic diseases (histiocytic sarcoma [HS]), however discrimination is challenging due to their overlapping pathological features. In the present study, novel cell lines and xenograft mouse models of systemic histiocytosis (SyH) and disseminated HS were established, and examined together with cell lines previously established from localized HS and Langerhans cell histiocytosis (LCH). The chromosomal numbers of the SyH and HS cell lines were abnormal, and their population doubling time and morphological features were comparable. Immunophenotypically, SyH and HS cells were CD204+/E-cadherin+ in vitro and in vivo, like their original tissues. Western blot analysis for E-cadherin revealed an immunopositive band of full-length E-cadherin (120 kDa) in cultured cells of localized HS and LCH but not in disseminated HS and SyH; expression level was weaker in localized HS than in LCH. An immunopositive band of fragmented E-cadherin (45 kDa) was detected in cell lines of disseminated HS and SyH. These results suggest that cultured SyH cells have features that are similar to disseminated HS, including chromosomal aberration, high proliferation activity, weak cell adhesion, and expression of fragmented E-cadherin. Fragmentation of the E-cadherin cell adhesion molecule may be associated with the loss of cell adhesion and increased abilities of invasion and migration of neoplastic cells. The established cell lines and xenograft mouse models will aid in understanding the pathogenesis and developing novel treatments of canine histiocytic proliferative disorders.

A Risk Model Composed of Complete Blood Count, BRAF V600E and MAP2K1 Predicts Inferior Prognosis of Langerhans Cell Histiocytosis in Children.

BackgroundIn children, Langerhans cell histiocytosis (LCH), which is the most prevalent histiocytic disorder, exhibits a wide variety of manifestations and outcomes. There is no standard prognosis evaluation system for LCH. We investigated the combined predictive significance of complete blood counts (CBCs), BRAF V600E and MAP2K1 in childhood LCH.MethodsA cohort of 71 childhood LCH patients was retrospectively studied. The prognosis predictive significance of platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), systemic inflammation response index (SIRI), systemic immune inflammation index (SII), BRAF V600E, and MAP2K1 were analyzed.ResultsHistiocyte Society (HS) classification of LCH patients was correlated with NLR, SIRI, and progression free survival (PFS), bone involvement was correlated with SIRI, liver involvement was correlated with NLR, SII, SIRI, and PFS, spleen involvement was correlated with SIRI, lung involvement was correlated with NLR and PFS, CNS involvement was correlated with PFS, while BRAF V600E was correlated with PLR, NLR, SIRI, SII, PFS, and OS (p <0.05). MAP2K1 was correlated with NLR, SIRI, PFS, and OS (p <0.05). Elevated NLR, PLR SIRI, and SII predicted inferior PFS and OS (p <0.05). PLR, NLE, SIRI, SII, BRAF V600E, and MAP2K1 were used to establish a risk model for stratifying the LCH patients into 3 different risk groups. Respective median PFS for low-, mediate-, and high-risk groups were not reached, 26, and 14 months (p <0.001), and all median OS were not reached (p <0.001).ConclusionThe risk model combined with CBCs, BRAF V600E, and MAP2K1 might be a promising prognostic system for LCH in children.

Impact of a Multidisciplinary Tumor Board on the Care of Patients with Histiocytic Disorders: The Histiocytosis Working Group experience.

IntroductionHistiocytic disorders pose significant diagnostic and management challenges for the clinicians due to diverse clinical manifestations and often non-specific histopathologic findings. Herein, we report the tumor board experience from the first-of-its-kind Histiocytosis Working Group (HWG).Materials and MethodsThe HWG was established in June 2017 and consists of experts from 10 subspecialties that discuss cases in a multidisciplinary format. We present the outcome of tumor board case discussions during the first 2 years since its inception (June 2017-June 2019).ResultsForty cases with a suspected histiocytic disorder were reviewed at HWG during this time period. Average number of subspecialties involved in HWG case discussion was 5 (range, 2-9). Histiocytosis Working Group tumor board recommendations led to significant changes in the care of 24 (60%) patients. These included change in diagnosis (n = 11, 27%) and change in treatment (n = 13, 33%).ConclusionOur report highlights the feasibility of a multidisciplinary tumor board and its impact on outcomes of patients with histiocytic disorders.

