Recurrent Aortic Thromboembolism Associated With TET2 Mutation in Chronic Myelomonocytic Leukemia.

Ten-eleven translocation 2 (TET2) plays a pivotal role in epigenetic regulation, cell differentiation, and the inflammatory response. It also mediates the transcriptional regulation for inflammatory cytokines, particularly interleukin-6. While loss-of-function mutation in TET2 has been associated with hematological malignancies, it has been increasingly recognized to cause atherosclerotic disease. The increased atherogenicity is thought to be the result of increased production of pro-inflammatory interleukin-1ß cytokines following activation of NLRP3 inflammasomes. We present a unique case of recurrent atherothrombosis in an elderly man who was diagnosed with chronic myelomonocytic leukemia in the setting of TET2 mutation.

Comparing malignant monocytosis across the updated WHO and ICC classifications of 2022.

ABSTRACT: The World Health Organization (WHO) classification of hematolymphoid tumors and the International Consensus Classification (ICC) of 2022 introduced major changes to the definition of chronic myelomonocytic leukemia (CMML). To assess its qualitative and quantitative implications for patient care, we started with 3311 established CMML cases (according to WHO 2017 criteria) and included 2130 oligomonocytosis cases fulfilling the new CMML diagnostic criteria. Applying both 2022 classification systems, 356 and 241 of oligomonocytosis cases were newly classified as myelodysplastic (MD)-CMML (WHO and ICC 2022, respectively), most of which were diagnosed as myelodysplastic syndrome (MDS) according to the WHO 2017 classification. Importantly, 1.5 times more oligomonocytosis cases were classified as CMML according to WHO 2022 than based on ICC, because of different diagnostic criteria. Genetic analyses of the newly classified CMML cases showed a distinct mutational profile with strong enrichment of MDS-typical alterations, resulting in a transcriptional subgroup separated from established MD and myeloproliferative CMML. Despite a different cytogenetic, molecular, immunophenotypic, and transcriptional landscape, no differences in overall survival were found between newly classified and established MD-CMML cases. To the best of our knowledge, this study represents the most comprehensive analysis of routine CMML cases to date, both in terms of clinical characterization and transcriptomic analysis, placing newly classified CMML cases on a disease continuum between MDS and previously established CMML.

A case of sudden hearing loss in a patient with chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia is a myeloid stem cell disease characterized by an abnormal production and accumulation of monocytic cells in association with other signs of myeloproliferation. Extramedullary manifestations of CMML are common and can affect the spleen, liver skin, and lymph nodes. However, otologic manifestations are extremely rare and could have occurred from either direct leukemic infiltration, hemorrhage of the cochlea, labyrinth, leukostasis, or infection. There is no standard treatment protocol for sensorineural hearing loss in CMML patients. More research is needed to improve the understanding of the pathogenesis of this condition, in order to provide better treatment options.

CSF3R-mutant chronic myelomonocytic leukemia is a distinct clinically subset with abysmal prognosis: a case report and systematic review of the literature.

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) chacaterized by persistent peripheral blood monocytosis, hypercellular bone marrow and dysplasia at least in one myeloid lineage. CMML shares much of its molecular landscape with other myeloid neoplasms, while differs from others such as chronic neutrophilic leukemia (CNL), given the high frequency of CSF3R mutations in the latter. In this article, we report a case of CSF3R-mutated CMML and dissect this rare entity by reviewing the medical literature, with the intent to understand how this rare mutation shapes CMML's clinical and morphological phenotype. CSF3R-mutated CMML emerges as a rare entity meeting the ICC/WHO diagnostic criteria for CMML and simultaneously showing clinical-pathological and molecular traits of CNL and atypical chronic myeloid leukemia, rising an important and difficult diagnostic and therapeutical issue.

STIMULUS-MDS2 design and rationale: a phase III trial with the anti-TIM-3 sabatolimab (MBG453) + azacitidine in higher risk MDS and CMML-2.

Patients with higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) unfit for hematopoietic stem cell transplantation have poor outcomes. Novel therapies that provide durable benefit with favorable tolerability and clinically meaningful improvement in survival are needed. T-cell immunoglobulin domain and mucin domain-3 (TIM-3) is an immuno-myeloid regulator expressed on immune and leukemic stem cells in myeloid malignancies. Sabatolimab is a novel immunotherapy targeting TIM-3 with a potential dual mechanism of reactivating the immune system and directly targeting TIM-3+ leukemic blasts suppressing the growth of cancer cells. Here, we describe the aims and design of the phase III STIMULUS-MDS2 trial, which aims to demonstrate the potential for sabatolimab plus azacitidine to improve survival for patients with higher-risk MDS and CMML-2 (NCT04266301). Clinical Trial Registration: NCT04266301 (ClinicalTrials.gov).

