Expanded Guidelines Offer Clearer Diagnosis for Classical, Special Variants of CMML

Recent guidelines highlight the need to distinguish chronic myelomonocytic leukemia (CMML) from conditions similar to other myeloproliferative neoplasms (MPN), provide standardized diagnostic procedures, and outline therapeutic options for adult patients with CMML.

The European Hematology Association (EHA) in collaboration with the European LeukemiaNet (ELN) published diagnosis and treatment guidelines for CMML at the end of 2018. Each recommendation was agreed upon by an international group of experts from Europe and the United States. The guidelines provided consensus and evidence-based recommendations for diagnostic criteria, prognosis, and treatment.¹

In addition, the Medical University of Vienna in collaboration with the Vienna Cancer Stem Cell Club and the Ludwig Boltzmann Institute for Hematology and Oncology, formerly the Ludwig Boltzmann Cluster Oncology, organized a Working Conference to discuss CMML in August 2018. The outcomes of this meeting were published inHaematologicaand include proposals on the diagnosis of pre-CMML conditions and updated minimal diagnostic criteria for classical and special CMML variants.²

Topics covered by the guidelines include diagnostic criteria, minimal diagnostic criteria for classical and special variants of CMML, classification of pre-CMML, and current and emerging treatments.

Diagnostic Criteria

With recent advances in knowledge of the molecular features and mechanisms of CMML, there is a need to define different variants of CMML, prephases, and CMML caused by related conditions. The 2016 classification update released by the World Health Organization (WHO) listed CMML as a disease that overlaps with myelodysplastic syndrome (MDS)/MPN.

The new diagnostic guidelines were updated to include criteria for distinguishing CMML from similar diseases. The recommendations published by the EHA and ELN suggest a more thorough investigation of the morphological features, flow cytometric phenotypes, cytogenetics, and molecular genetics, as well as providing a differential diagnosis of borderline diseases in CMML.¹

The initial diagnostic procedure of a patient suspected of CMML is assessment of blood and bone cellular morphology. The absolute number and percentage of monocytes, blasts, and immature myeloid cells in the peripheral blood are determined. Ideally, blood counts should be assessed for more than 3 months. To determine morphological characteristics, bone marrow cytology using staining procedures, assessment of dysplasia in all lineages, and calculation of percentage of monocytes and blasts are mandatory. A bone marrow biopsy is recommended to aid in the diagnosis of CMML. Biopsy results allow for cellularity, stromal changes, fibrosis, and marrow to be evaluated.¹

Next, flow cytometry analysis of peripheral blood monocytes can aid in the diagnosis and treatment of CMML. Results allow for changes in the antigen expression in myelomonocytic cells and the erythroid lineage to be distinguished. In addition, analysis of monocytosis differentiates CMML from reactive monocytosis. Furthermore, this technology can be used in routine practice to confirm the diagnosis in patients suspected of CMML. Also, flow cytometry analysis of monocytes can be used to monitor CMML response¹to standard and novel treatments. Thus, this method is useful for confirming CMML criteria and aids in the exclusion of similar diseases.²

Chromosomal abnormalities have been reported in 10% to 40% of patients, but the irregularities are not specific. The most frequent abnormalities are trisomy 8 and monosomy 7. Patients with these abnormalities have been assigned a very poor outcome by the Spanish cytogenetic risk stratification. Therefore, analysis of at least 20 mitoses is mandatory in diagnosis, and fluorescence in situ hybridization (FISH) to monitor chromosomes 7 and 8 is recommended if 1 or 2 metaphases with +8 or —7 are found.¹

Molecular genetic screening of 20 genes can detect an abnormality in over 90% of cases. Moreover, an average of 10 to 15 mutations can be found in the genome of patients with CMML. Despite the prototypical molecular fingerprint pattern that is often observed, the diagnostic or prognostic roles of the mutations have not been validated. Nevertheless, a minimum of 20 genes must be analyzed in patients selected for treatment. The recommendation is to analyze specific genes to determine specific treatment options.¹

To rule out similar diseases, take these steps: First, the absence ofBCR-ABL1should be assessed to exclude chronic myeloid leukemia (CML). Next, screen patients for theFIP1L1/ PDGFRAgene abnormality in rare cases of monocytosis with eosinophilia. Other genes should be studied if cytogenic analysis determined abnormalities. Finally, differentiate CMML from M4 acute myeloid leukemia (AML) by counting the promonocytes and adding them to the total blast percentage. Borderline cases must be analyzed with next-generation sequencing and flow cytometry.¹

Minimal Diagnostic Criteria for Classical and Special Variants of CMML

According to Valent et al,²the criteria issued by the WHO are sufficient for the diagnosis of the classical form of CMML. However, the guidelines require modification to diagnose special CMML variants. Therefore, the panel proposed a concept for minimal diagnostic criteria for both the classical and special variants of CMML. The concepts for the classical form include prerequisite criteria, morphologic criterion, and co-criteria (TABLE 1).²

