Tag: Myelodysplastic Syndrome

First Line REBLOZYL® Superior to Epoetin Alfa in Lower Risk Myelodysplastic Syndromes

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SUMMARY: It is estimated that in the US approximately 13,000 people are diagnosed with MyeloDysplastic Syndromes (MDS) each year. The prevalence has been estimated to be from 60,000 to 170,000 in the US. MyeloDysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias, mainly symptomatic anemia, with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. Majority of the individuals diagnosed with MDS are 65 years or older and die as a result of infection and/or bleeding, consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML).

Patients with Lower-risk MDS (Revised IPSS-Very Low, Low, or Intermediate risk ) often present with symptomatic anemia and these patients are in chronic need for RBC transfusions which in turn can result in iron overload and can have a negative impact on quality of life and Overall Survival. These patients are treated with Erythropoiesis Stimulating Agents (ESAs) as first line therapy. ESAs such as Darbepoetin alfa and Epoetin alfa are re-engineered and recombinant DNA technology products of Erythropoietin (EPO), and they stimulate erythropoiesis by binding and activating the EPO receptor. However, transfusion-dependent patients with serum EPO levels above 200 U per liter are less likely to respond to ESAs. Additionally, patients with MDS with ring sideroblasts have a shorter median duration of response to ESAs, than those who do not have ring sideroblasts. Patients with Lower-risk MDS with chromosome 5q deletion (del 5q) who are transfusion dependent are treated with Lenalidomide, regardless of previous treatment with ESAs. In contrast, only 39% of patients with non-del(5q) Lower-risk MDS receive second line therapy besides RBC transfusions, and there are few treatment options for patients who are refractory to, unresponsive to, or ineligible for ESAs. There is therefore an unmet clinical need for safe and effective treatment options, to reduce the RBC transfusion burden in these patients.

Signaling by the SMAD2 and SMAD3 pathway exerts an inhibitory effect on red cell maturation. This pathway is constitutively activated in the bone marrow cells of patients with MDS and diseases associated with ineffective erythropoiesis such as β-thalassemia. Luspatercept (REBLOZYL®) is a recombinant soluble fusion protein and is first-in-class erythroid maturation agent that enhances erythropoiesis by promoting late-stage Red Blood Cell precursor differentiation and maturation. It targets select Transforming Growth Factor (TGF)-β superfamily ligands such as GDF11, that regulate late-stage erythropoiesis. This results in a reduction in aberrant SMAD2 and SMAD3 signaling, thereby promoting late-stage RBC precursor differentiation and maturation. In the MEDALIST trial, Luspatercept significantly reduced the severity of anemia in patients with Lower-risk MDS with Ring Sideroblasts, who had been RBC transfusion-dependent, and who had disease that was refractory to, or unlikely to respond to ESAs.

COMMANDS trial is a global, randomized, controlled, open-label Phase III study, conducted to evaluate the efficacy and safety of Luspatercept in ESA-naive patients with Low Risk-MDS. This study included 354 eligible patients with lower-risk MDS as defined by the revised International Prognostic Scoring System (IPSS-R) criteria, with or without Ringed Sideroblasts. These patients had less than 5% bone marrow blasts and serum EPO levels less than 500 U/L and required red blood cell transfusions (defined as 2–6 RBC units/8 weeks for at least 8 weeks immediately prior to randomization). Patients were randomized 1:1 to receive Luspatercept (starting dose 1.0 mg/kg, titration up to 1.75 mg/kg) subcutaneous, once every 3 weeks for at least 24 weeks (N=178) or Epoetin alfa (starting dose 450 IU/kg, titration up to 1050 IU/kg, with a maximum permitted total dose of 80 000 IU)) weekly for at least 24 weeks (N=176). The median patient age was 74 years and both treatment groups were well balanced. Patients were stratified by baseline RBC transfusion burden (less than 4 units per 8 weeks versus 4 or more units per 8 weeks), endogenous serum EPO concentration (200 U/L or less versus more than 200 to less than 500 U/L), and Ring Sideroblast status (positive versus negative). The Primary endpoint was RBC independence for at least 12 weeks with a concurrent mean hemoglobin increase of at least 1.5 g/dL within the first 24 weeks.

At the planned interim analysis of 301 patients, 147 patients in the Luspatercept group and 154 patients in the Epoetin alfa group completed 24 weeks of treatment or discontinued earlier and the median treatment duration was 41.6 weeks for Luspatercept and 27.0 weeks for Epoetin alfa. Luspatercept was superior in efficacy compared to Epoetin alfa. Among patients receiving Luspatercept at the planned interim analysis, 58.5% achieved RBC transfusion independence for at least a 12-week consecutive period within the first 24 weeks, along with an increase in hemoglobin of at least 1.5 g/dL compared to 31.2% of patients receiving Epoetin alpha (P<0.0001). Luspatercept was effective regardless of baseline serum EPO, red blood cell transfusion burden, SF3B1 mutation status, or Ring Sideroblast status. These results were similar when comparisons of baseline serum erythropoietin and baseline RBC transfusion burden in subgroups were made. However, responses were different based on ring sideroblast status. Approximately 65% of Ringed Sideroblast positive patients on Luspatercept achieved the Primary endpoint compared to 26% on Epoetin alfa. Among Ringed Sideroblast negative patients, slightly more met this end point on Epoetin alfa (46% versus 41% respectively). The Secondary endpoints in the study included Hematologic Improvement-Erythroid Response of 8 weeks or more and RBC transfusion independence at 24 weeks or more and at 12 weeks or more. Similar to the Primary endpoint, Luspatercept was more effective than Epoetin alfa across these Secondary endpoints.

