Chronic Myelomonocytic Leukemia (CMML)

Chronic myelomonocytic leukemias (CMML), like all myeloid/myelodysplastic neoplasms, are rare diseases. With a proportion of about 20% of MDS, the incidence is around 0.5-1.0 per 100,000 per year. More men than women are affected (ratio about 2:1) with a median age at diagnosis around 76 years. With the current changes in population structure, this results in an increasing prevalence and higher incidence at advanced ages [1].

CMML are malignant diseases characterized by clonal hematopoiesis in the bone marrow. In more than 90% of patients, one or more somatic mutations are detectable by NGS (next generation sequencing). The mutations are devided into four categories:

• epigenetic regulator genes, such as EZH2, ASXL1, TET2, DNMT3A, IDH1, and IDH2,

• mutations in the spliceosome such as SF3B1, SRSF2, U2AF1 and others,

• mutations affecting DNA repair mechanisms (TP53),

• mutations affecting tyrosine kinases and transcription factors such as JAK2, KRAS, NRAS, RUNX1.

It is likely that multiple mutations occur in a staggered fashion, with the first mutations often found in the TET2 or the ASXL1 gene. Subsequently.second and probably more additional events occur, which then trigger the development of the disease. The most common mutations found in CMML are TET2 (60%), SRSF2 (50%), ASXL1 (40%) and RAS (10-30%). Regarding the phenotype of CMML with always associated monocytosis, one theory is that immature dysplastic granulocytes of the CMML clone produce α-defensin protein, which then inhibit macrophage colony-stimulating factor-induced differentiation of monocytic cells, leading to the presence of immature monocytes [2, 3].

Risk factors include exposure to organic solvents, prior radiation therapy, radioiodine therapy, and chemotherapy. Benzene were no proved risk factor in a cohort study, but this remains controversial. Notably, in cigarette smoking, the risk factor benzene accumulates as a major product. If relevant occupational exposure to organic solvents is suspected, a report should be made to the respective professional association [4, 5, 6].

In a large proportion of patients, CMML is diagnosed incidentally by an otherwise indicated blood test. Only a small proportion of patients have clinical symptoms that lead to diagnostis. General symptoms such as night sweats, weight loss, fatigue, and a reduced general condition are usual. The clinical symptoms of CMML are most fequently caused by the hematopoietic insufficiency. The clinical presentation is more similar to MDS or chronic MPN, with one of the two components becoming more prominent in the individual case. Patients with an MDS phenotype (MD-CMML) (leukocytes <13,000 µl) often have cytopenia in the peripheral blood with associated sequelae, such as neutropenia-related infections, thrombocytopenia with associated bleeding, and anemia requiring transfusion. At diagnosis, severe bleeding caused by thrombocytopenia is uncommon; petechiae, gingival bleeding, and a tendency to hematoma are more frequent. In the proliferative phenotype (MP-CMML) (leukocytes ≥13,000 /µl), splenomegaly, mostly asymptomatic, is present in approximately 50% of cases, hepatomegaly and lymphadenopathy are less frequent. Infiltration of myelomonocytic cells in the skin, pleura, and peritoneum may occur, particularly with leukocyte counts of ≥13000/µl in the peripheral blood. In a proportion of patients, CMML transforms into acute myeloid leukemia (AML), with a frequency of 15-30%. An increase of monocytes in the blood per se is not sufficient to postulate a progression of CMML, as infecions can also cause higher monocyte counts, which regress under successful treatment.

CMML is associated with autoimmune diseases more frequently than MDS. An autoimmune disease is present in approximately 20% of cases in CMML. Vasculitis, idiopathic thrombocytopenia (ITP), psoriasis, rheumatoid polyarthritis, and neutrophilic dermatosis (Sweet syndrome) are most common. Autoimmune phenomena may precede the initial diagnosis of CMML by years [10].

