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Subspecialties Hematology, Training and education, Oncology

SF3B1-Mutant Chronic Myelomonocytic Leukemia

Clinical history

82-year-old man with progressive exertional dyspnea for one year.

Pertinent physical exam

No hepatosplenomegaly. 

Complete blood count and differential (reference range)

Bone marrow morphology

Peripheral blood smear shows macrocytic anemia with leukocytosis and absolute monocytosis. Monocytes are morphologically atypical and include increased immature forms (promonocytes) (Giemsa A: 200x; B: 400x).

The bone marrow core biopsy is hypercellular for age (A; H&E 100x). There is myelomonocytic hyperplasia; megakaryocytes are small and dysplastic (B; H&E 200x). Erythroid precursors include increased left-shifted forms (C; H&E 400x). A reticulin stain shows mild reticulin fibrosis (D; 100x).

The bone marrow aspirate smears show trilineage dysplasia. Erythroid dysplasia (blue arrows) is characterized by nuclear contour irregularities, basophilic stippling of cytoplasm, and asynchronous maturation of cytoplasm and nucleus. Dysmegakaryopoiesis (green arrows) is manifested by increased small, hypolobated forms. Granulocytes (yellow arrows) are also dysplastic with increased hypolobated and hypogranular forms. Monocytes and monocytic precursors (orange arrows) are increased.

An iron stain performed on the bone marrow aspirate smear shows increased ring sideroblasts (red arrows) (Prussian Blue, 1000x).


Routine cytogenetic studies show an abnormal male karyotype – 46,XY,del(12)(p12)[19]/46,XY[1]

Next-generation sequencing

Next-generation sequencing studies showed the following mutations:

VAF: variant allele frequency.

Final diagnosis

SF3B1-mutant chronic myelomonocytic leukemia.

Case Discussion

The pathologist’s view
Though the diagnosis of myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) is unequivocal in this case, further subclassification is challenging, particularly if one attempts to stay within the current WHO classification scheme’s confines. When strictly applying the current WHO criteria (1), given the presence of dysplastic morphologic features and relative and absolute monocytosis, this case is best classified as chronic myelomonocytic leukemia (CMML), dysplastic subtype (WBC <13,000/μL). However, the presence of numerous ring sideroblasts is unusual and a direct manifestation of this neoplasm’s genetic profile, which harbors a dominant SF3B1 mutation. In our opinion, this case represents an example of a potentially distinct biologic entity, the so-called SF3B1-mutant CMML (2), which is not currently accounted for in routinely used classification schemes. Cases of SF3B1-mutant CMML typically present with predominant MDS-like features, distinct molecular profiles, and superior prognosis; therefore, appropriate classification and risk stratification directly impact patient management strategies.

The hematologist’s view

From a management perspective, CMML is challenging, thanks to its clinical and molecular heterogeneity. By demonstrating overlapping features of MDS and MPN, it necessitates an individualized treatment approach (3). This particular patient presented with macrocytic anemia, leukocytosis, and monocytosis with a normal platelet count. His bone marrow biopsy showed trilineage dysplasia with ring sideroblasts (RS). His karyotype showed 12p deletion (intermediate risk) and next-generation sequencing identified mutations involving SF3B1 (40 percent), SRSF2 (34 percent), ASXL1 (32 percent), RUNX1 (22 percent), SETBP1 (4 percent) and CSF3R (2 percent). Among these, truncating ASXL1 mutations are universally detrimental, predicting shorter overall and acute leukemia-free survival (4). SF3B1 and SRSF2 mutations both impact pre-mRNA splicing, with SRSF2 mutations most common in CMML (5). SF3B1 mutations strongly correlate with the presence of BM RS, are seen in 5 percent or fewer CMML patients, and associate with a predominantly dysplastic CMML subtype, with preserved platelet counts and a superior acute leukemia-free survival (2). The variant allele frequency burden of both splicing mutations is unusual and makes it difficult to predict the dominant clone. Splicing mutations are thought to be mutually exclusive, but can coexist (6). Finally, RUNX1 and SETBP1 mutations are seen in about 15 percent of CMML and confer an adverse prognostic impact (4,7). CSF3R T618I mutations are exceedingly uncommon in CMML and represent a known oncogenic driver for chronic neutrophilic leukemia (8); the significance of this subclonal mutation (VAF=2%) in the context of the patient’s disease is unknown.

For this patient, despite his dysplastic CMML subtype and favorable SF3B1 mutations, the ASXL1, RUNX1, and SETBP1 mutations are concerning for higher-risk disease. Given his age, he is not a stem cell transplant candidate. Hence, for the management of his anemia, I would first check his endogenous erythropoietin level. If <500, he would be a good candidate for recombinant human erythropoietin therapy. Although luspatercept, a first in class TGF-β modulator, has shown excellent activity in MDS-RS, it has not been approved for the management of anemia in CMML-RS (9). If his endogenous EPO is >500, or if he does not respond to erythropoietin, he would be a reasonable candidate for low-dose- hypomethylating agent therapy (10). Low doses of azacitidine and decitabine have been associated with epigenetic restoration of hematopoiesis and improved anemia. At our institute, we also strongly recommend that all CMML patients consider enrollment in clinical trials – because, other than stem cell transplant, there are currently no curative therapies.

Read on to discover our other myeloid cases...

Case 1: Clonal Cytopenia of Uncertain Significance or Myelodysplastic Syndrome?
Case 3: Myelodysplastic Syndrome with Excess Blasts and Fibrosis
Case 4: Elevating the Treatment Standard in Older Patients with AML

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  1. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. IARC: 2017.
  2. K Wudhikarn et al., “SF3B1-mutant CMML defines a predominantly dysplastic CMML subtype with favorable biological attributes,” Blood Adv, [In press] (2020).
  3. MM Patnaik, A Tefferi, “Chronic myelomonocytic leukemia: molecularly contaminated, but not defined,” Leuk Lymphoma, 57, 1751 (2016). PMMID: 27063331.
  4. MM Patnaik et al., “ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients,” Leukemia, 28, 2206 (2014). PMID: 24695057.
  5. MM Patnaik et al., “Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: prevalence, clinical correlates, and prognostic relevance,” Am J Hematol, 88, 201 (2013). PMID: 23335386.
  6. J Taylor et al., “Single-cell genomics reveals the genetic and molecular bases for escape from mutational epistasis in myeloid neoplasms,” Blood, 136, 1477 (2020). PMID: 32640014.
  7. EC DiFilippo et al., “Spectrum of abnormalities and clonal transformation in germline RUNX1 familial platelet disorder and a genomic comparative analysis with somatic RUNX1 mutations in MDS/MPN overlap neoplasms,” Leukemia, 34, 2519 (2020). PMID: 32060405.
  8. JE Maxson et al., “Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML,” N Engl J Med, 368, 1781 (2013). PMID: 23656643.
  9. P Fenaux et al., “The MEDALIST Trial: Results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept to treat patients with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) associated anemia with ring sideroblasts (RS) who require red blood cell (RBC) transfusions,” Blood, 132 (Supp 1), 1 (2018).
  10. E Jabbour et al., “Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN,” Blood, 130, 1514 (2017). PMID: 28774880.
About the Authors
Sanam Loghavi

Assistant Professor of Hematopathology, Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Kamran Mirza

Professor of Pathology and Director of the Division of Education Programs, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, United States.

Mrinal M. Patnaik

Associate Professor of Internal Medicine, Chair of the Acute Leukemia and Myeloid Malignancies Group, and Co-Director of the Epigenetics Developmental Laboratory, Mayo Clinic, Rochester, Minnesota, USA.

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