Atypical chronic myeloid leukemia (aCML), BCR-ABL1–negative is a rare myelodysplastic syndromes (MDS)/myeloproliferative neoplasm (MPN) for which no current standard of care exists.
Diagnosis of aCML
The diagnostic criteria that comprise the World Health Organization entity “aCML, BCR-ABL1 negative†represent a decades-long evolution of classifying diseases that exhibited morphologic similarity to CML but lacked both the Philadelphia (Ph) chromosome and BCR-ABL1 rearrangement.
Diagnosis of aCML first requires testing for the Ph chromosome and/or the BCR-ABL1 fusion gene to exclude classic CML.
In addition to histopathologic analysis of the peripheral blood (PB) and bone marrow (BM), contemporary evaluation of aCML should include myeloid mutation panel testing in addition to standard karyotyping.
Distinguishing aCML From Other Chronic Leukemias
Morphologic Criteria
Some cases of aCML have been given the historical moniker “CML-like syndrome†because both diseases exhibit BMs with hyperplastic myeloid hyperplasia and PB leukocytosis characterized by a spectrum of myeloid immaturity. However, on morphologic grounds, this is where the similarity ends.
Unlike BCR-ABL1–positive CML, aCML is characterized by prominent dysplastic granulopoiesis (e.g., the acquired Pelger-Huët anomaly typical of MDS; nuclear abnormalities including hypersegmentation, nuclear projections, and abnormally clumped nuclear chromatin; and abnormalities of cytoplasmic granules).
Multlineage dysplasia may be observed. In cases in which subtle dysplasia or borderline levels of myeloid immaturity or monocytosis are present, the morphologic distinction between aCML, BCR-ABL1–positive CML, chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia, or MDS/MPN (unclassified) can be challenging.
The following criteria are associated with aCML, and can help distinguish aCML other chronic leukemias:
- ≥10% immature myeloid cells (promyelocytes, myelocytes, and metamyelocytes) in the peripheral blood and/or dysplasia
- absent or minimally present basophilia (<2% of leukocytes)
- absent or minimally present monocytosis (<10% of leukocytes)
Genetic Features
In contrast to CML, which is operationally defined by the presence of BCR-ABL1, no single genetic lesion characterizes aCML. The mutations identified in aCML are commonly found in other myeloid neoplasms.
Some basic observations can be made about the molecular landscape of aCML: higher frequency mutations (eg, >20%) include SETBP1, ASXL1, NRAS/KRAS, SRSF2, and TET2, and lower frequency mutations (<10%) include CBL, CSF3R, JAK2, and ETNK1.
Prognosis
Patients with aCML have an estimated median survival between 14 and 30 months. aCML tends to exhibit a more aggressive clinical course than other MDS/MPN subtypes.
Increased WBC count (e.g., cutoffs of >40×109/L or 50×109/L), increased percentage of peripheral blood immature precursors, female sex, and older age are adverse prognostic factors for overall survival or leukemia-free survival.
Treatment Options
No standard of care exists for the treatment of aCML, and no consensus recommendations or risk-based treatment algorithms exist to help guide a watch-and-wait approach.
As seen in the FIGURE, my treatment algorithm begins with allogeneic hematopoietic cell transplantation (alloHCT) for eligible patients, regardless of the results of mutation testing, and encompasses hypomethylating agents (HMAs) and targeted agents (if mutation testing reveals a potentially actionable mutation).
Treatment with HMAs in aCML is a rational application of their established activity in MDS and CMML, but the experience with HMAs in aCML is limited. I consider their use as a bridging therapy for transplant-eligible patients and as stand-alone treatment of patients without an alloHCT or clinical trial option.
Additionally, I co-opt treatment strategies used for either MDS or MPN and apply them on a case-by-case basis to address a patient’s major clinical manifestations (e.g., leukocytosis, anemia, constitutional symptoms, splenomegaly, and potential for progression to acute myeloid leukemia). These secondline or adjunctive options may include JAK inhibitors (in the rare instances when CSF3R T618I or JAK2 V617F is present), pegylated interferon alfa, hydroxyurea, and/or erythropoiesis-stimulating agents.
Future Directions
Recent research has identified several promising therapeutic targets, including NRAS G12D, reactivation of the tumor suppressor PP2A, and SRSF2 mutations. Combination strategies using therapies targeting disease-associated mutations in conjunction with either HMAs or as an adjunct to alloHCT (either as a bridge to transplant or in the posttransplant setting to reduce relapse) should be evaluated.
Progress in aCML depends on enrollment of patients into clinical trials and molecular profiling of individuals, so that opportunities for targeted therapy can be exploited.
Reference
Gotlib J. How I treat atypical chronic myeloid leukemia. Blood. 2017;129:838-45.