Due to the tendency of monocytes to migrate into various tissues, monocytic organ infiltrations are not rare in CMML and are mostly associated with high peripheral leukocyte counts. Meningeosis leukaemica occurs very rarely and usually reflects a transition to acute leukemia. Gingival hyperplasia, which is frequent in monocytic differentiated acute leukemias, can rarely occur in CMML and is usually combined with an increase of leukocytes in the peripheral blood.

Thrombocytopenia in patients with CMML does not necessarily reflect dysplastic bone marrow insufficiency or infiltration by leukemic cells, but may rarely be due to classic ITP, which may occur years after the diagnosis of CMML [8, 9]. Usually, these patients show a good response to steroids.

CMML is a disease of older and therefore more frequently multimorbid patients. In recent years, it has become evident for a number of chronic hematological diseases (MDS, CLL, CML, Hodgkin's lymphoma) that comorbidity is an independent prognostic factor, which significantly influences overall survival. After diagnosis and assessment of prognosis, the therapy of CMML depends in particular on the age, general condition and comorbidities of the respective patient. Mild and asymptomatic cytopenias do not initially require therapy. Only when symptoms appear or proliferation increases therapy is required. Mild therapy with e.g. hydroxyucarbamide or demethylating substances is frequently possible in patients of limited general condition and with comorbidities after benefit-risk assessment. However, the application of these drugs may be difficult in very bad general condition and especially in high Charlson comorbidity index or MDS-CI [11]. For patients scheduled for SCT, the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) is suitable to estimate overall survival and risk of non-relapse-related mortality after allogeneic SCT.

CMML is usually dignosed when the causes of unclear leukocytosis, monocytosis or cytopenia are investigated. First clinical signs of CMML in older patients may be general symptoms (B symptoms), symptoms of splenomegaly or clinical consequences of cytopenias (anemia, bleeding, infection). Cytopenia, but also leukocytosis (in about 50% of cases) with monocytosis (average around 4.3 G/l) and increased blast counts are possible in the peripheral blood. By definition, CMML presents with persistent monocytosis of >500/µl in the blood, accounting for at least 10% of the leukocyte count, if a genetic aberrant marker is present; if there is lack of a genetic marker, persistent monocytosis of >1000/ µl is mandatory. In addition, 1 to 3 cell lineages in the bone marrow have dysplasia signs. Dysplasias of megakaryopoiesis and granulopoiesis are usually more prominent than of erythropoiesis. Due to monocytic/granulocytic hyperplasia in the bone marrow, erythropoiesis typically accounts for only about 15% of nucleated cells. Esterase staining allows visualizing variable degrees of monocytes in the bone marrow. The blast percentage (including promonocytes) in blood and bone marrow is by definition between 0 and 19%. The abnormal partitioning of peripheral blood monocyte subsets is a supportive criterion for the diagnosis of CMML.

According to the peripheral and medullary blast percentage, two types are distinguished: CMML 1 with peripheral blast percentage <5% and medullary blast percentage <10% and CMML 2 with peripheral blast percentage 5-19% and medullary blast percentage 10-19%. If peripheral and/or medullary blast percentage are ≥20%, a diagnosis of acute leukemia is made. The former CMML 0 subgroup was included into CMML 1 because the prognosis is similar to CMML 1, whereas CMML 2 has an indisputably worse prognosis.

Chromosome analysis is an obligatory part of the diagnosis of CMML. Approximately 80% of patients with CMML have a normal karyotype. Among chromosomal aberrations, loss of genetic material from chromosome 7 and trisomy 8 are more common. Molecular markers such as mutations of ASXL1, TP53, and of other genes are sometimes the only way to identify the clonal nature of the disease. In addition to WHO subgroups 0, 1, and 2, CMML is further classified according to leukocyte count into a dysplastic variant (leukocytes <13,000/µl) (MD-CMML) and a proliferative variant (leukocytes ≥13,000/µl) MP-CMML. The proliferative variant is usually associated with activated RAS pathway and has a worse prognosis. This classification is important from a prognostic point of view, furthermore it reflects the different clinical presentation.