JUVENILE XANTHOGRANULOMAS MASS CAUSED TESTICULAR TORSION A RARE OCCASION IN PEDIATRICS: A CASE REPORT

Background: Juvenile xanthogranulomas (JXG) is a histiocytic disorder, in a child below 5 years of age. Xanthogranulomatous orchitis (XGO) is a rare disease, it is an extremely rare inflammatory non-neoplastic destructive lesion of the testis, and a few cases have been reported to date. Aim: We reported a case of JXO presenting as a solitary mass in the left testicle causing testicular torsion in an 11-month-old child without manifestations of JXG elsewhere. Case presentation: the patient presented with an acute history of pain in his left hemi scrotum. An ultrasound study showed a 10 x 13 mm round tumor with a distinct boundary between the tumor and the irregular heterogeneous testicular tissue, Doppler ultrasound images submitted changes suggestive of testicular torsion. Surgery was performed that showed a necrotic left testicle, with and tumor-like lesion attached to the cord and overlapping the body of epididymis. A left orchiectomy was performed. Histopathology reported that the architecture of the testis was lost. Two cut sections in the mass nodular collections of abundant xanthomatous foamy macrophages. Xanthogranulomas was suggested. Conclusion: Because of the aggressive nature of this disease, curative treatment is by either radical or partial orchiectomy considered the goal standard for the final management outcome.

A rare case of pure cutaneous Rosai-Dorfman disease

Rosai-Dorfman disease (RDD) is a rare but usually benign non-Langerhans cell histiocytic disorder which commonly affects lymph nodes and frequently present with bilateral painless enlarged cervical lymph nodes with systemic symptoms. Although extra nodal tissue involvement is seen in considerable proportion, purely cutaneous involvement without affecting lymph nodes is very rare and forms a diverse clinical entity. Histopathology with immunohistochemical staining remains gold standard in diagnosing this rare entity. Different treatment modalities have been tried in case reports and treatment response is variable. Here we report a case of pure cutaneous RDD in a 21-yearold young female who was referred for staged excision.

Rosai-Dorfman Disease of Bone and Soft Tissue.

Rosai-Dorfman disease is a rare histiocytic proliferative disorder of unknown pathogenesis that may be diagnostically difficult in extranodal sites. It is commonly an unsuspected diagnosis when arising in bone and soft tissue, especially when it presents without associated lymphadenopathy. Its variable clinical presentation and nonspecific imaging findings make the diagnosis quite challenging, particularly in small biopsies. The problem is compounded by its less-characteristic histomorphologic features in comparison with nodal disease. Awareness of the potential diagnostic pitfalls in Rosai-Dorfman disease of bone and soft tissue should raise the degree of diagnostic accuracy. To review the clinical manifestations, imaging characteristics, and histomorphologic features of Rosai-Dorfman disease of bone and soft tissue along with a brief discussion of its differential diagnosis, pathogenesis, and current management. Thorough review of the literature with focus on clinical manifestations, imaging findings, key histomorphologic features, pathogenesis, and treatment. The diagnosis of Rosai-Dorfman disease of bone and soft tissue may be quite challenging because of its variable clinical presentation and nonspecific imaging findings. It may be asymptomatic without systemic manifestations or associated lymphadenopathy. The definitive diagnosis relies on histopathologic identification of the characteristic S-100-positive histiocytes demonstrating emperipolesis. Bone and soft tissue lesions tend to have lower numbers of characteristic histiocytes and less conspicuous emperipolesis and often demonstrate areas of fibrosis or storiform spindle cell areas resembling fibrohistiocytic lesions. Awareness of these unusual features is necessary in order to consider Rosai-Dorfman disease in the differential diagnosis when confronting these rare and often misleading lesions.

Juvenile xanthogranulomas in Asian children.

Juvenile xanthogranuloma (JXG) is the most common non-Langerhans cell histiocytic disorder. It can rarely be associated with systemic involvement. There is a paucity of literature on JXG in Asian children. We aim to describe the epidemiology, clinical features, systemic associations, histological features and outcome of a cohort of Asian children with JXG, and review the literature on the condition. We retrospectively reviewed the demographic, clinical and histological data of patients less than 16 years of age, diagnosed with JXG at our tertiary pediatric hospital between January 2002 and April 2019. A total of 147 children with JXG were identified, with a slight male preponderance of 53.1%. The median age of the onset was 15.5months, with 69.4% presenting before 2 years of age. There was no racial predilection. The most frequently involved site was the head and neck region (44.2%). The majority of patients (76.2%) presented with a solitary lesion. Spontaneous resolution was documented in 57.7% of our patients with mean duration to resolution of 18.8months. The proportion and speed of resolution did not differ in children with single or multiple lesions. No ophthalmologic complications were detected in our study cohort. JXG in children is generally limited to the skin and is rarely associated with systemic involvement, including the eye. Unless clinically indicated, the results from our study does not support routine screening for juvenile myelomonocytic leukemia, eye or systemic complications, even in the setting of multiple cutaneous JXGs.

