scholarly journals Hypomethylating Agents and Other Novel Strategies in Myelodysplastic Syndromes

2011 ◽  
Vol 29 (5) ◽  
pp. 516-523 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Pierre Fenaux
Keyword(s):  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Short Review ◽  
Natural Course ◽  
Hypomethylating Agents ◽  
Older Individuals ◽  
Survival Prognosis ◽  
Treatment Approaches

Over the last decade, treatment approaches for patients with myelodysplastic syndromes (MDS) have improved significantly. Treatment of MDS is tailored to the specific risk characteristics of the patient. In general, patients are divided into lower- and higher-risk categories. Without therapy, prognosis of patients with higher-risk MDS is poor, and treatments should be directed to improve survival. Prognosis of patients with lower-risk MDS is more heterogeneous, and therapies are usually directed to minimize transfusion needs and potentially to alter the natural course of the disease. Treatment options for patients with higher-risk MDS include hypomethylating agents (azacitidine and decitabine), intensive chemotherapy (ICT), and allogeneic stem-cell transplantation (alloSCT). The use of the hypomethylating agents has transformed the approach to this patient population, in particular older individuals, for whom ICT and alloSCT are not an option. In lower-risk MDS, treatment strategies are used sequentially and usually include observation in patients with low risk and no transfusion dependency, growth factors, and lenalidomide for patients with alteration of chromosome 5 and anemia. The use of hypomethylating agents is less understood in this group of patients. AlloSCT is usually reserved for patients with lower-risk MDS closer to the time of transformation. In this short review, we discuss treatment alternatives for patients with MDS and delineate some of the ongoing challenges, including the development of better front-line strategies for patients with higher-risk disease, the concept of altering the natural course of the disease in lower-risk MDS, and the development of new treatment approaches for patients who do not benefit from hypomethylating agents.

Prognosis of Myelodysplastic Syndromes

Hematology ◽  
2010 ◽  
Vol 2010 (1) ◽  
pp. 330-337 ◽  
Author(s):  
Guillermo Garcia-Manero
Keyword(s):  
Myelodysplastic Syndromes ◽  
Therapeutic Interventions ◽  
Prognostic Models ◽  
International Prognostic Scoring System ◽  
Molecular Characteristics ◽  
Hypomethylating Agents ◽  
Older Individuals ◽  
Molecular Alterations ◽  
Hematopoietic Disorders ◽  
Clinical Tools

AbstractThe myelodysplastic syndromes (MDS) are a very complex group of hematopoietic disorders. The degree of complexity relates not only to the intrinsic pathobiological characteristics of the disease, but also to the group of patients whom it affects most frequently: older individuals or those who have been exposed to prior forms of chemotherapy. It is therefore crucial to develop clinical tools to predict with a certain degree of precision the prognosis and outcome for patients with specific subtypes of MDS in specific clinical situations. At the present time, patients with MDS are diagnosed using a set of well-established histopathological criteria. Prognosis is established using classifications that include morphological features, percentage of blasts, and clinical and molecular characteristics such as peripheral cytopenias and cytogenetics. The International Prognostic Scoring System (IPSS) is a classic example of this type of classification. Over the last 5 years, there has been an intense effort to develop new prognostic systems for MDS, and new molecular alterations with potential prognostic value have been discovered. Over the same period of time, several new therapeutic interventions have been developed for patients with MDS. Biomarkers of response to these agents, in particular for the hypomethylating agents, are needed to predict clinical benefit. This review summarizes current prognostic models of MDS and new molecular alterations with potential prognostic potential.