It was concluded from this interim analysis that compared with Epoetin alfa, Luspatercept significantly improved RBC transfusion independence, and erythroid response, as well as duration of response, with no new toxiciites. The authors added that this innovative therapy with Luspatercept could represent a new standard of care for patients with RBC transfusion dependent Low Risk Myelodysplastic Syndromes. Long-term follow up will be needed to confirm these results and further refine findings in patients with Lower-Risk Myelodysplastic Syndromes, including non-mutated SF3B1 or Ring Sideroblast-negative subgroups.

Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. Platzbecker U, Della Porta MG, Santini V, et al. The Lancet. 2023; 402:373-385

FDA Approves Ivosidenib for Myelodysplastic Syndromes

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SUMMARY: The FDA on October 24, 2023, approved Ivosidenib (TIBSOVO®) for adult patients with Relapsed or Refractory MyeloDysplastic Syndromes (MDS) with a susceptible Isocitrate DeHydrogenase-1 (IDH1) mutation, as detected by an FDA-approved test. The FDA also approved the Abbott RealTime IDH1 Assay as a companion diagnostic device to select patients for Ivosidenib.

It is estimated that in the US approximately 13,000 people are diagnosed with MyeloDysplastic Syndromes (MDS) each year. The prevalence has been estimated to be from 60,000 to 170,000 in the US. MyeloDysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias, mainly symptomatic anemia, with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. Majority of the individuals diagnosed with MDS are 65 years or older and die as a result of infection and/or bleeding, consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML).

The International Prognostic Scoring System (IPSS) for MDS has 4 risk groups based on Total Risk Score (Low, Intermediate-1, Intermediate-2 and High). The three prognostic factors scored to predict the course of the patient’s disease include, percentage of blast cells in the bone marrow, type of chromosomal changes in the marrow cells and number of cytopenias (anemia, neutropenia or thrombocytopenia). Patients with low-risk MDS have an indolent disease course with a median survival of about 6 years with no therapeutic intervention. Patients with intermediate and higher-risk disease however have a shorter median survival even with treatment, with approximately a third of the patients progressing to AML within 3 years.

Patients with Low-risk MDS often present with symptomatic anemia and these patients are in chronic need for RBC transfusions. These patients are treated with Erythropoiesis Stimulating Agents (ESAs) as first line therapy. ESAs such as Darbepoetin alfa and Epoetin alfa are re-engineered and recombinant DNA technology products of Erythropoietin (EPO), and they stimulate erythropoiesis by binding and activating the EPO receptor. However, transfusion-dependent patients with serum EPO levels above 200U per liter are less likely to respond to ESAs. A majority of patients with higher-risk MDS are treated with hypomethylating agents such as Azacitidine and Decitabine and these agents can favorably modify the natural history of the disease, and have been shown to improve survival. However, outcomes are poor and no therapies currently exist for patients with Isocitrate Dehydrogenase 1-mutant Relapsed or Refractory MDS, following failure on a hypomethylating agent.

Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites, by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia and tumorigenesis in solid tumors and can result in inferior outcomes. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle. Approximately 20% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic cholangiocarcinoma, 30% of patients with Angioimmunoblastic T-cell lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations.

Ivosidenib is a first-in-class, oral, potent, targeted, small-molecule inhibitor of mutant IDH1. The FDA in 2018, approved Ivosidenib for adult patients with Relapsed or Refractory AML with a susceptible IDH1 mutation, and in 2019 approved Ivosidenib for newly diagnosed AML with a susceptible IDH1 (Isocitrate DeHydrogenase-1) mutation, in patients who are at least 75 years old or who have comorbidities that preclude the use of intensive induction.

The present FDA approval is supported by a pivotal Phase 1, open-label, multinational study, in which the safety, tolerability, and clinical activity of Ivosidenib was evaluated among patients with Relapsed or Refractory Myelodysplastic syndromes with an IDH1 mutation. In this study 18 eligible patients (N=18) received Ivosidenib 500 mg orally daily, continuous for 28-day cycles, until disease progression, unacceptable toxicity, or Hematopoietic Stem Cell Transplantation. The median treatment duration was 9.3 months. One patient underwent a Stem Cell Transplantation following Ivosidenib. IDH1 mutations were detected in peripheral blood or bone marrow by a local or central diagnostic test and confirmed retrospectively by the Abbott RealTime IDH1 Assay. The median age was 73 years and majority of patients had intermediate or high IPSS-R score at the time of screening for the study. The Primary efficacy end point was the Complete Response (CR) plus Partial Response (PR) rate. Secondary endpoints included duration of CR plus PR, duration of transfusion independence, and time to transfusion independence.

All observed responses were Complete Responses. The CR rate was 38.9%. The median time to Complete Response was 1.9 months and at the time of data cutoff, the median duration of Complete Responses was not estimable and ranged from 1.9 to 80.8+ months. Additionally, of the 9 patients who were transfusion dependent with Red Blood Cells or platelets at baseline, 67% became RBC and platelet transfusion independent during any 56-day post-baseline period. Of the 9 patients independent of both RBC and platelet transfusions at baseline, 78% remained transfusion independent during any 56-day post-baseline period. The most common adverse reactions included GI toxicities such as mucositis, diarrhea, constipation and nausea, fatigue, arthralgia, myalgia, cough, and rash. Differentiation syndrome was rare and manageable. It should be noted that Ivosidenib can also cause QTc prolongation.

It was concluded from this study that Ivosidenib induced durable remissions including a substantial proportion of Complete Remissions with an acceptable safety profile, in patients with Relapsed or Refractory Myelodysplastic syndromes with an IDH1 mutation. Further, a significant proportion of patients became or remained transfusion independent. This is the first targeted therapy approved for this indication.

