Myelodysplastic Syndrome ASH

Received: 2 April 2023 Revised: 21 May 2023 Accepted: 23 May 2023
DOI: 10.1002/ajh.26984
ANNUAL CLINICAL UPDATES IN

HEMATOLOGICAL MALIGNANCIES
Myelodysplastic syndromes: 2023 update on diagnosis,

risk-stratification, and management
Guillermo Garcia-Manero
Section of MDS, Department of Leukemia,

University of Texas MD Anderson Cancer Abstract
Center, Houston, Texas, United States
Disease overview: The myelodysplastic syndromes (MDS) are a very heterogeneous
Correspondence group of myeloid disorders characterized by peripheral blood cytopenias and increased
Guillermo Garcia-Manero, Anderson Cancer
risk of transformation to acute myelogenous leukemia (AML). MDS occurs more
Center, 1400 Holcombe Blvd, Houston,
TX 77030, USA. frequently in older males and in individuals with prior exposure to cytotoxic therapy.
Email: ggarciam@mdanderson.org
Diagnosis: Diagnosis of MDS is based on morphological evidence of dysplasia upon
Funding information visual examination of a bone marrow aspirate and biopsy. Information obtained from
MD Anderson Cancer Center; NIH,
additional studies such as karyotype, flow cytometry, and molecular genetics is usu-
Grant/Award Number: CA016672
ally complementary and may help refine diagnosis. A new WHO classification of
MDS was proposed in 2022. Under this classification, MDS is now termed myelodys-
plastic neoplasms.
Risk-stratification: Prognosis of patients with MDS can be calculated using a number
of scoring systems. All these scoring systems include analysis of peripheral cytope-
nias, percentage of blasts in the bone marrow, and cytogenetic characteristics. The
most commonly accepted system is the Revised International Prognostic Scoring
System (IPSS-R). Recently, genomic data has been incorporated resulting in the new
IPSS-M classification.
Risk-adapted therapy: Therapy is selected based on risk, transfusion needs, percent
of bone marrow blasts, cytogenetic and mutational profiles, comorbidities, potential
for allogeneic stem cell transplantation (alloSCT), and prior exposure to hypomethy-
lating agents (HMA). Goals of therapy are different in lower risk patients than in
higher risk and in those with HMA failure. In lower risk, the goal is to decrease trans-
fusion needs and transformation to higher risk disease or AML, as well as to improve
survival. In higher risk, the goal is to prolong survival. In 2020, two agents were
approved in the US for patients with MDS: luspatercept and oral decitabine/cedazur-
idine. In addition, currently other available therapies include growth factors,
lenalidomide, HMAs, intensive chemotherapy, and alloSCT. A number of phase 3
combinations studies have been completed or are ongoing at the time of this report.
At the present time there are no approved interventions for patients with progressive
or refractory disease particularly after HMA based therapy. In 2021, several reports
indicated improved outcomes with alloSCT in MDS as well as early results from
clinical trials using targeted intervention.
Am J Hematol. 2023;98:1307–1325. wileyonlinelibrary.com/journal/ajh © 2023 Wiley Periodicals LLC. 1307

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1308 GARCIA-MANERO
1 | D I S E A S E OV E R V I E W different from that of patients not previously treated with such an

agent with similar IPSS and IPSS-R scoring systems.18,19
Myelodysplastic syndrome (MDS) comprises a very heterogeneous
group of myeloid malignancies with very distinct natural histories.1
MDS occurs in 3–4 individuals per 105 in the US population.2 Preva- 2 | DI AGN OS I S
lence increases with age. In individuals age 60 and above, prevalence
is 7–35 per 105.2 Other series have reported higher rates.3 MDS The diagnosis of MDS is generally suspected based on the presence
affects more frequently males than females.2 Exposure to prior chemo of cytopenia. Diagnosis is confirmed by performing a bone marrow
or radiation therapy is a risk for the development of MDS. Work over aspiration and biopsy. Both procedures provide different information.
the last two decades has demonstrated that MDS is an heterogenous The bone marrow aspirate allows for detailed evaluation of cellular
group of malignancies arising from distorted hematopoietic stem cell morphology and evaluation of percent of blasts. The bone marrow
function,4 inflammatory and innate immune deregulation,5 deregu- biopsy allows for determination of bone marrow cellularity and archi-
lated apoptosis,6 and multiple genomic events.7 This combination of tecture. Diagnosis is established by the presence of dysplasia. A num-
molecular alterations results anemia, increased risk of infections, ber of morphological classifications are in place. The most recent one
8
bleeding, and transformation to acute myelogenous leukemia (AML). being the 2022 WHO classification (Table 1).20 Under this classifica-
A majority of patients with MDS will die from complications of MDS tion, MDS is now myelodysplastic neoplasm, acronym MDS. I believe
without transforming to AML and therefore the need for unique treat- changing the name is a mistake as these disorders are clearly syndro-
ment strategies for patients with MDS.8 Further adding importance to mic not just neoplasms. This is for instance demonstrated by its asso-
this concept is the discovery of the relation between comorbidities ciations with comorbities.10 In addition, a parallel effort was proposed
9 10
and clonal hematopoiesis and MDS suggesting an interplay by the ICC.21 My opinion is that the percentage of blasts in MDS
between MDS and the development of other conditions such as should be still considered up to 20%. Decreasing the percentage of
cardiovascular disease.11 blasts to 10% because prognosis is similar when compared to patients
MDS is usually suspected by the presence of cytopenia on a rou- with AML makes no scientific sense as prognosis does not equate
tine analysis of peripheral blood. This prompts evaluation of bone diagnosis. Using this paradigm, we could describe all diseases, solid
marrow cell morphology (aspirate) and cellularity (biopsy). A manual and liquid tumors, with a poor risk abnormality, that is, p53 mutation,
count of bone marrow blasts is fundamental for risk assessment. with the same name just because prognosis is poor or we can target it
Cytogenetic analysis helps in predicting risk and in selecting therapy. (i.e., IDH mutations in AML and glioblastoma). In addition, morphologi-
Once this information is collected, MDS risk can be calculated. cally MDS is different than AML. Details of these classifications have
Patients with MDS can be stratified according to several internation- been reviewed elsewhere.
ally accepted scoring systems. The original IPSS12 and the modified A number of additional tests are needed to complete the labora-
13
IPSS-R are the most commonly used systems. These two systems tory evaluation of a patient with MDS. It is well established that cyto-
are also important because they serve as part of the main eligibility genetic patterns are very heterogeneous in MDS.22 Cytogenetics are
14
criteria for past and ongoing registration clinical trials. Using IPSS
and IPSS-R, patients with MDS are generally divided in two different
broad subgroups: lower and higher risk disease. Patients with lower
TABLE 1 The fifth edition of the WHO MDS classification.20
risk disease by IPSS are those with low and intermediate-1 disease
and very, low and some subsets of intermediate risk by IPSS-R. MDS with defining genetic
Patients with higher risk disease are those with intermediate-2 and abnormalities Blasts
high risk by IPSS and some subsets of intermediate, high, and very MDS with low blasts and isolated 5q <5% BM and <2% PB
deletion (MDS-5q)
high-risk disease by IPSS-R. Because the IPSS-R divides patients into
five subsets, there is some controversy in terms of what subset of MDS with low blasts and SF3B1 <5% BM and <2% PB
mutation (MDS-SF3B1)
patients with IPSS-R intermediate disease should be considered lower
MDS with biallelic TP53 inactivation <20% BM and PB
or higher risk disease.15 Recently, molecular data has been incorpo-
(MDS-biTP53)
rated to calculate prognosis in MDS resulting in the new IPSS-M clas-
MDS, morphologically defined
sification.16 Several other important data points are needed when
MDS with low blasts (MDS-LB)
making treatment decisions in patients with MDS. These include age
MDS, hypoplastic (MDS-h)
of the patient, type and severity of comorbidity,17 significance and
number of cytopenias, transfusion needs, presence of specific geno- MDS with increased blasts (MDS-IB)
mic alterations (now computed by the IPSS-M), 16

