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This article explores the occurrence of treatment-emergent mutations in patients with myelodysplastic syndrome (MDS) with del(5q) who are being treated with lenalidomide. The study analyzes the genetic changes in 10 patients with MDS-del(5q) before and after lenalidomide therapy. The results reveal the emergence of TP53 mutations, as well as other mutations, during treatment. These findings contribute to our understanding of the genetic changes that occur during lenalidomide treatment in MDS-del(5q) patients and highlight the importance of monitoring mutations in these patients. The study also suggests the need for alternative therapies in cases where TP53 mutations are present. [Extracted from the article]

A20‐binding inhibitor of NF‐κB activation (ABIN1) is a polyubiquitin‐binding protein that regulates cell death and immune responses. Although Abin1 is located on chromosome 5q in the region commonly deleted in patients with 5q minus syndrome, the most distinct of the myelodysplastic syndromes (MDSs), the precise role of ABIN1 in MDSs remains unknown. In this study, mice with a mutation disrupting the polyubiquitin‐binding site (Abin1Q478H/Q478H) is generated. These mice develop MDS‐like diseases characterized by anemia, thrombocytopenia, and megakaryocyte dysplasia. Extramedullary hematopoiesis and bone marrow failure are also observed in Abin1Q478H/Q478H mice. Although Abin1Q478H/Q478H cells are sensitive to RIPK1 kinase–RIPK3–MLKL‐dependent necroptosis, only anemia and splenomegaly are alleviated by RIPK3 deficiency but not by MLKL deficiency or the RIPK1 kinase‐dead mutation. This indicates that the necroptosis‐independent function of RIPK3 is critical for anemia development in Abin1Q478H/Q478H mice. Notably, Abin1Q478H/Q478H mice exhibit higher levels of type I interferon (IFN‐I) expression in bone marrow cells compared towild‐type mice. Consistently, blocking type I IFN signaling through the co‐deletion of Ifnar1 greatly ameliorated anemia, thrombocytopenia, and splenomegaly in Abin1Q478H/Q478H mice. Together, these results demonstrates that ABIN1(Q478) prevents the development of hematopoietic deficiencies by regulating type I IFN expression. [ABSTRACT FROM AUTHOR]

Background: Myelodysplastic syndromes (MDS) are a group of clonal haematopoietic stem cell disorders characterised by ineffective haematopoiesis and cytopenia. Studies have reported differences in MDS between Asian and Western countries, but data from Taiwan are scarce. Materials and Methods: In this study we analysed the clinical and pathological features of 32 Taiwanese MDS patients with del(5q) (ie, del(5q) alone [Group A, n = 11], del(5q) with one additional cytogenetic abnormality other than monosomy 7 or del(7q) [Group B, del(5q)+1; n = 6], and del(5q) with =2 additional cytogenetic abnormalities [Group C, n = 15]). Results: Progression-free survival (PFS) and overall survival (OS) were more favourable for Group A than for Groups B (p < 0.05) and C (p ≤ 0.001). Multivariate analysis showed that age >70 years, thrombocytopenia, and karyotype other than del(5q) alone were poor prognostic factors. Among the patients that had World Health Organization (WHO)-defined MDS with isolated del(5q), one patient (9%) had a typical marrow morphology of 5q minus syndrome with erythroid hypoplasia and four patients (36%) had hypolobated megakaryocytes. In addition, PFS and OS were significantly more favorable for the patients with del(5q) alone than for those with del(5q)+1 (p < 0.05). Conclusion: The bone marrow morphology, clinical features, and prognosis of Taiwanese MDS patients with del(5q) were different from those associated with MDS with isolated del(5q) as defined in the current WHO classification. Researchers should compare different geographic regions and racial populations to determine whether geographic and racial differences exist with respect to MDS with del(5q.). [ABSTRACT FROM AUTHOR]

The 5q deletion syndrome is a relatively rare condition caused by the monoallelic interstitial deletion of the long arm of chromosome 5. Patients described in literature usually present variable dysmorphic features, behavioral disturbance, and intellectual disability (ID); moreover, the involvement of the APC gene (5q22.2) in the deletion predisposes them to tumoral syndromes (Familial Adenomatous Polyposis and Gardner syndrome). Although the development of gastrointestinal tract malignancies has been extensively described, the genetic causes underlying neurologic manifestations have never been investigated. In this study, we described a new patient with a 19.85 Mb interstitial deletion identified by array-CGH and compared the deletions and the phenotypes reported in other patients already described in the literature and the Decipher database. Overlapping deletions allowed us to highlight a common region in 5q22.1q23.1, identifying KCNN2 (5q22.3) as the most likely candidate gene contributing to the neurologic phenotype. [ABSTRACT FROM AUTHOR]

