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Myelodysplastic syndromes (MDS) are hematological malignancies classically defined by the presence of cytopenia(s) and dysmorphic myeloid cells. It is now known that MDS can be preceded by a pre-malignant condition called clonal cytopenia of unknown significance (CCUS), which associates a clonality marker with cytopenia in the absence of criteria of dysplasia. However, to date, it is not clear whether chromosomal abnormalities should be considered in the definition of CCUS or if they carry a prognostic impact in CCUS patients. In this study, we analyzed the clinico-biological features and outcomes of 34 patients who presented with one or more cytopenias, an absence of significant dysplasia, and a presence of a chromosomal abnormality (CA). We named this entity chromosomal abnormality with cytopenia of undetermined significance (CACtUS). We show that these patients are slightly older than MDS patients and that they more frequently presented with normocytic anemia. Most CACtUS patients exhibited only one unbalanced CA. The number and type of mutations were comparable between CACtUS patients and MDS patients. Regardless of the cytogenetic abnormality, the clinicobiological characteristics, overall survival, and risk of progression to high-risk (HR) MDS were similar between CACtUS patients and low-risk MDS patients. Thus, we suggest that CACtUS patients can be considered as HR-CCUS and should receive the follow-up regimen recommended for MDS patients., (© 2022 Wiley Periodicals LLC.)

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic, and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count, and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A, and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as Tumor Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid-to-myeloid ratio in bone marrow, although not altering their multilineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM, and CBL and mutations of ASXL1, SF3B1, and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Isolated trisomy 8 (+8) is a frequent cytogenetic abnormality in the myelodysplastic syndromes (MDS), but its characteristics are poorly reported. We performed a retrospective study of 138 MDS patients with isolated +8, classified or reclassified as MDS (excluding MDS/myeloproliferative neoplasm). Myeloproliferative (MP) features were defined by the repeated presence of one of the following: white blood cell count >10 × 10 9 /l, myelemia (presence of circulating immature granulocytes with a predominance of more mature forms) >2%, palpable splenomegaly. Fifty-four patients (39·1%) had MP features: 28 at diagnosis, 26 were acquired during evolution. MP forms had more EZH2 (33·3% vs. 12·0% in non-MP, P = 0·047), ASXL1 (66·7% vs. 42·3%, P = 0·048) and STAG2 mutations (77·8% vs. 21·7%, P = 0·006). Median event-free survival (EFS) and overall survival (OS) were 25 and 27 months for patients with MP features at diagnosis, versus 28 (P = 0·15) and 39 months (P = 0·085) for those without MP features, respectively. Among the 57 patients who received hypomethylating agent (HMA), OS was lower in MP cases (13 months vs. 23 months in non-MP cases, P = 0.02). In conclusion, MP features are frequent in MDS with isolated +8. MP forms had more EZH2, ASXL1 and STAG2 mutations, responded poorly to HMA, and tended to have poorer survival than non-MP forms., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

Karyotype according to the revised IPSS is a strong independent prognostic factor for overall survival (OS) in myelodysplastic syndromes (MDS), however established in untreated patients. The prognostic impact of cytogenetics and cytogenetic response (CyR) in MDS patients receiving azacitidine (AZA) remains uncertain. We examined the prognostic value of baseline cytogenetics and CyR for overall response rate (ORR) and OS in 702 AZA-treated higher risk MDS and low blast count acute myeloid leukemia (AML), including 493 (70%) with abnormal karyotype. None of the cytogenetic abnormalities had significant impact on ORR (43.9%) or complete response (15.35%), except 3q abnormalities and complex karyotypes, which were associated with a lower ORR. OS differed significantly across all R-IPSS cytogenetic subgroups (p<10 -4 ) but patients with non complex del(7q) had similar survival as patients with normal cytogenetics. CyR was achieved in 32% of the 281 evaluable patients with abnormal cytogenetics, was complete (CCyR) in 71 (25.3%) patients. We found no correlation between hematological response and cytogenetic response and 21% of the patients with CCyR did not achieve morphological response. In the 281 patients, we found no impact of CyR on survival, but when restricting to MDS (ie: <20% marrow blasts) achievement of CCyR was associated with better OS., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The myelodysplastic syndromes (MDS) are preleukemic diseases of elderly patients characterized by defective maturation of clonal hematopoietic progenitor cells resulting in peripheral blood cytopenias. Clonal chromosomal abnormalities are heterogeneous and can be detected in less than 50% of patients with de novo MDS and more frequently in secondary MDS (up to 80%). The karyotype plays an important role in the pathogenesis, diagnosis, and prognosis to evaluate the risk of leukemic transformation and, more recently, in treatment allocation. The gold standard for cytogenetic diagnosis in MDS is conventional chromosome banding analyses of bone marrow metaphases. The most frequent abnormalities are deletions and losses of chromosomes 5 (-5/5q-) and 7 (-7/7q-) and various isolated or combined abnormalities. Fluorescent in situ hybridization and array comparative genomic hybridization can reveal cryptic genetic abnormalities but are not recommended in routine diagnosis. New techniques including next generation sequencing revealed somatic driver mutations especially those affecting genes involved in RNA splicing or those harboring important prognostic value (TP53, ASXL1…) with potential applications in clinical practice in the future.

