Forging a path for chronic myelomonocytic leukaemia

At the end of 2018, the European Hematology Association, in collaboration with the European LeukemiaNet, published a diagnosis and treatment guideline for chronic myelomonocytic leukaemia (CMML), a rare clonal haematological malignancy characterised by absolute peripheral monocytosis, ineffective haematopoiesis, and an increased risk of transformation to acute myeloid leukaemia. This consensus-based guideline systematically reviewed available literature and was drafted following discussion by an international panel of experts, providing diagnosis, risk stratification, and treatment recommendations. Such a document is very welcome for a rare haematological malignancy, but the contents highlight the glaring lack of good clinical evidence for this disease. CMML has undergone several revisions in its classification, which reflects the complexity of the disease. CMML was recognised as a distinct clinical entity and classified as a subset of the myelodysplastic syndromes by the French-American-British Group in 1976. In 2001, it was provisionally reclassified (permanently in 2008) by the WHO as an overlap syndrome which features the characteristics of both myelodysplastic syndromes and myeloproliferative neoplasms. One striking issue which is highlighted from the recommendations is the lack of strong clinical evidence for treating the disease. To date, there has only been one randomised clinical trial specifically for CMML published. CMML can contain features of both myelodysplastic syndromes and myeloproliferative neoplasms, with symptoms that can include anaemia, thrombocytopenia, splenomegaly, and it is often excluded from clinical trials. At present, treatment ranges from watchful waiting to allogeneic stem-cell transplantation, the only treatment with curative intent for CMML, and most treatment is geared towards symptom management and reflective of its traditional classification as an myelodysplastic syndrome. Further consideration is that it primarily affects older people—the median age at diagnosis is 72 years—which brings along the added challenge of comorbidities and polypharmacy. The age of the patients also limits the utility of allogeneic stem-cell transplantation in this population, meaning the need for novel treatments is incredibly urgent. Extrahaematological manifestations are also not uncommon in CMML, with a reported prevalence of autoimmune manifestations occurring in 10–18% of patients. CMML has also been seen to be involved in skin lesions. Treating these symptoms as well can result in complex care programmes, in patients for whome care is already demanding. There are of course challenges associated with studying any rare disease—CMML has an incidence of around 1 per 100 000 individuals per year—but great advances can be made in rare cancers. Chronic myeloid leukaemia (CML) is a classic example. Before the advent of tyrosine kinase inhibitors, CML was a difficult to treat, rare, blood cancer. Now individuals who successfully respond to therapy can have very good survival outcomes. The US Food and Drug Administration (FDA) Office of Orphan Products Development aims to advance the evaluation and development of products that demonstrate promise for the diagnosis or treatment of rare diseases and offers incentives for sponsors towards the development of these products. This had led to an increase in approvals for drugs for rare haematological malignancies. Last year the FDA approved mogamulizumab-kpkc for the treatment of adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome, marking the first FDA approval of the drug specifically for Sézary syndrome. Another example comes from the approval of tagraxofusp-erzs (a CD123-directed cytotoxin) for patients with blastic plasmacytoid dendritic cell neoplasm. For CMML, there have been advances that can be built upon. Several prognostic scoring systems have been reported in recent years, and the underlying molecular genetics and cytogenetics have been studied, although the diagnostic or prognostic roles of mutations and their combinations have yet to be validated. In the meantime, low-dose chemotherapy, red blood cell support via transfusion, or erythropoietic stimulating factors remain the cornerstone of treatment for patients not eligible for allogeneic stem-cell transplantation. Although the new treatment guidelines are welcome, it is clear that there is still progress to be made. CMML is a rare disease, so international collaborative networks are key to establishing a solid clinical base to obtain the best possible evidence for patients with this disease. As our understanding grows, we can hope that further therapies are developed and tested, and that there will continue to be success stories for rare haematological malignancies. For the CMML treatment guidelines see https://journals.lww.com/hemasphere/Fulltext/2018/12000/Diagnosis_and_Treatment_of_Chronic_Myelomonocytic.7.aspxFor more about the FDA Office of Orphan Products Development see https://www.fda.gov/forindustry/developingproductsforrarediseasesconditions/default.htm For the CMML treatment guidelines see https://journals.lww.com/hemasphere/Fulltext/2018/12000/Diagnosis_and_Treatment_of_Chronic_Myelomonocytic.7.aspx For more about the FDA Office of Orphan Products Development see https://www.fda.gov/forindustry/developingproductsforrarediseasesconditions/default.htm