How I Treat In Brief
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concerned that he was evolving to MDS.
Commentary: When a mutation is present in
an older patient with a cytopenia, especially
a mutation commonly associated with clonal
hematopoiesis of indeterminate potential
(CHIP; including DNMT3A, TET3, or ASXL1
at a VAF<20%), it raises the possibility that the
mutation and the cytopenia may be unrelated.
Still, research has shown that patients with clonal
cytopenias of indeterminate significance (CCUS;
defined as the presence of unexplained persistent
cytopenias and mutations in leukemia-associated
driver genes yet do not meet WHO criteria for
MDS or acute myeloid leukemia [AML]) have a
substantial risk of progression to AML or MDS.
The risk is greatest for those with a higher muta-
tion burden (VAF >20%), more than one muta-
tion, or a mutation in a splicing factor.
In the future, it is possible that patients with
certain mutation patterns may be able to be di-
agnosed as “MDS without dysplasia,” given their
shortened life expectancy and a natural disease
history that is similar to that observed with MDS
diagnosed using current WHO criteria.
Case #3: Evaluating a Patient With an
Established MDS Diagnosis
A 64-year-old woman who had not had labora-
tory tests in more than five years presented with
pancytopenia and underwent marrow aspiration
and biopsy, which was consistent with MDS with
excess blasts type I. Multilineage dysplasia was
present, including 10 percent ring sideroblasts.
The karyotype showed monosomy 7 in 6/20
metaphases, del20q and loss of the X chromosome
in 8/20 metaphases, and 6 normal female meta-
phases. Mutation testing showed SF3B1 K700E
(VAF=26.8%) and TP53 V197M (VAF=16.0%).
lection outside the context
of a clinical trial.
Case 4: Revealing
Alternate Diagnoses
Fast Facts
A 72-year-old man had
✓ ✓ Next-generation sequencing (NGS) assays that test for subsets
moderate splenomegaly,
of MDS-associated gene mutations at the DNA level are widely
liver enlargement, and a few
available in clinical practice, but we are still learning how best to
retroperitoneal lymph nodes
use these assays.
that were also enlarged in
the 2- to 3-cm range. His
✓ ✓ NGS results may aid in selecting treatment or transplant decision
blood counts included a
making for MDS patients in selected circumstances.
hemoglobin of 11.1 g/dL,
✓ ✓ Caution should be used in interpreting NGS results, given the high
mean corpuscular volume
degree of allelic heterogeneity in MDS-associated genes.
93 fL, platelets of 140×10 9 /L,
✓ ✓ As NGS panels become less expensive, it seems likely that they
and WBC of 6.65×10 9 /L with
will move earlier in the diagnostic testing algorithm for patients
31 percent monocytes, 36
with cytopenias.
percent neutrophils, and 24
percent lymphocytes.
Bone marrow biopsy
was hypercellular for age
and consistent with chronic
myelomonocytic leukemia
diagnosis depends on the composition of the
type 1 (CMML-1). Karyotype was normal, and
sequencing panel. For example, for logistic and
an MDS-focused fluorescent in situ hybridiza-
workflow reasons, our institution uses a single
tion (FISH) was also unrevealing. Single-gene
NGS panel with genes associated with lymphoid,
testing for JAK2 was wild type. Biopsy of the
plasma cell, and myeloid disorders.
retroperitoneal lymph nodes demonstrated fibrosis,
Conversely, patients who are being evaluated
which was interpreted as reactive, and biopsy of the
for a plasma cell neoplasm or lymphoprolifera-
enlarged liver showed focal irregular fibrosis and
tive disorder may be found to have a CHIP-
areas of portal effacement.
associated mutation, which may complicate the
The patient was then referred to our center
evaluation, because these mutations are also
to assess whether his hepatic fibrosis might be
frequently associated with myeloid neoplasms.
paraneoplastic due to the CMML. Molecular typ-
Thus, there may be uncertainty about whether
ing of blood demonstrated ASXL1 G642fs* in 70.6
there is concomitant MDS or another myeloid
percent of 119 sequences reads, KIT D816V in 41.8
neoplasm being masked by the lymphoid or
percent of 593 reads, TET2 Q866* in 45.4 percent
plasma cell disorder, and this uncertainty may
of 1,442 reads, and TET2 Y1255* in 46.7 percent of
influence eligibility for a myeloma or lymphoma
302 reads.
treatment protocol.
After noting the KIT mutation, a pathologist
requested outside liver biopsy,
and lymph node blocks and
Caveats of Interpreting NGS Results
immunoperoxidase studies
When NGS results are interpreted or the consid-
revealed small aggregates of
eration of obtaining molecular typing in a patient
spindled cells within the fibrosis
with MDS or possible MDS is being assessed,
that were positive for mast cell
caution is indicated. In most publications to date,
tryptase and C-Kit and also
mutations have been treated as a binary variable –
aberrantly co-expressed CD25.
wild-type or mutant – but many MDS-associated
The patient’s serum tryptase
genes have a high degree of allelic heterogeneity,
level was found to be >500
and the specific allele may influence phenotype or
ng/mL and he had no mast
clinical behavior.
cell mediator symptoms. He
Also, mutations are often considered in isola-
was then treated on a com-
tion, but combinations of cooperating mutations
passionate-use protocol with
may influence outcomes differently than single
midostaurin and experienced
mutations, and mutations need to be interpreted in
clinical improvement. After he became resistant to
the context of other clinical and pathologic data.
midostaurin, he was treated with avapritinib (BLU-
Importantly, some observed variants detected
285), also by compassionate use, and regained
on NGS panels are germline rather than somatic,
response.
especially those with a VAF near 50 percent. The
somatic-versus-germline distinction is important
Commentary: Occasionally, NGS panels may
for many reasons, including allogeneic transplant
uncover an unexpected finding that reveals an
donor selection, monitoring of patients for non-
additional diagnosis or an alternative diagno-
hematologic complications, and family counseling.
sis. In this patient, the discovery of a KIT D816
There is great variability associated with the
mutation commonly associated with systemic
use of molecular testing to evaluate MDS – in the
mastocytosis (SM) led to additional studies,
available panels’ sensitivity and number of genes
which confirmed a diagnosis of SM with associ-
assayed, as well as in clinicians’ comfort and skill
ated hematologic disease and allowed selection
in interpreting results. Ongoing education is
of a targeted therapy that improved the patient’s
important, and molecular pathologists signing out
symptoms.
reports can help clinicians with clear, up-to-date
The likelihood of finding an additional
interpretations of variants. ●
There is great variability
associated with the use of
molecular testing to evaluate
MDS – in the panels and in
clinicians’ comfort and skill
in interpreting results.
Commentary: Molecular testing in patients
with an established diagnosis of MDS can
provide information that may influence risk
stratification and, in some cases, treatment
selection. For example, the presence of a muta-
tion in TP53, ETV6, ASXL1, EZH2, or RUNX1
effectively raises an MDS patient’s International
Prognostic Scoring System risk stratification
by one risk group and has been associated with
poor overall survival. With the exception of
rare targetable mutations, such as the IDH1/
IDH2 mutations for which U.S. Food and Drug
Administration–approved drugs are available (ap-
proved for patients with relapsed or refractory,
IDH1- or IDH2-mutated AML), though, NGS
results have relatively little influence on drug se-
110
ASH Clinical News
December 2018