Contributions
Abstract: S1557
Type: Oral Presentation
Presentation during EHA23: On Sunday, June 17, 2018 from 08:30 - 08:45
Location: Room A4
Background
Patients with lower-risk MDS that is relapsed/refractory to ESA have few treatment options. The first-in-class telomerase inhibitor imetelstat, which targets cells with short telomere lengths and active telomerase, has the potential to provide clinical benefit in this patient population.
Aims
Here we report updated safety and efficacy data from IMerge, an ongoing 2-part, global, phase 2/3 study of imetelstat in RBC TD patients with IPSS Low or Intermediate-1 (Int-1) risk MDS.
Methods
The IMerge population includes patients with MDS relapsed/refractory to ESA with a transfusion requirement of ≥4 units over 8 weeks prior to entry and ESA-naïve patients with sEPO >500 mU/mL. In Part 1 (open-label, single-arm), imetelstat 7.5 mg/kg was administered IV every 4 weeks (escalation to 9.4 mg/kg permitted after 3 cycles). The primary endpoint is the rate of RBC transfusion-independence (TI) lasting ≥8 weeks; secondary endpoints include safety, ≥24-week TI rate, time to and duration of TI, and hematologic improvement (HI) rate. Updated results for the first 32 patients enrolled in Part 1 (median follow up, 75.3 weeks) are reported here.
Results
Median age was 68.5 years. 59% of patients were IPSS Low and 41% Int-1. 13 patients (43%) had sEPO>500 mU/mL. 34% had a cytogenetic abnormality, including 22% with del(5q). Prior MDS treatments included ESAs (88%), lenalidomide (38%), and decitabine or azacitidine (HMAs) (25%); 41% were both lenalidomide and HMA naïve and non-del(5q). As of Jan 2018, RBC-TI ≥8-week was achieved in 38% of patients. Median time to onset of TI was 8 weeks with a median duration of TI of 23 weeks. 16% of patients achieved ≥24-week TI, and 63% achieved erythroid HI. Of 13 lenalidomide and HMA naïve and non-del(5q) patients, 54% achieved ≥8-week TI. Median time to onset of TI in the subset was 8 weeks with a median duration of TI of 43 weeks. 31% of these patients had ≥ 24-week TI, and 69% achieved erythroid HI. TI response did not differ based on the presence of ringed sideroblasts or baseline sEPO level (41% [7/17] ≤500 mU/L; 38% [5/13] >500 mU/L). Cytopenias, particularly neutropenia and thrombocytopenia, were the most frequently reported adverse events (AEs) overall and in the lenalidomide/HMA naive and non-del(5q) subset. The subset had a lower incidence of gr ≥3 neutropenia relative to the overall population (54% vs 66%) but a higher rate of gr ≥3 thrombocytopenia (62% vs 53%). Gr 4 neutropenia incidences were 41% overall and 38% for the subset. Overall, 28 patients (88%) had reversible LFT elevations by at least one grade. Four patients had gr 3 worsening of AST and/or ALT (1 also had gr 3 worsening of bilirubin), all of which were reversible. Eleven patients received growth factors during the study for treatment of an AE or ongoing medical history (n=10) or as prophylaxis (n=1).
Conclusion
Safety and efficacy reported here support continued investigation of imetelstat using the current dosing regimen of 7.5 mg/kg every 4 weeks in IPSS Low/Int-1 RBC TD MDS patients relapsed/refractory to ESA. AEs (mostly cytopenias) were predictable, manageable, and reversible. TI was observed in 38% and erythroid HI in 63% of patients with imetelstat therapy, with a 16% durable 24-week TI rate. Patients naïve to lenalidomide and HMAs and who lacked del(5q) had a 54% 8-week TI rate and responses were more durable (31% 24-week TI rate). To further validate these findings, additional patients meeting these criteria have been enrolled and are currently being followed.