Xanthogranuloma of nose in an adult: an uncommon presentation

&lt;p class="abstract"&gt;Xanthogranuloma is a relatively rare histiocytic cutaneous disorder that typically affects the pediatric age group. Its occurrence in adulthood is still rarer with only a handful of cases on the record. The present case report describes a case of adult-onset xanthogranuloma in a 49 years old lady who presented to the otorhinolaryngology clinic with a 6 months history of a nodule on the left side of the columella. There was no history of associated pain or bleeding from the site. Local examination revealed a 0.6×0.6 cm, non-tender, soft-to-firm, pinkish dome-shaped lesion with rounded edges. No similar lesions were found elsewhere. Excisional biopsy of the lesion was performed and microscopy showed a dermal lesion comprising of sheets of histiocytes admixed with lymphoplasmacytic infiltrate, touton giant cells and few spindle cells. A diagnosis of xanthogranuloma was rendered. A number of lympho-histiocytic lesions comes in the differential diagnosis of xanthogranuloma and hence it is important to be aware of such unusual presentations in order to make correct histological diagnosis.&lt;/p&gt;

BRAF Fusions in Histiocytic Disorders: Frequency and Clinical Characteristics

▪Background: Activation of extracellular-signal regulated kinase (ERK) is almost universal in histiocytic disorders and is driven by genomic alterations in the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinases (PI3K) pathways. While BRAFV600E mutations are well described in histiocytic disorders, less is known about BRAF fusions. The goal of our study is to describe the frequency and clinical characteristics of patients harboring BRAF fusions.Methods: We included patients with a diagnosis of histiocytic disorder seen at our institution from November 2016-June 2021. Only those who had adequate BRAF testing were included. The following were considered adequate BRAF testing: 1) unequivocally positive BRAF V600E immunostain with or without molecular confirmation; 2) successful multigene next generation sequencing (mostly Tempus â or FoundationOne â) if BRAF V600Eimmunostain was equivocal or negative. We also searched the literature for similar cases and compared BRAF fusions found in histiocytic disorders to those found in solid tumors and other hematologic conditions.Results: One hundred and twenty-six patients were included in this study. BRAF fusions were detected in 7 (6%) patients. The median follow-up for these patients was 1.4 years (95% CI: 0.4-not reached). The frequency according to disease subtypes is as follows: Erdheim-Chester disease (ECD; 2/46 [4%]), Langerhans cell histiocytosis (LCH; 1/41 [2%]), adult or juvenile xanthogranuloma (AXG/JXG; 4/7 [57%]), and histiocytic or Langerhans cell sarcoma (HS/LCS; 0/9 [0%]). The median age at diagnosis for our study cohort was 34 years (range, 7-81 years) and 5 were females. The clinical characteristics and nature of BRAF fusions of our 7 patients plus additional 13 cases from the literature are shown in Table 1. For the final cohort of 20 patients with BRAF-fusions, the median age was 16 years (range, 0.5-81 years) and most (56%) were females. The distribution by histiocytic subtypes is as follows: AXG/JXG (45%), LCH (40%), ECD (10%), HS/LCS (5%). Two patients received cobimetinib as frontline treatment in our cohort and achieved partial responses. Of these two patients, one completed 12 cycles (12 months) of cobimetinib and had a sustained PR while the other patient received 2 cycles before having to hold therapy due to intolerable adverse effects despite dose reduction. From literature review, another patient (LR-12) received cobimetinib as second line treatment and achieved complete response. We found 15 unique BRAF gene fusions with 4 being recurrent. Except for AGAP3-BRAF, none of these BRAF fusions in histiocytosis has been reported in solid tumors or hematologic conditions to date.Conclusions: BRAF gene fusions occur rarely (<5%) in histiocytic disorders. The only exception is AXG/JXG where more than half of the patients harbor BRAF gene fusions. These gene fusions are mostly distinct to histiocytosis and not found in solid tumors or other hematologic conditions. [Display omitted] DisclosuresBennani: Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board; Verastem: Other: Advisory Board.

