Intermediate-1 Risk Myelodysplastic Syndromes Research Articles

The IL-1β inhibitor canakinumab in previously treated lower-risk myelodysplastic syndromes: a phase 2 clinical trial.

In myelodysplastic syndromes (MDS), the IL-1β pathway is upregulated, and previous studies using mouse models of founder MDS mutations demonstrated that it enhances hematopoietic stem and progenitor cells' (HSPCs') aberrant differentiation towards the myeloid lineage at the expense of erythropoiesis. To evaluate whether targeting the IL-1β signaling pathway can rescue ineffective erythropoiesis in patients with MDS, we designed a phase 2 non-randomized single-arm clinical trial (NCT04239157) to assess the safety profile and efficacy of the IL-1β inhibitor canakinumab in previously treated lower-risk MDS patients. We enrolled 25 patients with a median age of 74 years; 60% were male, 16% had lower-risk MDS, 84% had intermediate-1 risk MDS according to the International Prognostic Scoring System score, and 80% failed hypomethylating agent therapy. The study met the primary endpoint of defining the clinical activity of canakinumab, and the secondary objective of determining the safety profile, including the rate of transfusion independence, the duration of response, progression-free survival, leukemia-free survival, and overall survival. The overall response rate was 17.4%, with all responses including hematological improvement. Sequential post-hoc prospective single-cell RNA sequencing analyses of HSPCs and bone marrow mononuclear cells at different time points during therapy showed that canakinumab's on-target effects in hematopoietic populations expressing the IL-1β receptor decreased the TNF-mediated inflammatory signaling pathway but rescued ineffective erythropoiesis only in the context of lower genetic complexity. This study demonstrates that better stratification strategies could target lower-risk MDS patients more effectively.

Imetelstat (Rytelo) for Myelodysplastic Syndromes

The FDA has approved imetelstat (Rytelo – Geron), a first-in-class telomerase inhibitor, for treatment of low- to intermediate-1 risk myelodysplastic syndromes (MDS) in adults with transfusion-dependent anemia requiring 4 or more red blood cell (RBC) units over 8 weeks who have not responded to, are no longer responding to, or are ineligible for erythropoiesis-stimulating agents (ESAs).

Imetelstat: First Approval.

Imetelstat (RYTELO™), an oligonucleotide telomerase inhibitor, is being developed by Geron Corporation for the treatment of myeloid hematologic malignancies. In June 2024, imetelstat was approved in the USA for use in adult patients with low- to intermediate-1 risk myelodysplastic syndromes (MDS) with transfusion-dependent anemia requiring 4 or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents (ESA). This article summarizes the milestones in the development of imetelstat leading to this first approval for the treatment of adult patients with low- to intermediate-1 risk MDS with transfusion-dependent anemia.

Clinical benefit of luspatercept treatment (tx) in transfusion-dependent (TD), erythropoiesis-stimulating agent (ESA)–naive patients (pts) with very low-, low- or intermediate-risk myelodysplastic syndromes (MDS) in the COMMANDS trial.

6565 Background: There is an unmet need for effective tx that provides durable benefit for pts with anemia due to lower-risk MDS (LR-MDS). Here we report clinically meaningful responses to luspatercept tx in TD, ESA-naive pts with LR-MDS in the COMMANDS trial. Methods: Eligible pts were ≥ 18 years of age, had LR-MDS with or without ring sideroblasts and < 5% bone marrow blasts, endogenous serum erythropoietin < 500 U/L, required red blood cell (RBC) transfusions (defined as 2−6 RBC units/8 weeks [wk] for ≥ 8 wk prior to randomization), and were ESA-naive. Pts were randomized 1:1 to subcutaneous administration of luspatercept (1.0–1.75 mg/kg) once every 3 wk or epoetin alfa (EA; 450–1050 IU/kg) once weekly for ≥ 24 wk. New assessments of clinical benefit reported here include achievement and duration of ≥ 50% reduction in RBC units transfused over ≥ 12 wk (wk 1–end of tx [EOT]), transfusion burden (TB) on tx (wk 1–24), time to first transfusion, achievement and cumulative duration of all separate RBC transfusion independence (RBC-TI) ≥ 12 wk response episodes, and mean hemoglobin (Hb) increase ≥ 1.5 g/dL over wk 1–24. Results: As of March 31, 2023, 151/182 (83.0%) luspatercept- and 121/181 (66.9%) EA-treated pts achieved ≥ 50% reduction in RBC units transfused over ≥ 12 wk (wk 1–EOT; P= 0.0002), with median (95% confidence interval [CI]) durations of 130.0 (120.6–not evaluable [NE]) and 77.0 (54.9–123.1) wk, respectively ( P = 0.0004). A greater proportion of luspatercept vs EA pts achieved ≥ 50% reduction in RBC units transfused over ≥ 12 wk (wk 1–EOT), regardless of baseline (BL) TB: 105/118 (89.0%) luspatercept vs 82/111 (73.9%) EA pts with BL TB < 4 RBC units/8 wk and 46/64 (71.9%) luspatercept vs 39/70 (55.7%) EA pts with TB ≥ 4 RBC units/8 wk. The median (interquartile range) number of RBC units transfused during wk 1–24 of tx was 1.0 (0–5.0) in the luspatercept arm and 3.0 (0–8.0) in the EA arm. The median (95% CI) time to first transfusion was 155.0 (80.0–266.0) days for luspatercept vs 42.0 (23.0–55.0) days for EA pts ( P < 0.0001). Among pts who achieved RBC-TI ≥ 12 wk (wk 1–24), 22/124 (17.7%) luspatercept pts vs 12/88 (13.6%) EA pts achieved ≥ 2 separate RBC-TI ≥ 12 wk response episodes and cumulative median (95% CI) duration of all response episodes was 147.9 (122.0–NE) wk in the luspatercept arm and 95.1 (73.1–NE) wk in the EA arm ( P = 0.0067). Mean Hb increase ≥ 1.5 g/dL over wk 1–24 was achieved by 135/182 (74.2%) luspatercept pts and 95/181 (52.5%) EA pts ( P < 0.0001). Conclusions: Significantly greater proportions of luspatercept vs EA pts achieved improvements in Hb levels, reduction in TB and RBC units transfused, and had durable RBC-TI responses. Luspatercept provided clinically meaningful outcomes, supporting its use as the preferred tx for ESA-naive pts with LR-MDS-associated anemia. Clinical trial information: NCT03682536 .

