Rytelo (imetelstat) / Geron - LARVOL DELTA

Efficacy of novel agents in the treatment of acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis (ASH 2025) - "Newer agents included for AML were Guadectiabine, Magrolimab, Alvocidib, Enasidenib, Flotetuzumab, Vadastuximab, Mitoxantrone, Pevonedistat, Entospletinib, Eprenetapopt, Belinostat, Onvansertib, Panobinostat, Cediranib Maleate, Nilotinib, Emavusertib, and anti-CD45 antibody (DOTA-BC8). The newer agents investigated for MDS included Rigosertib, Imetelstat, Pembrolizumab, Enasidenib, Sabatolimab, Ivosidenib, Elitercept, Pevonedistat, Emavusertib, Atezolizumab, and Olutasidenib...All patients were treated concomitantly with either azacitidine (77%) or decitabine (23%)... This meta-analysis and systematic review demonstrate promising efficacy for novel agents in AML and MDS patients. There is a need for prospective trials with larger patient populations to investigate these agents further."

Retrospective data • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • TP53

Correlation between interleukin (IL)-8 and tumor necrosis factor (TNF)-alpha levels and overall survival in patients (pts) with myelofibrosis (MF) relapsed or refractory (R/R) to a Janus-associated kinase inhibitor (JAKi) treated with imetelstat (IME) in the imbark trial (ASH 2025) - P2 | "In this post hoc analysis, IME tx resulted in dose-dependent reductions from BL of IL-8 andTNF-alpha levels, which corresponded with reductions in TSS or spleen volume. Furthermore, 8.9 mg/kgIME showed a longer survival benefit compared with 4.4 mg/kg IME in pts with higher BL IL-8 and TNF-alpha levels who face worse prognosis, although pt numbers were small. This hypothesis-generating,exploratory analysis identifies specific inflammatory cytokines reduced with IME tx and associatedreduction in spleen volume and symptoms that, together with previously presented data, suggestpotential disease-modifying activity in MF."

Clinical • Myelofibrosis • Oncology • CXCL8 • TNFA

A phase II study evaluating the efficacy and safety of imetelstat in patients with advanced myelodysplastic neoplasms or AML failing HMA-based therapy – interim analysis results of the IMpress study (ASH 2025) - P2 | "Platzbecker U, Lane S and Adès L contributed equally.A study by the European Myelodysplastic Neoplasms Cooperative Group (EMSCO)Introduction:Hypomethylating agents (HMAs), either as monotherapy or combined with venetoclax (VEN), arestandard of care for patients with higher-risk MDS (HR-MDS) or AML ineligible for intensivechemotherapy...Its clinical efficacy in HR-MDS or AML has not yet been established.The multicenter phase 2 IMpress trial (NCT05583552), led by EMSCO, evaluates safety and efficacy ofimetelstat sodium in HR-MDS or AML patients refractory, relapsing or intolerant following at least 6 or 4cycles of either azacitidine (AZA) or decitabine (DAC), respectively, or 3 cycles of VEN/AZA.In cohort 1 (ASH 2024), patients received 7.5 mg/kg i.v. once every 4 weeks for 4 cycles...Increased exposure to imetelstat in refractory, relapsing or intolerant AML/HR-MDS patients did notappear to be associated with additional toxicity. PE visit completion rose from..."

Clinical • Metastases • P2 data • Acute Myelogenous Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Myelodysplastic Syndrome • Neutropenia • Pneumonia • Respiratory Diseases • Septic Shock

The transition from myelodysplastic neoplasm to secondary acute myeloid leukemia is revealed by molecular analysis, while functional drug screening demonstrates novel sensitivity patterns with clinical implication (ASH 2025) - "There are only a limited number of agentsthat are FDA approved for treatment of MDS including BCL2 and IDH inhibitors, hypomethylating agents(HMAs), ESAs, luspatercept and imetelstat...For MDS patients, weidentified the most effective agents with the proportion of sensitive samples noted in parentheses:mitoxantrone (100%), olutasidenib (78%), venetoclax (67%), dinaciclib (67%), trametinib (67%), olaparib(56%), GSK3368715 (56%), pacritinib (44%), lenalidomide (44%), fludarabine (55%), tasquinimod (44%),veliparib (44%). For sAML patients, we identified lenalidomide, olutasidenib, GSK3368715 have high DSSsin all tested samples, while fludarabine, fedratinib, tasquinimod, trametinib, veliparib, mitoxantrone andolaparib have high DSSs in 75% of the AML samples...Cancer Research 2024), and our samples included SF3B1 and U2AF1 mutations.Summary This study of the transition of MDS to sAML highlights molecular changes and reveals new drugsensitivity with agents that could be..."