Summary: Evolution of erythrocyte transfusion‐dependent (RBC‐TD) anaemia associated with haploinsufficiency of the ribosomal protein subunit S14 gene (RPS14) is a characteristic complication of myelodysplastic syndromes (MDS) with del(5q) [MDS.del(5q)]. Evaluating 39 patients with MDS.del(5q), <5% of anaemia progression was attributable to RPS14‐dependent alterations of normoblasts, pro‐erythroblasts, or CD34+CD71+ precursors. Ninety‐three percent of anaemia progression and 70% of the absolute decline in peripheral blood Hb value were attributable to disappearance of erythroblastic islands (Ery‐Is). Ery‐Is loss occurred independently of blast excess, TP53 mutation, additional chromosome aberrations and RPS14‐dependent alterations of normoblasts and pro‐erythroblasts. It was associated with RPS14‐dependent intrinsic (S100A8+) and extrinsic [tumour necrosis factor α (TNF‐α)‐overproduction] alterations of (CD169+) marrow macrophages (p < 0.00005). In a mouse model of RPS14 haploinsufficiency, Ery‐Is disappeared to a similar degree: approximately 70% of Ery‐Is loss was related to RPS14‐dependent S100A8 overexpression of marrow macrophages, less than 20% to that of CD71highTer119− immature precursors, and less than 5% to S100A8/p53 overexpression of normoblasts or pro‐erythroblasts. Marked Ery‐Is loss predicted reduced efficacy (erythrocyte transfusion independence) of lenalidomide therapy (p = 0.0006). Thus, erythroid hypoplasia, a characteristic complication of MDS.del(5q), seems to result primarily from a macrophage‐associated failure of the erythropoietic niche markedly reducing the productive capacity of erythropoiesis as the leading factor in anaemia progression and evolution of RBC‐TD in MDS.del(5q). [ABSTRACT FROM AUTHOR]

Résumé: Les analogues de la thalidomide agissent par un mécanisme d'action original en induisant un rapprochement entre l'E3 ubiquitine ligase CRL4-CRBN et des protéines intracellulaires spécifiques, entraînant l'ubiquitination puis la dégradation protéasomale de ces protéines cibles. La destruction sélective de certaines protéines nécessaires à la survie des cellules tumorales se traduit par un effet cytotoxique direct, auquel s'ajoute un effet immunomodulateur indirect. Depuis les années 2000, les analogues de la thalidomide constituent la pierre angulaire du traitement du myélome multiple et des syndromes myélodysplasiques avec délétion 5q, et sont de plus en plus utilisés dans les lymphomes B. Le profil de toxicité est variable selon la molécule, la pathologie et les traitements associés, avec, au premier plan, la survenue de cytopénies, de thromboses veineuses et d'éruptions cutanées. Le développement de nouveaux analogues de la thalidomide, dont certains sont en essai clinique, devrait permettre d'étendre encore davantage les indications de cette classe thérapeutique. Thalidomide analogues exert their therapeutic effect through a novel and unexpected mechanism of action by inducing proximity between the CRL4-CRBN E3 ubiquitin ligase and specific intracellular proteins, leading to ubiquitination and subsequent proteasomal degradation of these substrate proteins. The selective destruction of target proteins that are essential for tumor cell survival results in a direct cytotoxic effect, which is accompanied by an indirect immunomodulatory effect. Over the last 20 years, thalidomide analogues have become a cornerstone for the treatment of multiple myeloma and myelodysplastic syndromes with 5q deletion. These drugs are also increasingly used for the treatment of B-cell lymphoma. Their toxicity profile mainly consists of cytopenia, venous thrombosis, and skin rashes, but depends on the molecule, the disease context, and concomitant treatments. The development of new thalidomide analogues, of which some are tested in clinical trials, should further extend the indications of this therapeutic drug class. [ABSTRACT FROM AUTHOR]

