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

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.