Safety and Preliminary Efficacy of DFV890 in Adult Patients with Myeloid Diseases: A Phase 1b Study

Background and Significance: Patients (pts) with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) have a high unmet medical need, with limited standard-of-care therapeutic approaches, particularly after failure of response to first-line agents, and with allogeneic hematopoietic transplant as the only potential curative option. Through the production of interleukin (IL)-1β and IL-18, the NLRP3 inflammasome has been implicated as a major driver of inflammation associated with acute and chronic inflammatory diseases. The NLRP3 pathway is activated in hematopoietic stem and progenitor cells and in the marrow microenvironment in myeloid neoplasms such as MDS and CMML contributing to ineffective hematopoiesis and clonal progression (Hamarsheh 2020; Basiorka 2016). DFV890, a small molecule NLRP3 inhibitor, blocks IL-1β and IL-18 secretion and pyroptotic cell death in response to a wide variety of NLRP3-dependent danger signals, both in vitro and in vivo. Therefore, DFV890 may disrupt the smoldering inflammation and provide disease-modifying benefits to pts by improving hematopoiesis. Study Design and Methods: This is an open-label, phase 1b, multicenter study with a randomized dose-optimization part and a dose-expansion part consisting of two groups evaluating DFV890 in pts with very low, low, or intermediate risk MDS (LR-MDS) per revised International Prognostic Scoring System (IPSS-R) criteria and low or intermediate-1 risk CMML (LR-CMML) per CMML-specific Prognostic Scoring System (CPSS) criteria (NCT05552469). Eligible pts must be 18 years of age, with an Eastern Cooperative Oncology Group performance status ≤2, candidates for serial bone marrow assessments who are willing to undergo a bone marrow aspirate/biopsy during the trial, and meet one of the following: (a) IPSS-R-defined LR-MDS who failed to respond to or did not tolerate erythropoiesis-stimulating agents (ESAs) or luspatercept or hypomethylating agents (HMAs) and pts with del 5q who failed to respond to or did not tolerate lenalidomide; (b) CPSS-defined LR-CMML who failed to respond to or did not tolerate hydroxyurea or HMAs. Key exclusion criteria include treatment with systemic antineoplastic or any experimental therapies within 28 days (or 5 half-lives, whichever longer); unresolved treatment-related toxicities prior to the first dose of study treatment; previous treatment with agents targeting the NLRP3 inflammasome and the IL-1 pathways; prior use (≤1 week or 5 half-lives, whichever is longer) of hematopoietic colony-stimulating growth factors, thrombopoietin mimetics or ESAs; and concomitant medications, known to modulate cytochrome P450 enzymes. DFV890 is administered orally twice daily (bid) for a minimum of 24 weeks (6 cycles of treatment [1 cycle=28 days]) until treatment discontinuation. In the dose-optimization part, pts are randomized to receive either low dose or high dose bid and stratified by indications. The recommended dose (RD) determined from this part is further explored in the dose-expansion part to confirm safety and tolerability of DFV890 and explore preliminary efficacy. The primary objective is to assess safety (incidence and severity of adverse events, and dose-limiting toxicities) and tolerability to then determine the optimal RD for DFV980. Secondary objectives include assessment of DFV890 pharmacokinetics, evaluation of the preliminary efficacy of DFV890 on transfusion burden, and hematologic improvement: time to onset of transfusion independence; duration of response, best overall response, overall response rate, progression-free survival, and time to progression; and reduction in spleen volume (for CMML). Key exploratory objectives include patient perceptions of tolerability as measured by patient-reported outcomes; and determination of genetic characteristics and potential predictive markers of efficacy and/or resistance. The study is currently enrolling in Singapore, Hong Kong, and the USA with plans to treat approximately 80 pts. The first patient first visit was achieved on May 8, 2023.

