Myelodysplastic syndromes (MDS), or myelodysplastic neoplasms (MDN), are conditions that are characterized by abnormal (dysplastic) cells in the bone marrow that result in the production of defective blood cells and/or low volume of one or more types of blood cells. Approximately 10,000 individuals are diagnosed with MDS in the United States annually. MDS is considered to be a type of cancer. MDS is not common in individuals younger than 50 years old, and the risk of developing MDS increases as the individual ages. Most cases of MDS have no identifiable cause, but there are some risk factors for the development of MDS, including exposure to tobacco smoke, ionizing radiation, and exposure to certain chemicals or heavy metals. Secondary MDS can result after an individual is treated with chemotherapy and/or radiation therapy as part of a cancer regimen. Genetic changes, some inherited, and others acquired, may lead to the development of MDS. The symptoms of MDS, such as lethargy, weight loss, frequent infections, and easy bleeding or bruising, are very general, so may be attributed to another cause. Lab tests may demonstrate low levels of red blood cells most often, but also white blood cells and/or platelets. These signs can also be attributed to other causes. A bone marrow biopsy will demonstrate immature cells (blasts) in the marrow. Long term, MDS may progress to acute myeloid leukemia (AML; about one in three individuals will be affected) or bone marrow failure.
Tests are done to look for specific gene or chromosome changes that might lead to the development of MDS (e.g., SF3B1, ASXL1, RUNX1). These, along with lab tests, are used for risk stratification of the individual, determining the treatment course, and predicting an individual's prognosis. Examples of risk stratification scoring systems include the Revised International Prognostic Scoring System (IPSS-R) and the Molecular International Prognostic Scoring System (IPSS-M). These scoring systems are used to categorize the individual as either lower risk MDS or higher risk MDS based on bone marrow characteristics, peripheral blood results, cytogenetics, and molecular features.
Standard therapies for MDS are often supportive, not treatments of the MDS. Individuals with MDS often require the transfusion of red blood cells (RBCs) and/or platelets. Erythropoiesis‐stimulating agents (ESAs) (e.g., epoetin alfa, epoetin beta, darbepoetin alfa), are commonly ordered to encourage the production of RBCs. ESAs may not be appropriate for all individuals (e.g., individuals with endogenous erythropoietin concentration >500 milliunits/milliliter [mU/mL]), or the individual may develop a resistance to the effects of the ESA, leading to the need for alternative therapies. Treatment with granulocyte-colony stimulating factors (G‐CSF) (e.g., filgrastim, pegfilgrastim) or granulocyte‐macrophage colony stimulating factors (GM‐CSF) (e.g., sargramostim) are commonly ordered to encourage the production of various white blood cells (WBCs). Thrombopoietin receptor agonists (TPO-RAs) (e.g., romiplostim, eltrombopag) are administered to encourage platelet (plt) production. A chelating agent (e.g., deferoxamine, deferasirox) may be given if the individual has undergone multiple RBC transfusions over a period of years and has developed iron overload. There are also some therapies that are used to treat MDS. Hypomethylating agents (e.g., azacitidine, decitabine), a type of chemotherapy, are some of the most effective drugs in the treatment of MDS, but do not work for everyone or can stop working as time progresses. For higher risk individuals, other chemotherapies may be used (e.g., cytarabine). Lenalidomide, an immunomodulator, is one type of targeted drug therapy that can be used to treat individuals with certain MDS genetic changes or karyotypes (e.g., del[5q]). Undergoing a hematopoietic stem cell transplant (HSCT) may lead to a long-term remission of MDS, but this requires the individual to tolerate an intense treatment regimen prior to receiving the transplant.
Imetelstat (Rytelo) is an oligonucleotide telomerase inhibitor that binds to the template region of the RNA component of human telomerase (hTR) resulting in inhibited telomerase enzymatic activity and prevention of telomere binding. Increased telomerase activity and hTR reverse transcriptase (hTERT) RNA expression have been reported in MDS and malignant stem cells and progenitor cells. Imetelstat (Rytelo) is believed to reduce telomere length, reduce proliferation of malignant stem and progenitor cells, and induce apoptotic cell death.
CLINICAL TRIAL
IMerge
The efficacy and safety of imetelstat (Rytelo) in transfusion-dependent individuals with low to intermediate-1 risk MDS that was relapsed or refractory to ESAs was evaluated in a phase 2 to 3, multicenter, open-label, single-arm clinical trial called Study to Evaluate Imetelstat (GRN163L) in Participants With International Prognostic Scoring System (IPSS) Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS) (NCT02598661). Transfusion dependence was defined as requiring at least four units of RBCs transfused over an 8-week period during the 16 weeks prior to study entry. The pretransfusion hemoglobin (Hgb) must have been 9.0 g/dL or less to count toward the four-unit total. For the phase 3 portion of the clinical trial, the participants could not have the del(5q) karyotype, and could not have previously been treated with a hypomethylating agent (HMA) or lenalidomide.
