A precision medicine approach to the myelodysplastic syndrome with isolated deletion 5q, 50 years after its discovery Free

In a letter to Nature in 1974, Van den Berghe et al reported on 3 patients who presented with a clinically similar hematologic disorder and an apparently identical chromosomal abnormality in the bone marrow.¹ These patients had long-standing macrocytic anemia that was refractory to conventional treatments, a low or normal white blood cell count, and a normal or elevated platelet count. Their bone marrow showed dysplastic features, particularly the absence of megakaryocytic nuclei lobulation. The chromosomal abnormality consisted of a deletion of the long arm of 1 chromosome 5, without translocation of the deleted segment. This aberration was detected in cultured bone marrow cells but not in lymphocytes or skin fibroblasts, indicating that it was a somatically acquired genetic lesion.¹ Additional investigations on the new hematologic syndrome associated with the 5q− chromosome were reported 1 year later by the same group in Blood.² 

For many years, the hematologic disorder associated with the 5q chromosomal abnormality has been designated the 5q− syndrome.³ In the 2001 World Health Organization (WHO) classification of myeloid neoplasms, this disorder was included as a specific myelodysplastic syndrome (MDS) subtype, termed MDS with isolated deletion 5q, or MDS-del(5q).⁴ As illustrated in Table 1, the diagnostic criteria for this entity have been subsequently refined, specifically in both the International Consensus Classification (ICC) and the 5th Edition of the WHO classification (WHO 2022) of myeloid neoplasms and acute leukemias.^5-8 This report illustrates how genomic profiling of well-characterized populations of patients with MDS has transformed our understanding of MDS-del(5q), whose management now requires a precision-medicine approach.

The deletion of the long arm of chromosome 5 or the loss of the whole chromosome 5 are common occurrences in myeloid neoplasms, including MDS, acute myeloid leukemia (AML), and therapy-related myeloid neoplasms (t-MNs).⁹ In many of these conditions, del(5q) is typically accompanied by additional chromosomal abnormalities, frequently resulting in a complex karyotype (CK). Conversely, in most patients with the condition identified by Van den Berghe et al, del(5q) is typically the sole identified cytogenetic abnormality, which indicates that it likely represents a founding genetic lesion (Figure 1A).^1,2,10 A few patients may exhibit 1 additional chromosomal abnormality in conjunction with del(5q), without experiencing a significant impact on clinical outcomes.¹⁰ In contrast, those carrying ≥2 additional chromosomal abnormalities (representing a CK) or an accompanying −7 or del(7q) cytogenetic abnormality have worse survival.^10,11 These observations led to the conclusion that a diagnosis of MDS-del(5q) can be made if there is 1 additional cytogenetic abnormality beyond the del(5q), except monosomy 7 or del(7q) , which was reflected in the revised 4th edition of the WHO classification published in 2016 (Table 1).⁵ 

The somatic deletion of MDS-del(5q) is interstitial (supplemental Figure 1, available on the Blood website).³ The prevalent chromosomal alteration is a 5q32-5q33 deletion, with the commonly deleted region (CDR) spanning ∼1.5 megabases and containing 44 genes and several microRNA (miRNA) genes, as described by Boultwood et al.^12,13 The 1- to 1.5-megabase CDR at 5q31 identified by Lai et al in patients with AML or more advanced forms of MDS, many of whom have additional chromosomal abnormalities, is distinct from the CDR of MDS-del(5q) because it is more proximal.^14,15 

Gene expression analysis of CD34⁺ cells from patients with MDS-del(5q) unequivocally demonstrated that most genes assigned to the CDR at 5q32-5q33 had reduced expression levels, consistent with the loss of 1 allele.¹⁶ This suggested that the pathogenesis of MDS-del(5q) is due to the haploinsufficiency of multiple genes located within the deleted region, a working hypothesis that has been confirmed by subsequent studies and is schematically depicted in Figure 1B.