Biomarker • Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • CD34 • FLT3 • JAK2 • NRAS • PTPN11 • SF3B1 • U2AF1

Elevated serum erythropoietin level is associated with unique clinical and genomic features, response to treatment, and outcomes in lower-risk myelodysplastic syndromes (ASH 2025) - "Finally, among 65 non-del5q LR-MDSpts who received lenalidomide, the HI rates were 22% (4/41), 50% (6/12), and 33.3% (4/12) based on EPOgroups. We did not have mature data on imetelstat responses, but it was reported to be similarirrespective of EPO level in clinical trials.There was a trend for higher AML transformation rate among pts with EPO >500,16/93 (17.2%), comparedto 11/109 (10.1%) for pts with EPO 200-500, and 130/1009 (12.9%) for those with EPO 500 compared to 500. The response to ESA and luspatercept is EPO-dependent, while treatment with azacitidine andlenalidomide maintain similar responses across EPO levels."

Clinical • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • RUNX1 • U2AF1 • ZRSR2

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 (ASH 2025) - P2/3 | "Introduction: IME is a first-in-class, direct, and competitive telomerase inhibitor approved for thetreatment (tx) of certain adult pts with LR-MDS with red blood cell (RBC) transfusion-dependent anemiawho are relapsed or refractory to/ineligible for erythropoiesis-stimulating agents. In this post hoc analysis, pts with ≥75% NEUT or ≥50% PLT reductions in the first 2 cycles ofIME tx were more likely to have greater Hb increases from pre-tx or to achieve an HI-E response. Thegreater Hb increase from pre-tx emerged as a main driver for achieving ≥8-wk and ≥24-wk RBC-TIresponses. Collectively, these data suggest that tx-emergent cytopenias with IME may be associated withpotential for clinical benefit, similar to lenalidomide in del5q MDS."

Clinical • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Neutropenia • Thrombocytopenia

Safety and efficacy results from A phase 1b study of R289, a dual irak 1/4 inhibitor, in patients with Relapsed/Refractory (R/R) lower risk myelodysplastic syndrome (LR-MDS). (ASH 2025) - P1/2 | "The median number of prior therapies was 3 (range 1-8); 76% were previouslytreated with luspatercept, 73% with an erythropoiesis stimulating agent, 67% with a hypomethylatingagent, and 6% with imetelstat. R289 was well-tolerated in this elderly, heavily pretreated LR-MDS patient population, themajority of whom were HTB at BL. The incidence of G3/4 cytopenias and infections was low. Allresponding patients had R835 plasma concentrations similar to those at which ≥50% LPS-inducedinhibition of cytokine release was observed in HS, indicating a potential threshold for dose response(≥500 mg QD)."

Clinical • P1 data • Constipation • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Infectious Disease • Inflammation • Myelodysplastic Syndrome • Pneumonia • Respiratory Diseases • HEY1 • IL1R1 • IRAK1 • TLR4

Long-term outcomes from the randomized, double-blind, placebo (PBO)-controlled, phase 3 imerge trial of imetelstat (IME) for lower-risk myelodysplastic syndromes (LR-MDS) (ASH 2025) - P2/3 | "Here, we report onsecondary endpoints, including OS, progression-free survival (PFS), progression to acute myeloidleukemia (AML), safety, and long-term outcomes by subgroups of interest in IMerge, as well as ad hocoutcomes, including OS by response. In IMerge, pts with RBC-TD LR-MDS who were R/R to/ineligible for ESAs and lenalidomide- andhypomethylating agent–naive were randomized 2:1 to IME (7.1 mg/kg active dose, equivalent to 7.5mg/kg IME sodium) or PBO. IME resulted in a favorable trend in OS, PFS, and time to progression to AML vs PBO in theoverall population; OS favored IME vs PBO in most subgroups. The OS results correlated with RBC-TI andHb rise in IME-treated pts. Although not statistically powered to detect significance, these analysessupport the clinical benefit of IME in pts with RBC-TD LR-MDS."