The phase 2 portion of the clinical trial enrolled 57 individuals. All participants received imetelstat (Rytelo) 7.5 mg/kg as an intravenous (IV) infusion every 4 weeks until there was disease progression, unacceptable toxicity, consent withdrawal, or it was deemed there was a lack of a response. The primary endpoint was the percentage of participants who were transfusion independent during any consecutive 8-week period over the course of 12 months. Key secondary endpoints included percentage of individuals who achieved 24 weeks of transfusion independence, time to the 8-week transfusion independence, duration of transfusion independence, and measures surrounding disease progression and adverse events. At the time of clinical cutoff, 14 of 57 individuals (25 percent) were continuing to receive the drug. There were multiple reasons for participant attrition: lack of efficacy (n=16), adverse events (n=14), individual consent withdrawal/refusal (n=6), disease progression (including transformation to AML in two individuals) (n=3), death (n=2), relapse (n=1), and physician decision (n=1). Thirty-seven percent (21/57) of participants achieved the primary endpoint of transfusion independence
for 8 consecutive weeks and 23 percent (13/57) achieved 24-week transfusion independence. The median time to achieve 8-week transfusion independence was 8.3 weeks (range, 0.1–100.6 weeks for all 57 individuals). The median duration of transfusion independence was 65 weeks (range, 17–140.9 weeks for all 57 individuals). For disease activity, the overall response rate (ORR) for all 57 individuals was 19 percent (9 percent [5/57] complete responses [CR], 11 percent [6/57] marrow CR [mCR], no partial responses [PR]). Of the individuals who experienced a CR or mCR, 46 percent had complete resolution of dysplasia. The majority of adverse events experienced by participants were hematologic. The percentages of all 57 individuals who experienced thrombocytopenia, neutropenia, or anemia were 61, 67, and 23, respectively. The percentage of all 57 individuals who experienced grade 3 or higher thrombocytopenia, neutropenia, or anemia were 54, 60, and 19, respectively. Most of these hematologic events resolved to grade 2 or lower within 4 weeks.
The phase 3 portion of the clinical trial was double blinded and placebo controlled. The study enrolled 178 individuals randomly assigned in a 2:1 ratio to imetelstat (Rytelo) or placebo. Participants received imetelstat (Rytelo) 7.5 mg/kg or placebo as an IV infusion every 4 weeks until there was disease progression, unacceptable toxicity, consent withdrawal, or it was deemed there was a lack of a response. The primary and secondary endpoints for the phase 3 portion of the clinical trial were similar to those for the phase 2 portion. Of the total participants, 118 were randomly assigned to imetelstat (Rytelo) and 60 were randomly assigned to placebo (one individual did not receive treatment so was not included in the results). At the time of clinical cutoff, 27 of 118 individuals (23 percent) were continuing to receive imetelstat (Rytelo) and 14 of 59 (24 percent) were continuing to receive placebo. The reasons for attrition were similar to those from the phase 2 portion of the clinical trial. There was one death in each cohort during treatment or within 30 days of stopping treatment. For the primary endpoint, 40 percent (47/118) of individuals in the study cohort versus 15 percent (9/59) in the placebo cohort achieved at least 8 weeks of transfusion independence (rate difference, 25 percent; 9.9–35.9; P=0.0008). The percentage of individuals who achieved 24-week transfusion independence was 28 percent (33/118) in the study cohort versus 3 percent (2/59) in the placebo cohort (rate difference, 25 percent; 12.6–4.2; P=0.0001). In long-term follow-up, 18 percent (21/118) of the study cohort versus 2 percent (1/59) of the placebo group achieved 1-year transfusion independence (P=0.0023). Of individuals who achieved 8-week transfusion independence, the median duration of transfusion independence was 51.6 weeks (range, 26.9–83.9 weeks) in the study group (47/118) versus 13.3 weeks (range, 8.0–24.9 weeks) in the placebo group (9/59) (P=0.0007). The majority of adverse events experienced by participants were hematologic. Grade 3 or 4 treatment-emergent adverse events occurred in 91 percent (107/118) of the study group versus 47 percent (28/59) of the placebo group, with 68 percent (80/118) of the study group experiencing neutropenia and 62 percent (73/118) experiencing thrombocytopenia. Most of these hematologic events resolved to grade 2 or lower within 4 weeks. Two percent of individuals in both cohorts experienced progression to AML (2/118 vs 1/59).
In the study cohort, 62 percent (73/117) of individuals were ring sideroblast positive and 37 percent (44/117) were ring sideroblast negative. In the placebo cohort, 62 percent (37/60) were ring sideroblast positive and 38 percent (23/60) were ring sideroblast negative. The primary endpoint was reached in 45 percent (33/73) of individuals who were ring sideroblast positive and 32 percent (14/44) of individuals who were ring sideroblast negative in the study cohort. The primary endpoint was reached in 19 percent (7/37) of individuals who were ring sideroblast positive and 9 percent (2/23) who were ring sideroblast negative in the placebo cohort. Continuous transfusion independence for at least 24 weeks was achieved by 33 percent (24/73) of individuals who were ring sideroblast positive and 20 percent (9/44) of individuals who were ring sideroblast negative in the study cohort. Continuous transfusion independence for at least 24 weeks was achieved by 5 percent (2/37) of individuals who were ring sideroblast positive and none (0/23) of individuals who were ring sideroblast negative in the placebo cohort. Among individuals with evaluable mutation data (110/118 [93 percent] in the study cohort; 55/60 [92 percent] in the placebo cohort), SF3B1, TET2, DNMT3A, and ASXL1 were the most frequently mutated genes. Reductions in variant allele frequency (VAF) of these mutations was greater in the study cohort than in the placebo cohort (P<0.001, P=0.032, P=0.019, P=0.146, respectively).
OFF-LABEL INDICATIONS
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company's off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