Phase 1/1b study of azacitidine and hedgehog pathway inhibitor sonidegib in patients with myeloid neoplasms.

BACKGROUND: Myeloid neoplasms (myelodysplastic syndrome [MDS], myelofibrosis, and chronic myelomonocytic [CMML]) are aggressive hematological malignancies for which, despite recent approvals, novel therapies are needed to improve clinical outcomes. The hedgehog (HH) pathway is one of the main pathways for cancer stem cells survival and several HH inhibitors (HHi) are approved in clinical practice. METHODS: Sonidegib (SON), an oral HHi, was tested in this phase 1/1b trial in combination with azacitidine (AZA, 75 mg/m2 days ×7) in patients with newly diagnosed and relapsed/refractory (r/r) chronic MN or acute myeloid leukemia (AML). RESULTS: Sixty-two patients (28 [45%] newly diagnosed) were treated in this study, including 10 patients in the dose-finding component and 52 patients in phase 1b. SON 200 mg oral daily on days 1-28 each cycle was deemed the recommended dose for phase 1b. Out of 21 rrAML patients, two achieved response (one complete response/one morphologic leukemia-free state) with no responses seen in seven r/r MDS/CMML patients. In newly diagnosed AML/MDS, response was seen in six (three had complete remission, two had morphological leukemia-free status) of 27 patients. Median overall survival was 26.4 and 4.7 months for newly diagnosed MDS and AML, respectively. Safety was satisfactory with common (>20%) side effects including fatigue, constipation, nausea, cough, insomnia, and diarrhea. Only 7% of patients died in the study, and none of the deaths were deemed related to treatment. CONCLUSIONS: Our study shows that AZA + SON are a safe combination in a patient with MN. Similar to other hedgehog inhibitors, this combination yielded limited response rate in patients with myeloid neoplasms.

Plasmacytoid dendritic cells in the setting of myeloid neoplasms: Diagnostic guide to challenging pathologic presentations.

In this article, we describe three broad pathologic presentations of plasmacytoid dendritic cells (pDCs) that may be encountered in clinical practice, in which an association between pDCs and myeloid neoplasms is identified: (1) myeloid neoplasms with mature pDC expansion, most commonly seen in chronic myelomonocytic leukaemia (CMML); (2) myeloid neoplasms with pDC differentiation, in which pDCs show a spectrum of maturation from early immature pDCs to mature forms, most commonly seen in acute myeloid leukaemia (AML); (3) myeloid neoplasms associated with blastic plasmacytoid dendritic cell neoplasm (BPDCN), either stemming from the same precursor or representing an independent clonal process. Additionally, we also discuss AML with pDC-like phenotype, in which myeloblasts show immunophenotypic features that may mimic those seen in pDCs. Using these presentations, we provide a diagnostic algorithm for appropriate pathologic classification, while attempting to clarify and homogenize nomenclatures pertaining to different biologic states of pDCs.

Optimization of monocyte gating to quantify monocyte subsets for the diagnosis of chronic myelomonocytic leukemia.

BACKGROUND: The presence of >94% classical monocytes (MO1, CD14++/CD16-) in peripheral blood (PB) has an excellent performance for the diagnosis of chronic myelomonocytic leukemia (CMML). However, the monocyte gating strategy is not well defined. The objective of the study was to compare monocyte gating strategies and propose an optimal one. METHODS: This is a prospective, single center study assessing monocyte subsets in PB. First, we compared monocyte subsets using 13 monocyte gating strategies in 10 samples. Then we developed our own 10 color tube and tested it on 124 patients (normal white blood cell counts, reactive monocytosis, CMML and a spectrum of other myeloid malignancies). Both conventional and computational (FlowSOM) analyses were used. RESULTS: Comparing different monocyte gating strategies, small but significant differences in %MO1 and percentually large differences in %MO3 (nonclassical monocytes) were found, suggesting that the monocyte gating strategy can impact monocyte subset quantification. Then, we designed a 10-color tube for this purpose (CD45/CD33/CD14/CD16/CD64/CD86/CD300/CD2/CD66c/CD56) and applied it to 124 patients. This tube allowed proper monocyte gating even in highly abnormal PB. Computational analysis found a higher %MO1 and lower %MO3 compared to conventional analysis. However, differences between conventional and computational analysis in both MO1 and MO3 were globally consistent and only minimal differences were observed when comparing the ranking of patients according to %MO1 or %MO3 obtained with the conventional versus the computational approach. CONCLUSIONS: The choice of monocyte gating strategy appears relevant for the monocyte subset distribution test. Our 10-color proposal allowed satisfactory monocyte gating even in highly abnormal PB. Computational analysis seems promising to increase reproducibility in monocyte subset quantification.