UPDATED SUBSTUDY RESULTS FOR IVOSIDENIB IN IDH1-MUTANT RELAPSED/REFRACTORY MYELODYSPLASTIC SYNDROME. Dinardo C, Roboz G, Watts JM, et al. Hemasphere. 2023 Aug; 7(Suppl): e75740ab. DOI: 10.1097/01.HS9.0000969800.75740.ab.

Efficacy of Low Dose Decitabine and Azacitidine in Lower Risk Myelodysplastic Syndrome

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SUMMARY: It is estimated that in the US approximately 13,000 people are diagnosed with MyeloDysplastic Syndromes (MDS) each year. The prevalence has been estimated to be from 60,000 to 170,000 in the US. MyeloDysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias, mainly symptomatic anemia, with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. Majority of the individuals diagnosed with MDS are 65 years or older and die as a result of infection and/or bleeding, consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML).

The International Prognostic Scoring System (IPSS) for MDS has 4 risk groups based on Total Risk Score (Low, Intermediate-1, Intermediate-2 and High). The three prognostic factors scored to predict the course of the patient’s disease include, percentage of blast cells in the bone marrow, type of chromosomal changes in the marrow cells and number of cytopenias (anemia, neutropenia or thrombocytopenia). Patients with low-risk MDS have an indolent disease course with a median survival of about 6 years with no therapeutic intervention. Patients with intermediate and higher-risk disease however have a shorter median survival even with treatment, with approximately a third of the patients progressing to AML within 3 years.

Patients with Low-risk MDS often present with symptomatic anemia and these patients are in chronic need for RBC transfusions. These patients are treated with Erythropoiesis Stimulating Agents (ESAs) as first line therapy. ESAs such as Darbepoetin alfa and Epoetin alfa are re-engineered and recombinant DNA technology products of Erythropoietin (EPO), and they stimulate erythropoiesis by binding and activating the EPO receptor. However, transfusion-dependent patients with serum EPO levels above 200U per liter are less likely to respond to ESAs. A majority of patients with higher-risk MDS are treated with hypomethylating agents such as VIDAZA® (Azacitidine) and DACOGEN® (Decitabine) and these agents can favorably modify the natural history of the disease, and have been shown to improve survival. However, the role of the hypomethylating agents in lower-risk MDS has not been established.

To better understand the role of hypomethylating agents in adult patients with previously untreated MDS, with low or Intermediate-1 risk MDS or Chronic MyeloMonocytic Leukemia (CMML), the researchers conducted a long-term analysis, of a previously reported randomized Phase II study of low dose Decitabine versus low dose Azacitidine, in lower-risk MDS and MDS/myeloproliferative neoplasms (Jabbour E, et al. Blood. 2017;130:1514-1522). The aim of this study was to better understand the impact of attenuated hypomethylating agents dosing, in patients with lower-risk MDS.

A total of 113 patients (N=113) were randomly assigned with a Bayesian response-adaptive design to receive either Decitabine 20 mg/m2 IV daily (N=73) or Azacitidine 75 mg/m2 IV daily (N=40) on days 1-3 of every 28-day cycle, between November 2012 and February 2016. Responding patients were allowed to continue therapy indefinitely. Bone marrow aspiration and/or biopsy were performed at the end of course 2 and every 3 months during the first year, and then every 3 to 6 months thereafter. Patients who had received other prior treatments for MDS, including growth factors, were eligible. Hydroxyurea treatment was permitted to control leukocytosis before study therapy. The authors in their previous publication reported that at a median follow up of 20 months, hypomethylating agents induced high response rates in patients with lower-risk MDS. The researchers in this extension analysis of lower-risk MDS patients, evaluated the Duration of Response, Event-Free Survival (EFS), and Overall Survival (OS), with a median follow-up of 68 months. The median number of treatment cycles was 15.

The Overall Response Rate was 67% in the Decitabine group and 48% in the Azacitidine group (P=0.042). Of the 59 patients who were transfusion dependent, 32% became transfusion independent (Decitabine 41% and Azacitidine 15%; P=0.039). The median duration of transfusion independency was 22 months. Among those patients who were transfusion independent at baseline, 9% became transfusion dependent after therapy. With a median follow-up of 68 months, the median overall Event-Free Survival was 17 months and median Overall Survival was 33 months. No early deaths were observed.

The authors concluded that low dose hypomethylating agents can induce durable response of transfusion independency in patients with lower-risk MDS, and response to hypomethylating agents can be associated with favorable clinical outcomes in this patient group.

Low-Dose Decitabine versus Low-Dose Azacitidine in Lower-Risk MDS. Sasaki K, Jabbour E, Montalban-Bravo G, et al. DOI:https://doi.org/10.1056/EVIDoa2200034

Noninvasive Evaluation of Myelodysplastic Syndrome in Patients with Unexplained Anemia

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SUMMARY: It is estimated that in the US approximately 13,000 people are diagnosed with MyeloDysplastic Syndromes (MDS) each year. The prevalence has been estimated to be from 60,000 to 170,000 in the US. MyeloDysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias, mainly symptomatic anemia, with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. Majority of the individuals diagnosed with MDS are 65 years or older and die as a result of infection and/or bleeding, consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML).

Elderly patients with mildly symptomatic anemia (macrocytic anemia) or pancytopenia are initially evaluated for B12, folate and iron deficiency, as well as hypothyroidism and hemolysis. The next recommended test for unexplained anemia is bone marrow examination, which is the current gold standard for diagnosis of MDS. However, this procedure is invasive and can be painful, and is occasionally associated with infectious and bleeding complications. For these reasons, many patients and their physicians may avoid this procedure, potentially delaying access to effective treatments.

