Chronic Myelomonocytic Leukemia Associated Adult Langerhans Cell Histiocytosis: A Descriptive and Comparative Study
Authors: Chauvel Eva , Emile Jean-François , Garnier Alice , Bouzy Simon , Barbarot Sebastien , Lagrue Eric , Neel Antoine 
Published: December 2024

INTRODUCTION

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasm in which dendritic cell langerhans-type infiltrate various organs in particular bones, lung, skin and pituitary gland. Pathogenesis involves oncogenic events activating the RAF-MEK-ERK pathway. LCH is a protean disease which mostly affect children. Adult LCH (aLCH) is not exceptional but less well studied compared to other histiocytoses, e.g. Erdheim-Chester Disease. The association between aLCH and chronic myelomonocytic leukemia (CMML) has long been reported but its clinico-radiological and molecular landscape has not been compared with usual aLCH cases.

The aim of this study was to describe the characteristics of patients with CMML-associated aLCH compared to conventional aLCH cases.

METHODS

We conducted a retrospective monocentric study including patients with LCH (pathology-proven by biopsy or typical clinico-radiological presentation) followed in Nantes University Hospital between 2000 and 2022. Pediatric cases (&lt;15 years) and isolated pulmonary aLCH were excluded. Published observations were compiled after systematic literature review (Pubmed).

RESULTS

In our cohort of 42 extra-pulmonary aLCH patients, 4 had a CMML. Median age at LCH diagnosis was 72.5 years. Among the 4 CMML patients, 3 had multisystem LCH : one cutaneous and digestive tract form, one cutaneous and pulmonary and one cutaneous and pituitary form. One patient had a single-system LCH (cutaneous). CMML was diagnosed prior to LCH in one case, simultaneously in one, and at LCH relapse for the others. There were two CMML-0, one CMML-1 and one CMML-2 secondary to a myelodysplasic syndrome. No patient was treated for LCH. One patient received Azacitidine, resulting in remission of CMML and LCH. Three patients died, including one from untreated aggressive pulmonary LCH involvement.

Twelve published CMML-aLCH cases were identified. Two were excluded (an isolated pulmonary LCH and one not described). In our study, we compared the phenotype of 14 CMML-aLCH with 38 conventional aLCH.

In comparison with controls, aLCH-CMML were significantly older (72,25 vs 37,66y; p&lt;0.001). There was no difference between the 2 groups, in the proportion of single system disease (57,14% vs 44,74%, p=0,5464).

The aLCH-CMML group had a striking mucocutaneous presentation (100% vs 18.4%; p&lt;0.0001), and spared bones (0% vs 89.4%; p&lt;0.0001). Gastro intestinal involvement was found in five aLCH-CMML patients (28,57%) versus 3 (7.89%) in controls (p=0.0745).

Pulmonary involvement was present in 14,29% of aLCH-CMML, versus 39,47% of controls (p=0.1).

Involvement of central nervous system, mainly represented with diabetes insipidus was rare in both groups (1/14; 7.1%, vs. 5/38; 13,16%, p=0.99).

The CMML diagnosis was concurrent in 7 cases (50%), while 6/14 (43%) were diagnose during LCH follow-up or at relapse. LCH molecular data were scarce (half of cases were published before 2010). We identified 4 BRAF V600E mutations among aLCH-CMML patients.

We performed NGS sequencing on peripheral blood mononuclear cell from 2 of our 4 patients, revealing a TET2 mutation in one and numerous mutations in the other (KRAS, TET2, ZRSR2, SH2B3, CBL).

Eleven of the LCH-CMML patients (78%) died, 6 (54%) due to LCH-CMML (4 from CMML and 2 due to an aggressive LCH). The median age at death was 72 years. Median time from LCH diagnosis to death was 2 years (IQR:1-4.25).

DISCUSSION

We report the first comparative study of aLCH-CMML. Expectedly, this association is observed in older patients. The clinical phenotype is strikingly distinct from conventional aLCH, and characterized by a predominance of mucocutaneous and/or digestive involvement. The poor prognosis is mainly driven by CMML but may occasionally result from and unusually aggressive organ LCH involvement (e.g. lung).

CONCLUSION

In older adults a diagnosis of LCH should prompt a systematic search for CMML, both at diagnosis and during follow-up, especially if skin and/or mucosa are involved. Complete blood counts should be carefully examined, as monocytosis often goes unnoticed in early CMML.

Our results need to be consolidated with additional well-characterized observations. Gathering more molecularly-documented cases could also enlighten the probable clonal relationship between the 2 diseases. How LCH-associated CMML compared to isolated CMML remains to be investigated.