Targeted therapies in myelodysplastic syndrome

Therapeutic alternatives for patients with myelodysplastic syndrome (MDS) have expanded in recent years but remain limited. While agents approved by the US Food and Drug Administration (FDA), including azacitidine, decitabine, and lenalidomide, have yielded hematologic and cytogenetic responses in a substantial portion of patients, these therapies are not curative. Active investigation of novel targets with biological relevance in myelopoiesis has stimulated the pharmacologic development of a multitude of agents that show promise in the treatment of MDS. Many of these drugs have entered or completed early phase clinical testing in MDS and include immunomodulatory agents, immunosuppressive therapies, survival signal inhibitors, thrombopoiesis-stimulating agents, pharmacologic differentiators, and anti-angiogenic and apoptotic agents. As we continue to collect clinical experience with these agents, the repertoire of available therapeutics for the treatment of MDS will expand and provide a foundation for novel therapeutic combinations.     

Combination strategies in myelodysplastic syndromes

The myelodysplastic syndromes (MDS) consist of an array of clonal hematological malignancies resulting from disorders of pluripotent hematopoietic stem cells. MDS is associated with a poor overall prognosis and patients are categorized as higher risk and lower risk on the basis of the International Prognostic Scoring System. Currently, lenalidomide, azacitidine, and decitabine are the only three FDA-approved drugs for MDS. Traditional therapies for MDS involve the administration of single agents providing either supportive measures or disease-modifying effects directed to slowing progression to acute myeloid leukemia (AML) and improving survival. Recently, however, there has been increasing evidence suggesting that the combination of drugs with different mechanisms of action offers substantial benefit in the form of diminished side effects, improved overall survival, and delayed progression to AML. Multiple studies indicate that when compared with traditional monotherapies, combining various medications with non-overlapping mechanisms of action and toxicities may result in significant benefit for patients with MDS. A variety of combination therapies with growth factors, DNA methytransferase inhibitors, histone deacetylase inhibitors, and immunosuppressant treatments provide encouraging data indicating that the successful future of MDS treatment rests in the combination of multiple treatments modalities to achieve improved clinical outcomes.     

Myelodysplasia: when to treat and how

Myelodysplastic syndrome (MDS) is a disorder of hematopoietic stem cells characterized by ineffective hematopoiesis. The result is pancytopenia leading to transfusion-dependent anemia, an increased risk of infection or bleeding, and a potential to progress to acute myeloid leukemia (AML). MDS is most prevalent among older individuals, many of whom also suffer from other medical conditions. MDS is classified according to World Health Organization criteria and the International Prognostic Scoring System. Supportive care remains the mainstay of therapy. Those with low-risk MDS can often be monitored for an extended period of time without specific therapy, whereas those with intermediate- or high-risk MDS benefit from treatment. Currently, only azacitidine is approved for the treatment of MDS. Several new agents are being tested, including inhibitors of angiogenesis (thalidomide, lenalidomide), farnesyl transferase inhibitors (lonafarnib, tipifarnib), and DNA methyltransferase inhibitors (azacitidine, decitabine). Lenalidomide appears particularly effective in patients with low-risk MDS with the deletion of chromosome 5q31. Allogeneic stem cell transplantation is an alternative for high-risk MDS. With advances in transplantation techniques, this treatment can be offered to an increasing number of patients. However, it is necessary to assess each patient's disease individually and to evaluate prognostic factors, other treatment options, and the appropriateness and timing of transplantation.     

Demonstration of additional benefit in adding lenalidomide to azacitidine in patients with higher-risk myelodysplastic syndromes

Lenalidomide and azacitidine are active in MDS patients, and may complement each other by targeting the bone marrow microenvironment and the malignant clone. A recent Phase I trial testing the lenalidomide and azacitidine combination yielded encouraging results; however, lenalidomide’s contribution was unclear. In this study, 18 higher-risk MDS patients were treated with the combination for seven cycles, after which lenalidomide was discontinued in eight patients who achieved a complete response, with azacitidine monotherapy continuing until disease progression. We report on three patients who relapsed on monotherapy with excess blasts at 12, 19, and 24 months, in whom lenalidomide was then resumed in combination with azacitidine. Each patient, one with normal cytogenetics at relapse; one with a 18 abnormality; and one with del(4q25), recaptured a complete response that was sustained for 5, 7, and 7+ months. We conclude that the addition of lenalidomide to azacitidine provides additional clinical benefit over azacitidine monotherapy.     

