Question 1 

Which statement about epidemiology and clinical features of atypical CML is correct?

Correct answer: C. Symptoms of atypical CML may be related to anemia and thrombocytopenia.

Expert Perspective
The exact incidence of atypical CML is unknown, but the median patient age at diagnosis is in the seventh and eighth decade of life.^1,2 The peripheral blood is always involved with the bone marrow; in fact, peripheral blood leukocytosis ≥ 13 × 10⁹/L, due to increased numbers of neutrophils and their precursors (promyelocytes, myelocytes, and metamyelocytes) constituting ≥ 10% of the leukocytosis is one of the diagnostic criteria for atypical CML (Figure 1); splenic and hepatic involvement is not uncommon.¹ Symptoms of the disease may be related to anemia and thrombocytopenia and/or splenomegaly.¹ 

Question 2

Which statement about microscopy in atypical CML is correct?

Correct answer: A. Dysgranulopoiesis is one of the diagnostic features for atypical CML.

Expert Perspective
Dysgranulopoiesis (eg, hypogranular and hypolobated neutrophils, abnormal chromatin clumping, pseudo–Pelger-Hüet neutrophils) is one of the major diagnostic features that characterize atypical CML, along with peripheral blood leukocytosis ≥ 13 × 10⁹/L, from increased numbers of neutrophils and their precursors (promyelocytes, myelocytes, and metamyelocytes, not blasts)—hence, its inclusion in the myelodysplastic/myeloproliferative neoplasm category (Table 1).¹ Moderate anemia is common, and the red blood cells may show changes indicative of dyserythropoiesis (40% of cases). Unlike atypical CML, chronic neutrophilic leukemia lacks dysplastic features and has < 10% circulating immature myeloid cells.¹ Dysplasia in the megakaryocytic lineage may or may not be present in atypical CML. Basophils constitute < 2% of the peripheral blood leukocytes, and the basophil count is a part of the diagnostic criteria for atypical CML.¹ 

Question 3

Which statement about diagnostic criteria in atypical CML is correct?

Correct answer: C. WHO criteria for polycythemia vera should be excluded to make a correct diagnosis of atypical CML.

Expert Perspective 
The absolute monocyte count may be increased, but the percentage of peripheral blood monocytes is < 10%. Bone marrow is hypercellular with granulocytic proliferation and dysplasia -(Figure 2).¹ The WHO criteria for polycythemia vera, essential thrombocythemia, primary myelofibrosis, and BCR-ABL1–positive CML should be excluded to make a correct diagnosis of atypical CML. Blasts are usually < 5% and are always < 20% of the peripheral blood leukocytes and bone marrow cells.¹

Question 4

Which statement about cytochemistry and immunophenotype in atypical CML is correct?

Correct answer: A. There are no specific cytochemical abnormalities in atypical CML.

Expert Perspective
It is correct that there are no specific cytochemical abnormalities for the diagnosis of atypical CML.¹ Also, there are no specific immunophenotypic characteristics. Immunohistochemistry staining with CD14 or CD68R on a significant number of bone marrow cells facilitates the identification of monocytes, and such findings should call into question the diagnosis of atypical CML.¹ 

Question 5

Which statement about genetic profiling in atypical CML is correct?

Correct answer: B. CSF3R mutation is uncommon in atypical CML.

Expert Perspective
The presence of the PCM1-JAK2 fusion gene does not favor the diagnosis of atypical CML; moreover, the absence of PDGFRA, PDGFRB, or FGFR1 rearrangements is also required to diagnose atypical CML. CSF3R mutation is uncommon and is present in 10% of patients with atypical CML; this mutation is found in a larger proportion of patients with chronic neutrophilic leukemia. Data indicate that ETNK1³ and SETBP1⁴ mutations are relatively common in atypical CML. 

Question 6

Which statement about prognosis in atypical CML is correct? 

Correct answer: C. Patients with atypical CML who undergo allogeneic hematopoietic cell transplantation (allo-HCT) may have better outcomes.

Expert Perspective
About 30% to 40% of patients with atypical CML develop acute myeloid leukemia, and most of the remaining patients die of bone marrow failure (although splenomegaly is not uncommon).¹ Age > 65 years, female gender, white blood cell count > 50 × 10⁹/L, thrombocytopenia, and hemoglobin level < 10 g/dL have been reported to be adverse prognostic findings.1 However, patients who receive allo-HCT may have better outcomes compared with patients who are treated with conventional chemotherapy alone.⁵ 

Acknowledgment: Faiz Ahmed Hussain, MD, Department of Internal Medicine, Jackson Park Hospital, Chicago assisted in preparing this manuscript. ■

DISCLOSURE: Drs. Abutalib and Medeiros reported no conflicts of interest.

REFERENCES 

1. Orazi A, Bennett JM, Bain BJ, et al: Atypical chronic myeloid leukemia, BCR-ABL1-negative, in Swerdlow SH, Campo E, Harris NL, et al (eds): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, pp 87-89. Lyon, France, International Agency for Research in Cancer, 2017.

2. Wang SA, Hasserjian RP, Fox PS, et al: Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms. Blood 123:2645-2651, 2014.

3. Gambacorti-Passerini CB, Donadoni C, Parmiani A, et al: Recurrent ETNK1 mutations in atypical chronic myeloid leukemia. Blood 125:499-503, 2015.

4. Piazza R, Valletta S, Winkelmann N, et al: Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet 45:18-24, 2013.

5. Koldehoff M, Beelen DW, Trenschel R, et al: Outcome of hematopoietic stem cell transplantation in patients with atypical chronic myeloid leukemia. Bone Marrow Transplant 34:1047-1050, 2004.

FIGURE 1: Peripheral blood smear examination in a patient with atypical CML shows marked leukocytosis and increased neutrophils including immature neutrophilic precursors. Courtesy of S.A. Wang, MD, The University of Texas MD Anderson Cancer Center.

FIGURE 2: Bone marrow biopsy specimen in a patient with atypical CML shows a markedly hypercellular bone marrow with a predominance of myeloid precursors. Courtesy of S.A. Wang, MD, The University of Texas MD Anderson Cancer Center.