The researchers in this study developed a noninvasive algorithm, to help diagnose or exclude MDS, without bone marrow evaluation. To develop this web-based app, 502 patients diagnosed with MDS based on bone marrow evaluation were randomly selected from the European MDS registry and this sample was combined with 502 controls with unexplained anemia, aged 50 years and older, who had normal findings on bone marrow evaluation. Patients with bone marrow involvement as a part of a hematological or other disease or with any degree of bone marrow dysplasia could not serve as controls. The authors using a logistic regression model were able to classify patients into 1 of 3 categories: probable MDS, probably not MDS, and indeterminate. The initial model that was developed by the researchers was further improved using the new Gradient-Boosted Models (GBMs), adding more variables based on their known association with MDS. They included 10 routinely measured and readily available demographic, clinical, and laboratory variables such as Age, Sex, Hemoglobin, White Blood Cell count, Platelet count, Mean Corpuscular Volume, Neutrophils, Monocytes, Glucose, and Creatinine, as well as including more patients. A web app was developed that would help clinicians diagnose, and more importantly rule out MDS noninvasively, without bone marrow examination.

The researchers then calculated Positive Predictive Values and Negative Predictive Values assuming a 20% prevalence of MDS within the population of patients to which the model would be applied in practice (patients with unexplained anemia, in whom other causes of anemia have been excluded, who would likely undergo bone marrow examination in clinical practice). Approximately 90% of the MDS patients had anemia, about 35-40% of them had neutropenia, thrombocytopenia or bicytopenia, and about 15% had pancytopenia, all according to WHO criteria. Using the more severe cytopenia criteria as would be used for the International Prognostic Scoring System (IPSS) score, about 50% of MDS patients were severely anemic, about 20-25% of patients were neutropenic, thrombocytopenic, or bicytopenic, and 5% were pancytopenic.

It was noted that this tool was reliably able to separate patients with and without MDS. This model had a sensitivity of 88% and specificity of 95%. In this patient population with unexplained anemia, probable MDS and probably not MDS could be determined in 86% of patients, leaving it to the patient and the physician to discuss whether the bone marrow evaluation should be performed in the indeterminate group, to make the definitive diagnosis. The researchers also determined the robustness of this model in patients with neutropenia, thrombocytopenia, as well as in those with bicytopenia and pancytopenia. It was noted that the predictive model continued to be reliable, especially in its ability to rule out MDS in almost all of these categories, with Negative Predictive Values all above 90% and relatively narrow 95% Confidence Intervals (CIs). Moreover, the lower boundaries of the 95% CI were all above 90%. However, when it came to making a diagnosis of MDS, the accuracy was somewhat diminished. The researchers attributed this to smaller number of patients in these groups, and further added that patients with multiple cytopenias should have bone marrow evaluation, irrespective of the model prediction. Based on this algorithm, the researchers developed a web-based predictor calculator which would serve as a practical tool for clinicians. The limitations of this algorithm are that morphology, blast percentage, genetics, and cytogenetics have not yet been integrated into the model.

It was concluded that based on this MDS model, a web-based computer app has been developed, to help the physician community to primarily exclude MDS in a cytopenic individual and also predict the possibility of MDS, without performing an invasive bone marrow evaluation. The authors plan to not only improve the predictive power of the model by increasing the number of measured variables, but also validate this model with independent prospective patient data, and develop a predictive prognostic tool, in addition to diagnosis.

A predictive algorithm using clinical and laboratory parameters may assist in ruling out and in diagnosing MDS. Oster HS, Crouch S, Smith A, et al. Blood Adv. 2021;5:3066-3075.

Myelodysplastic Syndromes: Managing Anemia due to Ineffective Erythropoiesis in Patients with MDS Requiring RBC Transfusions

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Dr-M-Yair-Levy

Written by: Dr. M. Yair Levy, Texas Oncology
Promotional Content Sponsored by: Bristol Myers Squibb
Dr. Levy is a paid consultant for BMS and was compensated for his contribution in drafting this article.

 

Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid malignancies characterized by multilineage cytopenias, including anemia.1 In MDS, stem cells lack the ability for differentiation and maturation, resulting in bone marrow dysfunction and poor blood cell production, in particular red blood cells (RBCs).2 Anemia is present in the majority of patients with MDS and, at diagnosis, anemia is the most common cytopenia present in patients with MDS.1 Anemia in MDS is linked to bone marrow dysfunction characterized by ineffective erythropoiesis.2

Ineffective erythropoiesis in MDS may lead to anemia requiring RBC transfusions and is characterized by increased proliferation of erythroid progenitors, increased death of erythroid precursors, and impaired erythroid maturation.3,4 In fact, 94% (515/546) of patients with MDS received RBC transfusions in the SEER-Sound registry from 2001 to 2007, 13% of whom had ring sideroblasts.5 Ring sideroblasts are erythroblasts with iron-loaded mitochondria associated with anemia that can be identified by iron staining and the results can be found on pathology reports.6

The presence of anemia despite increased proliferation of progenitor cells is indicative of ineffective erythropoiesis in MDS.3,4 There is a need to help address anemia due to ineffective erythropoiesis in patients with MDS requiring RBC transfusions after erythropoiesis stimulating agent (ESA) failure. REBLOZYL® (luspatercept-aamt), the first and only erythroid maturation agent, is approved for the treatment of anemia failing an ESA and requiring 2 or more RBC units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).7 REBLOZYL is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.7 The approval of REBLOZYL by the FDA marked the first new treatment indicated for patients with MDS in 14 years.8 In my clinical experience, the results that I’ve seen in patients with lower-risk MDS-RS are consistent with those seen in the MEDALIST clinical trial, as discussed below.