Keywords: hydrogel scaffold; MDS-L; MDS-L-2007; MDS-LGF; myelodysplastic syndromes (MDS); NSG mice; NSGS mice; xenograft mouse model EN hydrogel scaffold MDS-L MDS-L-2007 MDS-LGF myelodysplastic syndromes (MDS) NSG mice NSGS mice xenograft mouse model 415 419 5 04/19/21 20210415 NES 210415 Myelodysplastic syndrome (MDS) represents a group of heterogeneous haematopoietic disorders characterised by diverse clinical symptoms varying from mild anaemia to multilineage cytopenia.1,2 Importantly, one-third of MDS patients will exhibit a transformation towards acute myeloid leukaemia,3,4 increasing the complexity of the disease aetiology. Our study provides an in-depth characterisation of both the MDS-L-2007 and MDS-LGF subclones and reports the development of a novel indolent high-risk MDS phenotype model using the MDS-LGF cells. Overall, our observations underline that the two MDS cell lines (MDS-LGF and MDS-L-2007) present with quite drastic differences in major key phenotypes characterising MDS (i.e. del5q and TET2 mutation). MDS-L, MDS-L-2007, MDS-LGF, myelodysplastic syndromes (MDS), hydrogel scaffold, NSGS mice, NSG mice, xenograft mouse model. [Extracted from the article]

Azacytidine (AZA) remains the mainstay of therapy for patients with high-risk Myelodysplastic syndrome (HR-MDS). Nevertheless, methylation studies were not able to link the AZA-mediated DNA hypomethylation with the response and/or the outcome of HR-MDS patients [[2]], whereas resistance to AZA appears to be multifactorial, engaging diverse processes that involve pharmacological [[3]] and molecular [[4]] pathways. AZA treatment failed in patient#1 when he was at LR-MDS stage, but, in contrast to the reported outcomes, his MDS progressed after 50 months and he survived for more than 7 years after AZA failure. In contrast to the above, the gradual hematologic recovery and normalization of blood counts of patient#2 five months after stopping AZA clearly suggest a chiefly chemotherapeutic rather than an epigenetic effect of AZA since the latter requires continuous AZA administration. [Extracted from the article]

CRBN is a substrate receptor for a ubiquitin ligase, so at that stage we thought that lenalidomide was probably an inhibitor of the ubiquitin ligase, as most drugs act as inhibitors. The Journal of Clinical Investigation NEWS 1 Benjamin Ebert wins the 2021 ASCI/Stanley J. Korsmeyer Award Benjamin L. Ebert has been honored by the American Society for Clinical Investigation (ASCI) with the Stanley J. Korsmeyer Award, an annual prize in recognition of outstanding scientific contributions and excellence in mentorship (Figure 1). Instead, CR8 is a molecular glue between a core component of the ubiquitin ligase, the DDB1 adaptor protein, and CDK12, which is not normally part of a ubiquitin ligase. [Extracted from the article]

Background: Hemophilia B is an X‐linked recessive disorder caused by mutations in the F9 on Xq27.1. Mainly males are affected but about 20% of female carriers have clotting factor IX activity below 0.40 IU/ml and bleeding problems. Fragile‐X syndrome (FMR1) and FRAXE syndrome (AFF2) are well‐known causes of X‐linked recessive intellectual disability. Simultaneous deletion of both FMR1 and AFF2 in males results in severe intellectual disability. In females the phenotype is more variable. We report a 19‐year‐old female with severe intellectual disability and a long‐standing bleeding history. Methods: A SNP array analysis (Illumina Human Cyto 12‐SNP genotyping array) and sequencing of F9 were performed. Laboratory tests were performed to evaluate the bleeding diathesis. Results: Our patient was diagnosed with mild hemophilia B after finding an 11 Mb deletion of Xq26.3q28 that included the following genes among others IDS,SOX3,FMR1,AFF2, and F9. Conclusion: The case history demonstrates that a severe bleeding tendency suggestive of a hemostasis defect in patients with intellectual disability warrants careful hematological and genetic work‐up even in the absence of a positive family history. This case history demonstrates that a severe bleeding tendency suggestive of a hemostasis defect in patients with intellectual disability warrants careful hematological and genetic work‐up even in the absence of a positive family history. [ABSTRACT FROM AUTHOR]

Objective: The most typical cytogenetic aberration in myelodysplastic syndromes is del(5q), which, when isolated, is associated with refractory anaemia and good prognosis. Based on high rates of erythroid response and transfusion independence, Lenalidomide (LEN) became the standard treatment. This multi- centre study was designed to supplement Italian Registry data on LEN by addressing prescription, administration appropriateness, haematological and cytogenetic responses and disease evolution. Methods: MORE study was an observational, non- interventional, multi- centre, retrospective and prospective study. Cases were recruited from 45 Haematological Centres throughout Italy. Data were collected from the Italian National Registry for Lenalidomide administration and supplemented by a MORE data form. Results: Data from 190/213 patients were analysed. In all, 149 had been diagnosed by conventional cytogenetics (GROUP A) and 41 only by FISH (GROUP B). Overall erythroid response was obtained in 92.8% of cases. Overall cytogenetic remission was achieved in 22.6% of cases. Disease progression occurred in 15.6% of cases. Clonal cytogenetic evolution characterised progression to AML but not to higher risk MDS. Conclusions: Erythroid response to Lenalidomide was similar in MDS with isolated del(5q) and with del(5q) plus one anomaly. Progression to AML or higher risk MDS showed different cytogenetic features. [ABSTRACT FROM AUTHOR]