However, the special variants require a modified set of guidelines. The following are the special variants of CMML: oligomonocytic CMML, CMML associated with systemic mastocytosis, CMML with a concomitant myeloid neoplasm expressing a classical MPN driver, CMML with expression of a molecular MPN driver, and CMML with associated lymphoid neoplasms. Although the guidelines for diagnosis of the special variants are similar to classical CMML, key features distinguish them (TABLE 2).²

Prephases of CMML

Factors that may contribute to the selection and growth of premalignant neoplastic clones include somatic mutations, epigenetic modifications, chronic inflammation, and aging-related processes. In other myeloid neoplasms, these instances are known as clonal hema-topoiesis of indeterminate potential (CHIP), clonal cytopenia of unknown significance, age-related clonal hematopoiesis, and clonal hematopoiesis with oncogenic potential. Non-clonal conditions may exist with monocytosis, while other patients may not develop a hema-topoietic neoplasm. Therefore, this nonclonal prephase is known as idiopathic monocytosis of unknown significance. If CHIP-like mutations are found but no hematopoietic neoplasm is diagnosed, the condition should be considered clonal monocytosis of unknown significance. Idiopathic cytopenias of unknown significance can be a prephase of CMML, especially in patients with idiopathic thrombocytopenia of unknown significance. Finally, oligomonocytic CMML is considered a prephase of CMML because of the elevation in blood monocytes. Thus, the prephases of CMML may be of clonal or nonclonal origin.²

Current and Emerging Treatments

A detailed risk assessment must be performed on patients with CMML due to the diversity of the disease and short overall survival (OS). The EHA/ELN panel recommends that a risk stratification assessment be performed with CMML-specific models and that it incorporate mutational analysis.

Once the risk assessment has been completed, treatment options—including watchful waiting, stem cell transplant, and non-transplant therapeutics—are determined. Patients without an abundance of marrow blasts, symptomatic cytopenias, or major signs of myeloproliferation are candidates for watchful waiting. Treatments must begin, however, if patients experience any other complications.¹

The recommended form of treatment is allogeneic hematopoietic stem cell transplantation (HSCT) as it is the only curative therapy for CMML. According to proposed CMML prognostic scores, patients are classified into lower-risk or higher-risk CMML and their performance status determined. Higher-risk patients younger than 70 years with a stem cell donor and <10% marrow blasts may be selected for transplantation. In addition, lower-risk patients with poor-risk features and an available donor may be selected for transplant strategies. Patients deemed ineligible for HSCT are provided with nontransplant treatment options.¹

These include intensive therapy, hypomethylating agents, low-dose chemotherapy, erythropoietic stimulating factors, red blood cell transfusions, management of thrombocytopenia, and new experimental drugs. Intensive chemotherapy is not recommended, since CMML is a chemoresistant disease; however, it can be used prior to HSCT. This treatment regimen may also be used for patients if the diagnosis is indistinguishable between CMML and acute myelomonocytic leukemia.

Less-intensive disease-modifying therapies, such as the hypomethylating agents, should be considered in patients with more than 10% of blasts or a >5% blast excess with significant cytopenias or myeloproliferation. Furthermore, low-dose chemotherapy with hydroxyurea (Hydrea) may be used in proliferative CMML without significant cytopenias. In patients with CMML with significant anemia, erythropoietic stimulating factors or red blood cell transfusions may be performed. In addition, iron chelation therapy may be considered for patients who have undergone red blood cell transfusion.

Next, patients with severe thrombocytopenia in the absence of an excess of marrow blasts should be given a short course of steroids. Importantly, patients with special variants of CMML might benefit from specific therapies depending on the gene affected. Several new drug classes are being investigated, but few clinical trials include patients with CMML. Thus, the panel encourages investigators to include patients with CMML in trials designed for MDS and/or AML. In summary, non-transplant therapies may aid in disease control but many cases result in relapse.¹

These guideline recommendations aim to facilitate in the diagnosis of pre-CMML, classical CML, and special CMML variants through providing more specific diagnostic criteria and condition definitions. However, the guidelines are a collection of expert opinions and an adaptation of MDS guidelines. Because clinical evidence is lacking, the guidelines recommend that patients with CMML be included in clinical trials in the future.

References

1. Itzykson R, Fenaux P, Bowen D, et al, on behalf of the European Hema- tology Association, the European LeukemiaNet. Diagnosis and treatment of chronic myelomonocytic leukemias in adults: recommendations from the European Hematology Association and the European LeukemiaNet.
2. HemaSphere. 2018;2(6):e150. doi: 10.1097/HS9.0000000000000150. 2. Valent P, Orazi A, Savona MR, et al. Proposed diagnostic criteria for classical CMML, CMML variants and pre-CMML conditions [published on- line May 2, 2019].Haematologica. doi:10.3324/haematol.2019.222059.