As the first and only erythroid maturation agent, REBLOZYL enhances erythroid maturation through differentiation of late-stage erythroid precursors. REBLOZYL works by binding several TGF-β superfamily ligands, thereby diminishing Smad2/3 signaling and increasing the number and quality of mature RBCs in preclinical models.7

REBLOZYL was FDA approved for MDS-associated anemia based on the efficacy and safety outcomes of the pivotal phase 3 MEDALIST trial.7,9 The MEDALIST trial was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial of 229 adult patients with IPSS-R very low-, low-, or intermediate-risk MDS-RS (<5% bone marrow blasts, presence of ring sideroblasts of ≥15% or ≥5% with an SF3B1 mutation) who required RBC transfusions (≥2 RBC units/8 weeks) were randomized 2:1 to REBLOZYL (n = 153) or placebo (n = 76).7,9 Patients were also required to have had an inadequate response to prior treatment with an ESA (defined as response that is no longer maintained after at least 8 doses of recombinant human erythropoietin or 4 doses of darbepoetin alfa), be intolerant of ESAs, or be ineligible for ESAs (serum EPO >200 U/L).7,9 The MEDALIST trial excluded patients who had del 5q MDS, a white blood cell count >13 Gi/L, neutrophils <0.5 Gi/L, platelets <50 Gi/L, or who had prior use of a disease-modifying agent for treatment of MDS.7

REBLOZYL was administered 1 mg/kg subcutaneously every 3 weeks for at least 24 weeks or until unacceptable toxicity, loss of efficacy, or disease progression. Patients could have their dose increased to 1.33 mg/kg and then to 1.75 mg/kg. Patients received dose increases if they did not achieve transfusion independence after two doses or 6 weeks at 1 mg/kg and 1.33 mg/kg. All patients received best supportive care, which included RBC transfusions as needed.7

In MEDALIST, 36% (83/229) of all patients in the trial were 75 years of age or older, including patients up to 95 years.7,9 95.2% (218/229) of all patients in the trial were ESA-exposed, while only 4.8% (11/229) were ESA-naive, with serum EPO >200 U/L.7,9 All patients in the trial had ring sideroblasts (≥15% ring sideroblasts or ≥5% ring sideroblasts with an SF3B1 mutation), and the majority (206/229) had an SF3B1 mutation.7,9 All patients except 1 were classified as having very low- to intermediate-risk MDS by the IPSS-R criteria.7 57% (130/229) of patients had a baseline RBC transfusion burden <6 RBC units/8 weeks.7

The primary endpoint in MEDALIST was RBC transfusion independence (RBC-TI), defined as the absence of any RBC transfusion during any consecutive 8-week period occurring entirely within the first 24 weeks of treatment.7 Approximately 3 times greater percentage of patients receiving REBLOZYL achieved the primary endpoint of RBC transfusion independence than placebo: 37.9% (58/153) vs 13.2% (10/76; common risk difference [95% CI]: 24.6 [14.5, 34.6]; P < 0.0001), respectively.7 These data support that in patients requiring ≥2 RBC units/8 weeks, REBLOZYL should be started after at least 2 to 3 months of an inadequate response to ESAs.7,9

Key secondary endpoints in MEDALIST were based on RBC transfusion independence (absence of any RBC transfusions) during any consecutive 12-week period occurring entirely within weeks 1 to 24 and 1 to 48. 28.1% (43/153) of patients receiving REBLOZYL achieved transfusion independence ≥12 weeks occurring entirely within weeks 1 to 24 vs 7.9% (6/76) of patients receiving placebo (common risk difference [95% CI]: 20.0 [10.9, 29.1]; P = 0.0002). For weeks 1 to 48,* 33.3% (51/153) of patients receiving REBLOZYL achieved transfusion independence ≥12 weeks vs 11.8% (9/76) of patients receiving placebo (common risk difference [95% CI]: 21.4 [11.2, 31.5]; P = 0.0003).7
*The median (range) duration of treatment was 49 weeks (6–114 weeks) on the REBLOZYL arm and 24 weeks (7-89 weeks) on the placebo arm.

REBLOZYL provided RBC transfusion independence vs placebo in patients with MDS-RS and MDS/MPN-RS-T, based on the WHO 2016 classification. Of patients who were diagnosed with MDS-RS, 34.1% (46/135; 95% CI 26.1, 42.7) of patients receiving REBLOZYL achieved transfusion independence vs 12.3% (8/65; 95% CI 5.5, 22.8) receiving placebo. Of patients who were diagnosed with MDS/MPN-RS-T, 64.3% (9/14; 95% CI 35.1, 87.2) of patients receiving REBLOZYL achieved transfusion independence vs 22.2% (2/9; 95% CI 2.8, 60.0) receiving placebo. Of patients who were diagnosed with other types of MDS (MDS-EB-1, MDS-EB-2, and MDS-U), 75% (3/4; 95% CI 19.4, 99.4) of patients receiving REBLOZYL achieved transfusion independence vs 0% (0/2; 95% CI 0.0, 84.2) receiving placebo.7

RBC transfusion independence was also examined by baseline RBC transfusion burden. Of patients requiring 2 to 3 RBC units/8 weeks at baseline,† 80.4% (37/46; 95% CI 66.1, 90.6) of patients receiving REBLOZYL achieved transfusion independence vs 40% (8/20; 95% CI 19.1, 63.9) receiving placebo. Of patients requiring 4 to 5 RBC units/8 weeks at baseline,‡ 36.6% (15/41; 95% CI 22.1, 53.1) of patients receiving REBLOZYL achieved transfusion independence vs 4.3% (1/23; 95% CI 0.1, 21.9) receiving placebo. Of patients requiring ≥6 RBC units/8 weeks, 9.1% (6/66; 95% CI 3.4, 18.7) of patients receiving REBLOZYL achieved transfusion independence vs 3% (1/33; 95% CI 0.1, 15.8) receiving placebo.7

†Includes patients who received 3.5 units.
‡Includes patients who received 5.5 units.

