7 research outputs found
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Health-related quality of life (HRQoL) in patients with untreated higher-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML) receiving glasdegib + azacitidine (AZA)
7527
Background: Glasdegib + AZA showed promising remission rates and overall survival in an analysis of BRIGHT MDS & AML 1012 in patients (pts) with MDS, AML and CMML. Here we assess the impact of glasdegib + AZA on HRQoL in this ongoing Phase Ib study. Methods: Untreated pts with MDS, AML and CMML ineligible for intensive chemotherapy received glasdegib (100 mg QD) + AZA (75 mg/m
2
/D on D1–7 q28D). Pt-reported outcomes (PRO) that characterize HRQoL were measured using the MD Anderson Symptom Inventory (MDASI)-AML/MDS, Pt Global Impression of Severity (PGI-S), and Pt Global Impression of Change (PGIC) tools. PRO were assessed at baseline (BL; except the PGIC), D7 and D15 of cycle (Cyc) 1, D1 of each subsequent Cyc and at end of treatment. Data cutoff: Sept 11, 2019. Results: For the MDS (n=30, including 3 with CMML) and AML (n=30) cohorts, median (range) number of Cyc started was 5 (1–14) and 5 (1–15), respectively. HRQoL over time, as determined by MDASI-AML/MDS, is shown in the Table, with mean scores indicating low symptom burden over time. For the PGI-S, both cohorts showed similar trends in pt’s impression of current leukemia symptoms remaining constant over time (i.e. absent to mild). For the PGIC, pt’s impression of change of leukemia symptoms since starting study medication remained constant over time (i.e. no to minimal change) for the MDS cohort and showed improvement in the AML cohort (i.e. minimal change to much improved). Conclusions: Glasdegib + AZA is a promising first-line treatment option that does not negatively impact the HRQoL of pts with MDS, AML and CMML ineligible for intensive chemotherapy. Clinical trial information: NCT02367456 . [Table: see text
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Glasdegib in combination with azacitidine (AZA) in patients (pts) with untreated higher-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML): Effects on marrow recovery and transfusion independence
7526
Background: Glasdegib, an oral inhibitor of the Hedgehog signaling pathway, is approved in the USA in combination with low-dose cytarabine to treat pts with newly diagnosed AML unable to receive intensive chemotherapy due to comorbidities or age (≥75 years). Glasdegib + AZA showed promising remission rates and overall survival with a generally well-tolerated and manageable safety profile in an analysis of BRIGHT MDS & AML 1012 in pts with MDS, AML and CMML. Here we evaluate early hematopoietic recovery and transfusion independence with glasdegib + AZA in this ongoing Phase Ib study. Methods: Untreated pts with MDS, AML and CMML ineligible for intensive chemotherapy received glasdegib (100 mg QD) + AZA (75 mg/m
2
/D on D1–7 q28D). Data cutoff: Sept 11, 2019. Results: Among pts with MDS (n=30; including 3 with CMML), median duration of treatment was 5.0 months (range, 0.4–15.5). Recovery of absolute neutrophil count (ANC), hemoglobin (Hb) and platelets at 2 thresholds started in cycle (Cyc) 1 (Table). Early platelet recovery correlated with response to treatment; 54% (7/13) of pts with platelets ≥100,000/µL at Cyc 2, D1 achieved complete or partial remission vs 0% (0/13) of pts with <100,000/µL, P=0.002. Start of Cyc 2 was delayed due to AEs in 8% (2/26) of pts. 54% (7/13) of evaluable pts transfusion dependent at baseline (BL) became transfusion independent. Among pts with AML (n=30), median duration of treatment was 5.0 months (range, 0.3–14.9). ANC, Hb and platelet recoveries started in Cyc 1 (Table). 9% (2/23) of pts had Cyc 2 dose delays due to AEs. 64% (9/14) of evaluable pts transfusion dependent at BL became transfusion independent. Clinical trial information: NCT02367456 . Conclusions: Glasdegib + AZA shows promising rates of survival with early marrow recovery in the up-front treatment of pts with MDS, AML and CMML ineligible for intensive chemotherapy. The association between early hematopoietic recovery and efficacy in the MDS cohort merits further study. [Table: see text
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IMerge: A phase 3 study to evaluate imetelstat in transfusion-dependent subjects with IPSS low or intermediate-1 risk myelodysplastic syndromes that are relapsed/refractory to erythropoiesis-stimulating agent treatment
TPS7056
Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients (pts) with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomeres and active telomerase, characteristics observed in MDS pts across all disease stages. IMerge (MDS3001) is a Phase 2/3 global study of imetelstat for TD pts with non-del(5q) LR MDS post ESA therapy. The results from Phase 2 part indicated that imetelstat achieved durable RBC transfusion independence (RBC-TI) and the most frequently reported adverse events were manageable and reversible grade ≥3 cytopenias. Among 38 pts with median follow-up of 24 months, 8-week, 24-week and 1-year TI rates were 42%, 32% and 29%, respectively; these responses were seen across different LR MDS subtypes. Median TI duration was 20 months and the longest TI was 2.7 years. A high and durable hematologic improvement-erythroid (HI-E) rate of 68% for a median duration of 21 months were also achieved. Reduction of variant allele frequency of mutations by imetelstat treatment was observed in some pts and correlated with clinical benefits (Platzbecker et al EHA 2020; Steensma et al JCO 2020). These results support the Phase 3 part of the trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 3 part of the study is open for enrollment to adult pts with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs placebo that will enroll approximately 170 pts and will be conducted at approximately 120 centers in North America, Europe, Asia and Middle East. Imetelstat is administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of HI-E, the amount and relative change in RBC transfusions, rate of CR or PR, overall survival, progression of MDS, pharmacokinetics, and quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. The study is currently recruiting pts. Clinical trial information: NCT02598661
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IMerge: Results from a phase 3, randomized, double-blind, placebo-controlled study of imetelstat in patients (pts) with heavily transfusion dependent (TD) non-del(5q) lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESA)
7004 Background: Unmet needs remain for red blood cell (RBC) TD pts with LR-MDS R/R or ineligible for ESA. In P2 of the IMerge study (NCT02598661), heavily RBC TD ESA R/R non-del(5q) LR-MDS pts naive to lenalidomide and hypomethylating agents (len/HMA) treated with imetelstat, a telomerase inhibitor, achieved durable and continuous transfusion independence (TI). We report primary data from the P3 study of imetelstat in such pts. Methods: Heavily RBC TD ESA R/R non-del(5q) LR-MDS pts naive to len/HMAs were randomized 2:1 to receive imetelstat 7.5 mg/kg or placebo every 4 wks. Primary endpoint was 8-wk TI; subgroup analyses included IPSS risk, prior transfusion burden and ring sideroblast (RS) status. Secondary endpoints included 24-wk TI, TI duration and hematologic improvement-erythroid (HI-E). Variant allele frequency (VAF) changes were explored. Results: As of Oct 2022, 178 pts were randomized. The primary endpoint was met (Table); 39.8% vs 15.0% of pts receiving imetelstat vs placebo, respectively, achieved 8-wk TI. The rate of 8-wk TI was significantly higher with imetelstat vs placebo across subgroups, including RS negative pts. Median TI duration was significantly longer for imetelstat vs placebo, 51.6 vs 13.3 wks, P 80% were reversible to Grade ≤2 within 4 wks. Conclusions: For this LR-MDS pt population, imetelstat demonstrated statistically significant and clinically meaningful efficacy with high 8- and 24-wk TI rates, prolonged TI duration and increased hemoglobin. VAF reduction and its correlation to clinical endpoints support imetelstat’s disease-modifying potential. Safety results were consistent with prior reported experience. Clinical trial information: NCT02598661 . [Table: see text
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Clinical benefit of luspatercept in patients (pts) with lower-risk MDS (LR-MDS) and high transfusion burden in the phase III MEDALIST study
7554
Background: Anemic pts with LR-MDS and high baseline RBC transfusion burden (HTB) have very few treatment options and constitute a pt population with significant clinical unmet need. In this secondary analysis of the MEDALIST trial (NCT02631070), we sought to evaluate the clinical benefit of luspatercept in this pt population. Methods: MEDALIST is a randomized, placebo (PBO)-controlled, phase 3 study evaluating the efficacy and safety of luspatercept in pts with anemia due to LR-MDS with ring sideroblasts (RS) (Fenaux & Platzbecker et al. NEJM. 2020;382:140-51). Pts were aged ≥ 18 years; had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS; were refractory, intolerant, or unlikely to respond to erythropoiesis-stimulating agents (serum erythropoietin > 200 U/L); and had anemia requiring regular RBC transfusions (≥ 2 units/8 weeks in the 16 weeks prior to randomization). 