The RPS14 gene maps to chromosome 5q33.1 and encodes a ribosomal protein that is a component of the 40S ribosomal subunit. The reduced expression of this gene was documented in hematopoietic cells from patients with MDS-del(5q).¹⁶ Ebert et al then demonstrated that haploinsufficiency of RPS14 is the underlying cause of the erythroid dysfunction.¹⁷ RPS14 protein deficiency interferes with the normal formation of the 40S ribosomal subunit, thereby impairing erythroid differentiation. The mechanism is analogous to that of Diamond-Blackfan anemia, an inherited autosomal dominant disorder associated with germ line mutations in ribosomal protein genes, such as RPS19.¹⁸ 

In both patients with MDS-del(5q) and animal models of the disease, the defective formation of the 40S ribosomal subunit leads to upregulation of the p53 pathway in erythroid cells.^19-22 A mouse model of the 5q− syndrome was generated by Barlow et al using large-scale chromosomal engineering.¹⁹ Mice with haploinsufficiency of the Cd74-Nid67 interval (syntenic to the CDR of the human 5q− syndrome and including Rps14) recapitulated the key features of the human disease, including macrocytic anemia and megakaryocytes with round or nonlobulated nuclei. This mouse model displayed defective bone marrow progenitor development and an accumulation of p53 protein with increased apoptosis in bone marrow cells. The progenitor cell defect was rescued by intercrossing the “5q− mouse” with p53-deficient mice, providing evidence that a p53-dependent mechanism plays a role in the pathophysiology of the 5q− syndrome.¹⁹ 

In a murine model with conditional inactivation of Rps14, ribosomal haploinsufficiency was found to induce overexpression of p53 and a related impairment in erythroid differentiation, characterized by defective generation of orthochromatic erythroblasts.²² Patients with MDS-del(5q) typically exhibit relative erythroid hypoplasia, likely because the defective ribosome biogenesis limits erythroid proliferation.²³ 

The pathophysiologic process that leads to MDS consists of the growth and expansion of a mutated clone, whose selective advantage is provided by a somatic genetic lesion occurring in a self-renewing hematopoietic stem cell.⁸ In MDS-del(5q), the clonal advantage of mutant hematopoietic cells originates from the haploinsufficiency of ≥1 genes that are located in the deleted region.

The tumor suppressor gene CSNK1A1, which encodes casein kinase 1A1, exhibits a reduction in gene expression of ∼50% in hematopoietic cells from patients with MDS-del(5q).¹⁶ In a murine model, Csnk1a1 haploinsufficiency was found to induce hematopoietic stem cell expansion and a competitive repopulation advantage.²⁴ Additionally, recurrent somatic mutations in the nondeleted CSNK1A1 allele were detected in patients with MDS-del(5q).^24-26 Collectively, these observations indicate that CSNK1A1 haploinsufficiency leads to clonal expansion of del(5q)-mutant hematopoietic cells (Figure 1B). This conclusion has been recently corroborated by studies of genetic barcoding in murine models.²⁷ 

In the report by Sokal et al, the striking morphologic abnormality concerned megakaryocytes, whose nuclei “were generally small, round or oval, and nonlobulated”; additionally, affected patients showed “normal to elevated platelets (300 000 to 500 000).”² 

These morphologic and clinical findings likely reflect, at least in part, the dysregulated miRNA activity caused by the 5q deletion. MiRNAs are noncoding RNAs that regulate biologic processes by silencing gene expression posttranscriptionally.²⁸ Their haploinsufficiency is therefore expected to increase the expression of targeted genes. Starczynowski et al observed that deletion of chromosome 5q32-5q33 is associated with the loss of 2 miRNAs, MIR145 and MIR146A.²⁹ Using animal models, they demonstrated that the loss of these miRNAs in hematopoietic cells results in activation of innate immune signaling, dysmegakaryopoiesis, and thrombocytosis.²⁹ Similarly, Kumar et al showed that the combined loss of MIR145 and RPS14 in murine models leads to alterations of the megakaryocytic differentiation that are analogous to those of patients with MDS-del(5q).³⁰ 

In a study of patients with lower-risk MDS, including MDS-del(5q), Woll et al investigated whether the underlying genetic lesion occurred in hematopoietic stem cells capable of self-renewal or more differentiated progenitor cells.³¹ Collectively, the findings of this study indicate that MDS is propagated by rare and distinct cancer stem cells capable of self-renewal.³¹ In a portion of patients with MDS-del(5q), no recurrent driver mutation could be identified through targeted or exome sequencing, confirming that del(5q) represented the initiating genetic lesion. At variance, in patients with MDS with del(5q) associated with CK and advanced disease, del(5q) was a secondary hit, often preceded by TP53 mutation.³² 

