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Severe, often refractory anemia is characteristic of the myelodysplastic syndrome associated with chromosome 5q31 deletion. We investigated whether lenalidomide (CC5013) could reduce the transfusion requirement and suppress the abnormal 5q31- clone in patients with this disorder.
One hundred forty-eight patients received 10 mg of lenalidomide for 2...
Context in source publication
Context 1
... to severe neutropenia and/or thrombocytopenia was present in 44 (27%) and 28 (17%) patients, respectively. All patients had a chromosome 5q31 deletion identified by either standard metaphase analysis [N=147] or fluorescence in situ hybridization (FISH) [N=1] (Table 2). One hundred ten patients (74%) had an isolated deletion 5q [del(5q)], whereas only 40 patients (27%) fulfilled criteria for the 5q-syndrome. ...
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Citations
... In this study, patients with del5q had a statistically significant higher erythroid response rate of 83%; compared to an erythroid response rate of 57% in patients with a normal karyotype and 8% in patients with other karyotype abnormalities [38••]. In a follow-up phase 2 trial in RBC transfusion-dependent (RBC-TD) MDS with del5q, lenalidomide achieved RBC-transfusion independence (RBC-TI) in 67% of patients [39]. This culminated in a phase 3, randomized, placebo controlled study of lenalidomide in RBC-TD patients with del5q MDS. ...
Opinion statement
A majority of patients with lower-risk myelodysplastic syndrome (MDS) will present with or develop anemia. Anemia in MDS is associated with decreased quality of life and may correlate with decreased progression-free survival and overall survival. In this state of the art review we summarize current risk stratification approaches to identify lower-risk MDS (LR-MDS), the natural history of the disease, and meaningful clinical endpoints. The treatment landscape of LR-MDS with anemia is also rapidly evolving; we review the role of supportive care, erythropoietin stimulating agents, lenalidomide, luspatercept, hypomethylating agents (HMAs), and immunosuppressive therapy (IST) in the management of LR-MDS with anemia. In patients with deletion 5q (del5q) syndrome lenalidomide has both efficacy and durability of response. For patients without del5q who need treatment, the management approach is impacted by serum erythropoietin (EPO) level, SF3B1 mutation status, and ring sideroblast status. Given the data from the Phase III COMMANDS trial, we utilize luspatercept in those with SF3B1 mutation or ring sideroblasts that have an EPO level < 500 U/L; in patients without an SF3B1 mutation or ring sideroblasts there is equipoise between luspatercept and use of an erythropoietin stimulating agent (ESA). For patients who have an EPO level ≥ 500 U/L or have been previously treated there is not a clear standard of care. For those without previous luspatercept exposure it can be considered particularly if there is an SF3B1 mutation or the presence of ring sideroblasts. Other options include HMAs or IST; the Phase III IMERGE trial supports the efficacy of the telomerase inhibitor imetelstat in this setting and this may become a standard option in the future as well.
... Patients with del 5q and transfusion-dependent anemia can be treated with lenalidomide, which is a thalidomide analogue that promotes erythropoiesis [27,33,50]. ESAs are still often used in first-line management of transfusiondependent anemia in del5q MDS patients; however, many of these patients are resistant to ESAs and the use of lenalidomide is warranted since transfusion independence can be achieved in more than 60% of the patients [51][52][53]. Patients with TP53 mutations are less likely to respond to lenalidomide; this subgroup will need closer follow-up given the Content courtesy of Springer Nature, terms of use apply. Rights reserved. ...
Purpose of Review
Myelodysplastic syndromes/neoplasms (MDS) represent a diverse group of pathologically distinct diseases with varying prognoses and risks of leukemia progression. This review aims to discuss current treatment options for elderly patients with MDS, focusing on patients ineligible for intensive chemotherapy or allogenic hematopoietic stem cell transplantation (HSCT). The challenges associated with treatment in this population and emerging therapeutic prospects are also explored.
Recent Findings
Recent advancements in molecular diagnostics have enhanced risk stratification by incorporating genetic mutations, notably through the molecular International Prognostic Scoring System (IPSS-M). Lower-risk MDS (LR-MDS) treatment ranges from observation to supportive measures and erythropoiesis-stimulating agents (ESAs), with emerging therapies like luspatercept showing promise. High-risk MDS (HR-MDS) is treated with hypomethylating agents (HMAs) or allogenic HSCT, but outcomes remain poor.
