Noninvasive Evaluation of Myelodysplastic Syndrome in Patients with Unexplained Anemia

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

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

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)

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)

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

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

REBLOZYL® Reduces Blood Transfusion Requirements in Patients with Lower-Risk Myelodysplastic Syndromes

SUMMARY: It is estimated that in the United States 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.
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. 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<0.001). 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

Telomerase Inhibitor Imetelstat Provides Durable Transfusion Independence in Myelodysplastic Syndrome

SUMMARY: It is estimated that in the United States 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 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. 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).

Management of patients with MDS includes supportive care with Erythropoiesis Stimulating Agents (ESAs), hypomethylating agents such as VIDAZA® (Azacitidine) and DACOGEN® (Decitabine), Immunomodulatory agents such as REVLIMID® (Lenalidomide), and Immunosuppressive agents such as AntiThymocyte Globulin (ATG) and Cyclosporine. Symptomatic patients with MDS are often treated with either VIDAZA® or DACOGEN® as these agents have been shown to improve survival in higher-risk MDS patients. It has remained unclear however, if one is better than the other.

Erythropoiesis Stimulating Agents (ESAs) are first-line therapy for anemia associated with lower-risk non-del(5q) MDS. 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. There are however limited treatment options for RBC Transfusion Dependent (TD), Low Risk (IPSS Low/Int-1) MDS patients, who are Relapsed/Refractory to ESAs. There is therefore an unmet clinical need for safe and effective treatment options, to reduce the RBC transfusion burden in these patients. Imetelstat is a first-in-class Telomerase inhibitor that targets cells with short telomere length and active Telomerase, a feature often observed in some MDS patients across all stages of their disease. Higher Telomerase activity and shorter Telomeres in the blood cells of some patients with lower-risk MDS are known to predict for shorter overall survival.

IMerge is an ongoing global Phase II/III study of Imetelstat in RBC Transfusion Dependent patients with Low Risk-MDS (IPSS Low or Int-1). Previously reported data have demonstrated clinical benefit with Imetelstat in Low Risk-MDS patients inducing durable Transfusion Independence (Steensma et al ASH 2018 Abstr463). The authors now reported updated efficacy data in Low Risk, non-del(5q) MDS patients, Relapsed/Refractory to ESAs and Lenalidomide/HypoMethylating Agents naïve, from the open-label, single-arm Part 1 of IMerge study.

Part 1 of the IMerge study included patients with Low Risk MDS, who were heavily transfused (4 or more units /8wks), were Refractory or Relapsed on ESA or had serum EPO level of more than 500 mU/mL. This part of the study included 38 patients who were non-del(5q) and had not received either Lenalidomide/HypoMethylating Agents. Imetelstat was administered at 7.5 mg/kg IV every 4 weeks. The median patient age was 72 years, median baseline RBC transfusion burden was 8U/8weeks (range 4-14), 37% of the patients had IPSS Intermediate-1 risk score, 71% had WHO 2001 classification RARS (Refractory Anemia with Ringed Sideroblasts) or RCMD-RS (Refractory Cytopenia with Multilineage Dysplasia and Ringed Sideroblast) subtype and 32% with evaluable serum EPO levels had baseline level of more than 500 mU/mL. The Primary endpoint was 8-week Transfusion Independence rate. Secondary endpoints included 24-week Transfusion Independence rate, Safety, Duration of Transfusion Independence, and Hematologic Improvement rate. The median follow up was 12.1 months. The authors in this publication reported long-term efficacy, safety and biomarker data from these 38 patients.

