De Novo and Therapy-Related Myelodysplastic Syndromes: Analogies and Differences 

Giuseppe Leone¹, Emiliano Fabiani^2,3 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.

Introduction

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.

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Table 1

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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)

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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

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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.

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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.

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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).

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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.

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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).

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Figure 4. Patient characteristics in de novo vs therapy-related MDS (data from Kuendgen et al.[17] Leukemia 2021).

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Abnormalities of chromosome 5

Chromosome 7 abnormalities

Chromosome 17 abnormalities

Chromosome 20

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.

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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.

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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

Treatment

Conclusions

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