Giuseppe Leone1, Emiliano Fabiani2,3 and Maria Teresa Voso3.
1 Università Cattolica del Sacro Cuore, Roma, Italy.
2 Department of Biomedicine and Prevention, University Tor Vergata, Rome, Italy.
3 UniCamillus-Saint Camillus International University of Health Sciences, Rome, Italy.
Published: May 1, 2022
Received: March 26, 2022
Accepted: March 27, 2022
Mediterr J Hematol Infect Dis 2022, 14(1): e2022030 DOI
10.4084/MJHID.2022.030
This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0),
which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
|
Abstract
The
aim of our review has been to give an appropriate idea of analogies and
differences between primitive MDS (p-MDS) and t-MDS throughout an
accurate reviewing of English peer-reviewed literature focusing on
clinical, cytogenetic, epigenetic, and somatic mutation features of
these two groups of diseases. Therapy-related MDS (t-MDS) are
classified by WHO together with therapy-related acute myeloid leukemia
(t-AML) in the same group, named therapy-related myeloid neoplasm. However,
in clinical practice, the diagnosis of t-MDS is made with the same
criteria as for primitive MDS (p-MDS), and the only difference is a
previous non-myeloid neoplasm. The prognosis and the consequent therapy
can be established following the same criteria as for p-MDS, and the
therapy is generally decided using the same criteria. We stress the
possible difference in cytogenetics, mutations, and epigenetics to
distinguish the two forms. Actually, there is no marker specific for
t-MDS either in cytogenetics, epigenetics, or mutations; however, some
alterations are also frequent in t-MDS and, in general, they induce a
poorer prognosis. So, the high-risk forms in t-MDS are prevalent. The
present literature data suggest classifying the t-MDS as a subgroup of
MDS and introducing some parameters to evaluate the probability of
previous therapy in inducing MDS. An important issue remains the
patient’s fitness, which strongly influences the outcome.
|
Introduction
The
myelodysplastic syndromes (MDS) are a group of clonal bone marrow (BM)
neoplasms characterized by ineffective hematopoiesis, manifested by
morphologic dysplasia in hematopoietic cells and by peripheral
cytopenia(s).[1]
In the last WHO classification,[1]
like in the former, MDS include various subgroups, but not
therapy-related MDS (t-MDS), which are classified together with
therapy-related acute myeloid leukemias (t-AML) and constitute the
group of therapy-related myeloid neoplasms (t-MNs). This remains a
distinct category of patients who develop a myeloid neoplasm following
cytotoxic therapy (chemo-radio) for a non-myeloid neoplasm. By no means
is the exposure history alone enough to prove causation, considering
that not all anti-cancer drugs are leukemogenic. However, the
adjunctive characteristics, like time of onset and type of drug
distinguishing therapy-related from primitive (p-MDS) neoplasms, are
vague and not specific, considering that diagnosis is made with the
same criteria as for p-MDS.[2]
This review
highlights the analogies and differences between the de novo and
therapy-related MDS to establish some criteria that should inform the
clinician in determining the prognosis and therapy of t-MDS, which are
all considered unfavorable in the present WHO classification tout court.
References
are based on the English literature reported by PUBMED, Web of Science,
and SCOPUS having as keywords, Myelodysplastic Syndromes de novo and
therapy-related, Radiation and Myelodysplastic Syndromes, Drug-related
Myeloid Neoplasm.
MDS Diagnosis and Risk Classification
Myelodysplastic
syndrome diagnosis is based on peripheral blood (PB) counts, on the
presence of dysplastic changes, and blasts in PB and bone marrow.[3]
Diagnosis of both de novo and therapy-related MDS follow the same
criteria. Since a single biological or reliable genetic diagnostic
marker has not yet been discovered for MDS, quantitative and
qualitative dysplastic alterations of bone marrow precursors and
peripheral blood cells are still fundamental for diagnostic
classifications.[3] The minimal diagnostic criteria
for MDS include the presence of bone marrow-specific alterations, i.e.,
one or more of the following characteristics: dysplasia in at least 10%
of at least one of the major hematopoietic lineages, at least 15% or 5%
ring sideroblasts (without or with SF3B1 mutation, respectively), or
5-19% myeloblasts in bone marrow smears.[3] In the
presence of a refractory cytopenia but no morphological evidence of
dysplasia, specific chromosomal abnormalities detected by conventional
karyotyping or FISH are considered presumptive evidence for MDS.[3]
Since morphology alone is often insufficient to reach a final
diagnosis, it should be integrated but not replaced, by other
investigations such as flow cytometry, cytogenetics, and molecular
studies, in vitro culture of hematopoietic progenitors.[1,3,4]
However, if multilineage dysplasia, chromosomal aberrations, and proof
of clonality are absent, the diagnosis may be difficult.[3] Flow cytometry can also help to assess the diagnosis of MDS.[4]
Apart from the history of previous chemotherapy and radiotherapy, there
are not, at present, laboratory features clearly distinguishing
therapy-related (t-MDS) from primitive (de novo) MDS (p-MDS).
Our
first aim is to investigate if there are diagnostic features derived
from morphology, cytogenetics, epigenetics, and molecular studies in
the present literature, favoring the diagnosis of de novo or
therapy-related MDS. If this possibility does not exist, it is logical
to conclude that t-MDS should be considered a special subgroup of MDS.
Considering
the importance of the morphology in MDS diagnostics, the first question
could be if the morphology and the subtypes of MDS are different in de
novo versus therapy-related MDS. Therapy-related myelodysplastic
syndrome is generally classified according to morphologic schemes used
for de novo MDS.[5] Different studies agree that there are no substantial differences in morphology between de novo and therapy-related MDS.[5,6] However, the morphologic subclassification of t-MDS, based on the percentage of blasts, may not be clinically relevant.[7]
A study of the Chicago group found no differences in 81 patients with
therapy-related MDS concerning median survival times among patients
classified into the different WHO subgroups of MDS or taking into
account their bone marrow blast percentage; these results indicate a
uniformly poor outcome in t-MDS regardless of morphologic
classification.[7] The cytogenetic stratification by
the International Prognostic Scoring System (IPSS) guidelines or
karyotypic complexity was prognostically significant, independently
from the bone marrow blast number. This datum was fundamental to
classifying t-AML and t-MDS in the same group of therapy-related
myeloid neoplasm.[1] However, it was not confirmed by
a more recent study derived from a database of MD Anderson Cancer
Center and Massachusetts General Hospital, including 660 patients who
met the strict WHO criteria for t-MN after excluding 137 patients with
>30% blast in the bone marrow. In this group, a blast percentage
>5 was an independent risk factor of a bad prognosis.[8]
The
group of therapy-related neoplasm includes MDS and AML
post-chemotherapy, post-radiotherapy, and possibly post-benzene.