Lenalidomide is currently used as a targeted therapy for patients with MDS-del(5q), capable of suppressing the mutant clone and restoring normal hematopoiesis.⁸ However, its initial development was for a more limited purpose, namely the amelioration of anemia that had been previously observed with thalidomide in patients with MDS.³³ 

The first clinical trial on the use of this thalidomide analogue in patients with MDS showed cytogenetic responses in patients with del(5q).³⁴ Therefore, a subsequent phase 2 trial investigated whether lenalidomide could reduce the transfusion requirement by selectively targeting the mutant clone in patients with MDS-del(5q).³⁵ Patients were risk-stratified using the International Prognostic Scoring System (IPSS) and 94% of patients had lower-risk MDS.³⁶ This study demonstrated that lenalidomide can indeed target the del(5q) clone, eliminating or reducing the need for transfusions. A phase 3 randomized trial subsequently established that lenalidomide treatment (5 or 10 mg per day) can achieve transfusion independence in ∼60% of patients with MDS-del(5q) (supplemental Table 1).³⁷ However, less than one-third of patients achieved complete cytogenetic remission, and after a median duration of response of ∼2 years, most patients experienced reappearance or reexpansion of the del(5q) clone and recurrence of transfusion dependence.^8,38 Additionally, lenalidomide treatment involved grade 3 to 4 adverse effects in most patients, primarily severe neutropenia (supplemental Table 1). Ultimately, there was no statistically significant difference in the median overall survival rates between the placebo group and the 2 lenalidomide groups.

Real-world studies on the use of lenalidomide in patients with (MDS)-del(5q) have yielded worse results. In a Mayo Clinic study, the proportion of patients showing complete cytogenetic remission was very low (12%), whereas most individuals (65%) eventually discontinued treatment.³⁹ Of 118 patients enrolled in the HARMONY Alliance study, 70 (59%) had discontinued lenalidomide because of intolerance.⁴⁰ 

The SintraREV trial aimed to investigate whether an early intervention of low doses of lenalidomide (5 mg per day) for 2 years could delay transfusion dependency in patients with anemia with MDS-del(5q) who were not already transfusion dependent.⁴¹ Patients were risk-stratified using the revised IPSS (IPSS-R), and all but 1 had very low or low IPSS-R risk.⁴² The study was conducted at 22 centers and enrolled 61 patients over 8 years; 40 patients were assigned to receive lenalidomide, and 21 were given placebo. Lenalidomide treatment was found to delay the time to transfusion dependency but had no impact on overall survival. Complete cytogenetic response was observed in 28 of 40 patients receiving lenalidomide. Approximately 50% of patients discontinued the study medication prematurely during the study period; as would have been anticipated, a significantly greater number of treatment-related adverse events were observed in patients receiving lenalidomide.

In vitro studies clearly showed that lenalidomide had selective cytotoxic effects on del(5q) hematopoietic progenitor cells, resulting, in part, from inhibition of the haplodeficient Cdc25C and PP2Acα phosphatases.⁴³ The major mechanism through which lenalidomide suppresses the del(5q) clone has been elucidated more recently. This compound promotes ubiquitination and proteasomal degradation of casein kinase 1A1, inducing stem cell failure.^24,44 In patients with MDS-del(5q), hematopoietic cells harboring del(5q) have a single copy of the CSNK1A1 gene and reduced production of casein kinase 1A1, which renders these cells more sensitive to the effects of lenalidomide compared with normal cells.⁴⁴ 

Despite lenalidomide targeting mutant hematopoietic cells, this is not a curative treatment.³⁸ Almost all patients who achieve complete or partial cytogenetic response subsequently experience recurrence or expansion of the del(5q) clone, and relapsing patients are at elevated risk of disease progression and leukemic transformation.

In light of the preceding observation that MDS-del(5q) is propagated by rare cancer stem cells, Tehranchi et al tested the hypothesis that these stem cells might be selectively resistant to lenalidomide treatment.^31,45 They identified a subset of mutant stem cells (phenotypically defined as CD34⁺, CD38^−/low, CD90⁺) that persisted under treatment and subsequently expanded at the time of relapse.