percentage of blasts, MDS-IB1 5%–9% BM or 2%–4% PB
cytogenetic profile, potential for allogeneic stem cell transplantation MDS-IB2 10%–19% BM; or
(alloSCT), and importantly prior treatment with a hypomethylating 2%–19% PB
agent (HMA). This is fundamental as the biology and natural history of MDS with fibrosis 5%–19% BM; or
2%–19% PB
patients with MDS that have been treated with an HMA is very
GARCIA-MANERO 1309
FIGURE 1 Cytogenetic classification of MDS. Adapted from Schanz et al (reference23).
of importance to calculate prognosis of patients and in some subsets 2.1 | ICUS, clonal hematopoiesis of indetermined
of patients to select the most effective form of therapy. The most potential, and CCUS
recent cytogenetic risk classification in MDS includes 5 different sub-
groups including 20 different alterations (Figure 1).23 Cytogenetic pat- Because diagnosis of MDS is based on morphological assessment, it
terns are not stable in MDS and a significant fraction of patients can can be subjective particularly in patients with early low risk disease
acquire additional cytogenetic changes with disease evolution. This and minimal dysplasia. It is calculated that diagnostic discrepancy can
phenomenon is associated with increased risk of transformation to occur at the time of initial presentation in close to 20% of patients.27
24
AML and worse survival. New techniques to assess large structural This has obvious implications for therapeutic decision making and
chromosomal changes, such optical genome mapping, have been patient counseling. In general, diagnosis is obvious in patients with
reported to be able to perform cytogenetic analysis without the need excess blasts. The problem is in patients without excess blasts were
to culture marrow cells or band interpretation. This results in lower diagnosis is based on dysplasia. Clinical assessment is needed in
percentage of failed assays.25 These technologies are moving into patients with minimal or not diagnostic evidence of dysplasia. In these
CLIA hematopathology laboratories. cases, it is recommended that other causes of cytopenia be excluded.
A number of other assays can be used to help in the diagnosis of Routine tests include the analysis of anemia and thrombocytopenia,
MDS. These include flow cytometry, fluorescent in situ hybridization and exclusion of cause of blood loss or inflammatory processes. When
(FISH) and genomic sequencing techniques. Flow cytometry can help suspected, evaluation of GI tract needs to be considered. Once other
in the identification of abnormal phenotypic patterns and can be of potential causes of cytopenia are excluded, additional diagnostic tools
help in cases of minimal dysplasia. Because the significant heteroge- including cytogenetic evaluation, flow cytometry and, more recently,
neity of cytogenetic alterations in MDS, there is no evidence that a DNA sequencing, can help define the diagnosis and predict patient
panel of FISH probes could replace routine 20 metaphase cytogenetic outcomes. Patients with cytopenia but no dysplasia are considered to
analysis. Thus, in our opinion FISH and flow cytometry should not be have idiopathic cytopenia of undetermined significance (ICUS). A frac-
considered part of the standard work up evaluation procedure of the tion of these patients may have cytogenetic abnormalities or somatic
patient with MDS and should be used in specific situations. Thanks to mutations in genes recurrently mutated in myeloid malignancies.28,29
the discovery of multiple genetic mutations in MDS, we now have The presence of a somatic mutation in the context of cytopenias with
access to clinical tools for molecular annotation of patients with MDS. no diagnostic criteria for MDS is now considered a clonal cytopenia of
These can be of use to complement other diagnostic tools. A majority undetermined significance (CCUS).30 This distinction is supported by
of MDS patients, will carry at least one or more somatic mutations in data which suggests that, although close to 25% of patients with ICUS
genes involved in DNA methylation, chromatin regulation, RNA splic- may ultimately develop MDS or AML, this risk significantly increases
ing, transcription regulation, DNA repair, cohesin function, or signal in the presence of a clonal mutation from 9% to 82% at 5 years, par-
transduction.7,26 ticularly in the presence of highly predictive mutation patterns.28,31
1310 GARCIA-MANERO
TABLE 2 Characteristics of ICUS/CHIP/CCUS.7,28,29,56
Features CHIP ICUS CCUS MDS

Cytopenia No Yes Yes Yes
Dysplasia No No or minimal (nondiagnostic No or minimal (nondiagnostic Yes
for MDS) for MDS)
Somatic Yes at a variant allele frequency ≥2%. Most No. ICUS defined by absence • Yes, as in CHIP Yes. Up to 85%
mutations commonly: DNMT3A, TET2, ASXL1 of clonality of patients
Risk of Very low (0.5%–1% per year) outside of Very low Up to 80% at 5 years but -
progression therapy related setting. determined by mutational
patterns.
Abbreviations: CCUS, clonal cytopenia of undetermined significance; CHIP, clonal hematopoiesis of indeterminate potential; ICUS, idiopathic cytopenia of
undetermined significance; MDS, myelodysplastic syndromes.
A detailed evaluation and careful differential diagnosis between ICUS, prognostic scores are currently in use in MDS. The IPSS12 has been in
CCUS, and MDS is therefore essential (Table 2). The presence of place since 1997. This score has been discussed in prior versions of
clonal somatic mutations have also been reported in hematopoietic this manuscript.41 It has been replaced by en-large by the IPSS-R.13
cells from older individuals without evidence of hematological disor- The IPSS-R includes different cut off points of cytopenias when com-
der.32,33 This is considered as age-related clonal hematopoiesis of pared to IPSS and incorporates a more comprehensive cytogenetic
30
indetermined potential (CHIP). Clonal hematopoiesis has also been score.13 IPSS-R is now the standard tool to assess risk. The IPSS-M
34
identified as a risk factor for therapy-related MDS and AML. was recently published and is has been validated by a number of cen-
Patients with evidence of clonal hematopoiesis are also at increased ters.16,42 This analysis was developed using data from 2957 patients
risk to develop MDS.33 There is significant interest in the evaluation from 24 centers. The model includes detailed information regarding
and potential treatment of patients with CHIP or CCUS. This stands p53 (mono versus biallelic mutations) and incorporates 16 genes. This
from the relationship between other systemic disorders, for instance tool has not been tested yet in specific subsets of patients such as
cardiovascular disease, and CHIP/CCUS and the hypothesis that by those treated with hypomethylating agents or HMA failure.
treating CHIP/CCUS we could prevent progression to myeloid neo- It is also apparent that the natural history of patients with lower
plasm (MN). A number of centers are developing “CHIP clinics” and risk disease is very heterogeneous.43 We evaluated outcomes in a
clinical trials. Potential targets include IL-1, splicing alterations, and large series of patients with low or int-1 disease by IPSS. We found
IDH mutations among others. Recently, Weeks et al. have proposed a that prognosis varied significantly in patients with lower risk MDS and
prognostic model of CHIP/CCUS. In addition, data presented at ASH were able to develop a lower risk MDS specific prognostic score.43
2022 indicated that the most frequent mutation in CHIP/CCUS is This has significant implications for the development of specific inter-
DNMT3A. This is associated with a relative low frequency of progres- ventions for patients with lower risk disease. This model has been val-
sion to MN.35 This data may allow proper selection of individuals with idated on several occasions and it is being used to identify patients
CHIP/CCUS for therapy or more intensive interventions. with poor prognosis lower risk disease that could be candidates for
A subset of patients of importance are those with MDS/MPN fea- early intervention. Bejar et al. published data indicating that patients
tures. These are patients with evidence of a myeloproliferative compo- with poorer prognosis and lower risk disease accumulate a higher
nent (with or without fibrosis). At the present time, with the exception number of mutational events than the better risk counterpart.44 This
of chronic myelomonocytic leukemia, we do not fully understand the data provides a potential molecular basis for the identification of this
36
natural history of patients with MDS/MPN. In our center, they are group of patients and poorer prognosis. The new IPSS-M should really
currently treated as MDS but studies are ongoing to clarify this issue. help clarify the prognosis in patients with lower risk features such as
Of note, specific MDS/MPN subtypes have particular mutational pro- diploid cytogenetics and low percentage of blasts.
files and may benefit from specific therapeutic approaches. An example MDS occurs in older patients that suffer from comorbidities.
includes patients with MDS/MPN with ring sideroblasts and thrombo- None of the systems discussed above include impact of comorbidity
cytosis who typically have mutations in SF3B1 and JAK237,38 and may in the calculation of the natural history of MDS patients. To study this
have good response to therapy with lenalidomide.39 issue, we used a comprehensive comorbidity score known as ACE-27
in a cohort of 500 patients with MDS.17 Presence of comorbidity had
a significant independent impact on survival and a prognostic score
3 | RISK STRATIFICATION could be developed that included age, IPSS, and ACE-27 score. The
same results were obtained using IPSS-R.45 This data indicates the
The prognosis of patients with MDS is very heterogeneous and thus need to add comorbidity scores in MDS. Other groups have confirmed
the need to develop prognostic systems that allow risk stratification the importance of comorbidity scores in MDS.46
and help in the timing and choice of therapy. Apart from the intrinsic Additional prognostic scoring systems include systems for hypocel-
prognostic value of morphological classifications,40 a number of lular MDS47 and for therapy related MDS.48 However, conventional
GARCIA-MANERO 1311
risk stratification models such as IPSS-R, MDACC model, or the WPSS 5 | R I S K A D A P T E D TH E R A P Y