According to some reports, the behavior of these last neoplasms could
be like de novo ones. The drugs more frequently associated with the
insurgence of MDS are reported in table 1.
 |
Table 1
|
Nardi et al.,[5]
studying three groups of MDS patients, primitive, radiotherapy related
(XRT), and chemotherapy-related (C/CMT), showed that the distribution
of MDS types according to the WHO Classification for
non–therapy-related (primary) MDS and the blood counts at presentation
were similar among the three groups. Only 27% of the XRT patients had
intermediate-2 or high IPSS scores, compared with 60% of the C/CMT
patients. Patients in the XRT group had IPSS scores significantly lower
than the C/CMT patients p<.001) but similar to the de novo
(p-MDS) MDS/CMML patients. These authors conclude that patients with
t-MN after XRT alone had a superior overall survival (p < .006) and
a lower incidence of high-risk karyotypes (p <.01 for AML and <
.001 for MDS) compared with patients in the C/CMT group. (Table 2)
 |
Table 2. Cytogenetic
abnormalities in 306 patients with t-MDS/t-AML (t-MDS 224, t-AML 82).
Balanced chromosomal translocations are very rare in t-MDS where
abnormalities of chromosomes 5 or/and 7 are prevalent. From Smith et
Al.[20] Blood. 2003
|
 |
|
In
contrast, there were no significant differences in survival or
frequency of high-risk karyotypes between the XRT and de novo groups.
AML and MDS diagnosed in the past decade in patients after receiving
XRT alone differ from t-MN occurring after C/CMT and share genetic
features and clinical behavior with de novo AML/MDS. These results
suggest that post-XRT MDS/AML may not represent a direct consequence of
radiation toxicity and warrant a therapeutic approach similar to de
novo disease. Similarly, the MDS secondary to benzene (Bz) also seems
to have characteristics not similar or identical to t-MDS/AML, as
supposed in the past.[11,12]
Irons et al.[12]
recently studied the prevalence of hematopoietic and lymphoid diseases
for 2,923 consecutive patients prospectively diagnosed in their
laboratory in Shanghai utilizing World Health Organization (WHO)
criteria. The Shanghai series of 722 cases of AML includes the most
extensive published series with documented Bz exposure and 644
unexposed de novo-AML cases. They also reported the clinical,
phenotypic, and molecular characteristics of MDS developing in 649
patients, of whom 80 were determined to have some Bz exposure. In as
much as t-MDS and t-AML are considered to be overlapping entities, they
initially were surprised to discover that MDS presenting in individuals
with chronic exposure to Bz at high concentrations (67–100 mg/m3)
did not exhibit a pattern of cytogenetic and phenotypic abnormalities
typically observed in t-MDS. In fact, in their MDS series, cases
associated with exposure to the highest concentrations of Bz (n 5 29)
were found to have a lower prevalence of clonal cytogenetic
abnormalities (24%) when compared with unexposed, that is, p-MDS cases
(30%) (n 5 569). Further, they did not observe an increase in clonal
deletions involving all or part of chromosomes 5 or 7 in Bz-exposed MDS
relative to unexposed MDS cases and in no instance involving 5/5q- as
the sole abnormality. The conclusion was that benzene exposed
MDS-Leukemia patients more closely resemble de-novo than
therapy-related MDS leukemia.
It is also very significant to
notice that the prognosis of both MDS de novo and therapy-related can
be evaluated by the same scoring systems.[8,14-17]
Of the different methods of stratifying t-MDS, the best seems to be the
IPSS-R (International Prognostic Scoring System, Revised), which
considers, in descending order, five major variables for evaluating
clinical outcomes, including cytogenetic risk groups, marrow blast
percentage, and depth of cytopenias (hemoglobin, platelet, and ANC
levels, respectively), therefore, to affirm that all t-MDS patients
have an unfavorable prognosis is not valid. In general, in the t-MDS
series, the proportion of high-risk patients is higher.[8,14-17]
Furthermore, in general, the survival of every category was lower for
t-MDS; however, patients with IPSS and MPSS had a very low survival,
not significantly different in both patients with t-MDS and with p-MDS.[15]
In the study of Zeidan, patients with t-MDS had significantly inferior
survival than p-MDS (median, 19 vs. 46 months, respectively, P=0.005),
and patients with t-MDS had a higher prevalence of adverse prognostic
factors such as poor risk cytogenetics and higher blast percentages.
Although a less favorable clinical outcome occurred in each t-MDS
subset compared with p-MDS subgroups, FAB and WHO-classification,
IPSS-R, and WPSS-R (WHO-based Prognostic Scoring System-revised)
effectively separated t-MDS patients into different risk groups,
indicating that all established risk factors for p-MDS maintained
relevance in t-MDS, with cytogenetic features having enhanced
predictive power. Thus there is significant heterogeneity in clinical
outcomes in t-MDS with a small subset of patients having a more
indolent disease course, who might not necessarily benefit from
aggressive therapeutic interventions.[15,16] All this was confirmed in a large and multicenter study[17]
where the predictive power of IPSS-R was almost comparable top-MDS in
patients with a solid tumor as primary disease as well as in patients
after radiotherapy only. However, the predictive power was lower in
patients with a history of hematologic disease treated with
chemotherapy. It is important to highlight that this extensive work
demonstrated an unexpectedly high percentage of good-risk and normal
cytogenetics, concordantly with other more recently published data[8,15,16] Figure 1, 2.
 |
Figure 1. Differences
between p-MDS and t-MDS concerning the proportion of various risk
groups and the respective survivals. Ok et al.[8] Leukemia, 2014. |
 |
Figure 2. Comparison of
Overall Survival and time to AML of the same risk groups between p-MDS
and t-MDS same risk groups. Kuendgen et al.[17] Leukemia 2021. |
Cytogenetics
Cytogenetics
has a fundamental role in determining the prognosis of de novo MDS.
However, its importance in t-MDS has been taken into consideration only
recently.Recurrent chromosomal abnormalities are present in 40%–70% of patients with de novo MDS at diagnosis (Figure 3).