Acquired α-thalassemia myelodysplastic syndrome (MDS) (ATMDS) is an acquired syndrome characterized by a somatic point mutation or splicing defect in the ATRX gene in patients with myeloid disorders, primarily MDS. In a large MDS patient series, the incidence of ATMDS was below 0.5%. But no large series has yet assessed the incidence of ATMDS in microcytic MDS. In this study, we focused on patients with MDS and unexplained microcytosis, which was defined as absence of iron deficiency, inflammatory disease, or history of inherited hemoglobinopathy. Our data confirm the low frequency of ATRX mutations in MDS: 0% in an unselected clinical trial cohort of 80 low risk MDS, 0.2-0.8% in a multicenter registry of 2,980 MDS and 43% of MDS with unexplained microcytosis in this same registry. In addition, we reported four novel mutations of the ATRX gene in ATMDS. This study further determines the frequency of ATRX mutations and highlights the importance of microcytosis to detect ATRX mutations within MDS patients., (© 2015 Wiley Periodicals, Inc.)

TP53 mutations are found in 5-10% of MDS and AML, where they are generally associated with complex karyotype and an overall poor prognosis. However, the impact of TP53 mutations in MDS treated with azacitidine (AZA) remains unclear. We analyzed TP53 mutations in 62 patients with high risk MDS or AML treated with AZA. A TP53 mutation was found in 23 patients (37.1%), associated with complex karyotype in 18 (78.3%) of them. TP53 mutations had no significant impact on response or complete response to AZA (p=0.60 and p=0.26, respectively). By univariate analysis, OS was negatively influenced by the presence of TP53 mutation (median OS 12.4 months versus 23.7 months, p<10(-4)), abnormal cytogenetics (median OS 14.4 months vs 33 months, p=0.02) complex cytogenetics (median OS 12.7 months versus 23.7 months, p=0.0005), and a diagnosis of AML (median 14.5 months vs 21.2 months for MDS or CMML, p=0.02). By multivariate analysis, only TP53 mutational status (HR 2.89 (95% confidence interval 1.38-6.04; p=0.005) retained statistical significance for OS. Results were similar when the analysis was restricted to MDS and CMML patients, excluding AML (HR=2.46 (95% confidence interval: 1.1-6.4); p=0.04)). Thus, TP53 mutations strongly correlated with poorer survival in higher risk MDS and AML treated with AZA., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

TP53 mutations are frequent in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with complex karyotype that include del(5q) and are often associated with deletion of 17p. They have also recently been observed in MDS with isolated del(5q). We assessed the incidence of 17p deletion detected by fluorescence in situ hybridization (FISH) and of TP53 mutations detected by direct sequencing and their correlation and prognostic value in 26 MDS and 17 AML with del(5q). In the 20 cases with isolated del(5q) or one additional abnormality, no 17p deletion was found and 3 of the 18 cases analyzed (17%) had TP53 mutation. In the 23 patients with complex karyotype, 17p deletion was suspected by conventional cytogenetics in 15 cases and confirmed by FISH in 10 of them, while TP53 mutation was found in 8 of the 15 patients tested (53%), only five of whom had 17p deletion. In the whole patient series, TP53 mutations were associated with shorter survival (P = 0.07). We confirm the existence of TP53 mutations in 17% of MDS with isolated del(5q). In patients with del(5q) and complex karyotype, FISH and direct sequencing are complementary techniques to analyze TP53 abnormalities. Our findings also suggest that sequencing of the TP53 gene should be included in the study of patients with del(5q) as a single abnormality or in complex karyotype before lenalidomide treatment., (Copyright © 2012 Wiley Periodicals, Inc.)