The ELEMENT-MDS Trial: A Phase 3 Randomized Study Evaluating Luspatercept Versus Epoetin Alfa in Erythropoiesis-Stimulating Agent-Naive, Non-Transfusion-Dependent, Lower-Risk Myelodysplastic Syndromes

Background and Significance: Anemia is a common and debilitating symptom in patients with myelodysplastic syndromes (MDS), frequently leading to dependence on red blood cell (RBC) transfusions. Transfusion-dependent (TD) patients have worse overall survival and quality of life, and repeat transfusions are associated with complications, including iron overload. Erythropoiesis-stimulating agents (ESAs) are the standard treatment for anemia in patients with lower-risk (LR)-MDS, but many patients are ineligible for or refractory to ESAs, and responses are limited. Luspatercept, a late-stage erythroid maturation agent, is approved to treat TD patients with LR-MDS after ESA failure. In the phase 3 COMMANDS study, in ESA-naive patients with LR-MDS requiring transfusions, a significantly higher proportion of patients receiving luspatercept than epoetin alfa achieved RBC transfusion independence for ≥ 12 weeks with concurrent hemoglobin (Hb) increase ≥ 1.5 g/dL (weeks 1-24) (Platzbecker U, et al. Lancet 2023. doi: 10.1016/S0140-6736(23)00874-7). The potential of luspatercept to improve moderately severe chronic anemia and reduce RBC transfusion dependence has not yet been investigated in the majority non-transfusion-dependent (NTD) LR-MDS patient population. Preventing transfusion dependence is crucial for improving LR-MDS patient outcomes. The aim of this actively enrolling, phase 3, randomized, multicenter study is to compare the safety and efficacy of luspatercept versus epoetin alfa in reducing progression to RBC transfusion dependence in ESA-naive, NTD adult patients with anemia due to LR-MDS. Study design and methods: The ELEMENT-MDS study includes a 5-week screening period, a 96-week treatment period, an extension phase, and a post-treatment follow-up period (Figure). Target enrollment is 360 patients with anemia due to Revised International Prognostic Scoring System (IPSS-R) Very low-, Low-, or Intermediate-risk MDS. Eligible patients are ≥ 18 years of age with a confirmed MDS diagnosis, baseline serum erythropoietin (sEPO) levels ≤ 500 U/L, and symptomatic anemia defined as a score of moderate or worse on ≥ 1 Patient Global Impression of Severity (PGI-S) item (fatigue, shortness of breath, weakness, or dizziness). Participants must be RBC transfusion-independent per International Working Group 2018 criteria (no RBC transfusions within 16 weeks prior to randomization) and have baseline Hb ≤ 9.5 g/dL. Patients will be excluded if they have a del(5q) cytogenetic abnormality, unclassifiable MDS or myelodysplastic/myeloproliferative neoplasms, anemia due to reasons other than MDS, bleeding disorders, low absolute neutrophil or platelet counts, uncontrolled hypertension, previous acute myeloid leukemia diagnosis, or history of recent malignancies, among other reasons. Participants will be randomized 1:1 to receive luspatercept or epoetin alfa. Stratification factors include baseline sEPO levels, ring sideroblast status, and IPSS-R risk category. Patients will receive luspatercept once every 3 weeks at a starting dose of 1.0 mg/kg (escalation up to 1.75 mg/kg allowed) or epoetin alfa once a week at a starting dose of 450 IU/kg (escalation up to 1050 IU/kg allowed). The primary endpoint will compare the proportion of patients becoming TD (defined as requiring ≥ 3 RBC units/16 weeks) during any continuous 16-week interval in weeks 1-96. The key secondary endpoint is a Hb increase ≥ 1.5 g/dL sustained for ≥ 16 weeks during weeks 1-48. Additional secondary endpoints include time to RBC transfusion dependence, transfusion-free survival, time to achieve modified hematologic improvement-erythroid response, transfusion independence ≥ 24 weeks, and quality of life assessment. Safety endpoints include type and severity of adverse events and relationship to treatment, overall survival, and progression to high-risk MDS and acute myeloid leukemia. Summary: The results of this phase 3 study will determine the efficacy and safety of luspatercept as a therapy for ESA-naive NTD patients with LR-MDS, who have limited treatment options for anemia. The study is registered at ClinicalTrials.gov (NCT05949684) and EudraCT (2022-500430-29-00).

Phase 1b/2 Study Evaluating the Safety and Efficacy of Canakinumab with Darbepoetin Alfa in Patients with Lower-Risk Myelodysplastic Syndromes (MDS) Who Have Failed Erythropoietin Stimulating Agents (ESA)