In a study of 55 patients with lower-risk MDS-del(5q), Jadersten et al detected somatic mutations of TP53 in approximately a fifth of cases.⁴⁶ These mutations were associated with poor response to lenalidomide, lower probability of complete cytogenetic response, and an increased risk of leukemic transformation. This initial observation has been corroborated by several subsequent reports.^47-52 Additional studies indicated that the presence of somatic mutations in CSNK1A1 or RUNX1 also predicted a worse prognosis for patients with MDS-del(5q) treated with lenalidomide.^26,53 

To elucidate the molecular pathogenesis of t-MNs, Sperling et al analyzed the association between genotype and previous exposure to chemotherapy and/or radiotherapy in a cohort of 416 patients with t-MNs.⁵⁴ Approximately two-thirds of the patients had a primary diagnosis of solid tumors, whereas the remaining third had nonmyeloid hematologic cancers. A somatic mutation in TP53 was identified in 37% of patients, and most cases exhibited a TP53 multihit state. A significant association was established between TP53-mutant t-MNs and previous exposure to lenalidomide. Using mouse models, the authors subsequently demonstrated that lenalidomide treatment provides a selective advantage to Trp53-mutant hematopoietic stem and progenitor cells in vitro and in vivo.⁵⁴ 

The observation that lenalidomide treatment confers a selective advantage to TP53-mutant hematopoietic cells is relevant to the potential risks posed by lenalidomide treatment of patients diagnosed with MDS-del(5q), because some of these patients may carry a TP53 mutation.^55,56 

Montoro et al retrospectively investigated the clinical implications of TP53 mutations and their allelic state in a large cohort of patients with MDS-del(5q).⁵⁷ They adopted the 2016 WHO definition of MDS-del(5q), which did not exclude patients with TP53 multihit state.⁵ Of the 682 patients examined, 129 (19%) carried a somatic mutation in TP53: 98 patients had monoallelic TP53 mutation and 31 had TP53 multihit state.⁵⁷ Most of these patients received lenalidomide treatment at some point during their disease. The presence of either TP53 multihit state or monoallelic mutation with a variant allele frequency (VAF) of >20% was associated with inferior survival and higher risk of leukemic transformation.⁵⁷ 

Over the past 15 years, the application of massively parallel DNA sequencing has elucidated the genetic basis of MDS, thereby enabling the development of innovative diagnostic and prognostic methods.⁵⁸ The International Working Group for the Prognosis of MDS (IWG-PM) has made significant contributions to this field.^55,56,59 We have now conducted computational analyses using the database that was created for the IWG-PM studies. The findings of these analyses definitively support a precision medicine approach to the management of patients with MDS-del(5q), as outlined hereafter.

The recent IWG-PM study was conducted to investigate whether genomic alterations allow for the delineation of specific MDS molecular subtypes (supplemental Methods).⁵⁶ Eighteen distinct groups of MDS were identified and 1 of them was the del(5q) group (supplemental Figure 2).^55,56 

Within the IWG-PM cohort, 388 patients with MDS carried a deletion 5q as a chromosomal abnormality. Supplemental Figure 3 reports an oncoplot describing the gene mutations in these patients, with TP53 mutations observed in 54% of cases. By using a Sankey diagram, we investigated how these patients were classified according to the last 3 classifications of MDS (WHO 2016, WHO 2022, and ICC 2022) and the recent molecular taxonomy.^5-7,56 As illustrated in supplemental Figure 4, most patients with MDS with a deletion 5q were ultimately included in the TP53 multihit/CK group or the del(5q) group of the molecular taxonomy. As illustrated in Figure 2, these 2 subsets were associated with significantly different clinical outcomes, consistent with substantially different disease biology.