However, they are present in 90-95% of patients with t-MDS, frequently
in the context of complex karyotypes. Frequent chromosomal
abnormalities in patients with t-MDS post-alkylating agents include
−5/del(5q), −7/del(7q), and/or +8, whereas translocations involving
11q23 or 21q22, as well as t(15;17); Inv 16; t(17;19)(q22;12), have
been frequently reported in patients with prior exposure to
topoisomerase II inhibitors[18-23] (Table 2, Table 3).
 |
Figure 3. Frequency of
common cytogenetic abnomrmalities in p-MDS, subdivided into isolated,
with 1 additional anomaly, and complex anomalies (From Haase et al.[21]) |
 |
Table 3. t-MDS p-MDS. Zeidan et al.[14] 2017: Proportions of the different karyotypes and risk groups of t-MDS versus p-MDS. |
In t-MDS and
p-MDS, the same cytogenetics abnormalities are present. Are they indeed
similar, and do they have similar significance and prognosis? Some
chromosomal abnormalities are more frequent in t-MDS than in p-MDS;
however, there are no specific t-MDS karyotypes (Figure 3, 4).
Most chromosomal abnormalities present in t-MDS have in the past been
considered to have a poor prognosis, but this is not always true (Table 3).
 |
Figure 4. Patient characteristics in de novo vs therapy-related MDS (data from Kuendgen et al.[17] Leukemia 2021).
|
Abnormalities of chromosome 5
A typical example is a deletion of chromosome 5, which is considered favorable in p-MDS but unfavorable in t-MDS.[24-26]
To justify this discrepancy, Le Beau showed among others that there are
two minimally deleted regions (MDRs) on chromosome 5q: 5q31.2 in
patients with t-MN, de novo AML, and high-risk MDS; and 5q32 in those
with 5q– syndrome, now classified as MDS with isolated del(5q), which
has a good prognosis.[22,24] It is essential to distinguish the simple deletion of chromosome 5 from the syndrome of 5q-;[24]
furthermore, it should be mentioned that the deletion of chromosome 5
is frequently associated with another chromosome abnormality in the MDS
therapy-related, as -7/del 7, and this worsens the prognosis.[22,24] However, some authoritative papers report no differences between isolate del(5q) in t-MDS and p-MDS. Lessard et Al.[27]
report that the breakpoints for 5q vary,18 mainly from 5q11 to 5q35, so
the deletion size may be small (mainly 5q31), medium (size equivalent
to half of the long arm, whatever bands are involved), or large (almost
all the long arm). Thus, they distinguished 19 cases with small (17%),
27 cases with medium (25%), and 64 cases with large (58%) deleted
segments. They found no difference in the distribution of these
deletions in 28 therapy-related cases, with 6 small (21%), 5 medium
(18%), and 17 large deleted segments (61%). Similarly, Holtan and Al.,[28]
in their series of 130 patients with 5q deletion, of which 32 were
therapy-related, found that the breakpoints defined by G-banded
karyotyping poorly correlate with particular disease features.
Surprisingly, the survival of patients with treatment-related MDS was
equivalent to those with de novo MDS and del(5q). Morphologic features
associated with del(5q) are diverse. Most patients with del(5q) MDS do
not meet the criteria for WHO-defined 5q-syndrome, and the presence of
del(5q) does not appear to modify the clinical phenotype. Consequently,
in the IPSS-R applied to t-MDS, as for p-MDS, the 5q- appears to be a
favorable factor.[15-17] However, the effects of 5 deletion is influenced by additional mutations, including SF3B1and TP53.[29]
Chromosome 7 abnormalities
Isolated
monosomy 7 (−7), and/or partial loss of the long arm of chromosome 7
(del 7q) and –7/del(7q) with additional cytogenetic aberration(s) are
the second most frequent chromosomal abnormalities in p-MDS and are
associated with poor OS and high AML transformation rate. In t-MDS, it
plays a similar unfavorable prognostic role; they represent the most
frequent cytogenetic abnormalities and are frequently associated with
additional cytogenetic aberration, as 5q- deletions.[17,19,20]Recently Crisà[30]
et al. reported a large series of myelodysplastic syndrome patients
collected from some European centers with partial or total loss of
chromosome 7. Of this series (280 patients), 32 had a t-MDS, and the
outcome did not differ from that with p-MDS. The median number of
mutations per patient was 2 (range 0–8). Patients harboring ≥2
mutations had a worse outcome than patients with <2 or no mutations
(leukemic transformation at 24 months, 38%, and 20%, respectively,
p=0.044). Untreated patients with del(7q) had better overall survival
(OS) compared with those with −7 (median OS, 34 vs. 17 months,
p=0.034). In multivariable analysis, blast count, TP53 mutations, and
number of mutations were independent predictors of OS, whereas the
cytogenetic subgroups did not retain prognostic relevance.[30]However,
del(7q) detection in patients following cytotoxic therapies is not
always related to an emerging therapy-related myeloid neoplasm. Goswami
et Al.[31] described 39 patients who acquired del(7q)
as sole abnormality following cytotoxic therapies for malignant
neoplasms. The median interval from cytotoxic therapies to del(7q)
detection was 40 months (range, 4-190 months). Twenty-eight patients
showed an interstitial, and 11 a terminal 7q deletion. Fifteen patients
(38%) had del(7q) as a large clone and 24 (62%) as a small clone. With
a median follow-up of 21 months (range, 1-135 months), 18 (46%)
patients developed a therapy-related myeloid neoplasm, including all 15
patients with a large del(7q) clone and 3/24 (12.5%) with a small
clone. Of the remaining 21 patients with a small del(7q) clone, 16
showed no evidence of t-MN, and 5 had an inconclusive pathological
diagnosis. The authors conclude that isolated del(7q) emerging in
patients after cytotoxic therapy may not be associated with t-MN in
about half of patients. The clone size of del(7q) is critical; a large
clone is almost always associated with therapy-related myeloid
neoplasms, whereas a small clone can be a clinically indolent or
transient finding.[31]
Chromosome 17 abnormalities
Chromosome
17 (chr17) abnormalities are found in about 2% of patients with de novo
myelodysplastic syndrome and about 4.5 % of t-MN.[32,33] In a Spanish study,[32]
chromosome 17 abnormalities were classified into three groups: isolated
17 (20.5%), with one additional abnormality (8; 9.1%), and two or more
additional abnormalities (complex karyotype) (70.4%). Overall survival
and transformation to AML were the same in the first two groups, while
there was a significant difference with the patients with complex
karyotype. The Fenaux group,[33]
between 1982 and 1996, performed a cytogenetic analysis in 755 cases of
MDS and 754 cases of AML, classified according to FAB criteria.