Introduction: Pyroptosis is a form of inflammatory, caspase-1 dependent lytic cell death mediated by inflammasome activation and ultimately leading to enumeration of pro-inflammatory cytokines, particularly interleukin 1β (IL-1β) and is a key driver of MDS pathogenesis (Basiorka A, Blood 2016). Release of IL-1β by pyroptotic cells leads to paracrine stimulation of neighboring hematopoietic and stromal cells resulting in amplification of this circuit, myeloid derived suppressor cell (MDSC) accumulation as well as direct suppression of erythropoiesis. Thus, we investigated the combination of the IL-1β neutralizing antibody canakinumab in combination with darbepoetin in patients with ESA refractory lower risk MDS and present the final dose phase 1b data. Methods: Patients ≥ 18 years old with IPSS-R very low to intermediate risk MDS who were ESA refractory and hypomethylating agent (HMA) naïve with adequate organ function were eligible. Patients must have been RBC transfusion dependent or hemoglobin < 9 gm/dl with symptoms. Treatment consisted of subcutaneous (SC) canakinumab on day 1 of a 28 cycle (150mg dose level 1, 300mg dose level 2) and darbepoetin SC 300µg days 1 and 15 of each cycle for a total of 6 cycles with continuation of therapy for responding patients. The phase 1b portion utilized a 3+3 dose escalation design with 6 patients treated at the maximum tolerated dose (MTD) to define the recommended phase 2 dose (RP2D). Bone marrow (BM) disease assessments occurred every 3 cycles with response defined by IWG 2018 criteria. Quality of life was assessed by QUALMS (Abel A, Haematologica, 2016). Peripheral blood mononuclear cells (PBMCs) were obtained at disease assessments and day 15 of C1 for evaluation of adapter protein apoptosis associated speck-like protein containing a CARD (ASC) specks as a biomarker of inflammasome formation with quantification as previously described (McLemore A, Pyroptosis: Methods and Protocols, 2023). Total IL-1β of BM plasma was assayed by ELISA. Results: Nine patients enrolled with a median age of 71 (range: 61-85 years), 67% female with baseline IPSS-R, IPSS-M and mutation data shown in Table. By IPSS-M, 3, 3, 1, 2 patients were low, moderately-low, moderately high, and high-risk categories. All IPSS-M lower risk mutant patients had splicing mutations. The median number of mutations was 2 (range 0-5). 100% of patients were ESA refractory. Additionally, 33% and 56% were refractory to lenalidomide and luspatercept therapy, respectively. Eight (89%) patients were PRBC dependent at baseline (56% [n=5] with high transfusion burden). The median follow-up duration was 6.1 months (range 3-17.8). The most common adverse events were neutropenia (n=7), followed by thrombocytopenia (n=4), and abnormal liver function tests (n=4). There were two grade 3 adverse events including thrombocytopenia and colitis, both unrelated to study treatment. There were no dose-limiting toxicities or serious adverse events in the phase 1 portion. All patients achieved the best response as stable disease, and no one had progression disease. No patients achieved objective response or significant reduction in transfusion burden. There was no statistical improvement in total QUALMS score from baseline to end of treatment (P=0.72) nor in the individual components (i.e. physical burden, benefit finding and emotional burden, P=0.69, P=0.91, P=0.630; respectively) although several patients had individual improvements. The percentage of PBMCs with ASC specks at baseline ranged from 0.3945-2.978% (median 1.93%). ASC specks decreased significantly after cycle 1 of therapy and were durably suppressed over the course of treatment in a majority of patients (Figure). Extracellular IL-1β in bone marrow plasma robustly increased with treatment and remained elevated (representing non-functional IL-1β [canakinumab bound IL-1β]; P=0.002 cycle 6 versus baseline), supporting pharmacodynamic effect with no differences observed between DL1 and DL2. Conclusions: The combination of canakinumab and darbepoetin was safe and well tolerated and 300mg of canakinumab is the RP2D. Canakinumab inhibited inflammasome activation as evidenced by a reduction of ASC specks although this did not translate to clinical responses. Phase 2 of the study will focus on patients with lower transfusion burden and molecular subsets with highest IL-1β expression (e.g. TET2/ DNMT3A mutant).

Characteristics and Outcomes of Younger Adult Patients (Pts) with Myelodysplastic Syndromes (MDS): A Multicenter Retrospective Study

Introduction: MDS are primarily diseases of the elderly, with median age at diagnosis of 72 years. Focused data on clinical and molecular characteristics, as well as outcomes, in younger pts under age 60 years are limited. We conducted this multicenter retrospective study to describe pt characteristics, cytogenetic and molecular profiles, treatment modalities, and outcomes in younger pts with MDS, including adolescent and young adults (AYA). Methods: The study included pts diagnosed with MDS between 2002-2023 at 7 academic centers. We compared baseline characteristics, treatment, and outcomes of AYA (18-39 years) and younger adult (YA) pts (40-59 years). Responses were assessed using the modified IWG 2006 response criteria which included complete remission (CR), marrow CR (mCR), and hematologic improvement (HI). Wilcoxon rank sum test and Fisher's exact (and Chi-square) test were used to compare pt and disease characteristics for continuous and categorical variables, respectively. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using log-rank test. Results: A total of 173 pts were identified (AYA, N=50; YA, N=123). Median age at diagnosis was 50 years (range, 18-59), with 51% females. Baseline characteristics are shown in Table 1. Therapy-related MDS (t-MDS) was observed in 40 pts (23%) with the remaining classified as de novo MDS (N=133; 77%). Inherited bone marrow failure syndromes were documented in 15 pts (9%), with Shwachman-Diamond Syndrome (N=4) and Fanconi anemia (N=4) being the most frequent. Using the WHO 2016 classification, the most common subtypes of MDS in both the AYA and YA cohorts were MDS with multilineage dysplasia (38% vs 19%), MDS with excess blasts-2 (MDS-EB) (24% vs 29%), and MDS-EB-1 (16% vs 20%). Similarly, using the WHO 2022 classification, the most common subtypes were MDS with low blasts (50% vs 21%), MDS with increased blasts-2 (MDS-IB-2) (24% vs 24%), and MDS-IB-1 (16% vs 18%). Stratifying pts using the IPSS-R cytogenetic (CG) risk group, the most common CG risk category identified was good CG (34% vs 52%, p=0.012). Poor/very poor CG were present in 34% and 37% of the AYA and YA groups, respectively. STAG2 and NRAS mutations occurred more frequently in the AYA pts compared to the YA group, while the YA cohort was enriched for the following mutations: TP53, DNMT3A, SF3B1, SRSF2, and TET2 (Figure 1). In the AYA population, 18 pts (38%) had very low/low, 10 (21%) intermediate, and 20 pts (42%) had high/very high risk MDS using IPSS-R. In the YA population, 32 pts (26%) had very low/low, 32 (26%) intermediate, and 57 pts (47%) had high/very high risk MDS using IPSS-R. Twenty-seven percent of pts with very low to intermediate-risk MDS using IPSS-R were upstaged to moderate high to very high-risk MDS using IPSS-M. The majority of pts (AYA: 75%; YA: 63%, p=0.5) were transfusion independent at baseline. Single-agent hypomethylating agents were the most frequently used frontline therapy, used in 17 AYA pts (34%) and 58 YA pts (48%), with more AYA pts receiving upfront allogeneic stem cell transplantation (Allo-SCT) compared to YA pts (28% vs 5%). After frontline therapy (Table 1), an additional 14 AYA (28%) and 52 YA (42%) pts received Allo-SCT. In pts with IPSS-R intermediate to very high-risk, response rates (HI+CR+mCR+mCR with HI) to frontline therapies were 46% and 54.5% in the AYA and YA groups, respectively. After median follow-up of 24 months [range, 1-218], median OS was numerically longer in the AYA versus YA group (155 vs 53 months, p=0.2). AML transformation occurred in 24% and 20% of the pts in the AYA and YA groups, respectively. Median OS was significantly longer in de novo compared to t-MDS pts (56 vs 27 months, p=0.03). Median OS among Allo-SCT compared to non-SCT pts were not reached vs 155 months ( p=0.9) in the AYA group and 53 vs 54 months ( p=0.4) in the YA group. IPSS-R (very low+low vs intermediate vs high+very high) was able to distinguish differences in OS in the YA (133 vs 53 vs 17 months, p=0.0002) and AYA (155 vs not reached vs 18 months, p=0.006) pts, with the exception of the intermediate-risk group in the AYA cohort. Conclusions: In this study, d e novoMDS was seen in the majority of younger pts with MDS (both AYA and YA). Mutations in STAG2 and NRAS were more common in the AYA pts, while YA pts had MDS more enriched for TP53, DNMT3A, TET2 and splicing mutations. This study is still ongoing with a plan to compare the abovementioned groups to older pts (≥60 years) with MDS.