Current therapy of myelodysplastic syndromes

After being a neglected and poorly-understood disorder for many years, there has been a recent explosion of data regarding the complex pathogenesis of myelodysplastic syndromes (MDS). On the therapeutic front, the approval of azacitidine, decitabine, and lenalidomide in the last decade was a major breakthrough. Nonetheless, the responses to these agents are limited and most patients progress within 2 years. Allogeneic stem cell transplantation remains the only potentially curative therapy, but it is associated with significant toxicity and limited efficacy. Lack or loss of response after standard therapies is associated with dismal outcomes. Many unanswered questions remain regarding the optimal use of current therapies including patient selection, response prediction, therapy sequencing and combinations, and management of resistance. It is hoped that the improved understanding of the underpinnings of the complex mechanisms of pathogenesis will be translated into novel therapeutic approaches and better prognostic/predictive tools that would facilitate accurate risk-adaptive therapy.     

Optimizing the use of hypomethylating agents in myelodysplastic syndromes: Selecting the candidate,predicting the response,and enhancing the activity

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders that have a substantial impact on patients’ quality of life, in addition to causing significant morbidity and mortality. The hypomethylating agents (HMAs) azacitidine and decitabine are approved for use in the United States and in Europe for the treatment of MDS or acute myeloid leukemia (AML) and, in the case of azacitidine, prolong survival in higher-risk patients. Neither is curative, though, and given the lack of clear treatment guidelines after HMA treatment failure, it is imperative to optimize patient selection and identify the right timing of HMA treatment initiation and response evaluation to maximize patient benefit. Initiatives to improve outcomes have focused on HMA-based drug combinations to enhance HMA activity or treat MDS using complementary drug mechanisms of action. In this review, we will summarize the available data to aid decision-making while treating MDS patients with HMAs.     

Does early diagnosis and treatment of myelodysplastic syndromes make a difference?

Patients diagnosed with myelodysplastic syndromes (MDS) often ask their physicians whether earlier detection of disease or more prompt initiation of treatment might have resulted in a better outcome. The concept of starting therapy at an early point in the disease process when the clonal burden of abnormal hematopoietic stem cells may be lower and somatic mutational complexity less, and therefore treatment more likely to be effective, is attractive. However, at present there is no evidence that therapy with any of the available drugs for MDS (ie, erythropoiesis stimulating agents, lenalidomide, azacitidine or decitabine) early after diagnosis is associated with better outcomes than later initiation of drug therapy. For those patients who are eligible for allogeneic hematopoietic cell transplant and have a suitable donor, early transplant of lower-risk MDS is associated with worse outcomes compared to nontransplant approach, whereas early transplant therapy of higher-risk disease improves outcomes compared to delaying transplant. Here I review available data about MDS diagnostic patterns and early versus later diagnosis and therapy initiation.     

Has there been progress in the treatment of older patients with acute myeloid leukemia?

The treatment of older patients with acute myeloid leukemia (AML) has become increasingly important as the population ages. Progress, measured by overall survival rates, has improved in younger patients, perhaps due to the use of intensive post-remission therapies, but it is unclear what will enable progress for older AML patients. The older AML patient population is very heterogeneous, and both patient-specific and leukemia-specific factors must be taken into consideration when choosing the therapy that will most benefit each patient. In addition to standard and intensive chemotherapy regimens, a number of alternative therapies for previously untreated older AML patients are currently being investigated. These include gemtuzumab ozogamicin, azacitidine, decitabine, and clofarabine.     

