Atypical Chronic Myeloid Leukemia: A Rare Disease With Poor Prognosis

Microscopic, photorealistic image of chronic myeloid leukemia (CML) cells - Generated with Adobe Firefly

Treating a patient with atypical chronic myeloid leukemia (aCML) is a challenge that stems from its rare incidence and limited curative therapies.¹ Although it is still included in the heterogeneous group of myelodysplastic syndromes/ myeloproliferative neoplasms (MDS/MPN) by the World Health Organization, the last International Consensus Classification (ICC) renamed the disease as MDS/MPN with neutrophilia.²

Both classifications require a diagnosis of leukocytosis with more than 13 × 109/L, with greater than 10% of precursors and dysgranulopoiesis. Blasts in the peripheral blood and bone marrow should be no more than 20%, without monocytosis and basophilia. All the driver mutations that identified all Philadelphia chromosome (Ph)–positive (Ph+) and Ph-negative neoplasms should be absent, together with all tyrosine kinase gene fusions that identified the myeloid/ lymphoid neoplasms with eosinophilia.³

ICC classification also suggests the absence of peripheral eosinophilia and the possible appearance of cytopenia.² aCML occurs in 1 in 100 cases of Ph+ CML, and is more evident in older male patients.⁴ No specific cytogenetic alterations are associated with the disease, but only some recurrent aberrations such as trisomy 8, deletion of 20q, and isochromosome 17q can occur. ⁵ In recent years, next-generation sequencing approaches have identified a clonal architecture in this disease: A mutational landscape has been proved with hierarchical progress. ASXL1 and ETNK1 appear to be ancestral mutations in this disease, followed by SETBP1, usually as a secondary event. In the progression and final leukemic stage, other mutations can be acquired, such as CUX1, RAS, and RUNX1.⁶

ETNK1 mutations are clustered in a small region of the kinase domain, in heterozygosity, and encode for the ethanolamine kinase, which allows the transformation of ethanolamine in phosphoethanolamine. The mutation reduces the enzyme’s activity, increasing the mitochondrial activation with the production of reactive oxygen species and increased DNA damage.^7,8

SETBP1 mutations have been identified in 25% to 33% of patients with aCML, so they are not unique in this disease and are associated with high leukocyte count and lower hemoglobin and platelet counts. SETBP1 interacts with SET, a negative regulator of the tumor suppressor protein phosphatase 2A, with consequent increased repression of cellular proliferation.^9,10

Recently, it has been suggested that a close correlation exists between aCML and chronic neutrophilic leukemia (CNL); other than CSF3R being more commonly mutated in CNL, and EZH2 and TET2 more commonly mutated in aCML, no differences were detected in the remaining pathways affected, suggesting that the two diseases form a continuum.¹¹ In response to this observation, the National Cancer Database was analyzed and, although the genomic data are missing, a difference in overall survival (OS) was found, with a median of 15 months for aCML and 23 months for CNL.¹² The prognosis for aCML is poor: the median OS reported was 25 months with leukemic progression occurring in one-third of patients.³ Because of the rarity of the disease, only a few studies reported the possible prognostic factors associated with OS: being older than 65 years, being female, hemoglobin (Hb) less than 10 g/dL, and leukocytosis greater than 50 × 10⁹/L with increased immature circulating precursors.^4,6,13,14 Two different prognostic scores were also proposed, based on a small cohort of patients: the Modified MD Anderson Cancer Center score¹³ indicates being older than 65 years, Hb less than 10 g/dL, and white blood cell count greater than 50 × 10⁹/L are possible predictive factors, whereas Mayo Clinic indicates being older than 67 years, an Hb less than 10 g/dL, and TET2 mutation are negative factors.⁵

No consensus document or risk-based treatment algorithm is available for treating aCML. Allogeneic stem cell transplant remains the only curative option: a European Society for Blood and Marrow Transplantation analysis reported an OS rate at 5 years of 51%, but contrasting results were reported in a small series of patients.^15-17

Conservative treatment with hydroxyurea remains the mainstay of therapy, typically used to control the burden of disease.¹⁸ Interferon alpha has also been evaluated in some patients with complete or partial hematological control.¹⁹

Several cases treated with hypomethylating agents (HMAs), such as azacitidine or decitabine, have been reported: HMAs should be considered as a bridge to transplant in younger patients or as stand-alone therapy in patients without an option of care.^20,21 Targeted therapy with ruxolitinib (Jakafi) was tested in single-case reports and a phase 2 trial (NCT01787487).

Responses were observed in combination or a single agent in patients with CSF3R mutation at a low rate compared with patients with CNL who had the same mutation.^22,23 In CSF3R truncated mutation, the possible role of dasatinib (Sprycel) has been explored, but only in vitro.²⁴ Other pathways for targeted therapy have also been investigated, such as RAS. Trametinib (Mekinist), a MEK1/2 inhibitor, has been explored in single-case reports showing hematological control and transfusion independence.^25,26 aCML remains an orphan disease with limited therapeutic choices. New molecular targets and specific drugs should be evaluated for this disease with a poor prognosis and a high rate of acute transformation.

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