The diagnosis CMML is based on peripheral blood counts and bone marrow aspiration. In Table 1, the diagnostic criteria according to WHO 2022 are represented. Some patients with MDS and concomitant monocytosis formally develop CMML during the diesease course by exceeding 500 or 1000 monocytes/µl. These cases exhibit clinical and molecular characteristics of CMML already at initial diagnosis and are then classified as "oligomonocytic CMML" if they have a chromosomal or molecular genetic abnormality typical of CMML [12, 17]. A consensus group has developed the minimal diagnostic criteria for CMML in an expanded and more precise form [18]. To avoid misdiagnosis of an underlying systemic mastocytosis with monocytosis, a test for KIT D816V mutation should be included.

In principle, two different subtypes are distinguished, the dysplastic subtype (more MDS-typical with more cytopenias, dysplasias as well as more frequent cytogenetic aberrations) and the proliferative subtype (more similarity to myeloproliferative neoplasms with more frequent splenomegaly, higher leukocyte counts with left shift and extramedullary manifestations such as skin infiltrates or effusions). Regarding the leukocyte count, the diagnositc cutoff is <13 G/L for dysplastic CMML and ≥13 G/l for proliferative CMML.

The WHO classification 2022 further distinguishes between two CMML subgroups taking into account the blast content (see Table 3). The description of rare CMML variants, such as oligomonocytic CMML, CMML with associated systemic mastocytosis, CMML with concomitant myeloid/lymphoid neoplasia is available in a consensus paper referring to the details [18]. In parallel to WHO, an "International Consensus Classification" was proposed by another working group, which differs only marginally from the WHO proposals.

Important prognostic parameters for patients with CMML are patient-specific parameters such as age, gender and concomitant diseases and disease-specific parameters such as peripheral and medullary blast percentage, the extent of cytopenia, need for erythrocyte transfusion, chromosomal and molecular findings. MDS-specific prognosis scores are of limited value in assessment of prognosis because parameters important for MDS are rarely present in CMML. The best prognostic tools to date are the CPSS (CMML-specific prognostic scoring system, Table 4 and the CPSS-molecular, Table 5).

The CPSS includes the following parameters as risk factors to define 4 risk groups: a leukocyte count of >13,000/µl, a medullary blast percentage of ≥10%, regular transfusion requirements, and cytogenetic findings (Table 4). Molecular markers were added to the CPSS, and the blast threshold was lowered to >5%. This score (CPSS-M) also defines 4 risk groups and is especially appropriate for the identification of low-risk and high-risk patients (Table 5).

In absence of cytogenetic and molecular genetic data, the prognosis of patients with CMML can also be estimated using the Düsseldorf score [20, 24]. This score identifies a small group of low-risk patients and a small group of high-risk patients, whereas a large proportion of cases are assigned to the intermediate group.

It is essential to exclude other clonal myeloproliferative disorders, as well as reactive causes of splenomegaly, leukocytosis, monocytosis, and cytopenia. Similar, but reactive blood count changes, especially monocytosis, may appear during acute infections, sepsis, chronic infections, TBC, and rheumatic and autoimmune diseases. Other non-hematologic diseases, which can cause splenomegaly (liver and systemic diseases, infections, congenital storage diseases), are a matter of exclusion.

Clonal hematological neoplasms that may be relevant for differential diagnosis of CMML include other forms of MDS and MPN, in particular MPN with neutrophilia (formerly atypical CML) and PMF. Very rare but therapeutically relevant differential diagnoses of monocytosis are myeloid/lymphoid neoplasms with eosinophilia (PDGFRα or β rearrangement), with tyrosine kinase fusion genes (MLN-TK), hairy cell leukemia (splenomegaly and pancytopenia), or LGL leukemias. Monocytosis can also occur in the transformation from MDS or MPN to AML M4 or M5 and in systemic mastocytosis (KIT D816V mutation) (see Onkopedia guideline systemic mastocytosis (German Version)). However, there are also patients with CMML who acquire a KIT D816V mutation during the course of the disease. Differential diagnoses and appropriate diagnostic procedures are shown in Table 6.