seem equally valid in therapy related disease.49 It should be noted that
prognosis in t-MDS is strongly associated with presence of cytogenetic 5.1 | Current conceptual framework for the
alterations: diploid patients have prognosis not dissimilar to that of de therapy of MDS in 2023
novo patients.48,50
We divide patients into six different categories. First is the subset of
patients without morphological diagnosis of MDS that include ICUS,
4 | CYTOGENETIC AND MOLECULAR CHIP, and CCUS.56 Next, we divide patients with MDS into lower or
ALTERATIONS higher risk but further subdivided them based on whether they have
been exposed to an HMA: lower risk MDS, lower risk HMA failure,
Over the last decade, a number of very important studies have been higher risk and higher risk HMA failure.18 Finally, a group of patients
published describing comprehensive analysis of the incidence and clinical with extremely poor prognosis is that of patients with AML evolving
impact of multiple genetic lesions in MDS.51 Bejar et al. first published an from MDS particularly after HMA-based therapy. We are not going to
analysis of 18 genes using different techniques on 439 patients.52 Subse- discuss this last subset of patients on this review. In addition, clinical
quently, two major studies described the mutational landscape of MDS grade genomic is aiding in treatment decisions for all these subsets of
in larger series analyzing more genes.7,26 An European consortium patients. We discuss these five subsets of patients below. Figure 2
reported an analysis of mutations in 111 genes using next generation summarizes current treatment strategies for patients with MDS.
sequencing technology in a cohort of 738 patients.7 Frequency of com-
mon mutations is shown in Table 3. Since then, multiple other studies
describing the mutational landscape of MDS and its potential prognostic 5.2 | Treatment of ICUS/CHIP/CCUS
and therapeutic implications have been published. Despite the heteroge-
neity of some of these studies, mutations in genes such as RUNX1,7,26,44 The field of ICUS/CHIP/CCUS was transformed by pioneer work led
7,26,44,53,54 26,44
TP53, or EZH2 have consistently been associated with by Ebert and colleagues. Better understanding of these entities has
adverse prognosis while mutations in the splicing factor SF3B1 are associ- transformed our understanding of MDS and our approach to these
ated with favorable outcomes and prolonged survival.7,44,55 group of patients.33 Several important manuscripts have defined and
TABLE 3 Reported frequency of genetic lesions in MDS.52,166,178,179
Gene % Location Function

SF3B1 28 2q33 Splicing factor
TET2 21 4q24 Control of cytosine hydroxymethylation
ASXL1 14 20q11 Epigenetic regulator
SRSF2 12 17q25 Splicing factor
RUNX1 9 21q22 Transcription factor
TP53 8 17p13 Transcription factor
U2AF1 7 21q22 Splicing factor
EZH2 6 7q36 Polycomb group protein
NRAS 4 1p13 Signal transduction
JAK2 3 9p24 Tyrosine kinase
ETV6 3 12p13 Transcription factor
CBL 2 11q23 Signal transduction
IDH2 2 15q26 Cell metabolism, epigenetic regulation
NPM1 2 5q35 Phosphoprotein
IDH1 1 2q33 As IDH1
KRAS <1 12p12 Signal transduction
GNAS <1 20q13 G protein
PTPN11 <1 12q24 Protein phosphatase
BRAF <1 7q34 Raf kinase
PTEN <1 10q23 Phosphatase
CDKN2A <1 9q121 Cell cycle control
1312 GARCIA-MANERO
F I G U R E 2 Proposed treatment algorithm for