Myelosysplastic syndromes (MDS) include a heterogeneous group of clonal myeloid neoplasms characterized by ineffective hematopoiesis leading to blood cytopenias and a variable risk of progression into acute myeloid leukemia (AML). Although the hypomethylating agent azacitidine prolongs survival among patients with higher risk (HR)-MDS compared with conventional care, no drug has been shown conclusively to prolong survival or delay progression to AML among patients with lower-risk MDS (LR-MDS). Lenalidomide is the drug with the most impressive clinical activity in the subset of anemic LR-MDS patients who harbor a deletion of the long arm of chromosome 5 (5q-), where it leads to high rates of transfusion independence and cytogenetic responses. Furthermore, lenalidomide delays progression to AML and prolongs survival among responders. In this article, we review the recently recognized mechanisms of action of lenalidomide and discuss the most recent clinical data regarding its use in patients with both 5q- MDS as well as non-5q- MDS. Finally, we forecast the future directions to improve the efficacy of lenalidomide in MDS with and without 5q-. Cancer 2017;123:1703-1713. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Non-del(5q) transfusion-dependent low/intermediate-1 myelodysplastic syndrome (MDS) patients achieve an erythroid response with lenalidomide in 25% of cases. Addition of an erythropoiesis-stimulating agent could improve response rate. The impact of recurrent somatic mutations identified in the diseased clone in response to lenalidomide and the drug's effects on clonal evolution remain unknown. We investigated recurrent mutations by next-generation sequencing in 94 non-del(5q) MDS patients randomized in the GFM-Len-Epo-08 clinical trial to lenalidomide or lenalidomide plus epoetin ß. Clonal evolution was analyzed after 4 cycles of treatment in 42 cases and reanalyzed at later time points in 18 cases. The fate of clonal architecture of single CD34+CD38- hematopoietic stem cells was also determined in 5 cases. Mutation frequency was >10%: SF3B1 (74.5%), TET2 (45.7%), DNMT3A (20.2%), and ASXL1 (19.1%). Analysis of variant allele frequencies indicated a decrease of major mutations in 15 of 20 responders compared with 10 of 22 nonresponders after 4 cycles. The decrease in the variant allele frequency of major mutations was more significant in responders than in nonresponders (P < .001). Genotyping of single CD34+CD38- cell-derived colonies showed that the decrease in the size of dominant subclones could be associated with the rise of founding clones or of hematopoietic stem cells devoid of recurrent mutations. These effects remained transient, and disease escape was associated with the re-emergence of the dominant subclones. In conclusion, we show that, although the drug initially modulates the distribution of subclones, loss of treatment efficacy coincides with the re-expansion of the dominant subclone. [ABSTRACT FROM AUTHOR]

To find out prognostic factors and to investigate different therapeutic approaches, we report on 147 consecutive patients who relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndrome (MDS). Sixty-two patients underwent immunotherapy (IT group, second allo-HSCT or donor lymphocyte infusion), 39 received cytoreductive treatment alone (CRT group) and 46 were managed with palliative/supportive cares (PSC group). Two-year rates of overall survival (OS) were 32%, 6%, and 2% in the IT, CRT, and PSC groups, respectively ( P < .001). In multivariate analysis, 4 factors adversely influenced 2-year rates of OS: history of acute graft-versus-host disease (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.26 to 2.67; P = .002), relapse within 6 months (HR, 2.69; 95% CI, .82 to 3.98; P < .001), progression to acute myeloid leukemia (HR, 2.59; 95% CI, 1.75 to 3.83; P < .001), and platelet count < 50 G/L at relapse (HR, 1.68; 95% CI, 1.15 to 2.44; P = .007). A prognostic score based on those factors discriminated 2 risk groups with median OSs of 13.2 versus 2.4 months, respectively ( P < .001). When propensity score, prognostic score, and treatment strategy were included in Cox model, immunotherapy was found to be an independent factor that favorably impacts OS (HR, .40; 95% CI, .26 to .63; P < .001). In conclusion, immunotherapy should be considered when possible for MDS patients relapsing after allo-HSCT. [ABSTRACT FROM AUTHOR]

