A case-based presentation on CMML

At the European School of Haematology (ESH) 4th ‘How to Diagnose and Treat: CML/MPN’ meeting, Daniel Wiseman, MBBS, PhD, University of Manchester, Manchester, UK, presented two real-world cases from his clinical practice, using them to outline the current treatment algorithms in CMML and recent developments that have been made. Dr Wiseman highlights key takeaways from the recently published update to the consensus guidelines for CMML diagnosis, risk stratification, and management, which was published in the American Journal of Hematology in 2024.¹ Additionally, he discusses the latest prognostic scoring systems, which he notes could increase the number of patients diagnosed with CMML.

Finally, Dr Wiseman introduces the AMMO clinical trial (ISRCTN30808508), a Phase II trial comparing a novel oral hypomethylating agent (HMA), ASTX727, to hydroxyurea in patients with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes.² The trial recruited patients rapidly, and results are expected soon.

The management of CMML in the UK

As Dr Wiseman explains, the management of CMML begins with risk stratification of the patient to determine whether treatment is needed. He notes that current treatment options in the United Kingdom are limited, with hydroxyurea being a common choice for proliferative subtypes. The HMA azacitidine is available for some subgroups of patients, but Dr Wiseman notes that its efficacy in CMML is lower than in other hematological malignancies, such as MDS.

Therapeutic approaches being investigated for CMML

Several promising therapeutic approaches are being investigated for treating patients with CMML, with Dr Wiseman providing a comprehensive overview of the treatment strategies that are in advanced stages of development. These include the monoclonal antibody lenzilumab, a monoclonal antibody targeting LILRB4, and the JAK inhibitor pacritinib. 

Improving the understanding of blast-phase CMML

In around 30% of CMML patients, the disease undergoes transformation into the blast phase (BP-CMML).³ BP-CMML is defined by the accumulation of ≥20% primitive blasts within the bone marrow and/or peripheral blood, and is highly chemoresistant.³ As this entity is understudied, Dr Wiseman and his team aimed to investigate its disease biology and potentially define distinct phenotypes. Using a large biobank of samples, Dr Wiseman’s team identified significant heterogeneity among BP-CMML cases, with two distinct subgroups exhibiting different therapeutic sensitivity.³ This research may pave the way for more targeted and effective treatments for patients.

Prognostic and therapeutic implications of TP53 expression in CMML

Mutation of the TP53 tumor suppressor gene is the most commonly observed mutation in cancer, and TP53-mutated cases make up a significant proportion of patients with hematological malignancies such as MDS, MPNs, and acute myeloid leukemia (AML).⁴ Despite this, TP53 aberrations are rare in CMML. In a retrospective analysis of 1315 patients, the largest CMML cohort to date, only 2.4% of patients harbored a TP53 mutation.⁵ 

Dr Wiseman discusses his research in this area, highlighting the findings of a study conducted using data from 648 patients with CMML, which confirmed the rarity of the TP53 mutation in this patient population.⁶ Additionally, the study was the first to interrogate the prognostic implications of mutation-independent dysregulation of TP53, with data suggesting a role of TP53 expression in the aggressiveness of a patient’s disease and their therapeutic response. Patients with low expression had higher resistance to treatment with HMAs, distinctive biology, and poor prognosis.⁶ Dr Wiseman mentions subsequent in vitro investigations, which elucidated the potential for combining azacitidine with an MDMX/MDM2 inhibitor to restore HMA sensitivity in these patients.⁶ Although this remains to be investigated in the clinical trial setting, it may provide a promising therapeutic avenue for a patient population with poor prognosis.

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