Clinical • P3 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • SF3B1

Improvemf: Phase 1b trial of imetelstat plus ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis (ASH 2025) - P1, P2 | "The Phase 1b portion of IMproveMF is actively enrolling, with 3 patients enrolled as of July 21, 2025. Thefirst patient first treatment visit occurred on January 10, 2025."

Clinical • P1 data • Bone Marrow Transplantation • Fibrosis • Hematological Malignancies • Hepatology • Immunology • Infectious Disease • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm

Updates on Low/Intermediate-Risk MDS (ASH 2025) - "Upfront therapy for non-del5q MDS with isolated anemia can either be Luspatercept or ESA based therapy; with Luspatercept being favored in the setting of SF3B1 mutated MDS and/or in the presence of ring sideroblasts. The use of imetelstat for the management of anemia has been an exciting addition to the armamentarium although its use has been challenged by its side effect profile...Ongoing trials are evaluating novel pathways (i.e. IRAK inhibition) and or targeted therapies (i.e. IDH inhibition). These advances highlight a shift toward individualized care and better risk-adapted interventions."

Hematological Disorders • Myelodysplastic Syndrome • IRAK1 • SF3B1

FDA approval of imetelstat: a new era in the treatment of lower-risk myelodysplastic syndrome. (PubMed, Ann Med Surg (Lond)) - "Previously available treatments-including erythropoiesis-stimulating agents, lenalidomide, luspatercept, roxadustat, and azacitidine-have demonstrated variable efficacy and tolerability, with limited impact on long-term disease progression. Its approval underscores the importance of targeting fundamental disease mechanisms rather than merely alleviating symptoms. As additional data emerge from real-world settings and ongoing trials, Imetelstat may further reshape therapeutic algorithms and improve both quality of life and survival outcomes in this patient population."

FDA event • Journal • Review • CNS Disorders • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Psychiatry

Updates in low/intermediate-risk MDS. (PubMed, Hematology Am Soc Hematol Educ Program) - "New therapeutic options to reduce the red blood cell (RBC) transfusion burden have emerged since 2020 and include luspatercept and imetelstat. Erythropoiesis-stimulating agents and lenalidomide also address anemia and are generally recommended to start at the time of transfusion dependency, although emerging data suggest that an earlier start of these interventions might offer clinical benefits...Targeted therapy directed to the presence of an IDH1 mutation is U.S. Food and Drug Administration (FDA) approved for the rare IDH1 mutated MDS (<10% of the time) and consideration to use an IDH2 inhibitor for IDH2 mutated MDS (<5% of the time) is reasonable. Interestingly, IDH mutations seem to appear with increased frequency in older patients and in patients with underlying autoimmune/rheumatological disorders.1."

Journal • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Oncology • Rheumatology • Thrombocytopenia • IDH1

MODULE 4: Future Directions in the Management of MF (ASH 2024) - "This program is supported by educational grants from CTI BioPharma, a Sobi Company, Geron Corporation, GSK, Incyte Corporation and Karyopharm Therapeutics.Mechanism of antitumor activity of navitoclax and biological rationale for its evaluation for MF Available efficacy and safety findings from the Phase III TRANSFORM-1 study of navitoclax in combination with ruxolitinib versus ruxolitinib alone for patients with previously untreated MF Potential role of navitoclax in the up-front setting and ongoing evaluation for relapsed/refractory (R/R) disease in the Phase III TRANSFORM-2 study Rationale for the evaluation of BET inhibitors for MF; updated findings from the Phase III MANIFEST-2 study combining pelabresib to ruxolitinib for JAK inhibitor-naïve disease Scientific justification for the evaluation of selinexor for MF; early efficacy and safety findings with selinexor as monotherapy and in combination with ruxolitinib Ongoing evaluation of the combination of..."