Treatment with single-agent Imetelstat resulted in 8-week Transfusion Independence rate of 45% and the median Transfusion Independence duration was 8.5 months. Among those responding to Imetelstat, 59% remained transfusion free for over 24 weeks. The presence of Ring Sideroblasts or baseline serum EPO levels did not have an impact on 8-week Transfusion Independence rate. The 24-week Transfusion Independence rate was 26%. Erythroid Hematologic Improvement, defined as transfusion reduction by at least 4 units/8 weeks (IWG2006), was achieved in 68% of the patients. All patients (N=6) who had IPSS- Intermediate/poor cytogenetic risk achieved 8-week Transfusion Independence and 2 patients achieved partial cytogenetic response. Post treatment decrease in Telomerase (human Telomerase Reverse Transcriptase-hTERT) RNA level was observed in 73.5% of patients. Further, among patients with pre and post-treatment mutation analyses, six patients had SF3B1 mutations at baseline, and 2 patients who had a decrease in the mutation burden had longest Transfusion Independence duration on study. The most frequently reported adverse events were manageable and reversible grade 3 cytopenias.

It was concluded that treatment with single agent Imetelstat resulted in meaningful and durable Transfusion Independence, in Transfusion Dependent patients with non-del(5q) Lower-Risk MDS, who had relapsed or were refractory to ESA. Transfusion Independence was observed across different clinical subgroups, including patients with Intermediate and Poor cytogenetic risk, with a positive effect on malignant mutant clones. TREATMENT WITH IMETELSTAT PROVIDES DURABLE TRANSFUSION INDEPENDENCE (TI) IN HEAVILY TRANSFUSED NON-DEL(5Q) LOWER RISK MDS (LR-MDS) RELAPSED/REFRACTORY (R/R) TO ERYTHROPOIESIS STIMULATING AGENTS (ESAS). Fenaux P, Steensma DP, Eygen KV, et al. Presentation during European Hematology Association, Jun 15, 2019; 267420; S837

Luspatercept Reduces Blood Transfusion Requirements in MDS and Beta-Thalassemia

SUMMARY: Anemia is a common finding in patients with MyeloDysplastic Syndromes (MDS) and Beta-Thalassemia. These patients are in chronic need for transfusions which in turn can result in iron overload. Erythropoiesis Stimulating Agents (ESAs) are first-line therapy for anemia associated with lower-risk non-del(5q) MDS. 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. There are however 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. Beta-Thalassemia is an inherited hemoglobinopathy associated with an erythroid maturation defect and is characterized by ineffective erythropoiesis and impaired RBC maturation.Luspatercept-Restores-Red-Blood-Cell's-Ability-to-Mature

Luspatercept is a 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 Smad2/3 signaling thereby promoting late-stage Red Blood Cell precursor differentiation and maturation. The following two, separate phase III studies have shown reduced blood transfusions requirements in two separate patient populations.

The MEDALIST trial is a randomized, double-blind, placebo-controlled phase III study which evaluated the efficacy and safety of Luspatercept 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. 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 Luspatercept 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. 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 Luspatercept, 38% achieved the Primary endpoint of RBC transfusion independence for 8 weeks or more compared with 13.2% receiving placebo (P<0.0001). Further among those receiving Luspatercept, 28.1% achieved the key secondary endpoint of RBC transfusion independence for 12 weeks or more compared with 7.9% receiving placebo (P=0.0002). Additionally, patients receiving Luspatercept 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 (52.9% versus 11.8% during weeks 1-24; P<0.0001).

It was concluded that treatment with Luspatercept significantly decreased transfusion requirements among patients with low or Intermediate-risk MDS with Ring Sideroblasts.

The BELIEVE trial is a randomized, double-blind, placebo-controlled phase III study conducted to determine the efficacy and safety of Luspatercept in adult Beta-Thalassemia patients requiring regular RBC transfusions. In this study, 336 patients with Beta-Thalassemia or Hemoglobin E/ Beta-Thalassemia were randomized in a 2:1 to receive Luspatercept, at a starting dose of 1mg/kg with titration up to 1.25 mg/kg, or placebo, SC every 3 weeks for 48 weeks or more. Patients in both treatment groups continued to receive RBC transfusions and iron chelation therapy to maintain the same baseline Hgb level. Enrolled patients were 18 years or older and required regular RBC transfusions of 6-20 units in the 24 weeks prior to randomization with no transfusion-free period 35 days or more during that time. The median age was 30 years and 58% of patients were female. Patients received a median of 6 RBC units in the 12 weeks prior to treatment and 58% of patients in each treatment group had undergone splenectomy. The Primary endpoint was a 33% or more reduction in transfusion burden (with a reduction of 2 or more RBC units) during weeks 13–24, when compared with a 12-week baseline period.