Lenalidomide is approved for the treatment of transfusion-dependent (TD) del(5q) myelodysplastic syndromes (MDS). However, few data are available in patients with transfusion-independent (TI) del(5q) MDS. In the first, observational, part of this 2-part study, we assessed the impact of transfusion dependence on overall survival (OS) and non-leukemic death in untreated del(5q) MDS patients who were TD (n = 136), TI with hemoglobin (Hb) ≥10 mg/dL (n = 88), or TI with Hb <10 mg/dL (n = 96). In the second, interventional, part we assessed the quality-of- life (QoL) benefits and clinical efficacy of lenalidomide (10 mg/day) in 12 patients with TI del(5q) MDS and Hb <10 mg/ dL. In the untreated population, OS was significantly longer in TI than in TD patients (TI [Hb ≥10 g/dL], 108 months; TI [Hb <10 g/dL], 77 months; TD, 44 months). Transfusion dependence also negatively impacted non-leukemic death rates. In the interventional part of the study, baseline Hb levels were found to correlate significantly with physical (R = 0.666, P = 0.035) and fatigue (R = 0.604, P = 0.049) QoL scores. Median physical QoL scores improved significantly after 12 weeks’ treatment with lenalidomide (+12.5; P = 0.020). Evaluable TI patients experienced early increases in Hb levels, and all attained an erythroid response. Our findings suggest that TI patients with moderate anemia may benefit from early treatment with lenalidomide. [ABSTRACT FROM AUTHOR]

Mutations of CSNK1A1, a gene mapping to the commonly deleted region of the 5q- syndrome, have been recently described in patients with del(5q) myelodysplastic syndromes ( MDS). Haploinsufficiency of Csnk1a1 in mice has been shown to result in β-catenin activation and expansion of haematopoietic stem cells ( HSC). We have screened a large cohort of 104 del(5q) MDS patients and have identified mutations of CSNK1A1 in five cases (approximately 5%). We have shown up-regulation of β-catenin target genes in the HSC of patients with del(5q) MDS. Our data further support a central role of CSNK1A1 in the pathogenesis of MDS with del(5q). [ABSTRACT FROM AUTHOR]

Posaconazole was introduced as the primary antifungal prophylaxis ( PAP) in acute myeloid leukaemia ( AML) or myelodysplastic syndrome ( MDS) patients during remission induction chemotherapy. Data on breakthrough invasive fungal infections ( IFIs) from various centres are essential, as there are several considerations in treating IFIs in the posaconazole era. The aim of this study was to evaluate the effectiveness of posaconazole PAP and identify characteristics of IFIs at a single centre in Korea. We retrospectively reviewed consecutive patients with AML/ MDS undergoing remission induction chemotherapy between December 2010 and November 2013. Of the 424 patients, 140 received posaconazole and 284 received fluconazole prophylaxis. The incidence of breakthrough proven/probable IFIs (15.5% vs. 2.9%, P < 0.001) and empirical antifungal treatment ( EAFT) (45.8% vs. 12.9%, P < 0.001) decreased in the posaconazole group compared to the fluconazole group. In the posaconazole PAP group, two cases of breakthrough mucormycosis were noted among 13 proven/probable/possible IFI cases (15.4%). Overall and IFI-related mortality was 12.1% and 1.9% respectively. Fungus-free survival was significantly higher in the posaconazole group (74.7% vs. 87.1%, P = 0.028). Breakthrough IFIs and EAFT decreased significantly after posaconazole PAP. The benefit in fungus-free survival was noted with posaconazole PAP. Clinicians should be vigilant to identify non- Aspergillus IFIs with active diagnostic effort. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the impact of the mutation of casein kinase 1A1 (CSNK1A1) on the prognosis of myelodysplastic syndrome (MDS) and 5q chromosome deletion.

Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome (MDS) characterized by isolated erythroid dysplasia and 15% or more bone marrow ring sideroblasts. Ring sideroblasts are found also in other MDS subtypes, such as refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). A high prevalence of somatic mutations of SF3B1 was reported in these conditions. To identify mutation patterns that affect disease phenotype and clinical outcome, we performed a comprehensive mutation analysis in 293 patients with a myeloid neoplasm and 1% or more ring sideroblasts. SF3B1 mutations were detected in 129 of 159 cases (81%) of RARS or RCMD-RS. Among other patients with ring sideroblasts, lower prevalence of SF3B1 mutations and higher prevalence of mutations in other splicing factor genes were observed (P<.001). In multivariable analyses, patients with SF3B1 mutations showed significantly better overall survival (hazard ration [HR], .37; p = .003) and lower cumulative incidence of disease progression (HR = 0.31, P = .018) compared with SF3B1-unmutated cases. The independent prognostic value of SF3B1 mutation was retained in MDS without excess blasts, as well as in sideroblastic categories (RARS and RCMD-RS). Among SF3B1-mutated patients, coexisting mutations in DNA methylation genes were associated with multilineage dysplasia (P=.015) but had no effect on clinical outcome. TP53 mutations were frequently detected in patients without SF3B1 mutation, and were associated with poor outcome. Thus, SF3B1 mutation identifies a distinct MDS subtype that is unlikely to develop detrimental subclonal mutations and is characterized by indolent clinical course and favorable outcome. [ABSTRACT FROM AUTHOR]

A preterm neonate presenting with respiratory distress after birth was found to have a clival encephalocele, which is a variant of a basal encephalocele, and hypoplasia of the cerebellum. Genetic studies revealed a small deletion of the long arm of chromosome 5: 5q15 deletion. We report a rare variant of a basal encephalocele with a cerebellar malformation and 5q15 deletion. [ABSTRACT FROM AUTHOR]

BACKGROUND. Mutational inactivation in cancer of key apoptotic pathway components, such as TP53/p53, undermines cytotoxic therapies that aim to increase apoptosis. Accordingly, TPS3 mutations are reproducibly associated with poor treatment outcomes. Moreover, cytotoxic treatments destroy normal stem cells with intact p53 systems, a problem especially for myeloid neoplasms, as these cells reverse the low blood counts that cause morbidity and death. Preclinical studies suggest that noncytotoxic concentrations of the DNA methyltransferase 1 (DNMT1) inhibitor decitabine produce p53-independent cell-cycle exits by reversing aberrant epigenetic repression of proliferation-terminating (MYC-antagonizing) differentiation genes in cancer cells. METHODS. In this clinical trial, patients with myelodysplastic syndrome (n = 25) received reduced decitabine dosages (0.1-0.2 mg/kg/day compared with the FDA-approved 20-45 mg/m²/day dosage, a 75%-90% reduction) to avoid cytotoxicity. These well-tolerated doses were frequently administered 1-3 days per week, instead of pulse cycled for 3 to 5 days over a 4-to 6-week period, to increase the probability that cancer S-phase entries would coincide with drug exposure, which is required for S-phase-dependent DNMT1 depletion. RESULTS. The median subject age was 73 years (range, 46-85 years), 9 subjects had relapsed disease or were refractory to 5-azacytidine and/or lenalidomide, and 3 had received intensive chemoradiation to treat other cancers. Adverse events were related to neutropenia present at baseline: neutropenic fever (13 of 25 subjects) and septic death (1 of 25 subjects). Blood count improvements meeting the International Working Group criteria for response occurred in 11 of 25 (44%) subjects and were highly durable. Treatment-induced freedom from transfusion lasted a median of 1,025 days (range, 186-1,152 days; 3 ongoing), and 20% of subjects were treated for more than 3 years. Mutations and/or deletions of key apoptosis genes were frequent (present in 55% of responders and in 36% of nonresponders). Noncytotoxic DNMT1 depletion was confirmed by serial BM γ-H2AX (DNA repair/damage marker) and DNMT1 analyses. MYC master oncoprotein levels were markedly decreased. CONCLUSION. Decitabine regimens can be redesigned to minimize cytotoxicity and increase exposure time for DNMT1 depletion, to safely and effectively circumvent mutational apoptotic defects. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the impact of occurrence of chronic GVHD (cGVHD) and its severity on transplantation outcomes in a consecutive cohort of AML and myelodysplastic syndrome (MDS) patients who received unmanipulated haploidentical hematopoietic SCT (haplo-HSCT; n=324). The cumulative incidence of relapse was significantly decreased in patients with cGVHD compared with the non-cGVHD group (1 year: 3.2% vs 11.9%, P=0.002; 3 years: 6.0% vs 16.3%, P=0.002), particularly in those with mild cGVHD. The cumulative incidence of non-relapse mortality was comparable between patients with and without cGVHD. The probabilities of disease-free survival (DFS) were significantly better in patients with cGVHD than in those in the non-cGVHD group (1 year: 90.5% vs 78.5%, P=0.002; 3 years: 86.5% vs 71.5%, P<0.001), particularly in those with mild or moderate cGVHD; however, no significant impact of severe cGVHD on DFS was seen. Our findings highlight the close relationship between cGVHD and the immune-mediated GVL effect in patients with AML and MDS receiving unmanipulated haplo-HSCT; however, only mild or moderate cGVHD was associated with a lower risk of relapse translating into improved DFS. [ABSTRACT FROM AUTHOR]