Summary
Elderly MDS patients, often diagnosed after 70, pose challenges in treatment decision-making. The IPSS-M aids risk stratification, guiding therapeutic choices. For LR-MDS, supportive care, ESAs, and novel agents like luspatercept are considered. Treatment of HR-MDS involves HMAs or allogenic HSCT. Emerging treatments, including oral HMAs and novel agents targeting FLT3, and IDH 1/2 mutations, show promise. Future research should refine treatment strategies for this elderly population focusing on quality-of-life improvement.
... Del(5q) is one of the most common cytogenetic abnormalities in de novo MDS, occurring in approximately 10-20% of MDS patients (1)(2)(3). Treatment with lenalidomide (LEN) can lead to red blood cell-transfusion independence (RBC-TI) in 60 to70% of patients with RBC-transfusion dependent (RBC-TD) MDS with lower-risk and isolated del(5q), and to complete cytogenetic response (CCyR) in 30-40% of them (4)(5)(6)(7). Current practice in patients who attain RBC-TI is to continue LEN treatment inde nitely until loss of response or disease progression. ...
... Among extra-hematological toxicities, cutaneous rash and diarrhea are the most common AEs. More rarely thromboembolic events, in particular deep vein thrombosis, and hypothyroidism have also been reported (7,12,13). Furthermore, albeit a report by the Mo tt Cancer Center involving a large cohort of MDS patients did not show an increased risk of secondary malignancies in those treated with LEN, some concerns about its long-term cancerogenic potential still exist (14,15). Besides, despite the reduction in the cost of LEN in recent years, there is still concern about the healthcare resources utilization associated with the monitoring of potential side effects and the appearance or increase in clonal size of TP53 mutations. ...
Lenalidomide (LEN) can induce RBC transfusion independence (RBC-TI) in 60–70% of del(5q) myelodysplastic syndrome (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN in RBC-TI. We enrolled 118 patients with an IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment ≥ 12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients in RBC-TI allows prolonged maintenance of TI in a large subset of patients.
... List et al. examined long-term outcomes from the single-arm MDS-003 study [44] and demonstrated that the rate of TI in lower-risk participants with del(5q) 8 weeks after receiving lenalidomide was 65.5 percent, with 63 of 88 evaluable participants achieving a partial or complete cytogenetic response. Importantly, the duration of response was sustained, with a median duration of response of 2.2 years. ...
Myelodysplastic neoplasms (MDS) are a heterogenous clonal disorder of hemopoietic stem cells characterized by cytomorphologic dysplasia, ineffective hematopoiesis, peripheral cytopenias and risk of progression to acute myeloid leukemia (AML). Our understanding of this disease has continued to evolve over the last century. More recently, prognostication and treatment have been determined by cytogenetic and molecular data. Specific genetic abnormalities, such as deletion of the long arm of chromosome 5 (del(5q)), TP53 inactivation and SF3B1 mutation, are increasingly associated with disease phenotype and outcome, as reflected in the recently updated fifth edition of the World Health Organization Classification of Hematolymphoid Tumors (WHO5) and the International Consensus Classification 2022 (ICC 2022) classification systems. Treatment of lower-risk MDS is primarily symptom directed to ameliorate cytopenias. Higher-risk disease warrants disease-directed therapy at diagnosis; however, the only possible cure is an allogenic bone marrow transplant. Novel treatments aimed at rational molecular and cellular pathway targets have yielded a number of candidate drugs over recent years; however few new approvals have been granted. With ongoing research, we hope to increasingly offer our MDS patients tailored therapeutic approaches, ultimately decreasing morbidity and mortality.
... All n = 3 subclones from the patients 01-02, 01-05 and 01-17, which were driven by a mutation involved in methylation regulation (DNMT3A n = 1, IDH2 n = 1, TET2 n = 1; P01-17 carried two TET2 Mutations), were responsive on a molecular level profiles could help identifying better individual therapies [27]. In this context, the most notable successes are the use of Luspatercept in MDS with SF3B1 mutations and Lenalidomide in MDS patients with 5q deletion [2,28]. In contrast, there is no specific therapy available for the majority of lower risk patients without these specific lesions. ...