A Randomized Phase IIa Study of Vorinostat in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes: Preliminary Results

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5084-5084 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Lewis B. Silverman ◽  
Ivana Gojo ◽  
Laura Michaelis ◽  
Simrit Parmar ◽  
...  
Keyword(s):  
Adverse Events ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Treatment Options ◽  
Low Risk ◽  
Red Blood Cell Transfusion ◽  
Study Medication ◽  
Cutaneous Manifestations ◽  
Preliminary Results ◽  
Transformed Cell Lines

Abstract Effective treatment options for patients with lower-risk myelodysplastic syndromes (MDS) are limited. However, around one-third of patients experience transformation to acute myeloid leukemia, and absent transformation, complications of chronic cytopenias (including infection), and iron-overload syndromes can be fatal. Although 5-azacitidine, decitabine, and lenalidomide have improved treatment options for patients with MDS, these are not routinely used in patients with lower-risk disease. Histone deacetylase (HDAC) enzymes are overexpressed in several tumor types including MDS, and regulate transcriptional and post-transcriptional processes. Vorinostat (Zolinza®) has been shown to inhibit class I and II HDAC enzymes, and has been approved by the FDA for the treatment of cutaneous manifestations of T-cell lymphoma in patients with persistent or recurrent disease, on or following 2 prior systemic therapies. Vorinostat induces cell-cycle arrest, apoptosis, or differentiation in a variety of cultured transformed cell lines, and has demonstrated activity against leukemias in in vivo non-clinical models and in phase I and II clinical trials. Efficacy data in these early phase trials prompted an investigation of vorinostat monotherapy in lower-risk MDS. The potency and tolerability of vorinostat suggest it may be effective in the treatment of MDS. Here, we report preliminary results of a randomized phase II study evaluating once-daily and three-times-daily (tid) intermittent dosing schedules of vorinostat in patients with low and intermediate-1 risk MDS. Primary objectives included assessment of the efficacy, safety, and tolerability of vorinostat. Eligible patients were aged ≥18 years, had either previously untreated disease, or were ≥4 weeks from any prior treatment regimen (including growth factors). Patients’ performance status was ≤2 on the ECOG performance scale, they had adequate organ function, and were either red blood cell transfusion dependent or had a hemoglobin level of ≤11g/dL at the time of screening, or had platelets ≤100 × 109/L at the time of screening. Eligible patients were assigned to 1 of 2 oral dosing regimens: vorinostat 400 mg daily or vorinostat 200 mg tid. Treatment was administered over a 21-day cycle (14 days’ therapy and 7 days’ rest), with patients receiving up to 8 cycles, or until the patient experienced unacceptable toxicity, disease progression, or withdrew consent. In total, 18 patients (12 male, 6 female; mean age 67.4 years) have been randomized, including 5 with low-risk MDS and 13 with intermediate-1 risk MDS, as defined by the International Prognostic Scoring System. Of the patients enrolled, 12 (3 low-risk and 9 intermediate-1 risk MDS) were evaluable for response and have received between 2 and 6 cycles of treatment. Stable disease has been reported in all 12 patients, with a reported duration of between 22–146 days (low-risk MDS) and 1–136 days (intermediate-1 risk MDS). A total of 11/18 (61%) patients have discontinued, 2 due to adverse events (1 event of grade 4 neutropenia [unrelated to study medication] and 1 event of grade 3 neuropathy [drug related]), 1 due to deviation from protocol, 4 due to lack of efficacy, 3 due to physician decision, 1 due to progressive disease, and 1 because of withdrawal of consent. Most adverse events were gastrointestinal disorders: diarrhea in 10 patients (7 grade 1, 3 grade 2), nausea in 9 patients (6 grade 1, 3 grade 2), and vomiting in 6 patients (5 grade 1, 1 grade 2). Grade 4 neutropenia, anemia, and thrombocytopenia were observed in 2, 1, and 1 patients, respectively; however these were unrelated to study medication. Data from this study indicate that vorinostat administered in a 21-day cycle has acceptable safety and tolerability.

scholarly journals Animal models of regenerative medicine for biological treatment approaches of degenerative disc diseases