Haploinsufficiency of ribosomal proteins ( RPs) and upregulation of the tumour suppressor TP53 have been shown to be the common basis for the anaemia observed in Diamond Blackfan anaemia and 5q- myelodysplastic syndrome. We previously demonstrated that treatment with L-Leucine resulted in a marked improvement in anaemia in disease models. To determine if the L-Leucine effect was Tp53-dependent, we used antisense MOs to rps19 and rps14 in zebrafish; expression of tp53 and its downstream target cdkn1a remained elevated following L-leucine treatment. We confirmed this observation in human CD34+ cells. L-Leucine thus alleviates anaemia in RP-deficient cells in a TP53-independent manner. [ABSTRACT FROM AUTHOR]

The role of cytogenetics in the pathogenesis, diagnosis and prognostication of haematological neoplasms in general, and myelodysplastic syndromes (MDS) in particular, has already been recognised.1-5 Recently, cytogenetics also directs the appropriate treatment. The Mayo team confirms the very small incidence of MDS with BTs, only 21 out of 1088 evaluable patients (2%), compared with 42% of the patients with NK, 21% with CK, and 35% with UBTs. Coalesced multicentric analysis of 2,351 patients with myelodysplastic syndromes indicates an underestimation of poor-risk cytogenetics of myelodysplastic syndromes in the international prognostic scoring system. [Extracted from the article]

Myelodysplastic syndrome (MDS) are a heterogeneous group of hematologic malignancies characterized by ineffective hematopoiesis resulting in morphologic dysplasia and peripheral cytopenias. While the majority of these patients progress to acute myeloid leukemia (AML), rare reports exist of acute lymphoblastic leukemia (ALL) arising in patients with antecedent history of MDS or MDS/MPN [[1]]. [Extracted from the article]

Immunomodulatory drugs (IMiDs) are effective in the treatment of multiple myeloma (MM), myelodysplastic syndrome with deletion of chromosome 5q and other haematological malignancies. Recent studies showed that IMiDs bind to cereblon (CRBN), a substrate receptor of the CRL4–CRBN complex, to induce the ubiquitination and degradation of IKZF1 and IKZF3 in MM cells, contributing to their anti-myeloma activity. We aimed to determine whether the CRL4–CRBN complex proteins' expression predicts the prognosis of MM patients treated with IMiDs. Here, we evaluated the expression of CRL4–CRBN complex proteins and their downstream targets with immunohistochemistry (IHC) staining in 130 bone marrow samples from MM patients treated with thalidomide or lenalidomide-based regimens. We found that the expression of CRBN and CUL4A was associated with the superior IMiD-based treatment response (p = 0.007 and p = 0.007, respectively). Moreover, the CUL4A expression was associated with improved PFS (HR = 0.66, 95% CI 0.44–0.99; p = 0.046) and DDB1 expression showed a negative impact on OS both in the univariate (HR = 2.75, 95% CI 1.65–4.61; p = 0.001) and the multivariate (HR 3.67; 95% CI 1.79–7.49; p < 0.001) analysis. Overall, our data suggest that the expression of DDB1, CUL4A and CRBN assessed by IHC predicts the clinical course of MM patients and identifies patients with a high probability of responding to IMiD-based therapy. [ABSTRACT FROM AUTHOR]

Background: To estimate real-world outcomes in East Asian populations, we conducted a nationwide retrospective analysis of the efficacy and safety of lenalidomide for del(5q) myelodysplastic syndrome (MDS) patients with transfusion-dependent anemia in Korea., Methods: Patients aged ≥19 years who had received lenalidomide for the treatment of lower-risk, red blood cell (RBC) transfusion-dependent del(5q) MDS were selected. A filled case report form (CRF) with information from electronic medical records was requested from members of the acute myeloid leukemia (AML)/MDS Working Party of the Korean Society of Hematology. All the CRFs were gathered and analyzed., Results: A total of 31 patients were included in this study. Of 28 evaluable patients, 19 (67.9%) achieved RBC transfusion independence (RBC-TI). Female sex and the development of thrombocytopenia during treatment were associated with achieving RBC-TI. The most common non-hematologic toxicities were pruritus, fatigue, and rashes. All non-hematologic toxicities of grades ≥3 were limited to rash (12.9%) and pruritus (6.5%). Dose reduction was required in 15 of the 19 responders (78.9%). The most common final stable dosing schedule for the responders was 5 mg once every other day (31.6%)., Conclusion: Lenalidomide efficacy and tolerability were similar in the Asian del(5q) MDS patients and western patients. Dose reduction during treatment was common, but it was not associated with inferior outcomes.