Approximately one-fifth of patients in the del(5q) group of the molecular taxonomy had excess blasts (≥5% in the bone marrow). As shown in supplemental Figure 5, patients with excess blasts had worse clinical outcomes compared with those with a blast count of <5%. This observation supports excluding cases with excess blasts from the MDS-del(5q) category in the current ICC and WHO classifications.^6,7 However, the molecular taxonomy of MDS suggests a novel paradigm in which genetic subtypes represent the overarching basis of classification, whereas blast count designates a disease stage within specific molecular groups.⁵⁶ Table 2 illustrates this concept by distinguishing between the initial and advanced stages of MDS-del(5q). The initial stage is characterized by a blast count of <5%, whereas the advanced stage is characterized by a blast count ranging from 5% to 19%. Of note, the phase 2 clinical trial on the use of lenalidomide in MDS-del(5q) included patients with excess blasts, and most of them responded to treatment, which resulted in the normalization of their blast count.³⁴ 

As illustrated in supplemental Figure 6, 85% of patients with MDS belonging to the del(5q) group of the molecular taxonomy of MDS had at least 1 co-occurring somatic mutation, most commonly in DTA (DNMT3A, TET2, or ASXL1) genes, SF3B1, TP53 (monoallelic mutation), CSNK1A1, and RUNX1. Monoallelic TP53 mutations were significantly enriched in the del(5q) group, along with mutations in CSNK1A1, IRF1, and RAD50, the latter 3 genes being all located on 5q.⁵⁶ 

Of 195 patients classified in the del(5q) group of the molecular taxonomy of MDS, 29 did not have any other chromosomal aberrations or somatic gene mutations. Thus, they met the criteria for MDS with truly isolated del(5q), a condition in which del(5q) is the sole identified genetic lesion. Figure 3A shows that these patients had significantly better overall survival and lower risk of leukemic transformation than those with additional somatic genetic lesions. These differences in clinical outcomes persisted, although less notably, when the comparison was limited to patients with co-occurring DTA mutations, which are likely an expression of age-related clonal hematopoiesis (supplemental Figure 7).

As illustrated in Figure 3B, within the del(5q) group, patients carrying a concomitant mutation in SF3B1 exhibited significantly worse clinical outcomes than those lacking an SF3B1 mutation. The deleterious clinical consequences of this comutation have been previously reported in patients diagnosed with MDS-del(5q).⁶⁰ As SF3B1 mutations are the most frequent co-occurring mutations in MDS-del5q, identified in approximately one-fifth of patients (supplemental Figure 6), it is important to include this information as a molecular classifier within the diagnostic criteria (Table 2). A co-occurring mutation in RUNX1 was detected in only 6% of patients classified within the del(5q) molecular group but this concomitant genetic lesion was associated with very poor overall survival and very high risk of leukemic transformation (Figure 3C).

By contrast, there was no significant relationship between a monoallelic mutation in TP53, found in 17% of patients, and clinical outcomes (supplemental Figure 8). In the Mayo-Moffitt study, TP53 mutations occurred in ∼15% of patients with chronic phase disease and their prevalence increased significantly at the time of leukemic transformation.^50,51 In the recent study by Montoro et al, the overall survival of patients with MDS del(5q) patients with co-occurring monoallelic TP53 mutation (14% of the entire cohort) did not differ from that of patients without TP53 mutation.⁵⁷ Zampini et al performed longitudinal studies on patients with MDS who carried a TP53 mutation at diagnosis and then progressed to AML.⁶¹ Among 23 patients with the monoallelic mutation, 18 progressed to a multihit TP53 state before leukemic evolution.

Taken together, the above data indicate that comutation patterns may have different implications for clinical outcomes and treatment. Co-occurring mutations in SF3B1 or RUNX1 are associated with a more aggressive clinical course. In contrast, monoallelic TP53 mutations do not inherently affect clinical outcomes; however, they may evolve into TP53 multihit lesions under lenalidomide treatment, thereby leading to a t-MN.

As a group, patients diagnosed with MDS-del(5q) have superior overall survival when compared with the entire population of patients with MDS.⁵⁶ Nevertheless, considerable variability exists in clinical outcomes, which are influenced by several factors, including co-occurring genetic lesions. Thus, 5 decades after its initial identification, management of MDS-del(5q) now requires a precision medicine approach, as illustrated in Figures 4 and 5.