Tumor Mutational Burden in Histiocytic Neoplasms

▪BackgroundHistiocytic disorders are rare hematologic neoplasms characterized by their high clinical heterogeneity. Evidence of constitutive activation of the mitogen-activated protein kinase (MAPK) pathway in a number of these disorders has led to the increasing use of BRAF- and MEK-inhibitors as a therapeutic strategy. Response to these therapies is not universal and additional effective treatment options are required. Immune checkpoint inhibitors have proven effective for a wide array of malignancies. Tumor mutational burden (TMB), the total number of somatic pathogenic variants per coding region in a tumor genome, is a clinical biomarker associated with response to immunotherapy. We have previously reported preliminary findings of low TMB in a small cohort of patients with histiocytic neoplasms (Goyal G et al. Blood 2019). In this study, our aim was to confirm the findings in a larger clinical cohort using next generation sequencing studies.MethodsA retrospective review of adult patients consecutively seen at Mayo Clinic from 2017 to April 2021 and diagnosis of a histiocytic neoplasm was performed. Electronic records were queried for demographic and laboratory data of all patients who consented to undergo tumor-tissue next-generation sequencing with the Tempus-xT ® or xO ® assay (Chicago, IL), throughout the course of their evaluation. TMB was reported as the number of nonsynonymous mutations per coding area of a tumor genome. TMB across groups was compared via an independent-samples T-test or via analysis of variance and post hoc subgroup testing via Turkey's Test as required.ResultsSeventy-three patients were included in the study. Individual diagnoses included: Erdheim-Chester disease (ECD) in 31.5% (n=23), including 3 patients with overlap features of ECD and other histiocytoses; Rosai Dorfman disease (RDD) in 28.8% (n=21); Langerhans cell histiocytosis in 21.9% (n=16), histiocytic sarcoma (HS) in 5.5% (n=4), and other histiocytic neoplasms in 12.3% (n=10) including adult xanthogranuloma, xanthoma disseminatum, undifferentiated histiocytoses, and one case of Langerhans cell sarcoma.Median tumor percentage on analyzed samples was 30% (range 10%-90%) and was ≤20% in 29 samples. TMB was <1.0 mutations per megabase (mpMb) in 42.5% (n=31) and >5.0 mpMb in only 6 cases. Median TMB was 1.58 (range 0 - 5.26) for ECD, 1.08 (range 0 - 6.3) for LCH, 0.2 (range 0 - 5.8) for RDD, 3.19 (range 1.67 - 6.8) for HS, and 1.6 (range 0 - 7.5) for other histiocytic neoplasms (Figure 1). No clear association between increasing TMB and number of systems with histiocytic infiltration was observed (Figure 2). A significant increase in TMB was observed among the 5 cases of sarcoma as compared to the rest of the cohort (p=0.014). When not considering sarcomas, no differences were observed in TMB between patients with ECD, LCH, RDD or other histiocytoses (F=0.775; p=0.512).ConclusionIn this large cohort of histiocytic disorders, TMB was low compared to that historically seen in other neoplasms though this is likely influenced by tumor purity ≤20% in 29 cases. Only 6 tumors had TMB reports with mpMb above the threshold thought to be associated with an increased likelihood of response to PD-1/PDL1-targeted therapies (>5 mpMb). Our results suggest a low likelihood of response among histiocytic disorders using immune checkpoint inhibitors. Further exploration among malignant histiocytoses (HS and Langerhans cell sarcoma) is warranted given our findings of higher TMB compared with other histiocytic neoplasms. [Display omitted] DisclosuresBennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board.