Real world practices of luspatercept at an academic medical center.

Introduction: Luspatercept is approved for patients with very low-to intermediate-risk myelodysplastic syndrome (MDS). Dosing is based on pre-dose hemoglobin levels and transfusion requirements. This study aims to evaluate if a site with a pharmacist prospectively reviewing luspatercept doses achieves dose optimization, compared to a site that does not have a pharmacist prospectively reviewing doses. Methods: We performed a retrospective chart review involving patients age ≥18 years or older with MDS at a major academic medical center main campus, which does not have a pharmacist prospectively review luspatercept doses, and a satellite campus infusion center, which has a pharmacist prospectively reviewing doses. Patients included received at least one dose of luspatercept between January 1, 2017 through August 31, 2022. The primary endpoint is the percentage of off-label luspatercept doses not consistent with prescribing information (PI) recommended dose adjustments. Results: The study included 17 patients. Of the 162 doses evaluated, 37 (23%) were off-label. Off-label dosing at the main campus was more common than at a satellite location (29.6% vs. 2.4%; p < 0.003). More patients achieved transfusion independence at the satellite compared to the main campus (83.3% vs. 27.3% p < 0.39). Conclusions: There was a higher percentage of off-label dosing at a center without a pharmacist's prospective review vs. a center with a pharmacist's prospective review. On-label dose optimization may lead to a higher percentage of patients achieving transfusion independence. Enhancements in the current ordering and review process can be improved with the involvement of a pharmacist's prospective involvement at both centers.

Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in patients with lower-risk myelodysplastic syndromes

Splicing factor (SF) gene mutations are frequent in myelodysplastic syndromes (MDS), and agents that modulate RNA splicing are hypothesized to provide clinical benefit. JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, was evaluated in patients with lower-risk (LR) MDS in a multi-part, Phase 1, multicenter study. The objectives were to determine a tolerable dose and to characterize safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. JNJ-64619178 was administered on a 14 days on/7 days off schedule or every day on a 21-day cycle to patients with International Prognostic Scoring System (IPSS) Low or Intermediate-1 risk MDS who were red blood cell transfusion-dependent. Twenty-four patients were enrolled; 15 (62.5 %) patients had low IPSS risk score, while 18 (75.0 %) had an SF3B1 mutation. Median duration of treatment was 3.45 months (range: 0.03–6.93). No dose limiting toxicities were observed. The 0.5 mg once daily dose was considered better tolerated and chosen for dose expansion. Twenty-three (95.8 %) patients experienced treatment-emergent adverse events (TEAE). The most common TEAEs were neutropenia (15 [62.5 %]) and thrombocytopenia (14 [58.3 %]). JNJ-64619178 pharmacokinetics was dose-dependent. Target engagement as measured by plasma symmetric di-methylarginine was observed across all dose levels; however, variant allele frequency of clonal mutations in bone marrow or blood did not show sustained reductions from baseline. No patient achieved objective response or hematologic improvement per International Working Group 2006 criteria, or transfusion independence. A tolerable dose of JNJ-64619178 was identified in patients with LR MDS. However, no evidence of clinical benefit was observed.

MDS-367 A Phase II/III Trial of Oral Azacitidine (Oral-AZA) in Patients With Low- or Intermediate-Risk Myelodysplastic Syndromes (MDS)

MDS-367 A Phase II/III Trial of Oral Azacitidine (Oral-AZA) in Patients With Low- or Intermediate-Risk Myelodysplastic Syndromes (MDS)

A phase 2/3 trial of oral azacitidine (Oral-AZA) in patients (pts) with low- or intermediate-risk myelodysplastic syndromes (MDS).