229 pts were randomized 2:1 to luspatercept (starting dose 1.0 mg/kg; titration up to 1.75 mg/kg allowed) or PBO subcutaneously every 3 weeks. HTB was defined as ≥ 6 RBC units transfused/8 weeks. Results: 153 pts were randomized to luspatercept and 76 to PBO. As of July 1, 2019, 23/66 (34.8%) and 12/66 (18.2%) HTB pts receiving luspatercept achieved a ≥ 50% and ≥ 75% reduction from baseline in RBC transfusion burden over ≥ 24 weeks, respectively, vs 3/33 (9.1%; P = 0.0063) and 1/33 (3.0%; P = 0.0363) pts receiving PBO. 6/66 (9.1%) luspatercept-treated HTB pts and 1/33 (3.0%) PBO-treated HTB pt achieved RBC-transfusion independence (TI) ≥ 8 weeks in Weeks 1–24 ( P = 0.2699). The median (range) time to achieve RBC-TI with luspatercept was 50.0 days (1.0–100.0) and median (range) duration of RBC-TI in the luspatercept arm was 42.6 weeks (8.4–81.1). Mean number of transfusion events in Weeks 1–24 was 9.2 in the luspatercept arm vs 12.4 in the PBO arm (hazard ratio [95% confidence interval] 0.794 [0.660–0.956]). 65/66 (98.5%) luspatercept- and 29/33 (87.9%) PBO-treated HTB pts reported ≥ 1 treatment-emergent adverse event (TEAE); 11/66 (16.7%) and 3/33 (9.1%) pts, respectively, reported ≥ 1 TEAE leading to discontinuation. 28/66 (42.4%) luspatercept- and 15/33 (45.5%) PBO-treated pts reported ≥ 1 serious AE. Incidence of grade 3–4 TEAEs in HTB pts was similar between arms (53.0% luspatercept vs 54.5% PBO). Conclusions: Luspatercept treatment resulted in clinically significant reductions in transfusion burden and reduced number of transfusion events in HTB pts with LR-MDS with RS, with an acceptable safety profile consistent with the overall population. Clinical trial information: NCT02631070
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Longer-term RBC transfusion reduction in the phase III MEDALIST study of luspatercept in patients (pts) with lower-risk MDS with ring sideroblasts (RS)
7518
Background: MEDALIST (NCT02631070) is a randomized, placebo (PBO)-controlled, phase 3 trial evaluating the efficacy and safety of luspatercept, a first-in-class erythroid maturation agent, in pts with anemia due to lower-risk MDS (LR-MDS) with RS (Fenaux & Platzbecker et al. NEJM. 2020;382:140-51). Methods: Pts were aged ≥ 18 years; had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS; were refractory, intolerant, or unlikely to respond to ESAs; and required RBC transfusions (≥ 2 units/8 weeks in the 16 weeks prior to randomization). 229 pts were randomized 2:1 to luspatercept (1.0 mg/kg, titration to 1.75 mg/kg) or PBO subcutaneously every 3 weeks. This analysis evaluates long-term transfusion burden reduction with luspatercept in all pts in the MEDALIST trial. Results: As of July 1, 2019, 77/153 (50.3%) and 11/76 (14.5%) pts in the luspatercept and PBO arms, respectively, achieved ≥ 50% RBC transfusion burden reduction for ≥ 24 weeks ( P < 0.0001). The median longest single response episode was 131.6 weeks with luspatercept, and not estimable with PBO due to pts stopping treatment. In Weeks 9–24, mean change from baseline in RBC units transfused was −3.0 (95% CI −3.9, −2.1) vs +0.4 (95% CI −0.6, 1.4) in the luspatercept vs PBO arms. In Weeks 33–48, mean change in RBC units transfused in the luspatercept arm was −4.9 (95% CI −5.9, −3.9). In Weeks 1–24, mean number of transfusion visits was 5.9 vs 9.5 in the luspatercept vs PBO arms. Risk of recurrent transfusion visits in Weeks 1–24 for luspatercept vs PBO was 0.699 (95% CI 0.597, 0.819; P < 0.0001). Mean number (least squares [LS] mean) of RBC units transfused/48 weeks during Weeks 1–48 was 22.89 (23.28) vs 35.98 (35.20) in luspatercept vs PBO arms (LS mean difference −11.92 [95% CI −15.55, −8.28]; P < 0.0001). The mean number (LS mean) of RBC transfusion events over 48 weeks was 12.95 (13.14) vs 19.54 (19.15) in the luspatercept vs PBO arms (LS mean difference −6.00 [95% CI −8.16, −3.85]; P < 0.0001). LS mean change from baseline in serum ferritin was −2.7 µg/L vs +226.5 µg/L in luspatercept vs PBO (LS mean difference −229.1 µg/L; P = 0.0024) in Weeks 9–24; and −72.0 µg/L vs +247.4 µg/L in Weeks 33–48 (LS mean difference −319.5 µg/L; P = 0.0294). In Weeks 1–24, 38/127 (29.9%) vs 5/65 (7.7%) pts ( P = 0.0005) achieved major HI-E response per IWG 2018 criteria in luspatercept vs PBO arms, respectively. Conclusions: Luspatercept demonstrated clinical efficacy in pts with LR-MDS with RS and was associated with significant reductions in RBC transfusions (≥ 50%) and serum ferritin. Clinical trial information: NCT02631070