In patients with myelodysplastic syndromes (MDS), chromosome anomalies are detected by conventional cytogenetic studies (CCS) and/or interphase fluorescence in situ hybridization (FISH) of bone marrow (BM) samples and provide prognostic and diagnostic information, which can direct therapy. Whether peripheral blood (PB) can be substituted for bone marrow in these cases and can provide the same information remains unknown. Concurrent BM and PB specimens collected from 100 patients with recently diagnosed MDS were studied using both CCS and FISH. While 68% of BM samples showed an abnormal karyotype by CCS, only 31% of PB samples were abnormal by CCS. In 12% of patients, FISH and CCS were discordant due to the inability of the FISH panel to detect all possible abnormalities. However, only one case (1%) had a cryptic abnormality detected by FISH. BM and PB FISH were discordant in 3% of cases, most likely due to the smaller clone size in PB vs. BM. While PB should not be substituted for BM at diagnosis, it is a viable alternative for monitoring patients using the appropriate FISH probe(s)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Although lenalidomide is very effective in the treatment of anemia of lower risk myelodysplastic syndromes with 5q deletion (del 5q), concerns have been raised over the fact that this drug could trigger progression to acute myeloid leukemia in some patients., Design and Methods: Ninety-five transfusion-dependent patients with lower risk myelodysplastic syndromes with del 5q were treated with lenalidomide (10 mg/day, for 3 weeks every 4 weeks); six (6.3%) of the patients progressed to acute myeloid leukemia. This cohort of 95 lenalidomide-treated patients was compared to a historical control cohort of 99 patients with lower risk myelodysplastic syndromes with del 5q who never received lenalidomide, using a propensity score approach that can control for potential confounders in non-randomized comparisons., Results: The 4-year estimated cumulative incidence of leukemia was 9% in patients treated with lenalidomide and 15.8% in controls who did not receive lenalidomide (P=0.16)., Conclusions: Using a propensity score approach, we found no significant difference in acute myeloid leukemia progression and survival from diagnosis between the cohort treated with lenalidomide and the control cohort.

We treated 95 RBC transfusion dependent lower risk MDS with del 5q with Lenalidomide (10mg/day, 3 weeks/4 weeks). Median age was 70.4, median interval from diagnosis 29 months. IPSS was low in 31% and intermediate-1 in 69% patients. Del 5q was isolated, with 1 additional and >1 additional abnormality in 79%, 14%, and 6% patients, respectively. 62 (65%) patients achieved transfusion independence (TI). The only significant factor predicting TI was baseline platelet count >150 G/L and platelet decrease by at least 50% during the first weeks of treatment (p=0.001). Grade III-IV neutropenia and thrombocytopenia were seen in 74% and 37.9% of the cases, respectively, and 3 deaths were attributed to cytopenias. Eight (8%) patients developed deep venous thrombosis (DVT). Platelet decrease by less than 50% predicted a higher risk of DVT. Only 6 patients (6.3%) patients progressed to AML, but median follow-up time was short (18 months). We confirm the high rate of TI with Lenalidomide in lower risk MDS with del 5q. Very close patient monitoring for cytopenias and DVT is mandatory, especially during the first weeks of treatment., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Isolated 20q deletion is common in MDS and considered of good prognosis, but no large series have been reported. We compared characteristics of 62 MDS patients with isolated del 20q, 36 patients with del 20q and other cytogenetic abnormalities, and 1335 MDS patients without del20q. Significant differences between MDS with isolated del 20q and patients without del 20q were lower platelet count (mean 144 vs. 196 G/l, p=0.005), lower marrow blast count (mean 3.9% vs. 5.6%, p=0.0008), and higher reticulocyte count (mean 72.5 vs. 51.7 G/l, p=0.04). Ten (16%) patients with isolated del 20q had Hb>12 g/dl and platelets <100 G/l, compared to 7.3% of patients without del 20q (p=0.025). Review of marrow slides of those 10 patients showed that could be readily identified as MDS prior to cytogenetics. Fourteen percent of patients with isolated del 20q progressed to AML compared to 11% with one and 24% with several additional abnormalities. Median survival was 54 months in patients with isolated del 20q, not reached and 12 months for del 20q with one and several additional abnormalities, respectively (p=0.035) confirming the favorable prognosis of del 20q without complex abnormalities., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Transformation of Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs) to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) is associated with poor response to chemotherapy and short survival. Fifty-four patients with Ph-negative MPN (including 21 essential thrombocythemia [ET], 21 polycythemia vera [PV], 7 primary myelofibrosis, and 5 unclassified MPN) who had progressed to AML (n = 26) or MDS (n = 28) were treated with azacitidine in a patient-named program. Overall response rate was 52% (24% complete response [CR], 11% partial response [PR], 8% marrow CR or CR with incomplete recovery of cytopenias, 9% hematologic improvement) and median response duration was 9 months. Prognostic factors were for overall response the underlying MPN (71% vs 33% responses in ET and PV, respectively; P = .016); prognostic factors for CR achievement were the underlying MPN (14% CR for PV vs 43% for ET; P = .040) and World Health Organization classification at transformation (36% vs 12% CR in MDS and AML, respectively, P = .038). Recurrence of chronic phase features of the initial MPN was observed in 39% of the responders. Median overall survival was 11 months. Azacitidine gives encouraging results in Ph-negative MPN having progressed to AML or MDS, but response duration is short, and consolidation treatments have to be evaluated.