Sixty-nine of them (4.6%) had cytogenetic rearrangements leading to 17p
deletion, with 25 (36%) occurring after a primary neoplasm treated with
chemotherapy and/or radiotherapy; 21 were classified, according to FAB,
as MDS, and only 4 as AML. Eighteen patients had unbalanced
translocation between chromosome 17 and another chromosome, including
chromosome 5 in 8 cases, 7 in three cases, and 1 in one. Most
frequent primary neoplasms were hematologic, with a high prevalence of
Philadelphia-negative myeloproliferative neoplasms-, treated with
alkylating agents, hydroxyurea or radioactive phosphorus:[33]
About half of the patients, in addition, were typical in that they
occurred mainly after lymphoid malignancies treated with alkylating
agents, and also had monosomy 7 or del 7q. However, the remaining half
unexpectedly occurred in ET or PV treated mainly by hydroxyurea, 32P,
or pipobroman and rarely presented chromosome 7 abnormalities. p53
mutations and/or abnormal p53 expression were found in 16 of the 19
evaluable cases. Isolated
isochromosome (17q) has also been reported in patients with primary or
therapy-related MDS/MPN and AML by the MD Anderson Cancer Center.[34]
Myeloid neoplasms with isolated isochromosome 17q represent a distinct
clinicopathologic entity with myelodysplastic and myeloproliferative
features, high risk of leukemic transformation, and wild-type TP53.[34] The Hellenic 5‐azacytidine registry[35]
of 548 adult patients with MDS treated with 5‐azacytidine reports 32
patients with a chromosome 17 abnormality (6 with i[17q], 15 with ‐17,
3 with add[17p] and the rest with other rarer abnormalities, mostly
translocations). The presence of a chromosome 17 abnormality was
associated with poor prognostic features (high IPSS, IPSS‐R, and WPSS
scores) and a low overall survival rate (15.7 vs. 36.4 months for
patients without chromosome 17 abnormalities. The Brit et Al.[36]
study reported the long-term outcomes of 98 patients with AML or MDS
with chromosome 17 abnormalities, 55 had de novo MDS/AML, and 43 had
secondary MDS/AML. There were no differences between the two groups
regarding the presence of monosomal karyotype (69.1 % versus 67.4 %; p
= 0.51). Similarly, there was no significant difference in the
prevalence of complex karyotype (98.1 % versus 95.3 %; p = 0.41), or of
ch17 abnormalities at diagnosis between the two groups (87.3 % versus
83.7 %; p = 0.41).
Chromosome 20
20q
deletion is common in MDS, represents about 5% of all cases of p-MDS,
and is considered associated with a good prognosis. Braun et al.[37]
have reported for the Groupe Francophone des Myélodysplasies (GFM) over
almost 20 years, 62 cases of isolated chromosome 20 deletion and 36
patients with del 20q and other cytogenetic abnormalities, and 1335 MDS
patients without del20q. Characteristics of these patients were: lower
platelet, a low proportion of marrow blast, and high reticulocyte
counts. Median survival was 54 months in patients with isolated del
20q, not reached, and 12 months for del 20q with one or several
additional abnormalities, respectively (p = 0.035), confirming the
favorable prognosis of del20q without complex abnormalities.
Kanagal-Shamanna et al.[38] from MD Anderson Cancer
Center identified five cases of t-MN and 26 cases of de novo MDS with
isolated del(20q) over ten years.[38] All cases had a
long latency interval from the treatment of the primary malignancy to
the onset of t-MN, and all were associated with frequent bone marrow
dysplasia. del(20q) was the sole abnormality detected at the time of
diagnosis of t-MN in three cases, six years before diagnosis in one
case, and at the time of relapse of AML in one case. Three patients
with t-MDS had a relatively indolent clinical course, whereas two
presented with AML or developed AML shortly after t-MDS. The patients
with de novo MDS and isolated del(20q) frequently presented with anemia
and thrombocytopenia associated with bone marrow dysplasia. The median
overall survival was 64 months.[38] Frequently, these patients had minimal signs of dysplasia and an indolent course.[39]Yin, Peng, Shamanna et Al.[40]
identified 92 patients who acquired isolated del(20q) following
cytotoxic therapies for malignant neoplasms. Seventy-six patients
showed interstitial, and sixteen patients showed terminal 20q deletion.
The median interval from prior cytotoxic therapies to del(20q)
detection was 58 months (range, 5-213 months). With a median follow-up
of 23 months (range, 1-183 months), 21 (23%) patients developed a t-MN,
and 71 (77%) patients did not. In patients who developed a t-MN,
del(20q) was present in a higher percentage of metaphases (60 vs. 25%,
P<0.0001); persisted for a longer period (24 vs. 10 months,
P=0.0487); and was more often a terminal deletion (33 vs. 13%,
P=0.0006) compared with patients who did not develop t-MN. Clonal
evolution was only detected in t-MN (4 patients, 19%). These
data show that del(20q) emerging after cytotoxic therapy represents an
innocuous finding in more than two-thirds of patients. However, in
patients who develop a t-MN, del(20q) often involves a higher
percentage of metaphases, persists longer, and more frequently is a
terminal rather than an interstitial deletion.Cameron Yin et al.[41]
reported 64 patients with chronic lymphocytic leukemia (CLL) and
del(20q) as the sole abnormality in 40, a stemline abnormality in 21,
and a secondary abnormality in 3 cases. Fluorescence in situ
hybridization (FISH) analysis revealed an additional high-risk
abnormality, del(11q) or del(17p), in 25/64 (39%) cases. In most cases,
the leukemic cells showed atypical cytologic features, unmutated IGHV
(immunoglobulin heavy-chain variable region) genes, and ZAP70
positivity. The del(20q) was detected only after chemotherapy in all 27
cases with initial karyotype information available. With a median
follow-up of 90 months, 30 patients (47%) died, most due to CLL. Eight
patients developed a t-MN, seven with a complex karyotype. In 12 cases
without morphologic evidence of a myeloid neoplasm, combining
morphologic and FISH analysis, localized the del(20q) to the CLL in 5
(42%) cases and to myeloid/erythroid cells in 7 (58%) cases. The
del(20q) was detected in myeloid cells in all 4 cases of MDS. Together,
these data indicate that CLL with del(20q) acquired after therapy is
heterogeneous. In the cases with morphologic evidence of dysplasia, the
del(20q) likely resides in the myeloid lineage. However, in cases
without morphologic evidence of dysplasia, the del(20q) may represent
clonal evolution and disease progression. Combining morphologic
analysis with FISH for del(20q) or performing FISH on
immunomagnetically selected sub-populations to localize the cell
population with this abnormality may help guide patient management.Nilsson et al.,[42]
analyzed chromosome abnormalities in MM/MGUS, including 122 MM and 26
MGUS/smoldering MM (SMM) cases. Sixty-six (54%) MMs and 8 (31%)
MGUS/SMMs were karyotypically abnormal. Of these, 6 (9%) MMs and 3
(38%) MGUS/SMMs displayed myeloid abnormalities, that is, +8 (1 case)
and 20q- (8 cases) as the only anomalies, without any evidence of
MDS/AML. One patient developed AML, whereas no MDS/AML occurred in the
remaining eight patients. In one MGUS, FISH analyses revealed del(20q)
in CD34+CD38- (hematopoietic stem cells), CD34+CD38+ (progenitors),
CD19+ (B cells), and CD15+ (myeloid cells). These data indicate that
20q- occurs in 10% of karyotypically abnormal MM/MGUS cases and might
arise at a multipotent progenitor/stem cell level. Patients with sole
del(20q) chromosomal abnormality and without morphologic features of a
MN display variable clinical outcomes. To explore the potential risk
stratification markers in this group of patients, Ravindran et Al.