The safety of REBLOZYL at the recommended dose and schedule was evaluated in 242 patients with MDS-RS (n = 192) or other myeloid neoplasms (n = 50). The median time on treatment with REBLOZYL was 50.4 weeks (range, 3-221 weeks), with 67% of patients exposed for 6 months or longer and 49% exposed for >1 year.7

Among the 242 patients treated with REBLOZYL, 5 (2.1%) had a fatal adverse reaction. 4.5% (11/242) of patients discontinued REBLOZYL due to an adverse reaction and 2.9% (7/242) of patients had their REBLOZYL dose reduced due to adverse reactions. The most common (≥10%) all-grade adverse reactions included fatigue, musculoskeletal pain, dizziness, diarrhea, nausea, hypersensitivity reactions, hypertension, headache, upper respiratory tract infection, bronchitis, and urinary tract infection. The majority of adverse reactions with REBLOZYL were Grade 1 or 2 (mild to moderate). The most common (≥2%) Grade ≥3 adverse reactions included fatigue, hypertension, syncope, and musculoskeletal pain.7

IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Thrombosis/Thromboembolism
In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) REBLOZYL-treated patients. TEEs included deep vein thrombosis, pulmonary embolus, portal vein thrombosis, and ischemic stroke. Patients with known risk factors for thromboembolism (splenectomy or concomitant use of hormone replacement therapy) may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients at increased risk of TEE. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly.

Hypertension
Hypertension was reported in 10.7% (61/571) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3 to 4 hypertension ranged from 1.8% to 8.6%. In adult patients with MDS with normal baseline blood pressure, 26 (29.9%) patients developed SBP ≥130 mm Hg and 23 (16.4%) patients developed DBP ≥80 mm Hg. Monitor blood pressure prior to each administration. Manage new or exacerbations of preexisting hypertension using anti-hypertensive agents.

Embryo-Fetal Toxicity
REBLOZYL may cause fetal harm when administered to a pregnant woman. REBLOZYL caused increased post-implantation loss, decreased litter size, and an increased incidence of skeletal variations in pregnant rat and rabbit studies. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose.

ADVERSE REACTIONS
Grade ≥3 (≥2%) adverse reactions included fatigue, hypertension, syncope and musculoskeletal pain. A fatal adverse reaction occurred in 5 (2.1%) patients.

The most common (≥10%) adverse reactions included fatigue, musculoskeletal pain, dizziness, diarrhea, nausea, hypersensitivity reactions, hypertension, headache, upper respiratory tract infection, bronchitis, and urinary tract infection

LACTATION
It is not known whether REBLOZYL is excreted into human milk or absorbed systemically after ingestion by a nursing infant. REBLOZYL was detected in milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because many drugs are excreted in human milk, and because of the unknown effects of REBLOZYL in infants, a decision should be made whether to discontinue nursing or to discontinue treatment. Because of the potential for serious adverse reactions in the breastfed child, breastfeeding is not recommended during treatment and for 3 months after the last dose.

Please see full Prescribing Information for REBLOZYL

References:
1. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454-2465.
2. Cazzola M, Malcovati L. Myelodysplastic syndromes—coping with ineffective hematopoiesis. N Engl J Med. 2005;352(6):536-538.
3. Santini V. Anemia as the main manifestation of myelodysplastic syndromes. Semin Hematol. 2015;52(4):348-356.
4. Fontenay-Roupie M, Bouscary D, Guesnu M, et al. Ineffective erythropoiesis in myelodysplastic syndromes: correlation with Fas expression but not with lack of erythropoietin receptor signal transduction. Br J Haematol. 1999;106(2):464-473.
5. Ramsey SD, McCune JS, Blough DK, et al. Patterns of blood product use among patients with myelodysplastic syndrome. Vox Sang. 2012;102(4):331-337.
6. Malcovati L, Cazzola M. Recent advances in the understanding of myelodysplastic syndromes with ring sideroblasts. Br J Haematol. 2016;174(6):847-858.
7. REBLOZYL [Prescribing Information]. Summit, NJ: Celgene Corporation; 2020.
8. Steensma, D.P. Myelodysplastic syndromes current treatment algorithm 2018. Blood Cancer J. 2018;8(5):47.
9. Data on file, Celgene Corporation. Summit, New Jersey.

© 2021 Celgene Corporation.
REBLOZYL is a trademark of Celgene Corporation, a Bristol Myers Squibb company.
REBLOZYL is licensed from Acceleron Pharma Inc.
08/21 2007-US-2100270

FDA Approves Oral INQOVI® for Myelodysplastic Syndromes

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SUMMARY: The FDA on July 7, 2020, approved INQOVI®, an oral combination of Decitabine and Cedazuridine, for adult patients with MyeloDysplastic Syndromes (MDS), including previously treated and untreated de novo and secondary MDS with the following FAB subtypes – Refractory Anemia, Refractory Anemia with Ringed Sideroblasts, Refractory Anemia with Excess Blasts, Chronic MyeloMonocytic Leukemia (CMML), and Intermediate-1, Intermediate-2, and high-risk International Prognostic Scoring System (IPSS) groups.