The diagnostic process is initiated when a patient presents with a cytopenia of unknown origin, typically a macrocytic anemia.⁶² The identification of megakaryocytes with hypolobulated nuclei is an important diagnostic criterion, whereas conventional chromosome banding cytogenetics is the standard procedure for detecting del(5q) (Figure 1A). However, in a minority of patients, the interstitial deletion remains undetectable using this approach. An ad hoc study revealed that fluorescence in situ hybridization (FISH) of 5q31 can detect the 5q deletion in patients in whom the cytogenetic study fails because of a lack of metaphases, or who display an aberrant karyotype with chromosome 5 involvement that is not clearly del(5q).⁶³ This indicates that FISH of 5q31-5q33 should be performed in patients with suggestive dysmegakaryopoiesis and apparently normal chromosome banding analysis, using a FISH probe for a gene mapping specifically to the MDS-del(5q) CDR, such as CSF1R or SPARC.^13,64 In addition, single-nucleotide polymorphism array–based karyotyping can reveal unbalanced defects with high resolution and can also identify segmental uniparental disomy.⁶⁵ Finally, next-generation sequencing–based methodologies can be effective tools for the detection and mapping of the 5q deletion.^32,66 

Genomic profiling is now essential for the precision prognosis of MDS-del(5q).⁶⁶ Targeted gene panels should encompass a minimum of the 31 genes necessary for the calculation of the molecular IPSS (IPSS-M), and include also CSNK1A1. Genomic profiling approaches should include probes for copy number detection to capture chromosomal abnormalities, especially loss of heterozygosity, which can derive from chromosomal deletion or copy-neutral loss of heterozygosity.⁶⁶ This is particularly important for detecting TP53 multihit state, because TP53 multihit lesions are associated with genomic instability and high-risk disease, and now exclude MDS-del(5q) whereas defining a specific subtype of MDS, that is, TP53-mutant MDS.^55,66,67 Interestingly, single-nucleotide polymorphism array–based copy number detection may allow the identification of small TP53 biallelic clones with a VAF of <1%.⁶⁸ 

Current classifications of hematologic neoplasms are based on a combination of clinical, morphologic, and genomic data.⁶⁹ MDS-del(5q) is defined by cytopenia, presence of del(5q) alone or with 1 additional abnormality except monosomy 7 or del(7q), and absence of TP53 multihit lesions or excess blasts (Table 1). However, studies of genomic profiling have indicated that most patients carry additional genetic lesions that can variably affect clinical outcomes. So, we propose using blast count as a disease stage indicator and concomitant genetic lesions as molecular qualifiers to the MDS-del(5q) entity, as illustrated in Table 2 and Figure 4.

For patients belonging to the del(5q) group of the molecular taxonomy of MDS, the IPSS-M provides valuable risk stratification as illustrated in the supplemental Figure 9. All patients with higher-risk MDS-del(5q), as defined by an IPSS-M score of >0, may be considered for allogeneic transplantation. To determine their eligibility, additional factors must be considered, including patient-related risk factors, donor availability, and the patient's values and wishes.⁷⁰ 

The adoption of a patient-centered care model that leverages precision medicine criteria constitutes the optimal approach for the treatment of patients with MDS-del(5q).⁸ Therapeutic options include active surveillance, a medical treatment, and allogeneic transplantation; currently available medical treatments are summarized in Table 3. This table illustrates the complexity inherent to the approval processes by different regulatory agencies, namely, the US Food and Drug Administration and the European Medicines Agency, over time.^71-73 

Therapeutic decision-making should be based on the IPSS-M risk, as illustrated in Figure 5. Patients with lower-risk MDS-del(5q) are initially appropriate candidates for follow-up care or medical treatments. In contrast, those with higher-risk MDS-del(5q) should be considered for allogeneic transplantation.

Active surveillance with deferred treatment is the optimal approach for older adult patients with lower-risk MDS-del(5q) who do not require regular red blood cell transfusions. Erythropoiesis stimulating agents may be used in patients with anemia with serum erythropoietin levels below 200 mU/mL.⁸ At present, no evidence-based recommendations can be made regarding the use of luspatercept, as registration trials specifically excluded patients with MDS-del(5q) (Table 3).