Comparative clinical effectiveness of azacitidine versus decitabine in older patients with myelodysplastic syndromes

The hypomethylating agents (HMAs) azacitidine and decitabine are both approved for treatment of myelodysplastic syndromes (MDS) in the USA. In Europe, decitabine is not approved due to lack of survival advantage in randomized trials. The two drugs have not been compared in clinical trials. We identified patients diagnosed with MDS between 2004 and 2011 from the Surveillance, Epidemiology, and End Results (SEER)‐Medicare linked database in the USA who received ≥ 10 doses of either HMA. We estimated survival from HMA initiation with Kaplan–Meier methods and used multivariate Cox proportional hazards models to adjust for covariates. Analyses controlled for histological subtype and we conducted a subset analysis limited to patients with refractory anaemia with excess blasts (RAEB). In 2025 HMA‐treated patients, median survival was 15 months with no difference in survival based on the HMA received in adjusted analysis (decitabine versus azacitidine, hazard ratio = 1·06, 95% confidence interval: 0·94–1·19, P = 0·37). For RAEB patients (n = 523), median survival was 12 months, with no significant difference based on HMA received. No significant survival difference was found between azacitidine and decitabine in patients with MDS, including RAEB. Importantly, population‐based survival of azacitidine‐treated RAEB patients was substantially shorter than in the AZA‐001 clinical trial (11 versus 24·5 months).     

In vivo effects of decitabine in myelodysplasia and acute myeloid leukemia: review of cytogenetic and molecular studies

Low-dose demethylating agents such as 5-aza-2'-deoxycytidine (decitabine, DAC) and 5-azacytidine (azacitidine, Vidaza) have been explored for the treatment of myelodysplasia, acute myeloid leukemia, and hemoglobinopathies since the early 1980s, aiming to revert a methylator phenotype. Originally, the treatment rationale in hemoglobinopathies was to achieve demethylation of the hypermethylated and hence silent gamma-globin gene locus, thus reactivating synthesis of hemoglobin F (HbF). In myelodysplastic syndrome (MDS), cytogenetic analyses are mandatory for risk stratification and for monitoring response to drug treatment. The current knowledge regarding cytogenetic subgroups as predictors of response to low-dose decitabine in MDS as well as cytogenetic responses caused by demethylating agents is summarized in this review. Decitabine treatment is associated with a response rate that is higher in patients with high-risk cytogenetics (i.e., complex karyotype and/or abnormalities of chromosome 7) than in patients with intermediate-risk cytogenetics (two abnormalities or single abnormalities excluding 5q-, 20q-, and -Y). Following decitabine treatment of patients with abnormal karyotype, approximately one-third achieve a major cytogenetic response that can be confirmed by FISH analyses, while in two-thirds of patients, the abnormal karyotype persists but hematologic improvement may be observed during continued treatment. The most frequently studied gene in myelodysplasia is the cell cycle regulator p15(INK4b). Hypermethylation of p15(INK4b) in MDS is reversed during treatment with decitabine, resulting in reactivation of this gene. In hemoglobinopathies, treatment with demethylating agents leads to reactivation of fetal HbF (the gamma-globin gene locus also possibly being another target for reactivation in MDS), and thus, HbF may potentially act as surrogate marker for activity of decitabine. Other, thus far unidentified hypermethylated genes may also be targets for demethylating agents.     

Clinical experience with decitabine in North American patients with myelodysplastic syndrome

