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.

Asxl1 loss cooperates with oncogenic Nras in mice to reprogram the immune microenvironment and drive leukemic transformation.

Mutations in chromatin regulator ASXL1 are frequently identified in myeloid malignancies, in particular ∼40% of patients with chronic myelomonocytic leukemia (CMML). ASXL1 mutations are associated with poor prognosis in CMML and significantly co-occur with NRAS mutations. Here, we show that concurrent ASXL1 and NRAS mutations defined a population of CMML patients who had shorter leukemia-free survival than those with ASXL1 mutation only. Corroborating this human data, Asxl1-/- accelerated CMML progression and promoted CMML transformation to acute myeloid leukemia (AML) in NrasG12D/+ mice. NrasG12D/+;Asxl1-/- (NA) leukemia cells displayed hyperactivation of MEK/ERK signaling, increased global levels of H3K27ac, upregulation of Flt3. Moreover, we find that NA-AML cells overexpressed all the major inhibitory immune checkpoint ligands: programmed death-ligand 1 (PD-L1)/PD-L2, CD155, and CD80/CD86. Among them, overexpression of PD-L1 and CD86 correlated with upregulation of AP-1 transcription factors (TFs) in NA-AML cells. An AP-1 inhibitor or short hairpin RNAs against AP-1 TF Jun decreased PD-L1 and CD86 expression in NA-AML cells. Once NA-AML cells were transplanted into syngeneic recipients, NA-derived T cells were not detectable. Host-derived wild-type T cells overexpressed programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) receptors, leading to a predominant exhausted T-cell phenotype. Combined inhibition of MEK and BET resulted in downregulation of Flt3 and AP-1 expression, partial restoration of the immune microenvironment, enhancement of CD8 T-cell cytotoxicity, and prolonged survival in NA-AML mice. Our study suggests that combined targeted therapy and immunotherapy may be beneficial for treating secondary AML with concurrent ASXL1 and NRAS mutations.

Granulomatous dermatitis in the context of chronic myelomonocytic leukemia: More than just reactive infiltrates. An illustrative case report with literature review.

Traditionally, skin involvement in chronic myelomonocytic leukemia (CMML) has been considered to be either specific (leukemia cutis) or non-specific, with granulomatous dermatitis included in the latter group. More recently, the true nature of the myeloid cells present in the cutaneous infiltrates of this theoretically reactive dermatitis is being clarified with the use of new molecular techniques such as next-generation sequencing. The same mutations in bone marrow (BM) myeloid neoplastic cells and in the cells of cutaneous infiltrates have been found. We present the case of a 77-year-old man who presented with spread and treatment-resistant skin granulomatous lesions previous to the diagnosis of CMML. The same clonal mutations in SRSF2, IDH1, and RUNX1 were found in both skin and BM with resolution of the lesions after the initiation of azacytidine. In conclusion, we report an exceptional case in which specific granulomatous cutaneous lesions have preceded and allowed the earlier diagnosis of an underlying CMML and a review of all previous similar cases in the literature, including molecular alterations.

Genomic Landscape of Myelodysplastic/Myeloproliferative Neoplasms: A Multi-Central Study.

The accurate diagnosis and classification of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) are challenging due to the overlapping pathological and molecular features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). We investigated the genomic landscape in different MDS/MPN subtypes, including chronic myelomonocytic leukemia (CMML; n = 97), atypical chronic myeloid leukemia (aCML; n = 8), MDS/MPN-unclassified (MDS/MPN-U; n = 44), and MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T; n = 12). Our study indicated that MDS/MPN is characterized by mutations commonly identified in myeloid neoplasms, with TET2 (52%) being the most frequently mutated gene, followed by ASXL1 (38.7%), SRSF2 (34.7%), and JAK2 (19.7%), among others. However, the distribution of recurrent mutations differs across the MDS/MPN subtypes. We confirmed that specific gene combinations correlate with specific MDS/MPN subtypes (e.g., TET2/SRSF2 in CMML, ASXL1/SETBP1 in aCML, and SF3B1/JAK2 in MDS/MPN-RS-T), with MDS/MPN-U being the most heterogeneous. Furthermore, we found that older age (≥65 years) and mutations in RUNX1 and TP53 were associated with poorer clinical outcomes in CMML (p < 0.05) by multivariate analysis. In MDS/MPN-U, CBL mutations (p < 0.05) were the sole negative prognostic factors identified in our study by multivariate analysis (p < 0.05). Overall, our study provides genetic insights into various MDS/MPN subtypes, which may aid in diagnosis and clinical decision-making for patients with MDS/MPN.