In low-risk Myelodysplastic Neoplasms (MDS), increased activity of apoptosis-promoting factors such as tumor necrosis factor (TNFα) and pro-apoptotic Fas ligand (CD95L) have been described as possible pathomechanisms leading to impaired erythropoiesis. Asunercept (APG101) is a novel therapeutic fusion protein blocking CD95, which has previously shown partial efficacy in reducing transfusion requirement in a clinical phase I trial for low-risk MDS patients (NCT01736436; 2012-11-26). In the current study we aimed to evaluate the effect of Asunercept therapy on the clonal bone marrow composition to identify potential biomarkers to predict response. Bone marrow samples of n = 12 low-risk MDS patients from the above referenced clinical trial were analyzed by serial deep whole exome sequencing in a total of n = 58 time points. We could distinguish a mean of 3.5 molecularly defined subclones per patient (range 2–6). We observed a molecular response defined as reductions of dominant clone sizes by a variant allele frequency (VAF) decrease of at least 10% (mean 20%, range: 10.5–39.2%) in dependency of Asunercept treatment in 9 of 12 (75%) patients. Most of this decline in clonal populations was observed after completion of 12 weeks treatment. Particularly early and pronounced reductions of clone sizes were found in subclones driven by mutations in genes involved in regulation of methylation (n = 1 DNMT3A, n = 1 IDH2, n = 1 TET2). Our results suggest that APG101 could be efficacious in reducing clone sizes of mutated hematopoietic cells in the bone marrow of Myelodysplastic Neoplasms, which warrants further investigation.
... A study by List et al. examined long term outcomes from the single arm MDS-003 [43], and demonstrated that the rate of TI in lower risk participants with del(5q) 8 weeks after receiving lenalidomide was 65.5 percent, with 63 of 88 evaluable patients achieving a partial or complete cytogenetic response [44]. Importantly, the duration of response was sustained, with a median duration of response 2.2 years. ...
Myelodysplastic neoplasm (MDS) is a heterogenous clonal disorder of hemopoietic stem cells charac-terized by cytomorphologic dysplasia, ineffective hematopoiesis, peripheral cytopenias and risk of pro-gression to Acute Myeloid Leukemia (AML). Our understanding of this disease has continued to evolve over the last century. More recently prognostication and treatment are determined by cytogenetic and molecular data. Specific genetic abnormalities such as 5q deletion (del 5q), TP53 inactivation and SF3B1 mutation, are increasingly associated with disease phenotype and outcomes, as reflected in the recently updated 5th edition of the World Health Organization Classification of Hematolymphoid Tumors (WHO5) and International Consensus Classification 2022 (ICC 2022) classifications. Treatments are in-creasingly being tailored for patient specific phenotypes, and trials exploring the efficacy of targeted treatments are ongoing in this era of precision medicine.
... TI in 30% and TI at 24 weeks in 17.5% of patients [6]. Regarding MDS with del(5q), our data confirm the findings of the phase-II MDS-003 trial showing HI-E of 67%, the phase-III MDS-004 trial showing TI for 26 weeks or longer in 56.1% and the LE-MON5 with 67% of TI [24][25][26]. We observed no differences in PFS and OS between arms, nor between patients with or without del(5q). ...
A randomized phase-II study was performed in low/int-1 risk MDS (IPSS) to study efficacy and safety of lenalidomide without (arm A) or with (arm B) ESA/G-CSF. In arm B, patients without erythroid response (HI-E) after 4 cycles received ESA; G-CSF was added if no HI-E was obtained by cycle 9. HI-E served as primary endpoint. Flow cytometry and next-generation sequencing were performed to identify predictors of response. The final evaluation comprised 184 patients; 84% non-del(5q), 16% isolated del(5q); median follow-up: 70.7 months. In arm A and B, 39 and 41% of patients achieved HI-E; median time-to-HI-E: 3.2 months for both arms, median duration of-HI-E: 9.8 months. HI-E was significantly lower in non-del(5q) vs. del(5q): 32% vs. 80%. The same accounted for transfusion independency-at-week 24 (16% vs. 67%), but similar in both arms. Apart from presence of del(5q), high percentages of bone marrow lymphocytes and progenitor B-cells, a low number of mutations, absence of ring sideroblasts, and SF3B1 mutations predicted HI-E. In conclusion, lenalidomide induced HI-E in patients with non-del(5q) and del(5q) MDS without additional effect of ESA/G-CSF. The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10).
