Imetelstat Provides Promising, Durable Transfusion Independence in Lower-Risk MDS

Imetelstat (GRN163L) demonstrated meaningful and durable transfusion independence in patients with lower-risk myelodysplastic syndrome (MDS) that are non-del(5q), dependent on red blood cell transfusion, and are relapsed/refractory to treatment with erythropoiesis-stimulating agents (ESAs), according to long-term data from the phase 2 IMerge trial (NCT02598661) that were virtually presented during the 2020 European Hematology Association Annual Congress.¹

Results showed that 42% of patients (n = 16) achieved 8-week red blood cell transfusion independence (RBC-TI), with 75% (n = 12) of these responders showing a hemoglobin rise of at least 3 g/dL compared with pretreatment during the transfusion-free interval (TFI). Thirty-two percent (n = 12) of patients achieved a 24-week RBC-TI. Moreover, 29% (n = 11) of patients were transfusion free for more than 1 year; however, the longest TFI was 2.7 years. The rate of hematologic improvement-erythroid (HI-E) was also high at 68%.

Additionally, RBC-TI and HI-E proved to be durable. Notably, the median duration of RBC-TI was 20 months, which is the longest duration reported to date in patients with lower-risk MDS that are non-del(5q). The median duration of HI-E was 21 months.

Patients with transfusion-dependent LR-MDS, defined as low or intermediate 1 by the International Prognostic Scoring System (IPSS), who are relapsed/refractory to ESAs are an unmet need in that limited therapeutic options are available. It has been established that higher telomerase activity, expression of human telomerase reversion transcriptase, and shorter telomeres predict for shorter overall survival in patients with lower-risk MDS.

Imetelstat is a first-in-class telomerase inhibitor that is designed to target cells with short telomere lengths and active telomerase; the agent has demonstrated activity in myeloid malignancies.

Based on that activity, investigators decided to launch the phase 2/3 IMerge trial. Patients had to have lower-risk MDS, no-del(5q), with low or intermediate-1 IPSS, and have relapsed on or are refractory to ESA or have serum erythropoietin (EPO) levels of >500 mU/ml. Twenty-five patients had to have been naïve to hypomethylating agents and lenalidomide (Revlimid). Participants were also transfusion dependent, with a high transfusion burden of at least 4 units RBC/8 weeks. The primary end point of the trial is 8-week RBC-TI and key secondary end points include 24-week RBC-TI and duration of TI and HI-E.

A total of 38 patients were enrolled on the single-arm, open-label phase 2 trial2 and they received 7.5 mg/kg of intravenous imetelstat every 4 weeks. The median age was 71.5 years and 66% (n = 25) were male. Furthermore, the majority of patients (89%; n = 34) had an ECOG performance score of 0 or 1. Sixty-three percent (n = 24) of patients were classified as low IPSS risk, while 37% (n = 14) were classified as intermediate-1 IPSS risk. The median RBC transfusion burden was 8 units/8 weeks; 16% (n = 6) of patients had 4 to 5 units/8 weeks at baseline, and 84% of patients had 6 or more units/8 weeks at baseline.

Moreover, 71% (n = 27) of patients were classified as World Health Organization 2001 category RARS or RCMD-RS, while 29% (n = 11) were classified as RA, RCMD, or RAEB-1. The majority of patients, or 89%, were previously treated with ESAs.

Results showed that of the 42% of patients who achieved 8-week RBC-TI, the median time to onset was 8.3 months and the duration of TI was a median of 88.0 weeks (95% CI, 23.1-140.9). The cumulative duration of TI 8 weeks or more was a median of 92.3 weeks (95% CI, 42.9-140.9). Thirty-two percent (n = 12) experienced a hemoglobin rise of at least 3.0 g/dL during 8-week TI. Of the 32% of patients who achieved 24-week RBC-TI, 29% (n = 11) had a hemoglobin rise of 3.0 g/dL or more during TI. Notably, 29% of patients (n = 11) achieved 1-year TI.

With regard to major and minor responses with imetelstat per International Working Group (IWG) 2018 criteria, 37% (n = 14) of patients experienced a major response, achieving a 16-week RBC-TI, and more than half of patients (55%; n = 21) experienced a minor response with the treatment, achieving a 50% or higher transfusion reduction/16 weeks.

The clinical benefit with imetelstat was observed across different patient subgroups, with HI-E responses observed in patients with (refractory anemia with ring sideroblasts [RARS] and refractory cytopenia with multilineage dysplasia and ring sideroblasts [RCMD-RS]) and without ring sideroblasts (other). HI-E responses were also reported in patient subgroups with a high and very-high baseline transfusion burden (4-6 units and >6 units, respectively). Patients with serum EPO levels of 500 mU/mL or lower versus higher than 500 mU/mL also experienced HI-E responses.

Specifically, 74.1% of patients with RARS or RCMD-RS experienced an HI-E response, as well as 54.5% of patients without ring sideroblasts. Additionally, 64.7% of patients with a high baseline transfusion burden experienced a HI-E response versus 71.4% of patients with a very high baseline transfusion burden. Approximately 86% of patients classified to have an IPSS risk status of intermediate-1 experienced a HI-E response versus 58.3% of patients classified to have an IPSS risk status of low. With regard to serum EPO level, 72.0% of patients with an EPO level of 500 mU/mL or lower experienced a HI-E response as well as 66.7% of patients with an EPO level of 500 mU/mL or higher.

Earlier findings of the trial, which were published in 2018, showed that at a median follow-up of 25.8 months for the initial 13 patients, and 5.2 months for more recently included patients, the 8-week RBC-TI rate was 37% (n = 14/38).² Durability of 24-week TI responses was also reported, with a median duration of 10 months. Of the patients who achieved a durable TI, all showed a rise in hemoglobin of 3.0 g/dL or higher versus baseline during the TFI. Response rates proved to be similar in patients with RARS/RCMD-RS and other patients, at 33% versus 27%, respectively, and those with baseline EPO levels of at least 500 mU/mL and 500 mU/mL or lower, at 33% and 32%, respectively.

Regarding safety, reversible grade 3 or higher neutropenia and thrombocytopenia were each reported in 58% of patients. Liver function test (LFT) elevations were found to be mostly grade 1/2 in severity. Additionally, grade 3 LFT elevations were reported in 8% of patients and were reversible. Notably, the observed LFT elevations were not determined to be related to imetelstat per an independent Hepatic Review Committee.

No new safety signals were reported with the updated, long-term data from the trial.

The phase 3 double-blind, placebo-controlled stage of IMerge is currently ongoing and recruiting patients for enrollment.

References

1. Platzbecker U. 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). Presented at: 2020 European Hematology Association Annual Congress; June 11-14, 2020; Virtual. Accessed June 10, 2020. Abstract S183.
2. Study to evaluate imetelstat (GRN163L) in subjects with International Prognostic Scoring System low or intermediate-1 risk myelodysplastic syndrome (MDS). ClinicalTrials.gov. Updated May 20, 2020. Accessed June 10, 2020. bit.ly/2MS7pAd
3. Steensma DP, Platzbecker U, Van Eygen K, et al. Imetelstat treatment leads to durable transfusion independence (TI) in RBC transfusion-dependent (TD), non-del(5q) lower risk MDS relapsed/refractory to erythropoiesis-stimulating agent (ESA) who are lenalidomide (len) and HMA naive. Blood. 2018;132(suppl 1):463. doi:10.1182/blood-2018-99-114877