Myelofibrosis • Oncology

Long-Term Outcomes and Overall Survival from the Randomized, Double-Blind, Placebo-Controlled, Phase 3 IMerge Trial of Imetelstat for Lower-Risk Myelodysplastic Syndromes (Santini et al., Poster #2074) (GlobeNewswire) - "At a median follow-up of 45 months, the analysis showed a favorable trend toward improved secondary endpoints of OS, PFS, and time to AML progression for imetelstat-treated patients compared with placebo recipients in the overall population. OS favored imetelstat versus placebo in most predefined subgroups, regardless of transfusion burden, serum EPO (erythropoietin) level, and ring sideroblast positive or negative status. Additionally, OS outcomes were numerically improved in patients who achieved RBC-TI or hemoglobin improvement....These results suggest that imetelstat may provide meaningful long-term benefit for patients with lower-risk MDS who are transfusion independent, although the trial was not powered to detect statistical significance for OS."

P3 data • Myelodysplastic Syndrome

IMproveMF: Phase 1b Trial of Imetelstat Plus Ruxolitinib in Patients with Intermediate-1/2 or High-Risk Myelofibrosis (Mascarenhas, et al., Poster #2052) (GlobeNewswire) - "This poster reported enrollment progress and emerging observations from the Phase 1b IMproveMF trial evaluating imetelstat in combination with ruxolitinib for patients with intermediate-2 or high-risk myelofibrosis. The study is designed to determine safety, tolerability, and recommended dosing for future development....As of the July 2025 cutoff, the trial had enrolled three patients in part 2 of the study, with the first patient treated in January 2025. The part 1 dose escalation phase of the study is complete, with 8.9 mg/kg imetelstat IV every 4 weeks identified as the recommended dose to be combined with ruxolitinib."

Trial status • Myelofibrosis

Correlation between IL-8 and TNF-Alpha Levels and Overall Survival in Patients with Myelofibrosis Relapsed or Refractory to a JAKi Treated with Imetelstat in the IMbark Trial​ (Mascarenhas et al., Poster #5585) (GlobeNewswire) - "The findings showed that patients treated with imetelstat experienced dose-dependent reductions in IL-8 and TNF-a (proinflammatory cytokines), with the 8.9 mg/kg dose showing more pronounced effects compared to the 4.4 mg/kg dose. Reductions in these cytokines corresponded with reductions in total symptom score or spleen volume, consistent with previously reported clinical activity. A longer survival trend was observed in patients receiving the higher dose, particularly among patients with elevated baseline IL-8 and TNF-a levels, although subgroup sizes were small."

P2 data • Myelofibrosis

Correlation between Treatment-Emergent Cytopenias and Clinical Response with Imetelstat in Patients with Lower-Risk Myelodysplastic Syndromes: Analysis from the IMerge Trial (Zeidan et al., Oral #490) (GlobeNewswire) - "Across analyses looking at single clinical factors, patients who experienced ≥75% reductions in neutrophils or ≥50% reductions in platelets during the first two cycles of imetelstat had greater maximum Hb increases compared with those who did not experience such reductions. Numerically higher rates of ≥8- or ≥24-week RBC-TI were also observed in these groups. When the analyses accounted for multiple clinical factors at the same time, the associations between early cytopenias and Hb improvements remained consistent: ≥75% neutrophil reduction was associated with greater Hb increase, whereas maximum ≥50% platelet reduction was associated with achieving Hb rise ≥1.5 g/dL lasting ≥8 weeks. Further, Hb rise emerged as a main driver of achieving transfusion independence. A strong association between platelet and neutrophil reductions was also observed."

P2/3 data • Myelodysplastic Syndrome

Advanced Myelodysplastic Neoplasms or AML Failing HMA-based Therapy – Preliminary Results of the IMpress Study​ (Ades, et al, Poster #5115) (GlobeNewswire) - "The results showed that imetelstat administered at 7.1 mg/kg IV every 2 weeks in this patient population did not appear to be associated with additional toxicity, and that treatment-emergent adverse events were manageable in this heavily pre-treated population. While limited single-agent clinical activity was observed – consistent with the aggressive disease biology and prior treatment history – several patients were able to complete protocol-specified visits, and one remained on treatment at the time of the analysis....These findings suggest that single agent imetelstat has a predictable and manageable safety profile at this exposure in these advanced diseases and provides important insights for potential combination strategies in high-risk populations, where unmet needs remain substantial."