The use of lenalidomide should be limited to patients with symptomatic anemia who require regular red blood cell transfusions, (Table 3). Before deciding on using this treatment, information on TP53 mutation status is needed. A co-occurring monoallelic TP53 mutation with high VAF (ie, >20%) involves a higher risk of leukemic transformation under lenalidomide treatment, possibly because these patients may already carry small TP53 biallelic clones.^57,68 This risk must be discussed carefully with the patient in a process that takes full account of his/her values and wishes. If lenalidomide treatment is initiated, genomic profiling should be used to closely monitor the TP53-mutant clone.⁴⁹ 

For patients with higher-risk MDS-del(5q), allogeneic hematopoietic cell transplantation is currently the sole treatment that has the potential to cure the disease by eradicating del(5q)-mutant hematopoietic cells and establishing normal donor hematopoiesis.^70,74,75 Figure 6 and supplemental Table 2 illustrate the clinical outcomes of patients with MDS-del(5q) reported to the European Society for Blood and Marrow Transplantation registry between 2016 and 2020. The estimated overall survival rate is ∼50% at 4 years. For patients with higher-risk MDS-del(5q) who are not eligible for transplantation, treatment with a hypomethylating agent should be considered.⁷⁶ 

In younger patients with MDS-del(5q), the patient's eligibility for allogeneic stem cell transplantation should be assessed at the time of diagnosis following the recommendations of the European Society for Blood and Marrow Transplantation.⁷⁰ It is essential to consider disease-related and patient-related risk factors, donor availability, and the patient's choice based on personal goals. Once eligibility for transplantation has been established, the long-term therapeutic program can be defined. Supplemental Figure 10 illustrates a patient’s journey through MDS-del(5q), ending with a successful allogeneic transplantation from an unrelated donor.

Fifty years after the seminal paper by Van den Berghe et al based on chromosome banding analysis, molecular profiling in combination with conventional cytogenetics is now required for a precision medicine approach to MDS-del(5q).

Assessment of the TP53 allelic state is essential for distinguishing between MDS-del(5q) and TP53-mutant MDS, an aggressive myeloid malignancy characterized by TP53 multihit state. The IPSS-M risk assessment stratifies patients into lower-risk and higher-risk categories, enabling precise decisions regarding their eligibility for allogeneic transplantation and the optimal timing of this procedure. Clinical trials in patients with MDS-del(5q) should now incorporate genomic profiling into the trial design to elucidate the effects of investigational therapies on the clonal architecture of MDS-del(5q).⁶⁷ Specifically, genomic profiling can document the suppression of mutant clones with the restoration of normal hematopoiesis, as well as the emergence or expansion of abnormal clones under selective pressure.

In conclusion, this work illustrates how integrating morphologic, clinical, and genomic data of well-characterized patient populations can lead to the identification of distinct entities associated with different clinical outcomes that warrant specific treatments.⁶⁹ This is the next logical step in the process that Van den Berghe et al started by linking macrocytic anemia to the unusual morphology of megakaryocytes and a chromosomal abnormality in a study of 3 patients.¹ 

This special report is the result of a collaborative effort among investigators from the International Working Group for the Prognosis of MDS (IWG-PM), the European Society for Blood and Marrow Transplantation (EBMT), and MYNERVA (Myeloid Neoplasms Research Venture Associazione Italiana per la Ricerca sul Cancro [AIRC]. The IWG-PM consists of a group of international investigators whose focus is aimed at defining the clinical and biologic features of MDS. The Chronic Malignancies Working Party of the EBMT promotes clinical investigations on the role of hematopoietic cell transplantation in chronic malignancies. MYNERVA is a consortium of Italian investigators who, thanks to the financial support of the AIRC (Milan, Italy), have teamed up for a research initiative focused on myeloid neoplasms.

We dedicate this work to the memory of Herman Van den Berghe. After the description of a minute chromosome 22 in chronic myeloid leukemia by Nowell and Hungerford,⁷⁷ the short letter by Van den Berghe et al¹ represents the second cornerstone indicating that myeloid malignancies arise from somatic mutations of the genome.

Contribution: M.R., L. Malcovati, and M.C. conceptualized this special report, thoroughly reviewed the extant literature, performed statistical analyses of data available in the International Working Group for the Prognosis of MDS database, and drafted the manuscript; and all authors contributed to the design of the work and the interpretation of the data, reviewed the manuscript critically for intellectual content, and approved the final version to be published.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Mario Cazzola, Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Viale Golgi 19, 27100 Pavia, Italy; email: mario.cazzola@unipv.it.