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.

Cytokine-like protein 1-induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML.

Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to myeloid cell leukemia-1 (MCL1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point to the implication of the mitogen-activated protein kinase (MAPK) pathway in the resistance of CMML monocytes to death and reveal an autocrine pathway in which the secreted cytokine-like protein 1 (CYTL1) promotes extracellular signal-regulated kinase (ERK) activation through C-C chemokine receptor type 2 (CCR2). Combined MAPK and MCL1 inhibition restores apoptosis of monocytes from patients with CMML and reduces the expansion of patient-derived xenografts in mice. These results show that the combined inhibition of MCL1 and MAPK is a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis.

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.

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).

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.

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.

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.

Impact of age on the cumulative risk of transformation in patients with chronic myelomonocytic leukaemia.

In older patients with chronic myelomonocytic leukaemia (CMML) and limited life expectancy due to age and or comorbidities, it is particularly important to consider the risk of transformation for individualised treatment decisions. There is limited information on potential differences between younger and older CMML patients regarding the cumulative risk of transformation as well as haematological, molecular and biologic characteristics. We analysed data from the Austrian Biodatabase for CMML (ABCMML) to compare these parameters in 518 CMML patients. Categorisation of patients into 3 age-related groups: <60 years, 60-79 years and ≥80 years, showed a significantly lower risk of transformation at higher age by competing risk analysis, with a 4-year risk of 39%, 23% and 13%, respectively (P < .0001). The lower probability of transformation was associated with a lower percentage of blast cells in the peripheral blood (PB) of older patients. Furthermore, we provide a simple score based on age, PB blasts and platelet counts that allowed us to define subgroups of CMML patients with a different cumulative transformation risk, including a low-risk group with a transformation risk of only 5%. Our findings may facilitate reasonable treatment decisions in elderly patients with CMML.

Venetoclax/decitabine for a pediatric patient with chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome (MDS)/myeloproliferative disorder most commonly seen in the elderly. We describe an adolescent with monosomy 7 CMML presenting as central diabetes insipidus (DI), who was treated with venetoclax and decitabine as a bridge to hematopoietic stem cell transplantation (HSCT). Central DI is a rare manifestation of monosomy 7-associated MDS including CMML, itself a rare manifestation of GATA2 deficiency, particularly in children. Venetoclax/decitabine was effective for treatment of CMML as a bridge to HSCT.

Role of cedazuridine/decitabine in the management of myelodysplastic syndrome and chronic myelomonocytic leukemia.

Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are clonal hematopoietic stem cell disorders. Complex disease biology has posed significant challenge to the development of novel therapeutics. Despite myriad clinical trials, none have been superior to azacitidine and decitabine (DEC) therapy. These therapies present a substantial burden for patients with 5 and 7 days of parenteral treatment in an infusion clinic. To overcome this limitation, a fixed drug combination of oral DEC-cedazuridine (C-DEC), a cytidine deaminase inhibitor with documented safety profile was developed. This drug was recently approved by the US FDA, Australian TGA and Health Canada for newly diagnosed or previously treated intermediate or high risk by international prognostic scoring system, MDS and CMML. In this review, we detail the pharmacokinetic and clinical activity of C-DEC in the management of MDS and CMML.

Lay abstract Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia are rare types of blood cancers. When treatment for these conditions is required, azacitidine or decitabine are the most commonly used chemotherapies. These medications are administered into blood through a medical port. Since these cancers are common in elderly, management of the port and frequent visits to infusion centers for treatment leads to noncompliance with treatment plan. With addition of a new compound by name cedazuridine to decitabine, now a new US FDA-approved medication, INQOVI^® (decitabine and cedazuridine) can be taken by mouth at home. This new treatment has shown to be equally effective with a similar safety profile to decitabine. In this review article, we describe the investigational details and drug development of the oral medication, INQOVI^®.

Atypical cutaneous histiocytic eruption in a patient with chronic myelomonocytic leukemia: A case report.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell malignancy with features of both a myeloproliferative neoplasm and a myelodysplastic syndrome. We present a case of 72-year-old man with CMML who presented with generalized hemorrhagic papules and plaques which on histopathology showed a peculiar infiltrate of atypical mature histiocytes. The immunohistochemical markers for Langerhans cells, indeterminate dendritic cells, and plasmacytoid dendritic cells were negative. Next generation sequencing performed on the paraffin block of the leg biopsy specimen revealed identical ASXL1, SRSF2, and KRAS mutations as seen in the CMML clone of the peripheral blood. Along with recent literature, this case illustrates the spectrum of histiocytic and dendritic cell proliferations in CMML, many of which may be clonally related to the hematopoietic malignancy.