P2 data • Acute Myelogenous Leukemia • Myelodysplastic Syndrome

Clinical outcomes and safety in patients with lower-risk myelodysplastic syndromes treated with imetelstat: Substudy of the phase 3 IMerge trial. (PubMed, Br J Haematol) - No abstract available

Clinical data • Journal • P3 data • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Trial Update from IMproveMF, an Ongoing, Open-Label, Dose-Escalation and -Expansion, Phase 1/1B Trial to Evaluate the Safety, Pharmacokinetics, and Clinical Activity of the Novel Combination of Imetelstat with Ruxolitinib in Patients with Intermediate-1, Intermediate-2, or High-Risk Myelofibrosis (MF) (ASH 2024) - P1, P2 | "This trial is ongoing across the US at 6 sites and will continue to enroll at the 9.4 mg/kg imetelstat sodium dose level to confirm the RP2D before starting part 2. These early results demonstrate promise for the tolerability of the combination of IME+RUX in this pt population with high unmet needs."

Clinical • P1 data • PK/PD data • Anemia • Fatigue • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukopenia • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • CALR • JAK2

IMproveMF Update: Pharmacokinetics, Clinical Activity, and Biomarker Analyses From the Phase 1/1B Trial of Imetelstat Combined With Ruxolitinib in Patients With Intermediate-1–, Intermediate-2–, or High-Risk Myelofibrosis (MPN 2025) - No abstract available

Biomarker • Clinical • P1 data • PK/PD data • Myelofibrosis

Rytelo: Newly added patent in Orange Book (Orange Book) - Expiry on Mar 15, 2033

Patent • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

A Phase II Study Evaluating the Efficacy and Safety of Imetelstat in Patients with Advanced Myelodysplastic Neoplasms or AML Failing HMA-Based Therapy - Interim Analysis Results of the Impress Study (ASH 2024) - "Methods : The multicenter phase 2 IMpress trial led by the European Myelodysplastic Neoplasms Cooperative Group (EMSCO) evaluates the safety and efficacy of imetelstat in patients with HR-MDS or AML, refractory, relapsing or intolerant after at least six or four cycles of either azacitidine (AZA) or decitabine (DAC), respectively, or 3 cycles of venetoclax (VEN) plus AZA. Although adverse events were documented, they were all disease related to patients with HR-MDS and AML. Based on the observations in this first cohort, the protocol was amended to a more frequent dosing schedule for a second cohort of patients being enrolled and treated with this modified schedule starting in August 2024."

Clinical • Metastases • P2 data • Acute Myelogenous Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • Septic Shock

Overcoming Ven/Aza Resistance through Imetelstat-Mediated Lipophagy in Acute Myeloid Leukemia (ASH 2024) - "The autophagy inhibitors chloroquine (CQ), bafilomycin A1, or 3-methyladenine prevented imetelstat-induced cell death, lipid peroxidation, lipid ROS production, and colocalization of lipid droplets with the late endosomal marker LAMP-1...Importantly, increased fatty acid metabolism in pre-treatment AML LSCs is associated with resistance to venetoclax and azacitidine (ven/aza) combination therapy...Imetelstat is an acute inducer of lipophagy, promoting the formation of PUFA-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress resulting in ferroptosis in AML. These mechanistic insights may be leveraged to develop an optimized therapeutic strategy using imetelstat to target ven/aza resistant AML subclones, providing significantly improved disease control for AML."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Metabolic Disorders • Myelodysplastic Syndrome • Oncology • Thrombocytopenia • LAMP1

Improvement of Patient-Reported Outcomes Among Heavily Pretreated Patients with Lower-Risk Myelodysplastic Syndromes and High Transfusion Burden Treated with Imetelstat on the IMerge Phase 3 Trial (ASH 2023) - P2/3 | "Findings from multiple validated PRO questionnaires consistently show that patients with red blood cell transfusion-dependent LR-MDS enrolled into the IMerge randomized trial who were treated with imetelstat reported improved fatigue, dyspnea, and QUALMS composite scores (total and physical burden) compared with those in the placebo group. These data indicate that, in addition to improving transfusion burden in patients with LR-MDS, imetelstat targets multiple core symptoms of LR-MDS simultaneously, also improving PROs."

Clinical • P3 data • Patient reported outcomes • Anemia • Fatigue • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Pulmonary Disease