Review of Unrelated Donor Cord Blood Transplantation in Children over the Past 3 Decades

Review of Unrelated Donor Cord Blood Transplantation in Children over the Past 3 Decades

Efficacy of Cobimetinib in Rosai-Dorfman Disease

▪INTRODUCTIONRosai-Dorfman disease (RDD) is a rare histiocytic disorder associated with histiocytes expressing high level of macrophage colony stimulating factor receptor (c-fms). Mutations in mitogen-activated protein kinase (MAPK) pathway have been reported in RDD, indicating an underlying clonal process in some patients. Aberrant activation of MAPK pathway can occur due to mutations or high c-fms expression. Data on the use of MAPK/extracellular-signal-related kinase (ERK)-inhibitor therapy in RDD are very limited. Cobimetinib is a MEK inhibitor, which is listed in the National Comprehensive Cancer Network Compendium ® for the treatment of RDD. We present our retrospective experience of cobimetinib treatment in a large series of patients with RDD.METHODSFollowing approval of the institutional reviewed board, patients (pts) with RDD who were consecutively seen at Mayo Clinic and treated with cobimetinib between 2013-2021 were included. Response was assessed as described by Goyal et al (Haematologica 2020;105:2). Cobimetinib was given 20-60 mg once a day by mouth for 21 days in a 28-day cycle. Adverse events (AEs) were graded using the National Cancer Institute Common Toxicity Criteria v5.0. Time-to-event analyses were calculated from the time of treatment initiation, while duration of response was calculated from the time of 1 st response. Tumor genomic profile was analyzed using Tempus-xT ® assay (Chicago, IL), which includes targeted DNA sequencing (648 oncogenes) and whole transcriptome sequencing.RESULTSOf the 54 pts with RDD, ten were treated with cobimetinib and included in this study. The median follow-up was 16 months (m) [95% confidence interval (CI): 13-not reached (NR)] and most (n=8; 80%) were females. The median age at the time of treatment was 63 years (range: 36-74). Cobimetinib was used as first line therapy in four pts.Overall response rate was 70%, with 30% and 40% achieving complete (CR) and partial (PR) responses, respectively. One had stable disease (SD) and two had progressive disease (PD) (Table 1). The median progression-free-survival was 6.4 m (95%CI: 4.9-NR) and at 6 and 12 m, 67% and 50% of pts remained free from disease progression or death, respectively (Figure 1). The median duration of response was 7.6 m (95%CI: 3.1-NR). At the time of last follow-up, nine (90%) pts were alive. One pt died due to myelodysplastic syndrome with excessive blasts. She had multiple chemotherapy treatments before initiation of cobimetinib. Cobimetinib was discontinued in this pt due to grade 3 anemia and skin toxicity after 6 m of therapy and had SD as the best response.Median duration of treatment for the entire cohort was 6 m (range: 2-14). In the seven pts who responded, the median duration of treatment was 7 m (range: 2-14). Cobimetinib was discontinued in seven pts: disease progression (n=3; one disease progression after achieving PR and two PD while on therapy), grade 3 left ventricular systolic dysfunction (n=1), grade 3 diarrhea (n=1), grade 3 anemia (n=1), and grade 2 creatinine elevation (n=1). Five (50%) pts were started at a reduced dose of cobimetinib at the discretion of treating physician [20 mg (n=4) and 40mg, (n=1)]. Two pts were started at 60 mg and dose reduced to 20 mg after one cycle of treatment due to grade 2 skin toxicity in one and grade 2 skin toxicity and diarrhea in the other. Both pts achieved a PR but progressed after four and six cycles, respectively. One pt started at 40 mg and reduced to 20 mg due to grade 2 skin toxicity after two cycles achieving a PR. The response was sustained in this pt for at least 9 months, until the time of last follow-up (Table 1).Tissue molecular testing showed five pts with MAPK pathway alterations and all of them responded to therapy (CR=3 and PR=2). Of the other five pts who either did not have a MAPK pathway alteration (n=4) or had test failure (n=1), responses were observed in two (40%) pts, both PR (Table 1).CONCLUSIONOur study suggests that cobimetinib is an effective treatment in RDD, with responses observed in all pts having MAPK pathway alterations. Less than half of pts without a MAPK pathway alteration achieved a response. However, treatment discontinuations due to AEs were common despite dose reductions. Patients who were treated at low doses of cobimetinib also had remarkable clinical response. Further studies are needed in evaluating other MAPK pathway inhibitors with better toxicity profile to improve adherence and outcomes. [Display omitted] DisclosuresTobin: National Institutes of Health: Research Funding; Mayo Clinic Center for MS and Autoimmune Neurology: Research Funding; Mallinckrodt Pharmaceuticals: Research Funding. Bennani: Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Kymera: Other: Advisory Board. Vassallo: Pfizer: Research Funding; Bristol-Myers-Squibb: Research Funding; Sun Pharma.: Research Funding.