patients with MDS. Figure is discussed in the body
of the manuscript. BM, bone marrow; H, high;
HMA, hypomethylating agent; VH, very high;
INT-1, intermediate-1; L, low; MDS,
myelodysplastic syndrome; VL, very low;
5-AZA, 5-azacitidine.
contextualized ICUS/CHIP/CCUS a topic beyond this review.56 Today Recommendation: In 2023, patients with ICUS/CHIP/CCUS should
there is no data to support treatment of patients with ICUS/CHIP/ not be treated but followed preferentially in a dedicated “CHIP” clinic.
CCUS. Individuals with ICUS have very low risk of progressing to Attention should be paid to the care of comorbidities. Clinical trials could
MN. These individuals could be followed in the community. Patients be considered if available.
with CHIP and CCUS have molecular alterations, and in particular in
the context of cytopenia (CCUS), should be followed more frequently.
A number of institutions are developing “CHIP clinics” to follow such 5.3 | Options for patients with lower risk MDS
patients and develop guidelines of care. In our group, these patients
are followed with peripheral blood analysis every 6–12 months based Therapy in this subset of patients is based on transfusion needs. In
on degree of cytopenia and type of mutation. Another important find- general, patients that are transfusion independent are usually
ing associated with CHIP/CCUS is not only the increased risk of observed until they become transfusion dependent. This concept is
transformation to MN but also the collateral risk of associated comor- currently being challenged (see below). Below is a summary of agents
bidities.11 Therapies directed toward those comorbidities, that is, car- currently available for patients with lower risk MDS.
diovascular disease, are warranted and should be monitored in clinical Erythroid growth factor support: The use of erythroid stimulating
trials. agents (ESA) is common practice.59 A number of ESAs are available.
One very important subset of patients with CHIP/CCUS is the Response rates range from 30% to 60% depending on study.60 Data
group of patients that have received prior therapy for another malig- from the Swedish group indicated that addition of G-CSF to erythro-
nancy. Work by Wong et al showed that in patients with therapy- poietin increased responses rates. In a retrospective observational
related neoplasms (T-MN) with a p53 mutation, the mutation could be study, early introduction of this combination in patients with low risk
detected in bone marrow specimens obtained prior to the patient ever disease and minimally transfusion dependent patients had an impact
receiving any therapy for their primary malignancy.57 This finding is on survival.61 The Swedish group also developed an algorithm to pre-
important as it suggests that chemotherapy or radiation therapy used dict response to ESA.62 The French group also evaluated the impact
to treat primary malignancy may not cause DNA damage per se but of ESA on survival in a retrospective study of 284 patients and com-
expansion of clonally mutated hematopoietic cells that expand with pared it to a group of patients that formed the IPSS cohort.63 In this
time. Based on this concept, Takahashi and Padron et al in two inde- study patients treated with ESA had a better survival (HR for death
pendent but parallel studies demonstrated that CHIP/CCUS in was 0.43, 95% CI 0.25–0.72).63 Results from a recently published ran-
patients treated for another malignancy are at a very high risk of pro- domized placebo-controlled phase 3 study of darbepoetin alfa for
34,58
gression to T-MN. Of interest, the data from these two investiga- 147 patients with lower-risk MDS showed significantly higher ery-
tors indicated that this phenomenon was not restricted to p53 but throid responses (14.7% vs. 0%, p = .016) and reduction in transfusion
can be observed with any other gene mutated in CHIP/CCUS. Also of incidence in weeks 5–24 of therapy (36% vs. 59.2%, p = .008) with
importance is the observation from a study at MD Anderson that darbepoetin compared to placebo, with no significant differences
patients with lymphoproliferative process or multiple myeloma trea- between groups in the incidence of thromboembolic events, solid
ted with an autologous stem cell transplant are at particular risk of malignancies or transformation to AML.64 However, questions on
48
developing therapy related neoplasm. potential tumorigenic effect of these drugs has resulted in increased
GARCIA-MANERO 1313
scrutiny of their use. G-CSF is not approved by the FDA for patients study was also designed to clarify the issue of transformation to AML.
with anemia of MDS in the US. 10 mg daily was the superior arm and that there was no increased
Recommendation: A course of ESA with or without G-CSF is not incidence of transformation to AML in patients treated with lenalido-
contraindicated in most patients with low risk MDS with significant mide.71 Of importance, a report from the initial MDS-003 trial of
anemia without other cytopenia. Data indicates that early incorporation lenalidomide indicated a longer survival for patients responding to
of these agents is more effective. We maintain therapy for at least therapy.72
3 months to judge efficacy. In responding patients, we continue therapy Identifying patients at risk of treatment failure or transformation
until transfusion effect is lost. These recommendations may change once remains an essential aspect of management of 5q-MDS. Age
we have access to the results of the COMMANDS trial (see below). <65 years,73 bone marrow blast count >5%74,75 and transfusion
Luspatercept: The Medalist trial was reported in 2020.65 This was dependence have been associated with AML transformation.74 Sev-
a multicenter randomized trial of luspatercept for patients with red eral studies have suggested the role of TP53 mutations and karyotypic
cell transfusion dependent RARS that were not benefiting from ESAs complexity in disease progression and outcome.75–80 Mutations in
or were unlikely to benefit.65 Luspatercept modulates TGF-β signaling TP53 can be detected at early stages prior to therapy in 12%–17% of
in MDS resulting in improved erythropoiesis.66 This concept was ini- these patients,76–78,80 and TP53-mutant clones can emerge and
tially tested in preclinical mouse models and in phase 1 and 2 trials expand through the course of lenalidomide therapy and at the time
with luspatercept and the related compound sotarcept.67 Two hun- of disease progression.77,79 Various studies have reported lower
dred twenty-nine were randomized on the trial. One hundred fifty- response rates and lower likelihood of complete cytogenetic response
three to luspatercept and 76 to placebo. The primary end point of the in TP53-mutated compared with wildtype patients when treated with
study was red blood cell (RBC) transfusion independency (TI) for more lenalidomide.76,78,80 However, an analysis from a multicenter study
68
than 8 weeks following IWG06 criteria. Luspatercept resulted in an including 67 patients with 5q-MDS treated with lenalidomide did not
increase rate of TI in this subset of patients resistant to ESA. TI was confirm differences in TI rates or complete cytogenetic response
achieved in 37.9% of patients with luspatercept versus 13.2 in control based on TP53 mutational status.77 A trend to shorter response dura-
( p < .001). At more than 12 weeks, TI was documented in 33.3% of tion (6 vs. 16 cycles, p = NS) as well as higher risk of transformation
patients on luspatercept versus 11.8% in control. Median duration of and shorter event-free and overall survival were observed among
RBC TI was 30.6 weeks versus 13.6. Other endpoints such as hemato- patients with TP53-mutated 5q-MDS.
logical response-erythroid were also in favor of luspatercept. Toxicity Although current data supports initiating lenalidomide at the time
of this compound that is injected subcutaneously every 3 weeks was of transfusion dependence, data from a subset analysis from the mul-
acceptable without drug related mortality or increased risk of trans- ticenter RevMDS study including 381 patients treated with 10 mg
formation to AML. Based on this data, the US FDA approved luspater- daily of lenalidomide suggested that early intervention in transfusion
cept in 2020.65 Following the results of the Medalist trial, the independent patients with Hgb <10 g/dL may be associated with ery-
COMMANDS trial (NCT03682536) was designed to compare luspa- throid responses. In this study, among 12 TI patients with Hgb <10 g/
tercept versus an ESA in transfusion dependent patients with lower dL therapy with lenalidomide was associated with universal erythroid
risk MDS. This study has been completed and results are expected responses and improved QoL scores compared to pretreatment values
in 2023. (+12.5; p = .02).81 Following this lead, one of the most interesting
Recommendation: Luspatercept is the standard of care of patients contributions to field of MDS was presented at ASH 2023 by Diez-
with RARS that have not responded, lost response or are not candidates Campelo et al: the Sintra-Rev trial.82 In this study, European investiga-
65
to an ESA. tors randomized 60 transfusion independent patients with del5q-
Lenalidomide: Lenalidomide is approved for patients with lower MDS to 5 mg lenalidomide or placebo and measured the transfusion
69 70
risk MDS, anemia and alteration of chromosome 5. Phase I results free survival (TFS) in each arm. TFS was not reached in patients on
were confirmed in a subsequent phase II study of lenalidomide in the low dose lenalidomide arm versus less than 1 year for those on
patients with anemia and alteration of chromosome 5.70 In that study the placebo (p .003, HR 0.3, p .005). Furthermore, cytogenetic
148 patients received 10 mg of lenalidomide for 21 days every responses were documented in 94% of the lenalidomide patients ver-
4 weeks or daily. Of those, 112 had decrease need for transfusions sus 0% in the placebo. Uncensored data analysis did not show
(76%; 95% CI 68–82) and 99 patients (67%; 95% CI, 59–74) became improvement of median survival (8.4 vs. 7.4 years) but it is possible
transfusion independent. Response was fast: median time 4.6 weeks. that with more time these curves could separate. Of importance, there
The median rise of hemoglobin was 5.4 g/dL. Of interest, cytogenetic was no evidence of increased risk of transformation in patients with
responses were observed in close to 50% informative patients. Predic- p53 mutated disease. I believe this data is of importance as is one of
tors of response included presence of a platelet count of 100 109/L the first examples of successful early intervention in MDS.
and less than 4 prior units of red cells transfused. It should be noted Lenalidomide has been investigated in patients without chromo-
that in this study patients with a platelet count of less than some 5 alterations.83 In an initial study, 214 patients received lenali-
50 109/L were excluded. Subsequently, these results were con- domide 10 mg orally daily or 10 mg on days 1–21 of a 28-day cycle.
firmed in a phase III known as AZA-004 comparing two different Fifty six (26%) patients achieved transfusion independence after a
doses of lenalidomide (5 and 10 mg orally daily) versus placebo. This median of 4.8 weeks of therapy. Median response duration was
1314 GARCIA-MANERO
41 weeks. An international phase III, randomized, placebo-controlled Although these agents are not approved in the European Union
study including 239 transfusion-dependent lower-risk non-del5q MDS for patients with lower risk MDS, they are commonly used in the
patients confirmed the efficacy of lenalidomide in this setting.84 US. Currently, main use is for patients with multilinear cytopenia or as
Patients receiving lenalidomide 10 mg daily for 21 days where signifi- second line therapy. The main question in the US is the dose and
cantly more likely to achieve RBC transfusion independence for schedule of this class of compound in lower risk MDS. Work from the
≥8 weeks compared to placebo (26.9% vs. 2.5%, p < .001). Median original studies with oral azacytidine (now CC-486) indicated that
duration of TI was 30.9 weeks and TI was associated with significant lower exposures, as determined by pharmacokinetic profiling, resulted
improvement in HRQoL scores. In addition, higher response rates were in significant clinical activity.89,90 Based on this information, at MD
observed in patients with baseline endogenous EPO ≤500 mU/mL. Of Anderson we designed a series of clinical trials investigating attenu-
note, a recent study not only reported the negative impact of TP53 ated doses and schedules of both azacytidine and decitabine. These
mutations in response outcomes to lenalidomide in del5q MDS, but are summarized in Table 4. The first one was a randomized trial of
also suggested U2AF1 mutations may be likewise associated with a decitabine on a daily scheduled 3 days every 28 days compared to
lower likelihood of response both in del5q and non-del5q MDS and a weekly 3 also every 28 days.91 Although no differences were
that mutations in DEAD box RNA helicase genes (DDX41, DDX54, and observed between both arms, the ORR was 23% and drug related
85
DHX29) may be enriched among responders in non-del5q MDS. mortality was 0%. Median overall survival was not reached. 70% of
However, these findings have to be confirmed on larger studies. patients were alive at 500 days. This study was followed by a random-
Recommendation: The degree of response with lenalidomide in ized study comparing the 3-day decitabine schedule at a dose of
patients with lower risk MDS, anemia, good platelets and del5q makes it 20 mg/m2 versus azacytidine at a dose of 75 mg/m2 also for 3 days.92
the standard of care for this subset of patients. This is further reinforced From this data, it appeared that the attenuated schedule of decitabine
by the data on survival in responding patients.72 We do not consider this was more effective than that of azacytidine. This study was criticized
agent in patients with thrombocytopenia. Based on the results of the because potentially it was not comparing equivalent doses of the two
phase III randomized study, lenalidomide can be considered an option for HMAs. Based on this and to further study the activity of these two
selected red cell-transfusion-dependent patients with non-del5q MDS. drugs, a third study was designed by the US MDS consortium compar-
Evaluation of TP53 mutation status could be advisable in patients with ing 2 schedules of azacytidine (3 and 5 days) and one of decitabine
del5q MDS prior to starting therapy with lenalidomide. Although current (3 days) in both transfusion dependent and independent patients. This
evidence does not support withholding therapy with lenalidomide in study has completed planned accrual. The cumulative data from these
patients with TP53 mutations, these patients should be monitored closely studies and other trials from Cleveland Clinic using attenuated low
for signs of inadequate response, loss of response or progression. The final dose chronic schedules of decitabine93 support the use of lower doses
report of the Sintra-Rev trial could also support the use of low dose of HMAs in lower risk MDS. Indeed, the NCCN guidelines support this
lenalidomide in del5q-MDS transfusion independent patients. concept.14
Azanucleosides: Three azanuclesoides are approved for MDS: Different schedules of 5-azacitidine have been explored in MDS. In
5-azacitidine86 and 5-aza-20 -deoxycitidine (decitabine)87 and in 2020 a community study a 5 day schedule was compared to a 7 day 5-2-2
oral decitabine/cedazuridine (oral dac/ced, ASTX727).88 5-azacitidine schedule (weekend off) or a 5-2-5 schedule of 10 days.94 Fifty patients
is approved for all subsets of MDS whereas decitabine for those with were assigned to each arm (except 5-2-2 was 51 patients). Most patients
INT-1 disease and above. Oral dac/ced has the same indication than had lower risk disease. Hematologic improvement was achieved by
that of decitabine and is described below. 44%–56% of patients in each arm. Transfusion independency was
T A B L E 4 Results from 3 randomized