It is estimated that in the US approximately 13,000 people are diagnosed with MyeloDysplastic Syndromes (MDS) each year. The prevalence has been estimated to be from 60,000 to 170,000 in the US. MyeloDysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. Majority of the individuals diagnosed with MDS are 65 years or older and die as a result of infection and/or bleeding, consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML). CMML (Chronic MyeloMonocytic Leukemia) is a clonal hematopoietic malignancy characterized by accumulation of abnormal monocytes in the bone marrow and in blood. The incidence of CMML in the US is approximately 1,100 new cases per year. About 15-30% of patients with CMML develop AML. Patients with higher risk MDS and CMML are often treated with hypomethylating agents such as Decitabine (DACOGEN&reg) and Azacitidine (VIDAZA®). These agents are administered by IV infusion, or by large-volume subcutaneous injections.

INQOVI® is an orally-administered, unique fixed-dose combination of the DNA hypomethylating agent and DNA MethylTransferase (DNMT) inhibitor Decitabine, the active ingredient in Dacogen®, and the novel Cytidine deaminase inhibitor, Cedazuridine (35 mg Decitabine and 100 mg Cedazuridine). INQOVI® was designed to deliver Decitabine by oral administration. Cedazuridine prevents the degradation of Decitabine in the gut and liver by inhibiting Cytidine deaminase and the combination thereby permits the efficient delivery of Decitabine orally, at exposures that are equivalent to the approved intravenous form of Decitabine administered over 5 days.

The present FDA approval was based on data from two open-label, randomized, crossover clinical trials, ASTX727-01-B, which included 80 adult patients with MDS (IPSS Intermediate-1, Intermediate-2, or high-risk groups) or CMML, and ASTX727-02, which included 133 adult patients with MDS or CMML, including all FAB subtypes and IPSS Intermediate-1, Intermediate-2, or high-risk groups. In these two trials, patients were randomized 1:1 to receive INQOVI® orally in cycle 1 and Decitabine 20 mg/m2 intravenously in cycle 2 or the reverse order. Both oral INQOVI® and intravenous Decitabine were administered once daily on days 1 through 5 of a 28-day cycle. Starting with cycle 3, all patients received INQOVI® orally once daily on days 1 through 5 of each 28-day cycle, until disease progression or unacceptable toxicity. Both trials provided comparison of exposure and safety in the first two cycles between oral INQOVI® and IV Decitabine and description of disease response with INQOVI®. Comparison of disease response between the INQOVI® and IV Decitabine was not possible because all patients received INQOVI® starting from Cycle 3. The Primary endpoint was total 5-day AUC exposures of Decitabine following INQOVI® therapy compared with IV Decitabine, as measured across the first 2 cycles. Secondary endpoints included safety assessments, pharmacodynamic measurements, clinical responses, RBC transfusion independence, Leukemia-free survival, and Overall Survival.

ASTX727-01-B trial which included 80 patients demonstrated a Complete Response (CR) rate of 18% and median duration of CR of 8.7 months. Among the 41 patients who were dependent on RBC and/or platelet transfusions at baseline, 49% became transfusion independent during any consecutive 56-day post-baseline period. Of the 39 patients who were independent of both RBC and platelet transfusions at baseline, 64% remained transfusion independent during any consecutive 56-day post-baseline period.

ASTX727-02 trial, which included 133 patients, demonstrated a 99% geometric mean ratio of the 5-day cumulative Decitabine AUC following 5 consecutive once daily doses of the oral combination therapy, versus that of IV Decitabine, with a 90% Confidence interval between 93% and 106%. This confirmed equivalence of oral INQOVI® and IV Decitabine. Efficacy results demonstrated that 21% of patients achieved CR, and median duration of CR was 7.5 months. Among the 57 patients who were dependent on RBC and/or platelet transfusions at baseline, 53% became transfusion independent during any 56-day post-baseline period. Of the 76 patients who were independent of both RBC and platelet transfusions at baseline, 63% remained transfusion independent during any 56-day post-baseline period. The most common Adverse Events related to INQOVI® included fatigue, rash, dizziness, headaches, anorexia, nausea, diarrhea, constipation, mucositis, hemorrhage, myalgia, arthralgia, febrile neutropenia, and transaminase elevation.

It was concluded that INQOVI® which is a fixed-dose combination of Cedazuridine and Decitabine is a new treatment option for patients with MDS and CMML, and is an oral hypomethylating agent alternative to IV Decitabine.

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-oral-combination-decitabine-and-cedazuridine-myelodysplastic-syndromes

INQOVI® (Decitabine and Cedazuridine)

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The FDA on July 7, 2020 approved INQOVI® for adult patients with MyeloDysplastic Syndromes (MDS) including the following:
1) Previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (Refractory Anemia, Refractory Anemia with Ringed Sideroblasts, Refractory Anemia with excess blasts, and Chronic MyeloMonocytic Leukemia [CMML])
2) Intermediate-1, Intermediate-2, and high-risk International Prognostic Scoring System groups.

INQOVI® is a product of Astex Pharmaceuticals, Inc.

REBLOZYL® (Luspatercept-aamt)

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The FDA on April 3, 2020, approved REBLOZYL® (Luspatercept-aamt) for the treatment of anemia, failing an Erythropoiesis Stimulating Agent, and requiring 2 or more RBC units over 8 weeks, in adult patients with very low- to intermediate-risk MyeloDysplastic Syndromes with Ring Sideroblasts (MDS-RS), or with MyeloDysplastic/MyeloProliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T). REBLOZYL® is a product of Celgene Corporation.

FDA Approves REBLOZYL® for Patients with Lower-Risk Myelodysplastic Syndromes

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SUMMARY: The FDA on April 3, 2020 approved REBLOZYL® (Luspatercept-aamt) for the treatment of anemia, failing an Erythropoiesis Stimulating Agent, and requiring two or more RBC units over 8 weeks, in adult patients with very low- to intermediate-risk MyeloDysplastic Syndromes with Ring Sideroblasts (MDS-RS) or with Myelodysplastic/Myeloproliferative neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T).