Session topic: 10. Myelodysplastic syndromes – Clinical
Keyword(s): Myelodysplasia, Telomerase
Abstract: S1557
Type: Oral Presentation
Presentation during EHA23: On Sunday, June 17, 2018 from 08:30 - 08:45
Location: Room A4
Background
Patients with lower-risk MDS that is relapsed/refractory to ESA have few treatment options. The first-in-class telomerase inhibitor imetelstat, which targets cells with short telomere lengths and active telomerase, has the potential to provide clinical benefit in this patient population.
Aims
Here we report updated safety and efficacy data from IMerge, an ongoing 2-part, global, phase 2/3 study of imetelstat in RBC TD patients with IPSS Low or Intermediate-1 (Int-1) risk MDS.
Methods
The IMerge population includes patients with MDS relapsed/refractory to ESA with a transfusion requirement of ≥4 units over 8 weeks prior to entry and ESA-naïve patients with sEPO >500 mU/mL. In Part 1 (open-label, single-arm), imetelstat 7.5 mg/kg was administered IV every 4 weeks (escalation to 9.4 mg/kg permitted after 3 cycles). The primary endpoint is the rate of RBC transfusion-independence (TI) lasting ≥8 weeks; secondary endpoints include safety, ≥24-week TI rate, time to and duration of TI, and hematologic improvement (HI) rate. Updated results for the first 32 patients enrolled in Part 1 (median follow up, 75.3 weeks) are reported here.
Results
Median age was 68.5 years. 59% of patients were IPSS Low and 41% Int-1. 13 patients (43%) had sEPO>500 mU/mL. 34% had a cytogenetic abnormality, including 22% with del(5q). Prior MDS treatments included ESAs (88%), lenalidomide (38%), and decitabine or azacitidine (HMAs) (25%); 41% were both lenalidomide and HMA naïve and non-del(5q). As of Jan 2018, RBC-TI ≥8-week was achieved in 38% of patients. Median time to onset of TI was 8 weeks with a median duration of TI of 23 weeks. 16% of patients achieved ≥24-week TI, and 63% achieved erythroid HI. Of 13 lenalidomide and HMA naïve and non-del(5q) patients, 54% achieved ≥8-week TI. Median time to onset of TI in the subset was 8 weeks with a median duration of TI of 43 weeks. 31% of these patients had ≥ 24-week TI, and 69% achieved erythroid HI. TI response did not differ based on the presence of ringed sideroblasts or baseline sEPO level (41% [7/17] ≤500 mU/L; 38% [5/13] >500 mU/L). Cytopenias, particularly neutropenia and thrombocytopenia, were the most frequently reported adverse events (AEs) overall and in the lenalidomide/HMA naive and non-del(5q) subset. The subset had a lower incidence of gr ≥3 neutropenia relative to the overall population (54% vs 66%) but a higher rate of gr ≥3 thrombocytopenia (62% vs 53%). Gr 4 neutropenia incidences were 41% overall and 38% for the subset. Overall, 28 patients (88%) had reversible LFT elevations by at least one grade. Four patients had gr 3 worsening of AST and/or ALT (1 also had gr 3 worsening of bilirubin), all of which were reversible. Eleven patients received growth factors during the study for treatment of an AE or ongoing medical history (n=10) or as prophylaxis (n=1).
Conclusion
Safety and efficacy reported here support continued investigation of imetelstat using the current dosing regimen of 7.5 mg/kg every 4 weeks in IPSS Low/Int-1 RBC TD MDS patients relapsed/refractory to ESA. AEs (mostly cytopenias) were predictable, manageable, and reversible. TI was observed in 38% and erythroid HI in 63% of patients with imetelstat therapy, with a 16% durable 24-week TI rate. Patients naïve to lenalidomide and HMAs and who lacked del(5q) had a 54% 8-week TI rate and responses were more durable (31% 24-week TI rate). To further validate these findings, additional patients meeting these criteria have been enrolled and are currently being followed.
Session topic: 10. Myelodysplastic syndromes – Clinical
Keyword(s): Myelodysplasia, Telomerase