... Interestingly, lenalidomide is the only IMiD that was found to induce degradation of casein kinase 1A1 (CK1α), albeit with only a modest efficacy producing incomplete degradation at concentrations of up to 10 μM 10 . Nevertheless, the degradation of CK1α provides a mechanistic basis for lenalidomide's unique clinical efficacy in myelodysplastic syndrome (MDS) patients with deletion of chromosome 5q (del(5q)) 11 . This is attributed to the haploinsufficiency of the CK1α gene (CSNK1A1) encoded at chromosome 5q32, which heightens MDS sensitivity to the effects of lenalidomide-induced CK1α degradation. ...
Molecular-glue degraders are small molecules that induce a specific interaction between an E3 ligase and a target protein, resulting in the target proteolysis. The discovery of molecular glue degraders currently relies mostly on screening approaches. Here, we describe screening of a library of cereblon (CRBN) ligands against a panel of patient-derived cancer cell lines, leading to the discovery of SJ7095, a potent degrader of CK1α, IKZF1 and IKZF3 proteins. Through a structure-informed exploration of structure activity relationship (SAR) around this small molecule we develop SJ3149, a selective and potent degrader of CK1α protein in vitro and in vivo. The structure of SJ3149 co-crystalized in complex with CK1α + CRBN + DDB1 provides a rationale for the improved degradation properties of this compound. In a panel of 115 cancer cell lines SJ3149 displays a broad antiproliferative activity profile, which shows statistically significant correlation with MDM2 inhibitor Nutlin-3a. These findings suggest potential utility of selective CK1α degraders for treatment of hematological cancers and solid tumors.
... mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS. Notably, lenalidomide treatment has resulted in complete cytogenetic remission in approximately 50% of patients with MDS and achieving transfusion independence in around 70% of patients with del(5q) MDS patients (33,34). ...
The concept of induced protein degradation by small molecules has emerged as a promising therapeutic strategy that is particularly effective in targeting proteins previously considered "undruggable." Thalidomide analogs, employed in the treatment of multiple myeloma, stand as prime examples. These compounds serve as molecular glues, redirecting the CRBN E3 ubiquitin ligase to degrade myeloma-dependency factors, IKZF1 and IKZF3. The clinical success of thalidomide analogs demonstrates the therapeutic potential of induced protein degradation. Beyond molecular glue degraders, several additional modalities to trigger protein degradation have been developed and are currently under clinical evaluation. These include heterobifunctional degraders, polymerization-induced degradation, ligand-dependent degradation of nuclear hormone receptors, disruption of protein interactions, and various other strategies. In this Review, we will provide a concise overview of various degradation modalities, their clinical applications, and potential future directions in the field of protein degradation.
... 8 Other patient subgroups may respond to growth factors or immunosuppressive medications in varying degrees. 9 Danazol is a synthetic androgen with progestational and glucocorticoid properties that inhibits the production of tumor necrosis factor α and IL-1. 10,11 Additionally, danazol has proven useful in immunological cytopenias; its androgenic features, which promote healthy hematopoiesis and decrease neoplastic cell clones, are thought to be responsible for its efficacy. ...
... Some studies suggest patient benefit, whereas others have demonstrated a lack of efficacy. 2,8,9,15,16,[18][19][20][21] Telomere dysfunction as a pathogenic mechanism in various hematological disorders, particularly in bone marrow failure syndromes, has drawn more attention recently. 22,23 Telomeres are noncoding repeating sequences at the end of each DNA chromosome that help maintain chromosomal stability and prevent chromosomal abnormalities. ...
Purpose To study the potential utility of danazol for treating patients with myelodysplastic syndromes, with a focus on efficacy and adverse effects (AEs). Methods MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus were searched for relevant publications from inception June 1, 1950, until June 28, 2022. The studies were screened by title and abstract, followed by full-text screening. The quality of the included studies was assessed via a prespecified set of questionnaires. Data on the efficacy measures and adverse outcomes were extracted and included in a descriptive summary. Results Nine studies consisting of 246 participants were included in our review. The overall quality of the included studies was fair. The age of the participants ranged from 61 to 78 years. In all 9 studies, more male patients had been enrolled than female patients. Overall, a proportion of patients in all the studies reported a desired major response to a danazol dose of 400 to 800 mg/day. Few studies did not observe any improvement in the platelet count. Elevated liver enzyme levels, weight gain, headache, dermatitis, and weakness were the most common AEs observed. One study reported a fatal intracerebral hemorrhage in 1 participant. Conclusions Danazol has been effective in increasing platelet count and hemoglobin level. Despite a few AEs, danazol is a safe drug for the treatment of patients with myelodysplastic syndromes.