Study N ORR % CR % TI % OS
trials of attenuated HMA dosing in lower
Low dose DAC12 risk MDS.
DAC daily x3 43 23 16 67 Not reached
DAC weekly x3 22 23 0 59 Not reached
41
DAC versus AZA
DAC daily x 3 73 70 37 32 Not reached
AZA daily x 3 40 49 36 16 Not reached
CC-486 versus placebo
CC-486 107 NA NA 30.8 17.3 months
Placebo 109 11.1 16.2 months
Note: Results from 3 randomized trials of attenuated HMA dosing in lower risk MDS. CC-486 was
presented at EHA 2020 and has not been formally published.
Abbreviations: AZA, azacitidine; CR, complete remission; DAC, decitabine; NA, not available; ORR, overall
response rate; OS, overall survival; TI, transfusion independency.
GARCIA-MANERO 1315
documented in 50%–64% of patients. There was a trend for better needed to determine whether these agents can modify the natural history
response rates and less toxicity with the 5-day schedule of 5-azacitidine. of lower-risk disease and be considered standard of care in the frontline
Therefore, it is reasonable to use a shorter (5 day schedule) of setting or after growth factor support, recent data supports the use of
5-azacitidine in lower risk MDS. these agents at lower doses particularly in patients with more adverse
The use of HMAs in lower risk MDS could be facilitated if enteral features. In the future oral HMAs may have a role in lower risk MDS.90,95
(oral) versions of these agents were available. Data on two of these Immune therapy: This is an area of controversy. It is accepted that
agents, oral dac/ced (ASTX727) and CC-486 (oral azacitidine), has a subset of patients with MDS are characterized by deregulation of
been published. Oral dac/ced is an oral agent that combines decita- both cellular and innate immunity.5,99,100 Based on this it will be logi-
88
bine with the cytidine deaminase inhibitor cedazuridine. CC-486 is cal that the use of immune-modulatory agents could have therapeutic
an oral form of azacytidine.95 CC-486 is not approved for MDS. Oral benefit in MDS. The NIH group pioneered these approaches. Agents
96
dac/ced has been studied in several phase 1 and 2 studies. In the studied include antithymocyte globulin (ATG), cyclosporine, steroids.
registration phase 3 trial, patients were randomized to two different These therapies have been modeled after therapy of aplastic ane-
sequences of either intravenous decitabine or oral ASTX727. This mia.99 The NIH group also developed an algorithm to predict response
allowed for intrapatient PK comparison. Results presented at ASH to this classes of agents.101 This model included younger age, HLA-
2019 demonstrated virtually identical pharmacokinetic profile DR15 positivity, and shorter duration of transfusion dependency.
between both IV decitabine and the oral version. Further supporting Using this algorithm, the NIH group reported that alemtuzumab, an
these results are equivalence on induction of global DNA hypomethy- antibody against CD52, has significant activity in patients with MDS
lation and early reports on clinical activity. An attenuated schedule of predicted to respond to immune suppressive therapy.102 The group at
oral dac/ced is being studied in patients with lower risk MDS. A com- Moffitt Cancer Center has suggested that a CD4/CD8 ratio could also
bination of oral azacytidine and cedazuridine is also being investi- be used to predict response.103 Our group has not been capable to
gated. CC-486 is an oral form of azacytidine but with significant lower reproduce some of the data discussed above. Response rates with
exposure due to limited absorption. CC-486 has been shown to ATG observed at MDACC are significantly lower than those of the
97
improve survival in a study of postconsolidation therapy in AML. A NIH.104 The most important predictor for response for us has been
98
randomized study of CC-486 has also been completed. In this study, the presence of marrow hypocellularity.105 This is consistent with the
499 patients were screened but only 216 were randomized. Of impor- results of Mufti et al in London.106
tance, although the study was designed for patients with lower risk Also recently the impact of ATG based therapy on survival has
MDS, patients were required to have both red cell transfusion depen- been questioned. Data from a Swiss study comparing ATG versus sup-
dent anemia and significant thrombocytopenia. This is a rare subset portive care indicated a higher response rate but no survival bene-
of patients with very poor prognosis.43 Indeed, applying IPSS-R fit.107 In this study, patients were randomized to a combination of
criteria,13 26%–30% of the patients enrolled on the study had high or horse ATG with cyclosporine versus best supportive care (BSC).
very-high risk criteria. The primary end point of the trial was RBC Forty-five patients received ATG + CSA and 43 patients received
TI. Results are also shown in Table 4. CC-486 was used at a dose of BSC. By month 6, 13 of 45 patients on ATG + CSA had a hematologic
300 mg orally daily for 21 days in 28 days cycles. RBC-TI at day response compared with four of 43 patients on BSC (p = .0156).
56 was 30.8% for CC-486 versus 11.1% with placebo (HR 3.6). This Despite higher response rates no significant effect on survival or
was 28% versus 5.6 at 84 days (HR 6.6). Duration of response was transformation was observed.
11.1 months versus 5 months. HI-P was also significantly better for The NIH group has also reported on the clinical activity of eltrom-
CC-486: 24.3% versus 14.3 (HR 4.6). Fewer patients progressed to bopag in patients with aplastic anemia as salvage therapy108 and in
AML with CC-486 than with placebo (7.5% vs. 16.7%). Despite the addition to standard immunosuppressive therapy.109 This data was of
marked effect on red cell transfusion needs and platelet responses, importance due to the fact that responses were multilineage and not
treatment with CC-486 did not result in an improvement in overall just restricted to platelets and significantly higher than those reported
survival (17.3 vs. 16.2 months). This is probably the result of early in historical cohorts with immunosuppressive therapy alone. A num-
death with CC-486 and the fact that patients on the placebo arm ber of studies are investigating this agent in MDS.
went to receive therapy once treatment was unblinded and/or that Recommendation: This is a particular difficult group of patients. A
potentially patients could be rescued with allogeneic stem cell majority of older patients cannot tolerate ATG and most patients are
transplantation. treated with some form of supportive care that could include cyclospor-
ine, growth factors and steroids. The impact of it is not known either. In
younger patients with severe hypoplastic MDS, alloSCT should be consid-
5.3.1 | Recommendation ered as soon as possible. For those that are not candidates, a combination
with horse ATG is recommended. We cannot recommend the use of alem-
Both 5-azacitidine and decitabine are used in the US in patients with tuzumab at the present time until more data from other clinical trials is
lower risk disease that are transfusion dependent. Most patients treated reported. The data on eltrombopag is of interest.
with these agents have failed or were not candidates for growth factor Allogeneic Stem cell transplantation: AlloSCT is usually not recom-
support or lenalidomide. Although results from randomized studies will be mended in patients with lower risk disease even if they are young.
1316 GARCIA-MANERO
This is based on data from Cutler et al using a Markov model.110 The receiving active therapy. We use iron chelation in patients with ferritin
anticipated early mortality with alloSCT cannot be overcome by the levels in excess of 2500 ng/mL but we consider all these patients for a
potential beneficial survival effect of alloSCT. This concept was con- clinical trial of iron chelation.
firmed by Koreth et al.111 Using another Markov model, the investiga-
tors analyzed the impact of reduced intensity transplant in older
patients with MDS. Patients with lower risk disease did not benefited 5.4 | Thrombomimetic agents
111
from this less toxic transplant approaches. In a study describing the
outcomes of 438 patients with lower-risk MDS after failure to HMAs, The use of thrombopoietin agonists for patients with lower-risk MDS
the overall survival of patients who underwent alloSCT was signifi- and thrombocytopenia has been explored in several studies. Initial
cantly longer to that observed in patients not receiving further ther- results of a study with romiplostin117 questioned its use in patients
apy, those receiving conventional chemotherapy or investigational with lower risk MDS, particularly due to complications related to dis-
agents (median survival of 39 months vs. 10 months, 28 months and ease transformation and marrow fibrosis. Results from an extension
17 months, respectively).19 study evaluating the use of romiplostin monotherapy in 60 patients
Recommendation: We generally do not recommend alloSCT in with Low or Int-1 IPSS and thrombocytopenia (defined as platelet
patients with lower risk disease at initial presentation. That said because count of ≤50 109 /L) reported 57% platelet responses with a
of time required for donor identification, we refer all potential candidate median response duration of 33 weeks and only 2 patients with pro-
patients for a transplant consult in anticipation of future needs. Patients gression to AML.118 A number of studies are evaluated eltrombopag
that are candidates for alloSCT and that had been exposed to multiple in MDS, another TPO agonist. Results from the phase 1 single-arm,
therapies (growth factors, lenalidomide, azanuclesoides, etc.) should be randomized portion of the phase 2 superiority EQoL-MDS study119
considered for transplantation. These patients are also candidates for evaluating the efficacy and safety of eltrombopag in patients with
clinical trials. Patients with hypoplastic MDS that are young should be lower-risk MDS where recently published and reported significantly
considered for alloSCT up front. higher platelet responses (47% vs. 3%, p = .0017) and fewer bleeding
Supportive care measures in MDS: A number of interventions can events (14% vs. 42%, p = 0.0025) in the eltrombopag arm compared
be used in patients with MDS. These include the use of prophylactic to placebo. No differences in leukemic transformation where
antibiotics and iron chelation. No randomized data exists to make for- observed (12% vs. 16%, p = .81). Although promising, the use of TPO
mal recommendation for any of these interventions. In our experience agonists should be restricted to clinical trials until additional data is