Coexisting Extra-Medullary Manifestation of Chronic Myelomonocytic Leukemia and Follicular Lymphoma: What's Between Neoplastic Follicles Matters.

We illustrate a rare case of coexisting extramedullary manifestation of CMML and new onset follicular lymphoma within the same core-needle biopsy of a lymph node. We discuss the differences between extramedullary hematopoiesis and extramedullary manifestation of myeloid neoplasms. We also highlight the importance of generous tissue sampling and thorough examination of nodal tissue in the setting of an established myeloid neoplasm to avoid missing rare but possible nodal involvement.

Srsf2P95H/+ co-operates with loss of TET2 to promote myeloid bias and initiate a chronic myelomonocytic leukemia-like disease in mice.

Recurrent mutations in RNA splicing proteins and epigenetic regulators contribute to the development of myelodysplastic syndrome (MDS) and related myeloid neoplasms. In chronic myelomonocytic leukemia (CMML), SRSF2 mutations occur in ~50% of patients and TET2 mutations in ~60%. Clonal analysis indicates that either mutation can arise as the founder lesion. Based on human cancer genetics we crossed an inducible Srsf2P95H/+ mutant model with Tet2fl/fl mice to mutate both concomitantly in hematopoietic stem cells. At 20-24 weeks post mutation induction, we observed subtle differences in the Srsf2/Tet2 mutants compared to either single mutant. Under conditions of native hematopoiesis with aging, we see a distinct myeloid bias and monocytosis in the Srsf2/Tet2 mutants. A subset of the compound Srsf2/Tet2 mutants display an increased granulocytic and distinctive monocytic proliferation (myelomonocytic hyperplasia), with increased immature promonocytes and monoblasts and binucleate promonocytes. Exome analysis of progressed disease demonstrated mutations in genes and pathways similar to those reported in human CMML. Upon transplantation, recipients developed leukocytosis, monocytosis, and splenomegaly. We reproduce Srsf2/Tet2 co-operativity in vivo, yielding a disease with core characteristics of CMML, unlike single Srsf2 or Tet2 mutation. This model represents a significant step toward building high fidelity and genetically tractable models of CMML.

Plasmacytoid Dendritic Cell Dermatosis Associated to Myeloproliferative/Myelodysplastic Neoplasms.

Cutaneous lesions in the setting of myeloproliferative neoplasms and myelodysplastic syndromes are poorly understood. We report 6 patients with pruritic papular eruptions composed of mature T-lymphocytes with large clusters of CD123-positive cells. Double immunohistochemical studies demonstrated a lack of myeloid cell nuclear differentiation antigen in the CD123-positive cells, which expressed SPIB, confirming that they were mature plasmacytoid dendritic cells. Four patients were diagnosed with chronic myelomonocytic leukemia and 2 with myelodysplastic syndromes (AREB-I and myelodysplastic syndromes with 5q deletion, respectively). All patients had a long history of hematological alterations, mainly thrombocytopenia, preceding the cutaneous disorder. Nevertheless, the skin lesions developed in all cases coincidentally with either progression or full-establishment of their hematological disease. Most cutaneous lesions disappeared spontaneously or after corticosteroid treatment. Molecular studies performed in both bone marrow and cutaneous lesions in 2 patients demonstrated the same mutational profile, confirming the specific, neoplastic nature of these mature plasmacytoid dendritic cells-composed cutaneous lesions.

Monocytosis and its association with clonal hematopoiesis in community-dwelling individuals.

Monocytosis may occur in numerous inflammatory conditions but is also the defining feature of chronic myelomonocytic leukemia (CMML). Clonal somatic mutations detectable in CMML may occur with aging in otherwise healthy individuals, so-called "clonal hematopoiesis" (CH). We investigated whether the combination of CH and monocytosis would represent an early developmental stage of CMML. We studied community-dwelling individuals with monocytosis (≥1 × 109/L and ≥10% of leukocytes) in the population-based Lifelines cohort (n = 144 676 adults). The prevalence and spectrum of CH were evaluated for individuals ≥60 years with monocytosis (n = 167 [0.8%]), and control subjects 1:3 matched for age and sex (n = 501). Diagnoses of hematological malignancies were retrieved by linkage to the Netherlands Cancer Registry (NCR). Monocyte counts and the prevalence of monocytosis increased with advancing age. Older individuals with monocytosis more frequently carried CH (50.9% vs 35.5%; P < .001). Monocytosis is associated with enrichment of multiple gene mutations (P = .006) and spliceosome mutations (P = .007) but not isolated mutated DNMT3A, TET2, or ASXL1. Persistent monocytosis over 4 years was observed in 30/102 evaluable individuals and associated with a higher prevalence of CH (63%). Myeloid malignancies, including 1 case of CMML, developed in 4 individuals with monocytosis who all carried CH. In conclusion, monocytosis and CH both occur at an older age and do not necessarily reflect clonal monocytic proliferation. In a fraction of older subjects with monocytosis, CH might constitute early clonal dominance in developing malignant myelomonocytic disease. Mutational spectra deviating from age-related CH require attention.