evaluated the mutational landscape by a 35-gene MN-focused
next-generation sequencing (NGS) panel and examined the association of
mutations to MN progression.[43] Fifty-five patients
with isolated del(20q) were studied over ten years, of whom 23 (41.1%)
harbored at least one mutation, and 16.1% of them progressed into MNs
during follow-up. Thus, all patients who progressed harbored one or
more pathogenic mutations at the time of isolated del(20q) diagnosis,
and the presence of mutations was a statistically significant risk
factor for MN progression. Additionally, among the 23 patients
harboring mutations, DTA epigenetic modifier mutations (DTA: DNMT3A, TET2, and ASXL1)
did not influence progression, whereas mutations occurring in the
non-DTA genes were differentially distributed in patients with and
without progression. The mutations involving non-DTA genes include
IDH1, IDH2, and BCOR, kinases CBL, PTPN11, JAK2, tumor suppressors TP53
and PHF6, and transcription factor RUNX1. In
conclusion, several studies show that chromosome 20 deletion in both de
novo and t-MDS has a favorable prognostic significance when isolated,
and its presence does not necessarily bring about a t-MN.
Somatic Mutations
Since
traditional morphology, cytogenetics, and flow cytometry failed to
identify clinical features differentiating t-MDS from p-MDS, several
authors are trying to define a molecular landscape able to distinguish
these two subgroups of MDS according to the presence of somatic
mutations in genes known to be involved in myeloid neoplasm
pathogenesis. Accordingly, 78 to 90% of MDS patients have one or more
oncogenic mutations. Furthermore, de novo MDS show a mutational profile
prevalently characterized by a high frequency of somatic mutations in
genes involved in spliceosome machinery[44,45]
(prevalently, SF3B1, SRSF2, U2AF1, and ZRSR2), DNA methylation
regulators (DNMT3A, TET2, IDH1and IDH2), histone modifiers (ASXL1 and
EZH2), transcription factors (RUNX1, TP53, and others) and signal
transduction genes (JAK2, KRAS, CBL).[45,46] Mutations
in the spliceosome machinery gene SF3B1 (Splicing Factor 3b Subunit 1)
were closely associated with specific MDS subgroups with ring
sideroblast (RS).[45.47] The
recently published data extrapolated from the dataset of the IWG-PM
(International Working Group for the Prognosis of MDS) strongly confirm
the enrichment of these mutations in refractory anemia with RS (RARS)
and refractory cytopenia multilineage dysplasia with RS (RCMD-RS) in
82% and 75% of cases, respectively.[48] Due to the tight association of SF3B1 mutations with the disease phenotype of RS,[49,50]
according to “The 2016 revision to the World Health Organization
classification of myeloid neoplasms and acute leukemia”, a diagnosis of
MDS-RS can be made if ring sideroblasts are >5% of nucleated red
cells, and a somatic mutation of SF3B1 is present, instead of 15% of RS
without mutation.[1] Several
reports suggest that SF3B1 mutations have a good prognostic value on
overall survival (OS) and risk of disease progression, and these
findings were recently confirmed in very low and low-risk IPSS-R
categories by the analysis of IWG data set.[46-50] Although
t-MN and p-MDS patients with very low or low IPSS-R show similar
biological and clinical characteristics, the RS phenotype in t-MN is
not associated with improved survival, even if mutations in spliceosome
machinery genes have been identified at higher frequency in p-MDS
compared to t-MN (56.5% vs. 25.6%, respectively)51 and among genes
belonging to this pathway, SF3B1 and U2AF1 are more frequently mutated
in p-MDS (25.9% vs. 6.2% and 7.4% vs. 1.6%, respectively). In contrast,
mutations in SRSF2 and ZRSR2 genes seem equally distributed. Singhal et
al. showed a similar frequency of RS in their p-MDS and t-MN cohorts
(29.6% vs. 24.8%), but RSs were 15% of erythroid cells in 21.3% of
p-MDS and in only 14.7% of t-MN.[51] Remarkably,
mutations in spliceosome pathway were identified in all patients with
p-MDS and 15% of RS (SF3B1, 96%), but only in 37% of t-MN with 15% of
RS (SF3B1, 32%), showing a less significant association of these
mutations with the RS phenotype. Moreover, the authors identified TP53
mutations in 29.5% of the entire cohort of t-MN patients and,
unexpectedly, in 92% of those with 15% RS and no SF3B1 mutations,
highlighting a new potential role of TP53 mutations in the context of
t-MN with RS. In this line, the median OS of t-MN with 15% RS (12
months) was significantly lower than that of p-MDS with 15% RS (38
months), pointing out the poor prognostic role of TP53 mutations also
in t-MN patients with RS and the weak association with SF3B1 mutations.[51] The group of MD Anderson Cancer Center reported similar data:[52]
Commonly mutated genes were TP53 (56.5%), TET2 (39.1%), SF3B1 (35.7%),
ASXL1 (30.4%), DNMT3A (17.4%), RUNX1 (17.4%) and SRSF2 (14.3%).
Compared with d-MDS-RS, TP53 mutation was more common, but SF3B1
mutation was less common in t-MDS-RS (p < 0.05). In t-MDS-RS,
Mutations in 4 genes (SF3B1, U2AF1, SRSF2, and ZRSR2) involving RNA
splicing were found in about 50% of patients compared to ˜90% in
d-MDS-RS. Overall survival was by far worse in t-MDS-RS compared to
d-MDS-RS (median overall survival: 10.9 months and 111.9 months in
t-MDS-RS and p-MDS-RS, respectively, p < 0.05). Progression to AML
was more common in t-MDS-RS (18.4% vs. 7.4% in t-MDS-RS and d-MDS-RS,
respectively, p < 0.05). Unlike de novo MDS, t-MDS-RS did not have a
different outcome than t-MDS without RS (median OS: 10.9 months vs.
14.3 months, respectively, p=0.2341). Mutation profiles suggest that RS
in t-MDS might be a secondary event in at least 50% of the cases or not
related to mutations in RNA splicing machinery, unlike p-MDS, where
they occur early and are associated with ineffective erythropoiesis.