Recent evidence demonstrates that epigenetic silencing of genes is associated with myelodysplasia and that a worse prognosis may be correlated with hypermethylation of certain genes, such as the cyclin-dependent kinase inhibitor p15. 5-Aza-2'-deoxycytidine (decitabine, DAC) is a nucleoside analog, which, at low doses, acts as a hypomethylating agent and is fivefold to tenfold more active than 5-azacytidine (azacitidine, Vidaza)--currently the only approved drug for treatment of myelodysplastic syndrome (MDS). Clinical studies have demonstrated that decitabine has activity in patients with MDS. Preliminary results of a phase III multicenter North American trial comparing low-dose decitabine to supportive care verified that therapy with decitabine resulted in higher response rates, improved quality of life, and prolonged time to leukemic transformation and/or death. However, further elucidation of its mechanism of action is required, as clinical response to decitabine does not correlate with demethylation of the p15 gene promoter or the repetitive DNA element LINE. Decitabine appears to upregulate both hypermethylated and nonmethylated genes. Ongoing studies aim to determine the optimal dose, schedule, and route of administration of decitabine, and to evaluate whether efficacy can be improved by using it in combination with other agents, such as histone deacetylase inhibitors.     

Immunomodulatory Therapy for Myelodysplastic Syndromes

Thalidomide and lenalidomide belong to the proprietary group of immunomodulatory drugs (IMiDs) that display broad biologic and pharmacologic properties. Encouraging results of clinical studies that evaluated the efficacy of thalidomide in patients with myelodysplastic syndromes (MDSs) led to the investigation of its structural analogue, lenalidomide, in patients with lower-risk MDS. The cumulative results of studies that tested lenalidomide in patients with interstitial deletion of chromosome 5q, ie, del(5q), showed a high frequency of both erythroid and cytogenetic responses (approximately 75% of patients), which led to US Food and Drug Administration approval of this agent for this cytogenetically defined MDS subset. A multicenter phase III study (MDS-002) that investigated the frequency of transfusion response in lower-risk non-del(5q) MDS patients showed that lenalidomide had significant erythropoietic activity, albeit less robust in lower-risk MDS without del(5q). These studies established lenalidomide as an active erythropoietic-remitting agent with novel cytogenetic-remitting activity in lower-risk MDS patients who would not otherwise benefit from therapy with erythropoietic growth factors. The National Comprehensive Cancer Network Clinical Practice Guidelines recently added lenalidomide to the therapeutic algorithm for MDS as front-line therapy for lower-risk MDS patients with del(5q) and transfusion-dependent anemia.     

Rapid loss of response after withdrawal of treatment with azacitidine: a case series in patients with higher‐risk myelodysplastic syndromes or chronic myelomonocytic leukemia

In patients with myelodysplastic syndromes (MDS), the likelihood of having a sustained response to azacitidine is increased by maximizing treatment duration. This is important as prognosis postrelapse is poor. There is also the concern that early termination of treatment may result in rapid disease progression. We reviewed outcomes in 13 patients who discontinued azacitidine (decitabine in one patient) while still responding to the treatment. Most patients rapidly relapsed; median time to progression was 5.4 months. Reasons for treatment discontinuation included comorbidities, infections, and patient choice. These findings illustrate the risk of prematurely terminating azacitidine therapy in MDS.     

Comparative analysis between azacitidine and decitabine for the treatment of myelodysplastic syndromes

The present study aimed to directly compare the efficacy and safety of azacitidine and decitabine in patients with myelodysplastic syndromes (MDS). We compared the overall response rate (ORR) (complete responses, partial responses, marrow complete responses, and haematological improvements), overall survival (OS), event‐free survival (EFS), time to leukaemic transformation, and adverse outcomes between azacitidine and decitabine. To minimize the effects of treatment selection bias in this observational study, adjustments were made using the propensity‐score matching method. Among 300 patients, 203 were treated with azacitidine and 97 with decitabine. Propensity‐score matching yielded 97 patient pairs. In the propensity‐matched cohort, there were no significant differences between the azacitidine and decitabine groups regarding ORR (44% vs. 52%), OS (26 vs. 22·9 months), EFS (7·7 vs. 7·0 months), and rate of leukaemic transformation (16% vs. 22% at 1 year). In patients ≥65 years of age, survival was significantly better in the azacitidine group (P = 0·017). Patients who received decitabine experienced more frequent episodes of grade 3 or 4 cytopenia and infectious episodes. We found that azacitidine and decitabine showed comparable efficacy. Among patients ≥65 years of age, survival was significantly better in the azacitidine group (ClinicalTrials.gov Identifier: NCT01409070).     