For the almost elderly patients, maintaining or improving quality of life and autonomy is the main goal of therapeutic efforts. In many asymptomatic CMML patients with mild cytopenia and lack of symptoms, a watch and wait strategy is appropriate. The indication for disease-specific therapy is depending on the stage of disease, age and clinical condition of the patient. In low-risk CMML patients (CPSS LOW and CPSS INT-1), therapy is mostly not indicated, which is in part due to the lack of validated therapeutic interventions. Patients with high-risk CMML (CPSS INT-2 and CPSS HIGH) should be treated cytoreductively, if necessary, also with the intention of delaying progression to AML [25, 33]. A treatment algorithm is shown in Figure 1.

Most patients with CMML are in advanced age. For these patients non-intensive therapies and good supportive care represent the basis of therapy. In younger patients with high-risk CMML, the possibility of allogeneic SCT has always to be considered first. High-risk CMML patients with dysplastic variant who do not qualify for this procedure may receive treatment with azacytidine. Patients with proliferative variant, should primarily treated with hydroxycarbamide, although azacytidine or decitabine may be effective, but are not approved [42]. As mentioned above, there was no advantage to using decitabine compared with hydroxycarbamide in a randomized trial of decitabine. Therefore, if applicable, its use should be considered only in cases of progression to AML (≥20% blasts). In cases of progression on standard treatment and high-risk constellations, patients should be included in ongoing clinical trials when possible. Further information is available from the Acute and Chronic Leukemia Competence Network, the Düsseldorf MDS Registry, and the German MDS Study Group. A European guideline summarizes the essential diagnostic and therapeutic procedures. The Austrian CMML Biodatabase [43] will help to provide sufficient material from CMML patients with appropriate data set (see links in chapter 14).

Clinical examination of spleen size and, if necessary, abdominal sonography are useful once a year. The intervals of the examination of blood count including differential blood picture and clinical chemistry depend on the individual course of the disease and the respective form and phase of therapy. In the initial phase of therapy, the controls should be more frequent. In case of reaching a stable phase, control intervals up to a quarter of a year or longer may be possible. Follow-up examinations of the bone marrow to detect transformation to acute leukemia are required according to the individual course. If there is evidence of progression (increasing anemia or thrombocytopenia, blasts in the peripheral blood, etc.), a follow-up examination of the bone marrow should be considered. Follow-up examinations of somatic mutations and karyotype are indicated if therapeutic consequences arise. Expansion of the present genetic aberrations or evolution with appearance of further genetic aberrations can occur. Both can influence the prognosis and the course of the disease.

The follow-up of CMML after allogeneic SCT does not differ significantly from the follow-up of other transplanted hemopathies. Center-specific guidelines should be followed, which often include quarterly follow-up in the first year, four-monthly follow-up in the second year, and six-monthly follow-up in subsequent years. This should include chimerism analysis, cytology, histology, and MRD tracking of CMML specific initial changes (cytometry of abnormal monocytes and blasts, karyotype abnormalities, mutations in NGS and molecular biology) in order to detect molecular relapse as early as possible and to be able to counteract it before morphological relapse. This can be done, for example, by withdrawal of immunosuppression, transfusion of donor lymphocytes, and hypomethylating therapy. Regular dermatologic, cardiologic, and gynecologic (in women) examinations should be performed after allogeneic transplantation to detect secondary malignancies early after allogeneic SCT. Even if it is assumed that a patient is cured, differential blood counts should be performed regularly, at least annually, to detect early relapse, secondary MDS, or secondary leukemia. Densitometry in regular intervals is also indicated.