2020 ◽  
pp. 153537022096912
Author(s):  
Demissew Shenegelegn Mern ◽  
Tanja Walsen ◽  
Anja Beierfuß ◽  
Claudius Thomé
Keyword(s):  
Animal Models ◽  
Biological Treatment ◽  
Chronic Back Pain ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Disc Disease ◽  
Treatment Approaches ◽  
Degenerative Disc ◽  
And Function

Degenerative disc disease (DDD) is a painful, chronic and progressive disease, which is characterized by inflammation, structural and biological deterioration of the intervertebral disc (IVD) tissues. DDD is specified as cell-, age-, and genetic-dependent degenerative process that can be accelerated by environmental factors. It is one of the major causes of chronic back pain and disability affecting millions of people globally. Current treatment options, such as physical rehabilitation, pain management, and surgical intervention, can provide only temporary pain relief. Different animal models have been used to study the process of IVD degeneration and develop therapeutic options that may restore the structure and function of degenerative discs. Several research works have depicted considerable progress in understanding the biological basis of disc degeneration and the therapeutic potentials of cell transplantation, gene therapy, applications of supporting biomaterials and bioactive factors, or a combination thereof. Since animal models play increasingly significant roles in treatment approaches of DDD, we conducted an electronic database search on Medline through June 2020 to identify, compare, and discuss publications regarding biological therapeutic approaches of DDD that based on intradiscal treatment strategies. We provide an up-to-date overview of biological treatment strategies in animal models including mouse, rat, rabbit, porcine, bovine, ovine, caprine, canine, and primate models. Although no animal model could profoundly reproduce the clinical conditions in humans; animal models have played important roles in specifying our knowledge about the pathophysiology of DDD. They are crucial for developing new therapy approaches for clinical applications.

How we treat higher-risk myelodysplastic syndromes

Blood ◽  
2014 ◽  
Vol 123 (6) ◽  
pp. 829-836 ◽  
Author(s):  
Mikkael A. Sekeres ◽  
Corey Cutler
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Myelodysplastic Syndromes ◽  
Risk Group ◽  
Treatment Options ◽  
International Prognostic Scoring System ◽  
Hypomethylating Agents ◽  
Hematopoietic Stem ◽  
Patient Goals ◽  
Interim Period

Abstract Higher-risk myelodysplastic syndromes (MDS) are defined by patients who fall into higher-risk group categories in the original or revised International Prognostic Scoring System. Survival for these patients is dismal, and treatment should be initiated rapidly. Standard therapies include the hypomethylating agents azacitidine and decitabine, which should be administered for a minimum of 6 cycles, and continued for as long as a patient is responding. Once a drug fails in one of these patients, further treatment options are limited, median survival is <6 months, and consideration should be given to clinical trials. Higher-risk eligible patients should be offered consultation to discuss hematopoietic stem cell transplantation close to the time of diagnosis, depending on patient goals of therapy, with consideration given to proceeding to transplantation soon after an optimal donor is located. In the interim period before transplantation, hypomethylating agent therapy, induction chemotherapy, or enrollment in a clinical trial should be considered to prevent disease progression, although the optimal pretransplantation therapy is unknown.

scholarly journals Advances in Personalized Therapeutic Approaches in Myelodysplastic Syndromes

2019 ◽  
Vol 17 (11.5) ◽  
pp. 1444-1447
Author(s):  
Rafael Bejar
Keyword(s):  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Hematologic Malignancies ◽  
Therapeutic Approaches ◽  
Current Standard ◽  
High Risk Disease ◽  
Current Standard Treatment ◽  
Rare Group

Often unrecognized and underdiagnosed, myelodysplastic syndromes (MDS) are a rare group of cancers in which the bone marrow fails to produce sufficient healthy blood cells. Although patients with lower-risk MDS can live for >5 years, those with high-risk disease that evolves into acute myeloid leukemia is associated with significantly lower overall survival. At the NCCN 2019 Annual Congress: Hematologic Malignancies, Dr. Rafael Bejar summarized current standard treatment options for patients with MDS and discussed the importance of genetic testing to identify mutations that may impact treatment. Finally, Dr. Bejar described emerging personalized treatment strategies for the management of this disease.

