Skip to Main Content

Advertisement intended for health care professionals

Skip Nav Destination

You Make the Call: When Would You Use Next-Generation Sequencing Data in the Management of Anemia?

January 24, 2022

February 2022

H. Joachim Deeg, MDH. Joachim Deeg, MD
Professor, Clinical Research Division,
Miklos Kohary and Natalia Zimonyi Kohary Endowed Chair,
Fred Hutchinson Cancer Research Center, Seattle, Washington

 

 


CLINICAL DILEMMA

A 76-year-old woman was referred for anemia. Her hemoglobin level was 8.5 g/dL, her mean corpuscular volume was 88 fL, and she had normal white blood cell and platelet counts. There was no evidence of hemolysis, and her ferritin level was 33 ng/mL. She was repleted with iron, but her anemia persisted with a hemoglobin level of 10 g/dL. She underwent a biopsy, and her bone marrow was normocellular (60% cellularity) with normal trilineage hematopoiesis and no dyspoiesis. Her iron stores were absent on iron stains of the aspirate. She has a normal metaphase karyotype, and fluorescence in situ hybridization (FISH) was negative for -5/5q31-, -7/7q31-, +8, and 20q12-. Next generation sequencing (NGS) noted several variants: DNMT3A, TET2, U2AF1, IKZF1, and MPL.

In retrospect, I’m not sure what to do with this NGS data, aside from continued observation and repeating bone marrow biopsy if worsening cytopenias develop. Should I have ordered the NGS?


EXPERT OPINION

In the absence of mutations, one could simply refer to this as a case of anemia or, more broadly, idiopathic cytopenia of undetermined significance (ICUS). The available data do not support a diagnosis of paroxysmal nocturnal hemoglobinuria. An erythropoietin level might be of interest. Apparently, the patient has a normal karyotype, but five mutations are reported. We do not know the variant allele frequency (VAF) nor the specific sites of these mutations, but the probable significance can be discussed.

The patient is 76 years old. At that age, somatic mutations are found in as many as 15% of individuals who do not carry a hematological diagnosis. Nevertheless, considering all the data, it appears that this patient has probable clonal cytopenia of undetermined significance (CCUS). If so, the prognosis is of greatest importance, since we know that CCUS can progress to myelodysplastic syndromes (MDS) and acute leukemia.

DNMT3A is involved in DNA methylation, and mutations have been reported in 3% to 20% of MDS cases. TET2, an epigenetic modifier found to be mutated in 20% to 25% of patients with MDS, has tumor-suppressor function, which appears to be lost upon mutation, basically leading to “oncogenic” function. Mutations in U2AF1, a spliceosome factor, have been observed in some 15% of MDS cases and are generally considered high risk. Ikaros, a transcription factor encoded by IKZF1, is expressed during hematopoiesis. It is involved in positive regulation of lymphocyte differentiation and negative regulation of cell proliferation and mutations are seen primarily in patients with B-cell acute lymphocytic leukemia, but infrequently also in myeloid malignancies. MPL is a gene that is mutated in a small proportion of patients with myeloproliferative neoplasms, but less frequently in MDS. Its presence raises the question of a myeloproliferative component.

Luca Malcovati, MD, and others have shown that patients with ICUS who have mutations with a VAF of ≥0.10 or with two or more mutations in genes that are recurrently mutated in myeloid disorders, such as CCUS, have a high probability of progression to MDS/acute myeloid leukemia.1 In particular, mutations in spliceosome genes such as U2AF1 and co-mutation patterns that involve TET2 or DNMT3A (or ASXL1) had a very high predictive value for progression. In fact, data suggest that the probability of evolution in patients with CCUS with one of the highly predictive mutation patterns was as high as 50% by two years and approached 100% by four years. (The probability was lower in the presence of other mutations or in the absence of mutations, i.e., in patients with ICUS).

It is a matter of debate at which point treatment should be initiated. Patients need to be followed closely for progressive changes in peripheral blood cell counts. A diagnostic bone marrow aspirate and biopsy should be repeated, maybe in six months, probably including another mutational analysis. Dependent upon follow-up findings, treatment options will need to be discussed with the patient. These would include hypomethylating therapy, possibly orally, alone or combined with venetoclax. While not necessarily standard therapy in a patient of this age, allogeneic hematopoietic cell transplantation may still be an option, dependent upon the patient’s preferences and co-morbid conditions.

Reference

Malcovati L, Galli A, Travaglino E, et al. Clinical significance of somatic mutation in unexplained blood cytopenia. Blood. 2017;129(25):3371-3378.


NEXT MONTH'S CLINICAL DILEMMA

A 60-year-old male patient presented with beta thalassemia minor and a hemoglobin level of 12.5 g/dL. He was noted to have persistently elevated serum ferritin levels by his primary care physician with the most recent being 999 mcg/L. The liver iron concentration (LIC) by MRI was 3.9 mg Fe/g dry weight, consistent with mild iron overload. Would you consider oral iron chelation in this patient?

How would you respond? Email us at [email protected].

Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.

Advertisement intended for health care professionals

Connect with us:

CURRENT ISSUE
November 2024

Advertisement intended for health care professionals

Close Modal

or Create an Account

Close Modal
Close Modal

Advertisement intended for health care professionals