Although in the last decade, the mutational profiles of p-MDS and t-MN
have been extensively analyzed, identifying 79% to 95% of patients
mutated in at least one gene, without significant differences in
cohorts, and none of the studied genes exclusively mutated in one of
them, the prevalence of cases mutated in specific genes seem to be
different.[52,53,54] Today,
mutations in the TP53 gene are considered the most frequent molecular
alterations identified in t-MDS/t-MN patients, with a frequency from 30
to 47%, according to both specific characteristics of the study cohort
and depth of sequencing technologies.[51-56] In these
series of patients, authors also identified a tight association of TP53
mutations with the presence of complex karyotype, defined as three
chromosomal abnormalities, in about 80% of cases, and a poor prognosis
compared to TP53 wild-type t-MN patients. In 2017, Lindsley et al.,
screening through t-NGS technology the mutational profile of a large
cohort of 1514 MDS patients undergoing Hematopoietic Stem Cell
Transplantation (HSCT), found interesting differences in the frequency
of TP53 mutations stratifying patients according to p-MDS and t-MDS
(311 patients) subgroups.[53] They found a higher
prevalence of TP53 mutations in t-MDS than p-MDS (38% vs. 14%,
respectively) and significantly shorter survival. Of note, in t-MDS,
the authors also identified a higher frequency of mutations in the TP53
regulator PPM1D compared to p-MDS (15% vs. 3%, respectively), reaching
the quote of 46% of mutations in TP53 or PPM1D.Furthermore,
the co-occurrence of TP53 and PPM1D mutations was higher in t-MDS than
stochastically expected in patients with PPM1D mutations alone (51%),
when compared with PPM1D and TP53 double wild-type patients, had a
similar frequency as those with TP53 mutations alone (39%) or double
mutated PPM1D and TP53 (54%).[53]
Although PPM1D gene
encodes a serine-threonine protein phosphatase, involved in the
cellular response to environmental stress and therefore to exposure to
leukemogenic therapies, through the inhibition of TP53 activity, PPM1D
mutated t-MDS patients without TP53 mutations did not show any
association with the presence of complex karyotypes and
adverse prognosis. Even if more frequent than
p-MDS, TP53 mutation characteristics in t-MDS and t-AML are similar to
de novo diseases.[55] Consistent with the
tumor-suppressive role of TP53, patients may harbor both mono- and
biallelic mutations. The International Working Group for Prognosis in
MDS[56] assembled a cohort of 3,324 with MDS and
studied the effect of TP53 allelic state on genome stability, clinical
presentation, outcome, and response to therapy.56 Outcomes of
monoallelic cases significantly differed with the number of
co-occurring driver mutations; for example, the 5-year survival rate of
monoallelic patients with no other identifiable mutations was 81%,
while it was 36% for patients with one or two other mutations, 26% for
patients with three or four other mutations, and 8% for patients with
more than five other mutations. Other
than prognostic predictors of outcome, acquired somatic mutations may
also play a pivotal role in the context of MDS susceptibility. In 2014
a real earthquake shocked the world of hematologists redefining the
borders between hematology and onco-hematology by discovering acquired
somatic mutations in the same genes previously known to be involved in
myeloid neoplasms in older people without traces of hematologic
disorders. In independent works, screening by whole-exome sequencing
(WES) in large cohorts of non-hematological patients, Genovese and
Jaiswal, identified a close association between hematopoietic stem cell
aging and the accumulation of somatic mutations in patients without
hematological malignancies.[57,58] These mutations,
now known as DTA (DNMT3A, TET2, and ASXL1), have been found enriched in
a linear relationship with age, with about 20% of mutations in people
80 years old. Although DTA genes were the most enriched, other genes
such as JAK2, SF3B1, PPM1D, and TP53 were found enriched in a linear
relationship with age, while others such as FLT3, NPM1, IDH1, and IDH2
were rarely found mutated in these subjects.[59]
These scenarios of clonal hematopoiesis, now defined as ARCH
(Age-related clonal hematopoiesis) or CHIP (Clonal hematopoiesis of
indeterminate potential) according to the VAF of identified mutations
(without a specific cut-off or 2%, respectively),[59]
have been linked to an overall increased risk of transformation to
hematological malignancy, with a risk of progression of about 0.5–1%
per year vs. <0.1% in non-CHIP carriers, and may represent a
pre-malignant state in p-MDS and t-MN, whose development can be
triggered by exposure to cytotoxic damage.[57,58,60]
In this line, several authors were able to identify pre-existing
somatic mutations, at very low VAF, in patients who developed a t-MN
after a chemo/radiotherapeutic treatment for a primary tumor or an
autoimmune disease, demonstrating the expansion of CHIP mutations and
their role as a predisposing factor for MN development.[61-66]
Very recently, Zeventer et al., using high-throughput t-NGS technology
(gene panel of 27 driver genes at a VAF of 1%), redefined the
prevalence of clonal hematopoiesis (CH) in a cohort of 621 individuals
aged 80 years extrapolated from the LifeLines cohort (Netherlands
database of 167,729 participants).[67] Clonal
hematopoiesis was identified in the peripheral blood of 61.5% of
individuals, without differences across gender. DNMT3A was mutated in
219 of 621 individuals (35%), 27% with multiple mutations. Similar
results were reported for TET2 (166 of 621 individuals (27%), with
multiple mutations in 24% of cases, while ASXL1, spliceosome machinery,
and TP53 variants were identified at lower frequencies (6%, 4%, and 3%,
respectively). Although CH was not associated with a higher risk of
death in the complex, individuals carriers of mutations in genes other
than DNMT3A and TET2 were at higher risk than wild-type controls (HR,
1.48; CI, 1.06-2.08). In the same line, the authors did not identify
any association between elevated risk of exposure to DNA damaging
toxicities (job-related exposure to pesticides, exposure to cytotoxic
and/or radiation therapy for primary cancer, and smoking status), and
both the prevalence of CH and the number of somatic variants.
 |
Figure 5. Mutational
profiles in myeloid neoplasms. Mutational profile of therapy-related
myelodysplastic syndromes (t-MDS) versus de novo MDS. Asterisk denotes
genes with a significant difference between t-MDS versus p-MDS. Ok et al. [56] Leukemia Res., 2015.