It is estimated that in the US approximately 13,000 people are diagnosed with MyeloDysplastic Syndromes (MDS) each year. MyeloDysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. Majority of the individuals diagnosed with MDS are aged 65 years and older and die as a result of infection and/or bleeding consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML).

Patients with Lower-risk MDS (Revised IPSS-Very Low, Low, or Intermediate risk ) often present with symptomatic anemia and these patients are in chronic need for RBC transfusions which in turn can result in iron overload and can have a negative impact on quality of life and Overall Survival. These patients are treated with Erythropoiesis Stimulating Agents (ESAs) as first line therapy. ESAs such as Darbepoetin alfa and Epoetin alfa are re-engineered and recombinant DNA technology products of Erythropoietin (EPO), and they stimulate erythropoiesis by binding and activating the EPO receptor. However, transfusion-dependent patients with serum EPO levels above 200 U per liter are less likely to respond to ESAs. Additionally, patients with MDS with ring sideroblasts have a shorter median duration of response to ESAs, than those who do not have ring sideroblasts. Patients with Lower-risk MDS with chromosome 5q deletion (del 5q) who are transfusion dependent are treated with Lenalidomide, regardless of previous treatment with ESAs. In contrast, only 39% of patients with non-del(5q) Lower-risk MDS receive second line therapy besides RBC transfusions, and there are few treatment options for patients who are refractory to, unresponsive to, or ineligible for ESAs. There is therefore an unmet clinical need for safe and effective treatment options, to reduce the RBC transfusion burden in these patients.Luspartercept-Restores-Red-Blood-Cell's-Ability-to-Mature

Signaling by the SMAD2 and SMAD3 pathway exerts an inhibitory effect on red cell maturation. This pathway is constitutively activated in the bone marrow cells of patients with MDS and diseases associated with ineffective erythropoiesis such as β-thalassemia. REBLOZYL® (Luspatercept) is a recombinant soluble fusion protein and is first-in-class erythroid maturation agent that enhances erythropoiesis by promoting late-stage Red Blood Cell precursor differentiation and maturation. It targets select Transforming Growth Factor (TGF)-β superfamily ligands such as GDF11, that regulate late-stage erythropoiesis. This results in a reduction in aberrant SMAD2 and SMAD3 signaling, thereby promoting late-stage RBC precursor differentiation and maturation. In a Phase II study, treatment of Lower-risk MDS patients with REBLOZYL® resulted in 38% of patients being transfusion independent for 8 weeks or longer and this benefit was even more so among patients with 15% or more ring sideroblasts.

The MEDALIST trial is a randomized, double-blind, placebo-controlled Phase III study which evaluated the efficacy and safety of REBLOZYL® in patients with anemia secondary to MDS, defined as Very Low-Risk, Low-Risk, or Intermediate-Risk with Ring Sideroblasts, according to the Revised International Prognostic Scoring System (R-IPSS). Eligible patients were refractory, intolerant, or ineligible to receive ESAs and required RBC transfusions. A total of 229 patients (N=229) were randomized 2:1 to receive either REBLOZYL® at a starting dose level of 1mg/kg SC with titration up to 1.75 mg/kg if needed (N=153), or placebo SC (N=76), every 3 weeks for 24 weeks or more. The median age was 71 years and median time from diagnosis was 41.8 months. Approximately 95% of patients had previously received ESAs and 90% had an SF3B1 mutation. SF3B1 mutation defines a homogeneous subgroup of MDS patients with Ring Sideroblasts, who have isolated erythroid dysplasia and favorable prognosis. The Primary endpoint was RBC transfusion independence for 8 weeks or more between week 1 and 24. A key Secondary endpoint was RBC transfusion independence for 12 weeks or more between week 1 and 24.

Among those receiving REBLOZYL®, 38% achieved the Primary endpoint of RBC transfusion independence for 8 weeks or more, compared with 13% receiving placebo (P<0.0001). Further among those receiving REBLOZYL®, 28% achieved the key Secondary endpoint of RBC transfusion independence for 12 weeks or more compared with 8% receiving placebo (P<0.001). The median duration of the longest, single continuous period of response to REBLOZYL® was 30.6 weeks, and 13.6 weeks in the placebo group. Among patients who had a baseline transfusion burden of 4 to less than 6 units per 8 weeks, 37% of those in the REBLOZYL® group and 4% of those in the placebo group had a response. Additionally, patients receiving REBLOZYL® were more likely to achieve an mHI-E (modified Hematologic Improvement-Erythroid) response, (defined as a reduction in transfusion of 4 or more RBC units per 8 weeks or a mean hemoglobin increase of 1.5 g/dL or more per 8 weeks, in the absence of transfusions), compared with patients receiving placebo (53% versus 12% during weeks 1-24; P<0.0001). A mean increase in hemoglobin level of at least 1 g/dL during weeks 1 to 24 was noted in 35% of patients who received REBLOZYL® and in 8% of patients who received placebo. The most common adverse events of any grade associated with REBLOZYL® included fatigue, diarrhea, asthenia, nausea and dizziness, and the incidence of adverse events decreased over time.

It was concluded that treatment with REBLOZYL® significantly reduced the severity of anemia in patients with Lower-risk MDS with ring sideroblasts, who had been RBC transfusion-dependent, and who had disease that was refractory to, or unlikely to respond to ESAs. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. Fenaux P, Platzbecker U, Mufti GJ, et al. N Engl J Med 2020; 382:140-151