TPS7083 Background: MDS, a heterogeneous group of clonal myeloid malignancies, are characterized by ineffective hematopoiesis and peripheral blood cytopenias, which can often lead to red blood cell (RBC) transfusion dependence and a risk of progression to acute myeloid leukemia (AML). In early clinical trials, 14- and 21-day (d) dosing regimens of the hypomethylating agent Oral-AZA were well tolerated and induced hematologic improvement (HI) in pts with lower-risk (LR) MDS. In a phase 3 trial, Oral-AZA 300 mg QD for 21d per 28d cycle significantly improved the rate of RBC transfusion independence (TI) and induced durable HI versus placebo (PBO) in patients (pts) with LR-MDS with RBC-transfusion-dependent anemia and thrombocytopenia (Garcia-Manero, et al. J Clin Oncol 2021). Grade 3/4 cytopenias were common in the Oral-AZA arm. Given the substantial clinical benefit of Oral-AZA observed in this setting, a new phase 2/3 trial is ongoing to further evaluate the 14d Oral-AZA regimen in pts with International Prognostic Scoring System Revised (IPSS-R)-defined low or intermediate (int)-risk MDS. Methods: This ongoing, multicenter, randomized, phase 2/3 trial (CA055-026; NCT05469737) will evaluate the safety and efficacy of Oral-AZA in pts with IPSS-R low- or int-risk MDS. Key eligibility criteria include ≥ 18 years, ECOG performance status score ≤ 2, and ≥ 1 cytopenia (anemia, thrombocytopenia, or neutropenia). Pts with an absolute neutrophil count &lt; 0.5 × 109/L within a week of randomization will be excluded. Informed consent will be obtained from all participants. The phase 2 portion will enroll and randomize ~42 pts 1:1 to receive open-label Oral-AZA 200 or 300 mg QD for 14d per 28d cycle, plus best supportive care (BSC), to determine the recommended phase 3 dose (RP3D). The primary endpoints are safety and rate of complete remission (CR) within 6 Tx cycles. The secondary endpoints are overall response rate (ORR), and packed (p) RBC-TI and platelet-TI sustained for 84d in ≤ 6 Tx cycles. ORR includes CR, partial remission (PR), marrow CR, and any HI, per IWG 2006 response criteria. In the phase 3 portion, ~188 additional pts will be enrolled and randomized 1:1 to Oral-AZA at the RP3D or PBO for 14d per 28d cycle, plus BSC. Pts in the PBO arm with stable disease at Tx cycle 6 disease assessment or with documented disease progression after ≥ 3 Tx cycles will have the option to cross over into the Oral-AZA arm. The primary endpoint is CR in ≤ 6 Tx cycles. The key secondary endpoint is 84d pRBC-TI. Other secondary endpoints include those described in the phase 2 portion plus overall survival, event-free survival, time to AML progression, iron parameters, health-related quality of life, healthcare resource utilization, and safety parameters. Pts who benefit from Oral-AZA in phase 2 or 3 may continue to receive Tx in an extension phase. Trial recruitment began in December 2022 and is ongoing. Clinical trial information: NCT05469737 .

10-year nationwide trends in incidence, treatment patterns, and mortality of patients with myelodysplastic syndromes in Denmark

Further temporal data on incidence, treatment patterns, and prognosis for patients with myelodysplastic syndromes (MDS) are needed. This study examined 10-year trends in incidence, treatment patterns, and all-cause mortality in a population-based cohort of 2309 MDS patients using Danish nationwide registries (2010–2019). We computed annual incidence rates overall and according to sex and age-groups. We examined temporal changes in the cumulative incidence of MDS specific treatments initiated within one year from diagnosis and temporal changes in the absolute risk of death and five-year adjusted hazard ratios (aHRs) for death, adjusting for age, sex and comorbidity. The age-standardized incidence rate of MDS per 100,000 person-years increased slightly from 5.3 in 2010 to 6.4 in 2019. Between 2010-2012 to 2016–2017, the use of azacitidine increased overall (8% to 22%), in patients with intermediate risk MDS (12% to 34%), and in patients with high-risk MDS (22% to 50%), while it remained stable (around 5%) for patients with low-risk MDS. The five-year aHR for death in the most recent calendar period compared to the earliest calendar period remained unchanged in patients with low-risk MDS, aHR = 0.90 (95% CI, 0.72–1.12) and in patients with high-risk MDS, aHR = 1.19 (95% CI, 0.89–1.61), while survival improved over time among patients with intermediate risk MDS, aHR = 0.67 (95% CI, 0.48–0.92). In conclusion the incidence of MDS slightly increased during a 10-year period in Denmark. The use of azacitidine increased markedly but five-year overall survival remained unchanged.

Efficacy and Safety of Luspatercept in Adult Patients with Transfusion-Dependent Anemia Due to Very Low, Low and Intermediate Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts, Who Had an Unsatisfactory Response to or Are Ineligible for Erythropoietin-Based Therapy: A Retrospective Multicenter Study By Fondazione Italiana Sindromi Mielodisplastiche (FiSiM ETS)