Background: We previously reported that the function and proliferation of natural killer cells in myelodysplastic syndromes are defective. T-cell receptor gammadelta T cells are other important components of innate immunity that have been recently implicated in the immune response against hematologic malignancies., Design and Methods: We evaluated the phenotype, function, and in vitro expansion of myelodysplastic syndrome patient-derived gammadelta T cells in response to interleukin-2 and bromohalohydrin pyrophosphate, a synthetic phosphoantigen with a potent T-cell receptor gammadelta agonist effect that specifically activates and amplifies this T-cell population., Results: Vgamma9Vdelta2 T cells, the major circulating gammadelta T-cell subset, were reduced in myelodysplastic syndromes, but mainly in myelodysplastic syndromes' patients with associated autoimmune diseases, suggesting that this anomaly was largely due to the autoimmune component. On the other hand, bromohalohydrin pyrophosphate-induced expansion of the Vgamma9Vdelta2 T-cell population in all 15 control samples, but in only 26 of 43 (60%) myelodysplastic syndromes patients. The response to bromohalohydrin pyrophosphate was independent of World Health Organization subtype, cytogenetic findings and International Prognostic Scoring System score. In responding myelodysplastic syndromes patients, expanded Vgamma 9Vdelta2 T cells exhibited normal cytolytic and secretory activity against leukemic and myelodysplastic syndromes cell lines; fluorescence in situ hybridization analysis indicated that these Vgamma 9Vdelta2 T cells were not derived from the myelodysplastic syndromes clone. However, these Vgamma 9Vdelta2 T cells from the MDS patients had limited proliferative capacity in response to interleukin-2 despite having normal expression of interleukin-2 receptor chains (alpha beta gamma )., Conclusions: These results, combined with our previous findings concerning natural killer cells, suggest that there are immune surveillance defects in myelodysplastic syndromes, which may contribute to the pathogenesis of these syndromes.

Defined by isolated del 5q and no excess of marrow blasts, the '5q- syndrome' is a specific type of myelodysplastic syndrome (MDS) with particular characteristics, including severe anaemia, frequent thrombocytosis, typical dysmegakaryopoiesis and favourable outcome. Its pathogenesis remains uncertain, particularly regarding the role of the inactivation of gene(s) situated in 5q. Until the advent of lenalidomide, repeated red blood cell (RBC) transfusions were generally the only treatment for 5q- syndrome, which was resistant to other therapeutic approaches. Lenalidomide can lead to RBC transfusion independence in at least two-thirds of cases of 5q- syndrome, and about one half of those responses are maintained after 2 years of treatment. Importantly, frequent complete pathological and cytogenetic responses are also obtained. Grade 3 or 4 neutropenia and thrombocytopenia, especially during the first 6-8 weeks of treatment, are the major side effects of lenalidomide, justifying close clinical and blood counts monitoring. Preliminary results suggest that lenalidomide is also active in MDS with del 5q other than the 5q- syndrome. The mechanisms of action of lenalidomide, although uncertain, appear to include targeting of the del 5q clone. Therefore, lenalidomide may have an effect on disease course and survival, which is currently being assessed in clinical trials.