Increased Number of Driver Mutations Is a Predictor of Response to Hypomethylating Agents in Patients with Myelodysplastic Syndromes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 51-51
Author(s):  
Guillermo Montalban-Bravo ◽  
Ana Alfonso Pierola ◽  
Feng Wang ◽  
Song Xingzhi ◽  
Elias J. Jabbour ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Research Funding ◽  
Advisory Board ◽  
Response To Therapy ◽  
Driver Mutations ◽  
Hypomethylating Agents ◽  
Risk Patients ◽  
Clinical Records ◽  
The Impact

Abstract INTRODUCTION: Hypomethylating agents (HMA) such as azacitidine and decitabine remain the standard of care for the treatment of myelodysplastic syndromes (MDS). Although responses are seen in 40-60% patients, median response duration is 12-14 months. Eventual loss of response is associated with poor outcomes. Multiple studies have tried do identify biomarkers of response. Presence of TET2 mutations has been associated to increased response in several studies. Clear identification of predictors of response is still required. METHODS: We evaluated a total of 180 previously untreated patients with MDS or CMML that received HMA therapy at The University of Texas MD Anderson Cancer Center. Next generation sequencing (NGS), analyzing a panel of 28 genes (ABL1, ASXL1, BRAF, DNMT3A, EGFR, EZH2, FLT3, GATA1, GATA2, HRAS, IDH1, IDH2, IKZF2, JAK2, KIT, KRAS, MDM2, MLL, MPL, MYD88, NOTCH1, NPM1, NRAS, PTPN11, RUNX1, TET2, TP53 and WT1) was performed prior to therapy with HMA. Clinical and demographic data was obtained from clinical records. Generalized linear models were used to study association of response rates (ORR=overall and CR=complete) and risk factors. Response was defined following 2006 IWG criteria. The Kaplan-Meier produce limit methods were used to estimate the median overall survival (OS) and leukemia-free survival (LFS). RESULTS: Patient characteristics are shown in Table 1. Median age at diagnosis was 67 years (range 20-88). A total of 108 patients (60%) had lower-risk MDS based on IPSS and 72 (40%) had higher-risk MDS. A total of 143 patients (79%) had MDS and 37 (21%) had CMML. Eighty-seven (49%) patients had normal karyotype with 36 (20%) having complex karyotype. Therapy consisted in azacitidine monotherapy in 60 (33%) patients, decitabine monotherapy in 55 (31%) and guadecitabine or combinations in 65 (36%). The ORR was 58% (105/180) with 66 (37%) patients achieving CR. A total of 123 (68%) patients had at least one detectable mutation. Median number of mutations was 1 (range 0-5). The most frequently detected mutations included TET2 (23%), TP53 (16%) and RUNX1 (12%) which were all present in >10% cases. Frequency of detected mutations is shown in Figure 1A. Presence of ASXL1 mutation was associated with decreased likelihood of achieving CR (OR 0.30, 95% CI 0.10-0.93, p=0.037). No differences in ORR were observed based on presence of any individual mutation or any other clinical characteristic. Presence of TET2 mutation was not significantly associated with an increased likelihood of response (OR 1.32, 95% CI 0.64-2.70, p=0.453) or CR (OR 1.30, 95% CI 0.64-2.65, p=0.469). We subsequently analyzed the impact of number of detected mutations on response to therapy. Presence of three or more detectable mutations was associated with lower ORR (OR 0.29, 95% CI 0.10-0.88, p=0.028) and a trend to lower likelihood of achieving a CR (OR 0.22, 95% CI 0.05-1.01, p=0.052). Mutations in ASXL1 (p=0.003), BRAF (p=0.021), DNMT3A (p=0.018), EZH2 (p=0.01), GATA2 (p=0.021), MLL (p<0.001), NRAS (p<0.001), PTPN11 (p=0.002), RUNX1 (p=0.015), TET2 (p=0.001) and WT1 (p=0.04) tended to appear in patients with three or more mutations. Presence of TET2 mutations did not predict for ORR (OR 1.83, 95% CI 0.78-4.25, p=0.163) or CR (OR 1.75, 95% CI 0.80-3.81, p=0.159) within cases with less than three mutations. The median follow up of the cohort was 14.5 months (range 2.4-101.3 months). Patients who did not achieve a response had significantly shorter OS (median OS NR vs 21.3 months, HR 1.68, 95% CI 1.03-2.73, p=0.037) (Figure 1B) and LFS (median LFS NR vs 34.3 months, HR 2.13, 95% CI 1.00-4.50, p=0.049) (Figure 1C). Achievement of a CR predicted for improved OS in patients with higher-risk MDS (median OS NR vs 14.6 months, p=0.046) but not in lower-risk patients (NR vs 27.3 months, p=0.239). No significant differences in LFS were observed based on achievement of CR in both higher (p=0.238) and lower risk patients (p=0.453). CONCLUSION: The number of driver mutations may be a new biomarker to predict response to therapy with HMA in patients with MDS and CMML. Presence of ASXL1 mutations may be associated with a decreased risk of achieving a CR. As previously reported, response to therapy with HMA impacts the OS and LFS of patients with MDS. Incorporating sequencing data at diagnosis may help predict response to therapy and patient outcomes. Table 1. Table 1. Figure 1. Figure 1. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. DiNardo:Celgene: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Agios: Other: advisory board, Research Funding. Daver:Sunesis: Consultancy, Research Funding; Ariad: Research Funding; Kiromic: Research Funding; Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; BMS: Research Funding; Karyopharm: Honoraria, Research Funding. Konopleva:Cellectis: Research Funding; Calithera: Research Funding.