patients with isolated neutropenia and MDS not receiving therapy are available.
not at significantly increased risk of infection to support recommenda- Recommendation: Thrombomimetics agents should be used with
tion of prophylactic antibiotics. Prophylactic antibiotics are commonly caution and likely only in refractory patients with no other options.
used in the context of active therapy for these patients. The role of
iron chelation in MDS has been clarified recently thanks to the reports
of the TELESTO trial112 discussed below. Data from thallasemias indi- 5.5 | Options for patients with relapsed or
cates that iron chelation has an important role in this setting. Iron refractory lower risk MDS and investigational
accumulation is frequent in MDS. The consequences of this are not new agents in lower risk MDS
fully understood in MDS. A study evaluating the impact of iron chela-
tion therapy on overall survival of transfusion-dependent lower-risk Treatment of patients with lower risk MDS is sequential. A common
MDS patients reported longer median overall survival from the time practice is to start growth factor support and then consider lenalido-
of transfusion-dependence in patients receiving chelation (5.2 years mide or an azanucleoside. In a recent large, multicenter, retrospective
113
vs. 2.1 years, p < .001). This survival advantage remained after study including 1698 patients with lower-risk non-del5q MDS,120
matched pair analysis adjusting for age, frailty, comorbidity, and early failure of ESAs was associated with a higher risk of AML pro-
R-IPSS. There is controversial data with regard to the serum ferritin gression. In a univariate and multivariable analysis, none of the
threshold which should trigger chelation.114 The NCCN guidelines second-line treatments, including HMAs, lenalidomide, and investiga-
recommend the use of chelation therapy in patients with ferritin levels tional agents, seemed to improve the OS of these patients signifi-
above 2500 ng/mL.115 Iron accumulation could have a role in trans- cantly. Although there are limitations to a retrospective analysis with
formation to AML116 and in the increased risk of infectious complica- high heterogeneity, this may suggest consideration of earlier interven-
tions known to occur on these patients. tion with disease modifying therapy (DMT) may be an option at least
for some lower-risk patients. A retrospective study evaluating the
impact of the timing of DMT on the likelihood of achieving TI among
5.3.2 | Recommendations 508 TD lower-risk MDS patients suggested early intervention
(≤3 months from start of TD) with lenalidomide or HMAs may be
We do not routinely recommend antibiotics in patients with isolated associated with higher rates of TI.121 In a randomized phase III study
neutropenia and MDS that are not receiving some form of cytotoxic or comparing lenalidomide 10 mg daily for 21 days as single agent or in
immunosuppressive therapy. We use prophylactic antibiotics in patients combination with ESAs in 131 RBC transfusion-dependent lower-risk
GARCIA-MANERO 1317
ESA-refractory non-del5q MDS patients,122 the erythroid response using the initial 3-day schedule. The major objective of the study was
rates after 4 cycles of therapy where 23.1% an 39.4%, respectively survival. Unfortunately, use of decitabine at this dose and schedule
( p = .044) with a median response duration of 18.1 and 15.1 months, was not associated with improved survival in patients with higher risk
respectively ( p = .47). Although growth factor support should be con- MDS.131 Despite all this data, the final dose and schedule of decita-
sidered frontline, this emerging data suggest early initiation of disease bine is not fully understood. Blum et al. have indicated that a 10-day
modifying agents may have to be considered as reasonable options. schedule of decitabine has significant activity in AML.132 Similar
However, randomized clinical trials will be required to support this results have been reported by other groups in recent years.133
therapeutic approach. Oral decitabine/cedazuridine96,134 was approved based on the
Patients that fail either lenalidomide or azanucleoside are candi- results of the Ascertain trial (NCT03306264) for the same indications
dates for clinical trials or alloSCT. There is no drug approved in the US of IV decitabine. Then final report of this study is expected in 2023.
for patients with lower risk MDS and HMA failure. The survival of This study confirmed the results of the initial phase 2 trial96 where
19
these patients was calculated to be between 14 and 17 months. oral dac/ven was shown to have almost identical PK and PD charac-
A number of agents are being studied for lower risk MDS. These teristics to IV decitabine. The current accepted dose of oral dac/dec is
include oral azacitidine90,95 and oral dec/ced, antagonists of Toll-like 35 mg/100 mg. The ORR in the phase 2 trial was 60% including a
5,123 124
receptor signaling such as OPN-205, p38MAPK (ARRAY-614), complete remission rate of 21% with a median survival of
siltuximab,125 bortezomib,126 ruxolutinib.127 None of these studies 18.3 months (unpublished). At ASH 2022, a subset analysis of the
has demonstrated so far enough activity to warrant larger studies. Ascertain trial in p53 mutated patients suggested that oral dac/ced
Lower risk HMA failure MDS in patients not candidates for alloSCT is was associated with significant survival both in patients with monoal-
a major unmet need. Recently, a press release has announced that lelic or biallelic p53 mutations. In that analysis of 44 patients (35% of
imetelstat, a telomerase inhibitor, was superior to placebo in transfu- the total Ascertain population) the median OS for p53 mutated
sion dependent patients with lower risk MDS post ESA. A report of patients was 25 months including 29 months for those with monoalle-
this data is expected in 2023. lic mutations and 13 with biallelic mutations. These figures appear
Recommendation: At the present time there is no drug approved for larger than those previously reported in other HMA series.135 Reasons
patients with HMA failure lower risk MDS. Only active option is alloSCT. for these results are not understood and need to be explored further.
Otherwise, patients should be considered for investigational clinical trial. 5-azacitidine has been studied in higher-risk MDS in two major
randomized multicenter trials: CALGB 9221136 and AZA-001.86 In the
CALGB 9221136 study, 191 patients with MDS were randomized
5.6 | Options for newly diagnosed patients with between 5-azacitidine (75 mg/m2/day for 7 consecutive days every
higher risk MDS 28 days) and best supportive care (BSC). Median age was 68 years.
Sixty percent of the patients in the 5-azacitidine group, compared
Options for patients with higher risk MDS have not evolved signifi- with 5% of control arm patients, responded to treatment ( p < .0001).
cantly since the last version of this paper. The azanucleosides remain The median time to leukemic transformation or death was 21 months
the standard of care of a majority of patients.128 in patients treated with 5-azacitidine versus 12 months in the BSC
Azanucleosides: Decitabine was studied in an initial randomized arm ( p = .007). No significant difference in survival was observed. A
87
comparing it to BSC. In this study the dose of decitabine was landmark analysis suggested a survival advantage for patients initially
15 mg/m2 IV infused over 3 h every 8 h for 3 days (at a dose of on 5-azacitidine or who had crossed-over to 5-azacitidine within
135 mg/m2 per course) and repeated every 6 weeks. Although there 6 months of inclusion on study (p = .03). A significant improvement in
was no clear benefit in terms of survival in this study, the use of deci- quality of life was documented in patients treated with 5-azacitidine
tabine was associated with a complete response rate of 9% and over- compared to BSC.137 AZA-001 was a randomized study designed to
all response rate of 17%. These results led to the approval of test the concept that treatment with 5-azacitidine resulted in
decitabine in the US. Based on the results of a phase I trial of decita- improved survival compared to a menu of standard of care options.86
bine performed at MDACC, a Bayesian randomized phase II trial of These included BSC, low dose cytarabine (ara-C) or AML-like therapy.
129
three different doses and schedules of decitabine was conducted. In AZA-001, 358 patients with higher-risk MDS were randomized to
In this study a 5-day schedule of decitabine administered daily at a either 5-azacitidine (as per CALGB9221 schedule) or to standard of
dose of 20 mg/m2 was shown to be superior to a 10-day or subcuta- care. Median age of patients was 69 years. Median survival was signif-
neous schedule. A multicenter phase II trial of decitabine (ADOPT) icantly better in patients treated with 5-azacitidine versus standard of
using the 5-day schedule confirmed the safety of this schedule care options: 24.5 months versus 15 months ( p = .0001). Progression
although response rates were lower than those reported by the to AML was significantly delayed, and RBC transfusion requirements
MDACC.130 In the ADOPT study the median number of courses and rate of infections were also significantly improved with
administered was 5, the CR rate was 17% and the median survival 5-azacitidine. The survival advantage with 5-azacitidine was irrespec-
was 19.4 months. No randomized survival study of a 5-day schedule tive of age (including patients older than 75 years), percent of marrow
of decitabine has been conducted in MDS. In parallel with this work, blasts (including patients with 20%–30% blasts, now classified as AML
European investigators developed a randomized study of decitabine using WHO criteria) or karyotype. This effect was significant when
1318 GARCIA-MANERO
compared to BSC and low dose ara-C. The number of patients treated advances in transplant technology are allowing the consideration of
with AML-like therapy was too small to allow comparison with older patients and alternative donors. Studies have suggested reduced
5-azacitidine. No consistent biomarkers of response to azanucleosides intensity conditioning may be able to achieve similar relapse-free and
have been developed. overall survival in patients with MDS,146 and that comorbidity and dis-
ease risk indexes may be more relevant in outcomes than chronologi-
cal age itself.147 This should result in greater number of older patients
5.6.1 | Recommendation benefitting from this potentially curative treatment modality. A recent