Background: Patients with lower-risk myelodysplastic syndromes (MDS) who develop red blood cells (RBC) transfusion-dependent anemia, experience worse quality of life and shorter survival. Therapeutic strategies after failure of erythropoiesis stimulating agents (ESAs) are limited. Regulatory approval of luspatercept in lower-risk MDS with ring sideroblasts (MDS-RS) offers a novel approach for the treatment of transfusion-dependent anemia in this subset of patients. However, data about luspatercept effectiveness in a real-world clinical setting are lacking. Here we report the results of a multicenter retrospective study including patients who were treated with luspatercept within the Italian compassionate use program. Methods: Eligible patients were ≥ 18 years old, had MDS-RS (2016 WHO classification), met criteria for very low, low, or intermediate IPSS-R risk; were receiving regular RBC transfusions (≥2 units/8 weeks in the 16 weeks before study entry); were refractory to or unlikely to respond to ESAs. Primary end point was transfusion independence (TI) for 8 weeks or longer during weeks 1 through 24; key secondary end point was TI for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48. Other secondary end points included erythroid response (defined by the IWG 2006 criteria), progression to acute myeloid leukemia (AML) and safety analyses. Exploratory analyses were performed to identify predictive factors for treatment response. Results: 184 patients who were enrolled in the Italian luspatercept compassionate use program between December 2020 and December 2021 were analyzed in this study. Median age at enrollment was 74 years (range, 31-88), median time since diagnosis was 43 months, and median time since onset of transfusion-dependence was 23 months. Overall, 123 (66.8%) patients had at least one comorbidity requiring ongoing treatment, 39 (21.2%) had at least three. Baseline median transfusion burden was 6 RBC units every 8 weeks (range, 2-25). At the time of data analysis (June 30, 2022), 130 (73.4%) patients completed at least 24 weeks of treatment. Median time on treatment was 301.5 days, and median follow-up time was 376 days. During the first 24 weeks of the trial, 59 (32%) patients had TI for 8 weeks or longer. The percentage of patients achieving TI increased to 38.6% in the first 48 weeks of the trial. Median duration of TI was 27.9 weeks. Focusing on secondary endpoints, 36 patients (19.6%) had TI for 12 weeks or longer during the first 24 weeks, 52 (28.3%) had TI for 12 weeks or longer considering the first 48 weeks of the trial. A reduction ≥ 4 RBC units/8 weeks during weeks 1-24 was seen in 66 patients (40.2%). Four (2.2%) patients evolved to AML. Serious adverse events were recorded in 27 (15.2%) patients and led to study discontinuation in 5 (2.8%). Overall, treatment was discontinued in 72 (40.7%) patients, mainly for lack of benefit (table 1) The maximum approved dose (1.75 mg/kg) of luspatercept was administered at least once in 144 (81%) patients. Among patients who achieved TI for 8 weeks or longer in the first 48 weeks, luspatercept dose (mg/kg) at response was 1, 1.33 and 1.75 in 31 (46.3%), 18 (29.9%) and 18 (29.9%%) patients, respectively. Logistic regression analysis showed that higher baseline transfusion burden was significantly associated with a lower probability of achieving TI. We identified 3 group of patients stratified according to baseline transfusion burden (group 1, ≤4 units/8 weeks; group 2, 5 to 7 units/8 weeks, group 3, ≥8 units/8 weeks) with a significantly different probability to achieve both the primary endpoint (51.9%, 35.2% and 16.7%, respectively, P<0.01) and the key secondary endpoint (30.8%, 24.1% and 9%, respectively, P<0.01). Patients with higher transfusion burden had higher luspatercept doses at first response (table 2). In patients with low probability to achieve TI (group 2 and 3), a reduction in transfusions equal or greater than 4 units/8 weeks was achieved in 66 (46.2%). Conclusion: Luspatercept was effective for the treatment of transfusion-dependent anemia in MDS-RS in a real-life setting. The benefit extended beyond the achievement of TI and produced a significant reduction in the number of RBC transfusions. Higher baseline transfusion burden was associated with a reduced probability to achieve TI; in these patients, the reduction of transfused RBC units appears a more reliable treatment target. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Evaluation of Red Blood Cell Metabolism in Patients with Low-Risk Myelodysplastic Syndrome (LR-MDS): A Proof-of-Concept Study

Low risk myelodysplastic syndromes (MDS) show high clinical heterogeneity ranging from mild anemia with nearly normal performance status to life-threatening cytopenias, frequent hospitalization, and disability. Anemia occurs in 80%-85% of patients and therapeutic strategies are still very limited mainly consisting of of erythropoiesis stimulating agents and red blood cell (RBC) transfusion support. Starting from the working hypothesis that the defective maturation of hematopoietic precursors may dampen the "functionality" of MDS-RBCs, we aimed at evaluating RBC metabolic pathway in anemic patients with LR-MDS. We focused on the glycolytic pathway, which is the prominent metabolic cascade in RBCs and is currently targeted with allosteric stimulators of pyruvate kinase (PK) enzyme in clinical trials of PK deficiency, thalassemia, and sickle cell diseases, which are also marked by ineffective erythropoiesis like MDS. Sixty-six consecutive anemic patients (i.e. Hb<11 g/dL) diagnosed with MDS according to WHO 2016 classification that met IPSS-R criteria for very low, low, or intermediate-risk MDS were enrolled in the study. All patients were sampled for peripheral blood at least 4 weeks after the last RBC unit to reduce possible blood donor contamination. The determination of activities of the glycolytic RBC enzymes pyruvate kinase (PK) and hexokinase (HK) (the terminal and initial steps of the glycolytic pathway), and of ATP levels was performed by standard spectrophotometric method according to Beutler et al, 1984. 2,3 DPG determination was tested by AssayGenie Kit in a subgroup of patients. Ektacytometric analysis by LoRRca MaxSis (Laser-Assisted Optical Rotational Cell Analyzer, Mechatronics, NL) was also performed in a subgroup of patients. As shown in table 1, patients were mainly elderly males, and mostly belonged to IPSS low (78%) and IPSS-R very low/low groups (85%). Median levels of PK activity were 13.7 IU/gHb, with a wide range (7.5-35.9) and were reduced in 23 cases (35%; normal reference range 11.9-16.7 IU/gHb); median values of HK activity were 2.3 (0.8-8.1), increased in 60 patients (91%; normal reference range 0.78-1.32 IU/gHb). This resulted in an abnormally reduced PK/HK ratio (median 5.45, range 2-15) in 63 subjects (95%; (normal reference range calculated on 167 normal subjects: 11.55 - 17.65). To asses if impaired glycolysis may result in altered RBC deformability or in lack of energy, ATP levels, 2,3 DPG, and ektacytometric curve were evaluated. Median ATP levels were 3.4 mcM/gHb (1.3-6.5), reduced in 33/56 tested patients (59%; normal reference range 3.6-4.9 mcM/gHb), of whom 32 had simultaneous reduction of PK/HK activity ratio (figure 1), and 11 decreased PK activity. Concerning 2,3 DPG levels preliminarily analysed in a subgroup of patients, they were close to the upper limit of the normal range (median, 389 nM/gHb, 318-639). Osmoscan, performed in 10 patients did not show altered RBC deformability. Preliminary data show decreased glycolytic activity in RBCs from patients with LR-MDS highlighted by reduced PK activity in more than 1/3 of cases, and increased HK activity in almost all subjects. This results in reduced RBC ATP content in up to 2/3 of patients (possibly due to reduced production or to increased consumption) indicating an overall lack of energy in MDS-RBCs. The latter may be an interesting target for allosteric PK stimulators and warrants further investigations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effects of Ker-050 on Iron Metabolism: Exploratory Analyses from an Ongoing Phase 2 Study in Patients with Myelodysplastic Syndromes