scholarly journals Setting Fire to ESA and EMA Resistance: New Targeted Treatment Options in Lower Risk Myelodysplastic Syndromes

2019 ◽  
Vol 20 (16) ◽  
pp. 3853 ◽  
Author(s):  
Anne Sophie Kubasch ◽  
Uwe Platzbecker
Keyword(s):  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Treatment Options ◽  
Targeted Treatment ◽  
Older Patient ◽  
Primary Resistance ◽  
Good Safety Profile ◽  
Recent Developments ◽  
Inflammatory Drugs ◽  
Made In

During the last decade, substantial advances have been made in the understanding of the complex molecular, immunological and cellular disturbances involved in the initiation as well as evolution of myelodysplastic syndromes (MDS). In 85% of the mainly frail and older patient population, anemia is present at the time of diagnosis and is thus a major therapeutic challenge. High rates of primary resistance to erythropoiesis-stimulating agents (ESAs), the currently only approved standard therapy to treat anemia in lower-risk MDS, demand the development of novel and efficient drugs with a good safety profile. Luspatercept, a ligand trap of activin receptor II, is able to promote late stage erythropoiesis even in patients failing prior ESA treatment. The presence of ring sideroblastic phenotype defines a subgroup of patients with higher response rates. Additionally, recent developments in clinical research using HIF-1 or telomerase modulation by roxadustat or imetelstat are promising. Other areas of translational research involve targeting the inflammasome by anti-inflammatory drugs in order to improve anemia. These efforts will hopefully pave the way for new targeted treatment options for anemic low-risk MDS patients.