MDS: Refining existing therapy through improved biologic insights

Advances in therapy can essentially be measured using two parameters; introduction of a new agent which benefits an increased number of patients over prevailing treatments or more selective use of an existing drug by matching it to the biologic characteristics associated with response. In reviewing the therapeutic landscape of myelodysplastic syndromes (MDS), both should be applied to gauge the advances in therapy. While several new drugs are currently in clinical trials for the treatment of MDS, three drugs were approved for use in the last decade and sufficient time has elapsed to take stock of the benefit they have produced in the outcome of patients both in terms of survival and quality of life. For the two hypomethylating agents, response remains limited to 50% patients at best, and no strategy has evolved to allow for pre-selection of likely responders, however, 5-azacytidine has been associated with improvement in the survival of higher risk patients. The benefit of lenalidomide was found to be greater for del(5q) patients with transfusion dependent anemia and lower risk disease right from the start, although a quarter of the non-del(5q) patients also experienced complete transfusion independence with this agent. It is in this latter group of non-del(5q) cases that a strategy for potentially preselecting likely responders is suggested by the finding of an expression profile associated with response. In this paper, we will focus on defining our current understanding of the mechanisms of action of the existing FDA approved drugs in order to identify therapeutic strategies that are suitable for specific MDS subtypes. We expect that through advancing biologic insights, the use of such therapies will become more selective and refined.     

Management of patients with higher-risk myelodysplastic syndromes after failure of hypomethylating agents: What is on the horizon?

The hypomethylating agents (HMA) azacitidine (AZA) and decitabine (DAC) are the standard of care for frontline treatment of patients with higher-risk myelodysplastic syndromes (MDS). As complete responses to HMAs are rare and typically not durable, HMA failure is a common clinical dilemma and associated with very short survival in most patients. Salvage therapies with various agents such as novel HMAs (guadecitabine, CC-486), and CTLA-4/PD1-type immune checkpoint inhibitors (ICPIs) have yielded mixed and only modest results at best in MDS patients with HMA failure. Thanks to advances in the understanding of the molecular and biologic pathogenesis of MDS, several novel targeted agents such as the BCL-2 inhibitor venetoclax, TP-53 refolding agent APR-246, IDH1/2 inhibitors, and novel ICPIs such as magrolimab and sabatolimab have been developed and demonstrated activity in combination with HMA in the frontline setting. However, clinical testing of these agents post HMA failure has been limited to date. Furthermore, the biology of HMA failure remains poorly defined which significantly limits rationale drug development. This highlights the importance of optimization of frontline therapy to avoid/delay HMA failure in addition to development of more effective salvage therapies.     

Decitabine: a historical review of the development of an epigenetic drug

The development of decitabine from its synthesis in 1964 to the submission of a registration file has been described. Although the unique DNA-demethylating capacity of decitabine is known for a long time, its application is under continuing investigation. The use of decitabine in MDS, AML, CML, stem cell transplant, sickle cell anemia and thalassemia looks promising. The epigenetic dose seems lower than the cytotoxic dose. Whereas most drugs have matured after 40 years, decitabine is only at the beginning of a new development phase in epigenesis.     

Myelodysplastic syndromes: 2012 update on diagnosis, risk-stratification, and management