|
In contrast,
mutations in selected driver genes, such as spliceosome machinery and
ASXL1, were identified at higher frequencies in exposed individuals (6%
vs. 1% and 7% vs. 2%, respectively).[67] In this
line, our group recently showed that patients CLL who developed a t-MN
following treatment with chemoimmunotherapy presented prior to
treatment start mutations in CHIP-related genes at a significantly
higher prevalence than a large cohort of control CLL. These data show
that CHIP increases susceptibility to t-MN also in the CLL context. In
the last few years, a rare mutation in MDS, the Nucleophosmin (NPM1)
mutation common in AML and associated with high remission rates and
prolonged survival with intensive chemotherapy, has assumed a
particular significance.[69] NPM1 mutations are rare in syndromes p-MDS (MDS/MPN), representing about 2% of all MDS.[70,71]
The different outcomes of these patients, if treated with intensive
chemotherapy or demethylating agent, induce to combine them in a
subgroup. The NPM1 mutations have been found even more rarely in t-MDS
and more frequently in t-AML.[71,72] Andersen et al.
observed NPM1 mutations in 7 of 51 patients presenting as overt t-AML,
as compared to only 3 of 89 patients presenting as t-MDS (P<0.037);
only 1 of 10 patients with NPM1 mutations presented chromosome
aberrations characteristic of the therapy-related disease, and 7q-/-7,
and 5q-/-5 the most frequent abnormalities of t-MDS/t-AML, were not
observed (P<0.002). This raised the question of whether some of the
cases presenting NPM1 mutations were, in fact, cases of de novo
leukemia or de novo MDS.[72] This same issue is
relevant in p-MDS, where the presence of NPM1 mutations is associated
with an increased rate of AML transformation, raising the question of
whether these MDS indeed represent AML at an early stage. All
these data highlight the potential role of acquired mutations and/or
cytogenetic abnormalities in the definition of de novo and
therapy-related MDS, which will have to be taken into account in the
next editions of the WHO classification.
Epigenetic Regulation
Changes
in gene expression not directly linked to changes in DNA sequence
constitute the fundamental concept of epigenetic regulation. Aberrant
differentiation in MDS can often be traced to an abnormal epigenetic
process represented by both gains and losses of DNA methylation
genome-wide and at specific loci, as well as mutations in genes that
regulate epigenetic programs, such as TET2 and DNMT3a, involved in DNA
methylation control, and EZH2 and ASXL1, involved in histone
methylation control.[72] Epigenetic
changes include various covalent modifications of nucleic acids and
histones, which finely coordinate the gene expression of single cells,
defining their role and phenotype. These regulatory mechanisms mainly
include DNA methylation, histone modifications, and chromatin
remodeling. Alterations in epigenetic regulation have been tightly
associated with cancer development and progression.[74]
Moreover, since all these mechanisms are reversible, the involved genes
are considered important epigenetic targets for drug development and
patient treatment. Of note, many genes involved in epigenetic
regulation, such as DNA methylation regulators (DNMT3A, TET2, IDH1, and
IDH2) and histone modifiers (ASXL1 and EZH2), have been identified as
being frequently mutated in MDS.[44-46] Epigenetic
regulation through DNA methylation is mainly driven by DNA
methyltransferase enzymes (DNMTs) by the addition of a methyl group (CH3) to a cytosine residue (5-methylcytosine) within a CpG dinucleotide.[75]
Regions enriched in CpG dinucleotides (CpG islands) have been found in
the promoter region of about 50% of human genes, but a methylation
enrichment was also found in enhancers and transcription factor binding
sites.[76] The
nucleoside analog azacytidine (AZA, Vidaza®, Celgene) and its deoxy
derivative decitabine (DAC, Dacogen®, Janssen)are able to stimulate
gene expression through DNA hypomethylation, following irreversible
DNMTs sequestration.[77] However, this action is reversible since inhibitors do not influence de novo DNMTs synthesis. In this line, de novo
DNMTs synthesis could explain the rapid relapse after treatment
interruption and the requirement for maintenance treatment as long as
the response persists.[78,79]Several
authors tried to identify specific DNA sequences or methylation
profiles useful as a marker of response to hypomethylating agents that
may help to support the decision to continue or stop hypomethylating
treatment.Although
gene-specific hypermethylation has been identified as a negative
prognostic factor in hematological malignancies, there is no complete
agreement on the role of specific candidate genes. Among
these, genes belonging to lineage commitment, apoptosis, cell cycle,
immune response, signal transduction, and cytoskeletal remodeling are
hypermethylated in MDS patients, and their expression could be
modulated by hypomethylating treatment.[80-85] In
addition, the hypermethylation of some promoter genes, like DAPK1,
E-cadherin, and thrombospondin-1, has been reported by several groups,
including ours, as more frequent in t-MDS than p-MDS.[86] Recently,
Reilly et al. characterized the methylation profile of 114 bone marrow
DNA samples from MDS patients using the bisulfite padlock probe (BSPP)
sequencing method to highlight differentially methylated regions of
genes belonging to different cellular pathways.[87] Their
results showed five unique methylation clusters, resulting from the
bioinformatics analysis “OncoGenic Positioning System Onco-GPS”, useful
to sub-classify MDS patients according to their methylation profile. In
particular, each methylation cluster was enriched for specific genetic
variants and cytogenetic alterations, although different mutational
profiles may share the same methylation state. Interestingly, their
data showed that the variants in splicing factor genes were mutually
exclusive and enriched in specific methylation subgroups.[87]
These authors did not observe statistically significant associations
between specific methylation clusters and clinical laboratory
parameters such as cytopenia or bone marrow blasts percentage. On the
other hand, the overall survival curves showed differences in patients
belonging to specific methylation sub-groups, identifying two major
patterns, demonstrating that, although genetic variants alone are
insufficient for determining the methylation profile of MDS patients,
the latter could be supplemental information for the prognostic
stratification.Finally,
they observed enrichment of cluster-specific methylated regions not
only in CpG islands belonging to promoter regions but also in distal
regulatory regions of the epigenome. Indeed, results showed an equal or
greater number of differentially methylated regions outside promoters.More
recently, Cabezón et al. performed a supervised global methylation
analysis of 75 high-risk MDS and secondary AML patients included in
CETLAM SMD-09 protocol and treated with HMA or intensive treatment
according to age, comorbidities, and cytogenetics. They were able to
identify a methylation signature defined by 200 probes, useful to
distinguish responder from non-responder patients under AZA treatment.[88] The
same authors also identified a methylation pathway that differentiated
patients according to their survival. In contrast, the methylation
signature detected at the time of diagnosis was not useful for
distinguishing patients who would relapse or progress.[88] In
this study, high-risk MDS and sAML showed a more heterogeneous pathway
of methylation than age-matched healthy controls, and this
heterogeneity precluded the separation of the patients into distinct
sub-groups.While many studies have explored the epigenome of de novo MDS, little is known about the epigenetics of t-MN and, in particular, t-MDS.