How we treat lower-risk myelodysplastic syndromes

Blood ◽  
2013 ◽  
Vol 121 (21) ◽  
pp. 4280-4286 ◽  
Author(s):  
Pierre Fenaux ◽  
Lionel Adès
Keyword(s):  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Iron Chelation ◽  
International Prognostic Scoring System ◽  
Hypomethylating Agents ◽  
First Line ◽  
Thrombopoietin Receptor ◽  
Red Blood Cell Transfusions

AbstractLower-risk myelodysplastic syndromes (MDSs) are defined as having low or intermediate 1 risk by the International Prognostic Scoring System and are characterized mainly by anemia in most cases. Supportive care—primarily red blood cell transfusions—remains an important component of their treatment, but exposes patients to insufficient correction of anemia, alloimmunization, and organ iron overload (for which the role of iron chelation remains debated). Treatment aimed at preventing anemia recurrence should therefore be used whenever possible. Erythropoiesis stimulating agents remain the first-line treatment of anemia in most lower-risk MDS without del(5q), whereas anemia of low-risk MDS with del 5q responds to lenalidomide in two-thirds of the cases, but this drug should be used cautiously because profound cytopenias may occur initially. Treatment after failure of those first-line therapies are disappointing overall, with many patients eventually requiring long-term transfusions, but encouraging results have been reported with hypomethylating agents and lenalidomide. Selected patients respond to antithymocyte globulins, and thrombopoietin receptor agonists are under investigation in lower-risk MDS with thrombocytopenia. Some patients, while remaining at a “lower risk” MDS level, have severe cytopenias and/or poor prognostic factors, found using newer prognostic parameters, or resistance to treatment, making them urgent candidates for more intensive approaches, including allogeneic stem cell transplantation.

scholarly journals Imetelstat Achieves Meaningful and Durable Transfusion Independence in High Transfusion–Burden Patients With Lower-Risk Myelodysplastic Syndromes in a Phase II Study

2021 ◽  
Vol 39 (1) ◽  
pp. 48-56
Author(s):  
David P. Steensma ◽  
Pierre Fenaux ◽  
Koen Van Eygen ◽  
Azra Raza ◽  
Valeria Santini ◽  
...  
Keyword(s):  
Phase Ii ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Treatment Options ◽  
Competitive Inhibitor ◽  
Telomerase Activity ◽  
Transfusion Independence ◽  
Human Telomerase ◽  
Transcription Expression ◽  
Rbc Transfusion

PURPOSE Patients with lower-risk (LR) myelodysplastic syndromes (MDS) who are RBC transfusion dependent and have experienced relapse after or are refractory to erythropoiesis-stimulating agent (ESA) have limited treatment options. High telomerase activity and human telomerase reverse-transcription expression in clonal hematopoietic cells have been reported in patients with MDS. Imetelstat, a first-in-class competitive inhibitor of telomerase enzymatic activity, targets cells with active telomerase. We report efficacy, safety, and biomarker data for patients with LR MDS who are RBC transfusion dependent and who were relapsed/refractory to ESAs. PATIENTS AND METHODS In this two-part phase II/III study (MDS3001), the primary end point was 8-week RBC transfusion independence (TI) rate, with key secondary end points of 24-week RBC TI rate, TI duration, and hematologic improvement-erythroid. RESULTS Data from the phase II part of the study are reported. Of 57 patients enrolled and treated (overall population), 38 were non-del(5q) and hypomethylating agent and lenalidomide naïve (subset population). The 8- and 24-week RBC TI rates in the overall population were 37% and 23%, respectively, with a median TI duration of 65 weeks. In the subset population, 8- and 24-week RBC TI rates were 42% and 29%, respectively, with a median TI duration of 86 weeks. Eight-week TI rate was observed across all subgroups evaluated. Cytogenetic and mutational data revealed a reduction of the malignant clones, suggesting disease modification activity. The most common adverse events were cytopenias, typically reversible within 4 weeks. CONCLUSION Imetelstat treatment results in a meaningful, durable TI rate across a broad range of heavily transfused patients with LR MDS who are ineligible for or relapsed/refractory to ESAs. Biomarker analyses indicated effects on the mutant malignant clone.

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