The risk of developing second primary malignancies (SPM) in patients (p) with breast cancer (BC) is higher than among the general population. Tamoxifen, chemotherapy and breast irradiation are associated with an increased risk of SPM. The aim of this study was to investigate the clinicopathological characteristics of the non BC SPM in p with primary diagnostic of BC. We conducted a retrospective study in a cohort of 2,111 women with BC diagnosed between 1975 and 2014 in a regional cancer institute in Spain. We evaluated the incidence and pattern of SPM per Warren and Gates criteria, and the impact of breast cancer treatment on SPM. 57p (2.7%) of the cohort developed a SPM, 13 of them (23%) had synchronous tumors and 44p (77%) had metachronous tumors. 10p (18%) developed a third primary malignancy and 1p (1.7%) developed a fourth primary malignancy. The most frequent SPM were hematological malignancies (HM) (11p, 19%), followed by endometrial (7p, 12.3%), gastric (7p, 12.3%), lung (6p, 10.5%), parotid tumors (6p, 10.5%) and melanoma (6p, 10.5%). The mean latency period for SPM was 62.7 months. HM were developed in 0.52% of the cohort of 2,111p. Myeloid neoplasms were diagnosed in 6p (0.28%). Among them, 1p developed chronic myeloid leukemia and 5p developed myelodysplastic syndromes (MDS), including refractory anemia with excess blasts-2 (2p) and 5q minus syndrome (2p). Lymphoid neoplasms were diagnosed in 5p (0.24%). The incidence of HM was similar in both anthracycline-treated and not treated p (0.48% and 0.58%, respectively). The incidence of HM in p treated with radiotherapy was higher than in p who did not receive radiotherapy (0.65% vs 0.19%). HM are the most frequent non BC SPM in p treated from BC; frequently they are therapy related neoplasms. Deescalating chemotherapy and radiotherapy in BC and finding genetic markers of early malignancy detection are mandatory. The authors. Has not received any funding. All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

The author discusses that M. Pfeistöcker et al., revealed that the present major scoring systems for patients with myelodysplastic syndromes (MDS) forecast result better at diagnosis that at later times in the disease, a point that should be regarded in decision making at follow-up. It says that natural course of MDS vary among subgroups.

Bone marrow mesenchymal stem cells (BM-MSCs) exhibit multiple abnormalities in myelodysplastic syndromes (MDS), including impaired proliferative and clonogenic capacity, altered morphology, increased senescence, impaired immunoregulatory properties, and reduced hematopoietic support capacity. Common signaling pathways, such as PI3K/AKT and WNT/β-catenin, regulate multiple MSC properties, including proliferation, differentiation, and cell–cell interaction. Here, with polymerase chain reaction arrays, we investigated the expression of 84 genes belonging to the PI3K/AKT signaling pathways in BM-MSCs isolated from patients with MDS, acute myeloid leukemia, and therapy-related myeloid neoplasms, using as a control BM-MSCs isolated from patients with untreated early-stage lymphomas without BM involvement. Statistically significant downregulation of GSK3β, SOS1, RASA1, and MTCP1 gene expression was observed in BM-MSCs isolated from patients with de novo MDS, as compared with controls. Moreover, expression of the GSK3β protein was reduced in MDS-derived MSCs, and was associated with concomitant reduction of phosphorylation at Ser-9. The role of GSK3β in the downstream WNT/β-catenin signaling pathway was assessed. We investigated β-catenin protein levels and expression of 84 genes belonging to the WNT target gene pathway using PCR arrays in MDS BM-MSCs, as compared with control BM-MSCs. GSK3β impairment translated into decreased β-catenin protein levels and downregulation of several WNT/β-catenin target genes (SOX9, EGR1, WISP1). These findings suggest that deregulation of genes involved in the PI3K/AKT and WNT signaling pathways may contribute to the phenotypical abnormalities of MDS BM-MSCs. [ABSTRACT FROM AUTHOR]