DISEASE OVERVIEW: The myelodysplastic (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). MDS occurs more frequently in older male and in individuals with prior exposure to cytotoxic therapy. DIAGNOSIS: Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry or molecular genetics is complementary but not diagnostic. RISK-STRATIFICATION: Prognosis of patients with MDS can be calculated using a number of scoring systems. In general, all these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the bone marrow and cytogenetic characteristics. The most commonly used system is the International Prognostic Scoring System. IPSS is likely to be replaced by a new revised score (IPSS-R) and by the incorporation of new molecular markers recently described. RISK-ADAPTED THERAPY: Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts, and, more recently, cytogenetic profile. Goals of therapy are different in lower risk patients than in higher risk. In lower risk, the goal is to decrease transfusion needs and transformation to higher risk disease or AML. In higher risk, the goal is to prolong survival. Current available therapies include growth factor support, lenalidomide, hypomethylating agents, intensive chemotherapy, and allogeneic stem cell transplantation. The use of lenalidomide has significant clinical activity in patients with lower risk disease, anemia and a chromosome 5 alteration. 5-azacitidine and decitabine have activity in higher risk MDS. 5-azacitidine has been shown to improve survival in higher risk MDS. A number of new molecular lesions have been described in MDS that may serve as new therapeutic targets or aid in the selection of currently available agents. Additional supportive care measures may include the use of prophylactic antibiotics and iron chelation. MANAGEMENT OF PROGRESSIVE OR REFRACTORY DISEASE: At the present time there are no approved interventions for patients with progressive or refractory disease particularly after hypomethylating based therapy. Options include cytarabine based therapy, transplantation and participation on a clinical trial.     

Thrombopoiesis‐stimulating agents and myelodysplastic syndromes

Thrombocytopenia in patients with myelodysplastic syndromes (MDS) is a frequent cause of haemorrhage‐related morbidity and mortality, and is associated with increased risk of leukaemic transformation and reduced overall survival. In addition, thrombocytopenia in MDS limits the tolerability and therapeutic efficacy of disease‐modifying therapies, such as azacitidine or lenalidomide. The recombinant human erythropoietin (rHuEPO) erythropoiesis‐stimulating agents, epoetin and darbepoetin, are an established component of anaemia management in lower‐risk MDS. Their success has, in turn, driven the development of haematopoietic growth factors targeting thrombocytopenia. While recombinant thrombopoietin (THPO) proved too immunogenic for clinical use, novel thrombopoiesis‐stimulating agents (TSAs) have the potential to reduce bleeding events, decrease dependency on platelet transfusions and extend exposure to disease‐modifying therapies. Two TSAs, eltrombopag and romiplostim, have demonstrated benefit in chronic immune thrombocytopenia purpura (ITP) and safety and efficacy data for use of these agents in MDS is growing. However, important safety concerns remain, such as the potential for stimulation of neoplastic myeloid clones by THPO agonists. In this narrative review, we discuss the rationale and biological mechanism for TSAs in MDS, describe the agents currently available and their mechanism of action, and present current clinical data relating to TSA safety and efficacy in the context of MDS.     

Comparison of 7-day azacitidine and 5-day decitabine for treating myelodysplastic syndrome

Two DNA methyltransferase inhibitors, azacitidine and decitabine, are currently approved for the treatment of myelodysplastic syndrome (MDS). Choosing between these drugs is an important practical issue. In this retrospective study, patients receiving AZA-7d (azacitidine 75 mg/m² subcutaneously?×?7 days, n?=?75) or DEC-5d (decitabine 20 mg/m² intravenously?×?5 days, n?=?74) were compared. The rates of hematologic response (complete response [CR]/partial response [PR]/marrow CR) were 12.0 % (AZA-7d) vs. 29.7 % (DEC-5d) (P?=?0.008), and the overall response rates (CR/PR/marrow CR/hematologic improvement) were 52.0 % (AZA-7d) vs. 63.5 % (DEC-5d) (P?=?0.155). Grade 3 or higher neutropenia occurred more frequently with DEC-5d (79.6 %) than with AZA-7d (72.2 %) (P?=?0.040). Overall survival probabilities at 2 years were 42.1 % (AZA-7d) vs. 42.2 % (DEC-5d) (P?=?0.944). Subgroup analysis revealed that AZA-7d associated with higher survival rates than DEC-5d in patients whose MDS duration exceeded 1 year or who had poor performance status. In conclusion, both AZA-7d and DEC-5d regimens were effective in treating patients with MDS. However, the two regimens differed in terms of clinical responses and toxicities. One hypomethylating regimen may be superior to the other regimen in particular subgroups.