report studying biological assignment in patients with higher risk MDS
The azanucleosides are the standard of care for most patients with higher ages 50–75 years suggested that survival on an intent to treat analysis
risk disease. No study has compared 5-azacitidine versus decitabine. was superior (48% at 3 years) on the donor arm versus 26% for the
Although response rates appear to be similar, only 5-azacitidine has been nondonor arm.148 Recent guidelines for alloSCT in MDS have been
associated with improvement of survival in a randomized trial. Based on proposed.149
this, we consider 5-azacitidine standard therapy for front line treatment There are several relevant practical questions regarding alloSCT
in higher risk MDS. in MDS. These include timing of transplant; and what to do with
AML-like chemotherapy: AML-like protocols in higher risk MDS patients that achieved a complete response to HMA prior to alloSCT.
have generally used classical anthracycline-araC combinations similar A study from the IBMTR indicated that early transplantation in
to those used in de novo AML.138,139 When used in MDS or AML higher-risk MDS was associated with longer life expectancy.110,111
post-MDS, AML-like therapy results in lower CR rates (40%–60%), Although data suggests longer survival with SCT in patients with
shorter CR duration (median duration of 10–12 months) and tend to higher risk disease, it should be noted that curves cross close to
be associated with more prolonged periods of aplasia than observed 3 years after initiation of therapy when compared with HMAs. It will
in AML. In addition, the feasibility of AML-like therapy is also reduced be important to identify who are long-term survivors that benefit the
by the advanced median age of patients with MDS. The most impor- most from transplant. A prospective study is comparing azanucleo-
tant prognostic factor of response to AML-like therapy is karyotype sides use versus transplant in MDS. In terms of what to do in respond-
and presence of TP53 mutations: patients with unfavorable karyotype ing patients, no recommendation can be given at this time. For
(7/del 7q or complex karyotype) or TP53 mutations have a low CR patients who experience failure to HMAs, transplant has been consid-
rate and short duration of response.140 This is of importance as, at ered an option but a recent retrospective study seemed to indicate
86
least in the AZA-001 study, patients with alterations of chromo- these patients are at high risk of post-transplant relapse compared to
some 7 had a significant benefit with 5-azacitidine versus other thera- responding patients.150 Prospective studies will be required to clarify
pies. Similarly, other prospective and retrospective studies report this. Other questions include whether or not alloSCT should be pre-
either similar or higher responses to azacitidine or decitabine in ceded by a cytoreductive regimen (with chemotherapy or perhaps
patients with MDS or AML with TP53 mutations compared to those HMAs). Many authors consider that when marrow blasts >10% at the
with wild type TP53 suggesting this should be considered the stan- time of transplant, because of the very high relapse risk post trans-
dard over chemotherapy for patients with these genomic abnormali- plant, pretransplant therapy is required. A report from the EBMTR has
ties.53,133,141,142 Currently, AML-like therapy is only recommended for indicated that long-term survival of patients with monosomy 7 is very
relatively younger patients with favorable karyotype that are candi- poor with alloSCT.151 Similarly, as we previously detailed, two major
dates for alloSCT. studies152,153 concluded that mutations in TP53, RUNX1, ASXL1,
Recommendation: The randomized AZA-001 study was not powered JAK2, and RAS pathway genes are associated with significantly shorter
to demonstrate the superiority of 5-azacitidine versus AML-like therapy. overall survival or relapse-free survival154 after alloSCT with TP53
The reason for this being that most investigators did not consider their mutations being particularly adverse. These results have significant
patients candidates for such therapy. Therefore, the question is who may implications for the use of alloSCT in MDS, as this suggests that the
be a candidate for AML therapy. In our practice this is restricted to youn- current practice of reserving transplant for poor prognostic features
ger patients with a high likelihood of response to the therapy, such as dip- may not be indicated. In patients at higher risk for relapsed post
loid patients or candidates for alloSCT. We rarely use AML therapy in alloSCT, data from a single arm trial indicated that post-transplant
older patients or in those with poor risk cytogenetics or TP53 mutation. hypomethylating use can improve outcome.155
AlloSCT: AlloSCT is reported to be the only curative treatment of Recommendations: All patients potential candidates for alloSCT
higher-risk MDS. Results from selected studies report prolonged DFS should be counseled regarding the possibilities of undergoing alloSCT.
in about 30%–50% of the patients.143 However, its use is mainly Optimally patients will be enrolled in an MDS specific clinical trial of
restricted to younger patients with an appropriate donor. Different alloSCT. Although alloSCT should be considered for patients with higher-
transplant modalities of different intensities and donor sources are risk MDS this may not be the case in patients with high risk mutations
now in use. Most of them remain investigational, with available stud- such as TP53, in whom, in our opinion, transplant may have to be consid-
ies including small numbers of patients with MDS and highly hetero- ered only if an optimal donor is available, optimal pretransplant response
geneous populations,144,145 and therefore in our opinion all patients has been obtained and if lower doses of post-transplant 5-azacitidine or
should be transplanted in the setting of a clinical trial. Current decitabine are considered. Lower doses of 5-azacitidine can also be
GARCIA-MANERO 1319
considered in patients at high risk for relapse post transplantation. I antibody against CD47 known as magrolimab.159 In recently published
endorse recently proposed US guidelines.149 study160 of 95 patients the combination resulted in an ORR of 75%
and a CR of 33 and the median survival was not reached. A random-
ized registration trial known as the Enhance trial has also been com-
5.7 | Investigational approaches for patients pleted (NCT0441748). Another potential target in MDS is TIM-3.161
with higher MDS This is being explored in several clinical trials with antibody known as
sabatolimab (MBG453). Tamibarotene, and ATRA-like compound, is
The results of the AZA-001 trial still represent the best standard of also being studied in a specific subset of patients.162
86
care for patients with higher risk disease. In that study, patients with Recommendation: All patients with MDS should be considered for an
higher risk MDS were randomized to either azacitidine or investigator investigational clinical trial when possible.
choice of therapy. Overall survival (24 months) was significantly supe-
rior to that of control. Although it is disputed that the median survival
of patients with higher risk MDS is indeed 24 months and likely 5.8 | HMA failure still a major unmet need in MDS
shorter, these results still represent the best data from a randomized
trial in this setting and therefore single agent azacitidine constitutes The prognosis of patients with HMA failure is very poor. Natural his-
the bar to improve. Multiple studies have attempted this. The status tory differs between patients still in a lower risk category where the
of combination phase III studies has recently being reviewed in survival is 15–17 months versus those with higher risk failure
detail.156 that have a survival of 4–6 months. A study with the multikinase
Several combinations have been studied. These are summarized inhibitor rigosertib in higher risk HMA failure identified two subsets
in Table 5. One consists on the combination of azacitidine with the of patients in the higher risk category: those with primary failure
BCL-2 inhibitor venetoclax. This combination follows successful data (never responded to HMA therapy) and those with secondary failure
with this combination in AML.157 Data from a multicenter trial of aza- (relapsed).163 At the present time, there is no therapy that has been
citidine and venetoclax was presented at ASH 2019 (Wei et al ASH shown to have significant activity for this group of patients. For
2019 abstract #568). This was a phase 1b study in previously patients with higher risk HMA failure options that have been investi-
untreated patients with higher risk MDS. Data from 57 patients was gated included rigosertib,163 venetoclax,158,164 guadecitabine among
presented. Venetoclax was used at doses of 100 mg orally to 800 mg several.
daily from 14 to 28 days in combination with standard dose azaciti- Cytogenetic and molecular NGS data have value when deciding
dine. The ORR was 77% with 37% of patients achieved CR. Although therapy, particularly AML-like approaches, in patients with HMA fail-
follow up was short, median survival had not been reached. Main ure MDS. Data from a phase II trial of clofarabine and low dose ara-C
issue was drug related cytopenia particularly at the higher doses of in patients with relapsed refractory MDS indicated that lower doses
venetoclax. A single center phase 1/2 study of the combination of of this combination in patients with diploid cytogenetics were associ-
azacitidine and venetoclax was published in 2022.158 In this study of ated with significant response rates and that response in this trial was
23 patients, the ORR was 87% and the median survival in the previ- associated with a median survival of 22 months.165 Therefore, select-
ously untreated group was not reached.158 A combination of oral ing patients for this type of therapy (i.e., diploid cytogenetics) could
dac/ced is ongoing. A phase 3 trial of azacitidine +/ venetoclax (the be associated with improved outcomes in this group of patients. This
Verona trial NCT04401748) has been completed. The second combi- observation is being followed with studies using lower doses of cladri-
nation of significant interest is the combination of azacitidine with an bine and low dose ara-C and in a phase 1 trial of CPX-351.
TABLE 5 Recent combinations for patients with HR MDS in first line.
Agent Aza + pevonedistat180 Aza + venetoclax158 Aza + magrolimab160 Aza + sabatolimab