It was noted that 21.4% of patients in the Luspatercept group achieved the Primary endpoint compared with 4.5% patients in the placebo group (P<0.0001). Towards the end of the trial, 20% of patients overall had decreased their transfusion units by one third or more, and 10% of patients had decreased their transfusions units by half or more. Overall, 70.5% of patients receiving Luspatercept achieved a 33% or more RBC transfusion reduction over any consecutive 12 weeks compared with 29.5% patients receiving placebo (P<0.0001).

It was concluded that treatment with Luspatercept resulted in significant reductions in RBC transfusion requirement, in adults with transfusion-dependent Beta-Thalassemia.

The most common adverse events included fatigue and muscle pain. It remains to be seen if Luspatercept would have similar efficacy in patients with high-risk MDS and patients with lower-risk MDS without ring sideroblasts.

The Medalist Trial: results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusion. Fenaux P, Platzbecker U, Mufti GJ, et al. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego. Abstract 1. https://ash.confex.com/ash/2018/webprogram/Paper110805.html

The Believe Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept in Adult Beta-Thalassemia Patients Who Require Regular Red Blood Cell (RBC) Transfusions. Cappellini MD, Viprakasit V, Taher A, et al. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego. Abstract 163. https://ash.confex.com/ash/2018/webprogram/Paper112435.html

DACOGEN® May Be Superior to VIDAZA® in Higher-Risk MDS Patients

SUMMARY: It is estimated that in the United States 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 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.

Management of patients with MDS includes supportive care with Erythropoiesis Stimulating Agents (ESA), hypomethylating agents such as VIDAZA® (Azacitidine) and DACOGEN® (Decitabine), immunomodulatory agents such as REVLIMID® (Lenalidomide), and immunosuppressive agents such as AntiThymocyte Globulin (ATG) and Cyclosporine. Symptomatic patients with MDS are often treated with either VIDAZA® or DACOGEN® as these agents have been shown to improve survival in higher-risk MDS patients. It has remained unclear however, if one is better than the other.

To address this question the authors conducted a phase II study, in which 113 patients with low (36%), intermediate (30%), and high (20%) – risk MDS, as determined by the Revised International Prognostic Scoring System (IPSS-R), were randomly assigned to receive either VIDAZA® 75 mg/m2 IV/SC daily (N=40) or DACOGEN® 20 mg/m2 IV daily (N=73), for 3 consecutive days, with the cycle repeated every 28 days. Patients received a median of 9 cycles. The primary endpoint was Overall Response Rate (ORR).

It was noted that the ORR was 70% and 49% for patients treated with DACOGEN® and VIDAZA® respectively (P=0.03). Cytogenetic response rates were 61% and 25% respectively (P=0.02). Thirty-two percent (32%) of patients treated with DACOGEN® became transfusion independent compared with 16% of patients treated with VIDAZA® Among patients with 5% or more bone marrow blasts, all responded to DACOGEN® whereas only 36% responded to VIDAZA® (P<0.001). With a median follow up of 20 months, the median Event Free Survival for patients treated with DACOGEN® was 20 months and 13 months for those treated with VIDAZA®, and these outcomes were negatively impacted by the presence of TP53 and ZRSR2 mutations. More patients in the DACOGEN® group experienced myelosuppression, and grade 3 toxicities were rare.

The authors concluded that lower doses of DACOGEN® and VIDAZA® are safe and effective in symptomatic patients with MDS, and DACOGEN® is more effective compared to VIDAZA®, in patients with higher-risk features. A randomized phase II study of low-dose decitabine versus low-dose azacitidine in lower risk MDS and MDS/MPN. Jabbour E, Short NJ, Montalban-Bravo G, et al. Blood. 2017 Aug 3. pii: blood-2017-06-788497. doi: 10.1182/blood-2017-06-788497. [Epub ahead of print]