Treatment
The therapy for MDS depends on the stage of the disease, age, comorbidities, and infections.[89-91] The stage has been historically risk-stratified using the International Prognostic Scoring System (IPSS) for MDS,[91] updated with the revised-IPSS (IPSS-R), in more recently by the molecular IPSS-M and the Euro MDS scores.[13,92]
The disease stage is risk-based on cytogenetic abnormalities, the
degree of cytopenias, and the percentage of bone marrow blasts. The
IPSS-R subdivides patients into five groups (very low-, low-,
intermediate-, high-, very high-risk) that differ in survival and risk
of leukemic transformation. This classification is clinically relevant
as the treatment approach differs between higher-risk and lower-risk
patient subgroups.[89] However, it has been well
recognized that some patients with lower-risk (LR)-MDS using IPSS or
IPSS-R do not fare well. Mutations are not considered in the risk
stratifications of IPSS and are particularly important in worsening the
prognosis in patients with normal cytogenetics.[92,93,94]
Therefore, inherent limitations of the current prognostic tools should
be recognized in making clinical decisions for individual patients.
Integrating molecular assessment in risk stratification tools in the
Euro-MDS and IPSS-M scores will likely increase their precision and
utility in clinical practice.[92-94]
Therapy-related MDS have been classified together with the t-AML in the
group of t-MN and considered to have the same poor prognosis,
independently of the number of blasts found in the marrow.[1,7]
However, in the last few years, it appeared more and more evident that
the prognosis of the t-MDS is well evaluated utilizing the same
parameter employed for p-MDS.[8,14,16] At variance with p-MDS,[21] most patients with t-MDS belong to high or very high risk categories, independently of the origin.[14,16] (Figure 1, 2; Table 3).
The treatment goals of p-MDS and t-MDS are the same: to alter the
natural history of the disease, decrease the risk of leukemic
progression, and improve survival. However, the only cure of either
p-MDS and t-MDS remains the allogeneic hematopoietic cell transplant
(HSCT), recommended option in such patients if they are candidates for
the procedure, following p-MDS established criteria.[95,96]
An unanswered question is whether the transplant should be performed
after the high-dose chemotherapy or immediately; a third hypothesis
could be after the azacytidine bridge.[97] In any case, like all treatments, HSCT is deeply influenced by cytogenetics and mutations.[53,56] In particular, the mutations P53, frequently associated with complex karyotypes, are strong negative prognostic factors in younger patients.[53,56]Nevertheless,
most patients are not candidates to transplant, so patients with p-MDS
or t-MDS are most often treated with the hypomethylating agents,
azacytidine or decitabine.[98-108] The
hypomethylating agents are both approved for MDS therapy by FDA and EMA
and are similarly effective in p-MDS and t-MDS in strict relationship
with cytogenetics and mutations found in the patient. Klimek et al.[100]
report results in 42 patients with therapy-related MDS treated with
either 5-azacitidine (AC) or 21-deoxy-5-azacitidine (DAC). Patients
were 25–85 (median 70) years of age and covered the entire spectrum of
MDS disease stages. As expected, 69% of patients had poor-risk
cytogenetics by IPSS criteria.[8,14]
The overall response rate was 38%, and complete remissions occurred in
six patients (14%). The median overall survival from the start of
therapy was 9.2 months. Thus, these results are very similar, if not
identical, to what has been reported with AC for all-comers, most of
whom have been patients with de novo MDS.The
demonstrated efficacy of demethylating agents has induced researchers
to improve their efficacy by adding other drugs; the anti-PD-1
antibodies seem to be the most promising.[108-109]
Furthermore, a series of targeted therapies are under investigation for
HR-MDS patients, such as the IDH1 and IDH2 inhibitors evaluated in
clinical trials with ivosidenib and enasidenib, respectively.[110,11]
Furthermore, there is a promising pipeline of novel agents under active
investigation in HR-MDS. For patients with LR-MDS, the treatment goals
are to improve their quality of life by managing the underlying
cytopenias and side effects. The majority of patients are anemic at
presentation, representing a major clinical challenge.[3]
Treatment options in this group of patients include active
surveillance, red blood cell (RBC) transfusions,
erythropoiesis-stimulating agents (ESAs), lenalidomide in patients with
del (5q), hypomethylating agents also as oral therapy (HMAs),
luspatercept in patients with ring sideroblasts, and immunosuppressive
agents in a select group of patients.[110,111]However, there is no experience of these new drugs in t-MDS, which constitutes about 10% of all MDS.[108]
In addition, therapy-related MDS patients are often excluded from
therapeutic clinical trials, so a comparison between de novo and
therapy-related MDS outcomes with the same stage and therapies is
difficult to find in the literature. Borate et al.[113]
in their initial search, examined 1148 therapeutic clinical trials on
MDS; however, excluding the trial, which did not mention t-MDS (831),
and trials that excluded specifically t-MDS, they found only 18 studies
(5.7%) that accrued 231 t-MDS patients in total, representing 3.2% of
the total accrued MDS trial patient population. In addition, fewer
t-MDS patients were accrued in therapeutic trials sponsored by
pharmaceutical sponsors vs. nonpharmaceutical sponsors (2.8% vs. 4.0%; P
5 .0073). This pattern of exclusion continues in actively enrolling
trials; only 5 (10%) of 49 studies specifically mention the inclusion of
t-MDS patients in their eligibility criteria. These results indicate
that therapeutic MDS trials seem to exclude t-MDS patients, rendering
study results less applicable to this subset of MDS patients, who often
have poor outcomes.[17,102,106]
Another problem is that in the trials, t-MDS are frequently included
together with t-AML as t-MN as reported by the WHO classification of
myeloid neoplasm.[1-114]
Conclusions
The characterization of t-MDS and t-AML[8,14,17]
has been recently improved with the use of advanced molecular
techniques, and although sharing some overlapping features, these
diseases exhibit substantial differences in molecular and cytogenetic
characteristics and clinical presentation. A future updated
classification should consider these issues, and the proposal to
separate t-MDS from t-AML should be discussed. In this line,
therapy-related MDS could become a subgroup of MDS. Indeed, since there
is no specific marker for therapy-related MN, the diagnosis is made on
an anamnestic base only, and this does not exclude that some cases of
p-MDS may present after cytotoxic therapy and be defined t-MDS but
still display genetic characteristics of p-MDS. The
same path has been taken in t-AML with recurrent translocations,
characterized by t(15;17), t(8;21), or inv(16), which, following recent
guidelines, should be treated according to patients’ fitness, and not
to a previous history of cytotoxic treatment, since the outcome of
these AMLs in similar in de novo and therapy-related forms.
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