A Case of Indeterminate Cutaneous Dendritic Cell Tumors in the Setting of Chronic Myelomonocytic Leukemia.

ABSTRACT: Chronic myelomonocytic leukemia (CMML) is a rare hematopoietic stem cell neoplasm. Indeterminate dendritic cell neoplasm (IDCN) is an extraordinarily rare histiocytosis that may manifest secondarily to CMML. A 75-year-old man with a 2-year history of CMML presented for multiple cutaneous lesions on his head and neck. Biopsy results yielded a dense diffuse infiltrate of large pleomorphic cells, which were positive for CD1a, S100, and CD56 with weak positivity for CD43 and CD68. Given his history of CMML, the patient was diagnosed with IDCN. This may indicate a progression of his CMML or transformation to acute leukemia; therefore, a systemic workup was recommended. IDCN may manifest secondary to a wide number of hematopoietic malignancies, with CMML being a rare occurrence. Recorded responses to phototherapy are reassuring, whereas systemic therapy may be appropriate for widespread cases. Remaining vigilant for cutaneous changes in patients with CMML will help prevent misdiagnosis and encourage prompt initiation of appropriate treatment.

Blastic Indeterminate Dendritic Cell Tumor Associated With Chronic Myelomonocytic Leukemia.

ABSTRACT: Indeterminate dendritic cell tumor (IDCT) is an exceedingly rare neoplasm that can be associated with hematopoietic malignancies. We report a case of multifocal cutaneous blastic indeterminate dendritic cell tumor (BIDCT) in a 75-year-old man with chronic myelomonocytic leukemia showing blastic histiocytoid morphology, positivity for CD1a and S100, and no expression of langerin. We present a literature review on the 11 reported cases of IDCTs/BIDCTs associated with chronic myelomonocytic leukemia (CMML), including this case. The clinicopathological characteristics have been summarized. The IDCT and CMML cells are clonally related in 4 tested cases. Patients with IDCT/BIDCT associated with CMML seem to have worse clinical outcomes compared with patients with IDCT not associated with CMML.

Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia.

Myeloid neoplasms are clonal hematopoietic stem cell disorders driven by the sequential acquisition of recurrent genetic lesions. Truncating mutations in the chromatin remodeler ASXL1 (ASXL1MT) are associated with a high-risk disease phenotype with increased proliferation, epigenetic therapeutic resistance, and poor survival outcomes. We performed a multi-omics interrogation to define gene expression and chromatin remodeling associated with ASXL1MT in chronic myelomonocytic leukemia (CMML). ASXL1MT are associated with a loss of repressive histone methylation and increase in permissive histone methylation and acetylation in promoter regions. ASXL1MT are further associated with de novo accessibility of distal enhancers binding ETS transcription factors, targeting important leukemogenic driver genes. Chromatin remodeling of promoters and enhancers is strongly associated with gene expression and heterogenous among overexpressed genes. These results provide a comprehensive map of the transcriptome and chromatin landscape of ASXL1MT CMML, forming an important framework for the development of novel therapeutic strategies targeting oncogenic cis interactions.

Unique Recognizable Histopathologic Variant of Palisaded Neutrophilic and Granulomatous Dermatitis that Is Associated With SRSF2-Mutated Chronic Myelomonocytic Leukemia: Case Report and Review of the Literature.

ABSTRACT: Palisaded neutrophilic and granulomatous dermatitis (PNGD) represents a cutaneous histopathologic reaction spectrum associated with several underlying disorders. Few cases of PNGD have been associated with chronic myelomonocytic leukemia (CMML), a malignant hematopoietic disorder with features in between those of a myeloproliferative neoplasm and myelodysplastic syndrome. We present a patient with a generalized papular skin reaction involving the neck, chest, and shoulders with histomorphological features on the spectrum of PNGD. Subsequent laboratory workup demonstrated a persistent mild monocytosis, raising concern for CMML. The diagnosis was ultimately confirmed with a bone marrow biopsy and associated mutational analysis through next-generation sequencing which identified deleterious variants in SRSF2, IDH2, and ASXL1. The findings in this case strengthen the previously made association between PNGD and SRSF2-mutated CMML and may help better define a unique recognizable clinical-histopathological-molecular subtype for dermatopathologists.