Genetic and epigenetic factors interacting with clonal hematopoiesis resulting in chronic myelomonocytic leukemia.

PURPOSE OF REVIEW: Since 2016, the WHO has recognized the significant phenotypic heterogeneity of chronic myelomonocytic leukemia (CMML) as a myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap disease. Although sharing many somatic mutations with MDS and MPN, the purpose of this review is to put recent biological findings of CMML in the context of evolutionary theory, highlighting it as a distinct evolutionary trajectory occurring in the context of clonal hematopoiesis. RECENT FINDINGS: Clonal hematopoiesis of indeterminate potential (CHIP), with a mutational spectrum and prevalence correlated with age, has been defined. Enriched in DNMT3A, TET2, and ASXL1 mutations, clonal evolution can progress into various evolutionary trajectories including CMML. Impact of founder mutations (primarily TET2) on increased hematopoietic stem cell fitness has been well characterized. Epistatic interactions between mutations and epigenetic events have been explored, both in CMML and its pediatric counterpart juvenile myelomonocytic leukemia, including CMML transformation to acute myeloid leukemia. Together, these findings have contributed significantly toward CMML evolutionary dynamics. SUMMARY: Despite relatively few 'driver' mutations in CMML, evolutionary development of chronic leukemia remains incompletely understood. Recent studies have shed light on the importance of studying epigenetic consequences of mutations and epistasis between key mutations to better understand clonal architecture and evolutionary dynamics.

The clinical and pathological panoply of systemic mastocytosis.

Mastocytosis is a rare disease with varied presentation, myriad symptomatology and variable prognosis. Most patients present with cutaneous disease and mediator-related symptomatology with a small subset having systemic disease (systemic mastocytosis, SM). A subset of the latter develops synchronous or metachronous haematologic neoplasms (SM-AHN), most commonly chronic myelomonocytic leukaemia (CMML). Advanced systemic mastocytosis (ASM) is seen in a relatively small number of patients and is usually associated with organ dysfunction, and may present with hepatosplenomegaly, lymphadenopathy and ascites with progression to leukaemic transformation (mast cell leukaemia/acute myeloid leukaemia) occurring in a few patients. This paper discusses the clinical and pathologic features of the entire spectrum of SM in adults.

Emerging drugs for the treatment of chronic myelomonocytic leukemia.

Introduction: Chronic myelomonocytic leukemia (CMML) is a clonal hematologic disorder with heterogenous prognosis, but with no curative therapies with exception of allogeneic transplant. Therapeutic options for patients with CMML are limited, and although hypomethylating agents such as azacitidine and decitabine are the standard of care, only 40% of patients achieve a response, and most responses are transient. Over the last 5 years, significant advances have been made in the understanding of the clonal landscape of CMML, some of the mechanisms associated to resistance to HMA, and other key biological processes involved in disease pathogenesis. Areas covered: The current article reviews the most relevant emerging therapies currently undergoing clinical trials for the treatment of previously untreated or relapsed CMML. Expert opinion: The presence of recurrent somatic mutations in CMML represents therapeutic opportunities to utilize specific small molecule inhibitors such as IDH, FLT3, MEK/ERK, PLK1, or splicing inhibitors and modulators. In addition, other novel agents such as immune therapies, BCL2 or MCL1 inhibitors and other monoclonal antibodies could lead to therapeutic advances. Identifying specific patient populations likely to benefit from some of these interventions, and development of optimal combinations will remain the challenge when determining their role in therapy.

Indeterminate Dendritic Cell Tumor as Cutaneous Involvement of Chronic Myelomonocytic Leukemia Successfully Treated With Phototherapy.

Indeterminate dendritic cell tumor (IDCT) is a rare disease composed of so-called indeterminate cells, a dendritic cell subset displaying histological and some ultrastructural and immunophenotypic features of Langerhans cells, but lacking Birbeck granules. We report a case of cutaneous IDCT occurring in a patient with chronic myelomonocytic leukemia (CMML) successfully treated with UV-A phototherapy. Next-generation sequencing studies of the CMML demonstrated mutations in TET2, ASXL1, and ZRS2 genes, also detected in the IDCT, demonstrating a clonal relationship between both tumors and confirming IDCT as a specific subtype in the spectrum of CMML-related cutaneous lesions.