Phase 3 1/2 2 2
Year 2021 2022 2023 2021
Objective EFS Safety, ORR ORR ORR
N 227 17 95 101
Population CMML, HR-MDS, AML HR-MDS MDS HR-MDS
ORR 32 82 75 56.9
CR 31 18 33 19.6
OS 16.8 Not reached Not reached
Abbreviations: AZA, azacitidine; CMML, chronic myelomonocytic leukemia; CR, complete remission;N, number; NA, not available; ORR, overall response;
OS, overall survival.
1320 GARCIA-MANERO
Recommendations: All patients with higher risk disease that have debate of whether we need bridge therapy prior to SCT.177 This
relapsed or refractory disease should be considered for an investigational probably likely related to the fact that single agent HMA may not be
clinical trial and potentially alloSCT. very effective in achieving deep responses in MDS and not due to the
fact that complete cytogenetic or molecular responses would not be
associated with better outcomes in the transplant setting. This is fur-
5.9 | Incorporating precision medicine in MDS ther complicated by the fact that we observe very high relapse rates
post-transplant in specific subsets of patients such as those with p53
One of the major advances in research in MDS has been the incorpora- mutations or complex cytogenetics.152 The advent of powerful new
tion of NGS assays, first in the laboratory, and now in the clinic. This combinations with magrolimab or venetoclax argue for total therapy
data is not only allowing better understanding and prognostication of that could render patients MRD negative pre transplant followed with
the disease but also design of targeted approaches for patients with post-transplant maintenance therapy either with targeted approaches
MDS. Genes of interest include SF3B1, IDH2, IDH1, Flt-3, p53, and the of HMAs. Further studies are needed in this area.
small subset of patients with NPM1 mutated disease. SF3B1 is involved
in gene splicing and is the most commonly mutated gene in MDS.166
Luspatercept is indicated for a patient population enriched for SF3B1. A 6 | CONC LU SIONS
selective inhibitor of SF3B1 is being studied in clinical trials.167 Agents
that target IRAK4 also seem to be dependent on splicing patterns.168 Better understanding of the pathobiology of MDS is resulting in
IDH1 and 2 are mutated in MDS in 5%–15% of patients respectively.169 newer approaches for patients with MDS. As a consequence, the
Initial data in AML studies that included a small group of patients with treatment landscape for patients with MDS is starting to change. Lus-
MDS suggested significant activity of IDH inhibitors also in MDS.170,171 patercept was the first agent approved for MDS since 2006. This was
A follow up study with enasidenib has demonstrated significant activity followed in 2020 by the oral HMA oral decitabine/cedazuridine
of this compound in MDS.172 Despite that Flt-3 mutations are very rare (ASTX727). In 2023, we expect the results of the upfront trial of lus-
173
in patients with MDS, they have been shown to occur in 15%–30% patercept in lower risk MDS (COMMANDS, NCT03682536) and of
of patients with HMA failure.174 Those patients tend to have laboratory imetelstat in second line (iMERGE NCT02598661). In addition, 2 large
evidence of leukocytosis. Data from an add back design with sorafenib phase 3 trials for higher risk disease have been completed (Verona
by Ravandi et al indicated significant activity of the addition of the Flt-3 and Enhance). Results with alloSCT continue to improve. All these
175
inhibitor to azacitidine in patients with HMA failure. This is being fol- efforts should result in the improvement of survival of patients
lowed by several small studies using second and third generation Flt-3 with MDS.
inhibitors in MDS. Mutation on the p53 gene have been reported in
close to 10% of patients with MDS.135 Most of them are therapy related ACKNOWLEDG MENTS
and have complex cytogenetics and therefore have a very poor progno- This work was supported in part by the University of Texas MD
sis. These patients tend to be resistant to conventional chemotherapy Anderson Cancer Center Support Grant CA016672 and by generous
and although seem to be sensitive to HMA-based therapy, responses philanthropic contributions to the MD Anderson's MDS/AML Moon
are short and prognosis still dismal.50 Of importance, presence of p53 Shot Program.
mutations is associated with a very high rate of relapse post transplanta-
tion.152 Despite initial data with APR-246, p53 mutations are still a major CONFLIC T OF INTER E ST STATEMENT
need. Finally, around 1% of patients with MDS carry a mutation on the GG-M reports no conflicts of interest.
NPM1 gene.176 Although it can be argued that these patients constitute
a rare subset of patients with AML, as those the presence of core bind- DATA AVAILABILITY STAT EMEN T
ing factor abnormalities, the reality is that morphologically these patients This is a review manuscript. Data reported here is publicly available.
are undistinguishable from other patients with higher risk MDS. A report
from a small series of patients from MD Anderson indicates a very high
OR CID
rate of response and potentially cure with a cytarabine type of approach
Guillermo Garcia-Manero https://orcid.org/0000-0002-3631-2482
followed by alloSCT.176172
Recommendation: We advocate the use of an NGS panel at baseline and
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Received: 2 April 2023 Revised: 21 May 2023 Accepted: 23 May 2023

ANNUAL CLINICAL UPDATES IN

Myelodysplastic syndromes: 2023 update on diagnosis,

Section of MDS, Department of Leukemia,

Am J Hematol. 2023;98:1307–1325. wileyonlinelibrary.com/journal/ajh © 2023 Wiley Periodicals LLC. 1307

1 | D I S E A S E OV E R V I E W different from that of patients not previously treated with such an

mic alterations (now computed by the IPSS-M), 16

FIGURE 1 Cytogenetic classification of MDS. Adapted from Schanz et al (reference23).

TABLE 2 Characteristics of ICUS/CHIP/CCUS.7,28,29,56

Features CHIP ICUS CCUS MDS

risk stratification models such as IPSS-R, MDACC model, or the WPSS 5 | R I S K A D A P T E D TH E R A P Y

TABLE 3 Reported frequency of genetic lesions in MDS.52,166,178,179

Gene % Location Function

F I G U R E 2 Proposed treatment algorithm for

T A B L E 4 Results from 3 randomized

TABLE 5 Recent combinations for patients with HR MDS in first line.

Agent Aza + pevonedistat180 Aza + venetoclax158 Aza + magrolimab160 Aza + sabatolimab

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