Correlation between treatment-emergent cytopenias and clinical response with imetelstat (IME) in patients (Pts) with lower-risk myelodysplastic syndromes (LR-MDS): Analysis from the imerge Trial

Abstract Introduction: IME is a first-in-class, direct, and competitive telomerase inhibitor approved for the treatment (tx) of certain adult pts with LR-MDS with red blood cell (RBC) transfusion-dependent anemia who are relapsed or refractory to/ineligible for erythropoiesis-stimulating agents. In the pivotal Phase 3 IMerge trial (NCT02598661), a significantly higher proportion of pts on IME vs placebo achieved ≥8-wk (40% vs 15%; P<.001) and ≥24-wk (28% vs 3%; P<.001) RBC transfusion independence (TI). The most common grade 3/4 tx-emergent adverse events with IME were neutropenia (68%) and thrombocytopenia (62%), typically occurring within the first 3 tx cycles and generally manageable and reversible. This post hoc analysis explored the possible association between IME-related cytopenias and Hb increase, a measure linked to RBC-TI achievement. Methods: Pooled pts from the 3 parts of IMerge (Phase 2/3 and QTc substudy) who received 7.1 mg/kg IME active dose (equivalent to 7.5 mg/kg IME sodium) were included. The relationship between percent reduction in platelet (PLT)/neutrophil (NEUT) counts occurring within the first 2 cycles of IME tx and subsequent outcomes was analyzed, including maximum (max) Hb increase from baseline (pre-tx Hb), hematologic improvement-erythroid (HI-E) per IWG 2006 criteria (defined as Hb rise ≥1.5 g/dL lasting 8 wk), and rates of ≥8-wk and ≥24-wk RBC-TI. Cytopenia levels were dichotomized at ≥50% reduction for PLTs and ≥75% reduction for NEUTs to assess categorical correlations with HI-E and RBC-TI responses (yes/no) using Fisher exact test and t test for group differences in Hb increase. Univariate linear regression was conducted to evaluate the association between continuous percent reduction in PLT/NEUT counts and max Hb increase. Multivariate analyses were conducted via stepwise linear regression (for max Hb increase) or logistic regression (for HI-E/TI response) with dichotomized percent reduction in PLT/NEUT counts in the presence of other baseline prognostic factors. An unadjusted nominal P value from each test was reported. Results: Data cutoff dates were 10/13/2023 (Phase 2/3) and 10/13/2024 (QTc substudy); 226 pts were included. Median values at baseline were 71 y of age, pre-tx Hb 7.8 g/dL, and PLT and NEUT counts 236×109/L and 2.6×109/L, respectively. Median IME tx duration was 34 wk. Pts with ≥50% max PLT reduction within the first 2 cycles of IME tx had a significantly greater mean max Hb increase from pre-tx (2.07 g/dL [n=169] vs 1.17 g/dL [n=39]; P=.003), HI-E rate (34.2% vs 11.9%; P=.005) and ≥24-wk RBC-TI rates (32.6% vs 7.1%; P<.001), and numerically greater ≥8-wk RBC-TI rates (42.4% vs 26.2%; P=.056) vs pts with <50% PLT reduction. As a continuous variable, PLT reduction remained significantly associated with Hb increase (P=.0095; linear regression). Similarly, pts with ≥75% max NEUT reduction within the first 2 cycles of IME tx had a significantly greater mean max Hb increase from pre-tx (2.53 g/dL [n=70] vs 1.58 g/dL [n=138]; P=.011), numerically greater HI-E rate (34.6% vs 27.7%), and comparable ≥8-wk (41.0% vs 38.5%) and ≥24-wk RBC-TI rates (30.8% vs 26.4%) vs pts with <75% NEUT reduction. As a continuous variable, NEUT reduction was also significantly associated with max Hb increase (P=.012). Multivariate analyses showed that the likelihood of achieving ≥8-wk and ≥24-wk RBC-TI was significantly correlated with the max Hb increase from pre-tx, g/dL (odds ratio [OR; 95% CI], 6.47 [3.73-11.24; P<.001] and 3.87 [2.66-5.64; P<.001], respectively). Multivariate analyses further confirmed that max Hb increase, g/dL, significantly correlated with ≥75% NEUT reduction (coefficient estimate [95% CI], 0.94 [0.32-1.57; P=.003]), and the likelihood of achieving HI-E significantly correlated with ≥50% PLT reduction (OR [95% CI], 4.16 [1.54-11.23; P=.005]). Conclusions: In this post hoc analysis, pts with ≥75% NEUT or ≥50% PLT reductions in the first 2 cycles of IME tx were more likely to have greater Hb increases from pre-tx or to achieve an HI-E response. The greater Hb increase from pre-tx emerged as a main driver for achieving ≥8-wk and ≥24-wk RBC-TI responses. Collectively, these data suggest that tx-emergent cytopenias with IME may be associated with potential for clinical benefit, similar to lenalidomide in del5q MDS. Further research is needed to confirm this on-target effect of IME resulting from its activity on clonal progenitor cells and subsequent recovery in blood cell production.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.