Background: Iron overload (IO) is an important clinical consequence of transfusion-dependent myelodysplastic syndromes (MDS). For patients with high transfusion burden (HTB), limited treatment options are available to effectively treat anemia and reduce transfusion dependence. Transfusion dependence is an independent predictor of poor prognosis in MDS. It is associated with IO and elevated ferritin, a marker of intracellular iron storage that also predicts poor prognosis in MDS. When adjusting for transfusion burden, each 500 µg/L increase in ferritin above 1000 µg/L is associated with a 30% greater risk of death (Malcovati et al. 2006). IO also disrupts osteoprogenitors and erythroid precursors within the osteohematopoietic niche, leading to abnormal bone turnover and ineffective erythropoiesis (Bulycheva 2015). While iron chelators have shown some efficacy in managing IO, they introduce toxicities and have little effect on transfusion burden. Unmet need remains for treatments that effectively address anemia, IO, and reduce transfusion dependence in patients with MDS, especially those with HTB. KER-050 is designed to alter signaling of TGF-β superfamily ligands, restoring balance to the osteohematopoietic niche, and promoting differentiation of erythroid and megakaryocytic precursors. It is a modified activin receptor type IIA ligand trap that inhibits TGF-β superfamily ligands, including activins A and B and growth and differentiation factors (GDFs) 8 and 11. To date, clinical data indicate that KER-050 induces sustained increases in reticulocytes and hemoglobin. Preliminary findings also show potential for KER-050 to induce erythroid response and reduce transfusion burden in patients with MDS, including those with HTB (Tan et al., 2022). KER-050 may also impact iron metabolism and this presentation explores the effects of KER-050 on indices of IO. Methods: This Phase 2 study is evaluating KER-050 in participants with very low- to intermediate-risk MDS. Data presented are from Part 1 Dose Escalation which included 16 weeks of KER-050 treatment across 5 cohorts (0.75 to 5 mg/kg). Iron chelator therapy was permitted at the discretion of the investigator provided patients had been on a stable dose for 8 weeks prior to C1D1. Markers of IO and hematopoiesis were assessed as exploratory endpoints over the 16-week treatment period. Analyses presented evaluate the effect of KER-050 on these markers. Baseline markers of bone turnover were also assessed. Results: A total of 31 patients were enrolled in Part 1 Dose Escalation; 26 were transfusion dependent, 18 with HTB (≥ 4 RBC units in 8 weeks prior to day 1). Seven HTB patients (38.9%) received iron chelator therapy. Baseline differences were noted in measures of iron status, erythropoiesis and bone turnover for non-transfused (NT), low transfusion burden (LTB), and HTB patients (Table 1). HTB patients had the highest baseline serum iron and ferritin levels. Preliminary findings indicate that KER-050 treatment was associated with decreases in serum ferritin for patients both with and without iron chelator therapy. Patients achieving transfusion independence (TI) experienced a 39.5% reduction (mean change: -619.4 ng/ml, range: -2118.4 to +243 ng/mL) in serum ferritin at Week 12 that was generally sustained at Week 16 and 20 (Figure 1). Similarly, over the same time period, serum iron and transferrin saturation (TSAT) decreased by 4.03 µmol/L (8.38%) and 5.3%, respectively, in patients achieving TI. Soluble transferrin receptor (sTfR) increased by 32.2% and remained elevated at subsequent visits. Summary: Preliminary data from the 16-week Dose Escalation in this ongoing phase 2 study reveal differences in baseline iron biomarkers indicative of increasing iron overload with increasing transfusion burden. While nearly half of HTB patients received iron chelator therapy, this group had markedly elevated ferritin compared to NT and LTB patients at baseline. KER-050 treatment was associated with reductions in serum ferritin, irrespective of the use of iron chelation. Patients achieving TI experienced decreases in ferritin, iron and TSAT concurrent with increases in sTfR that were generally maintained through follow-up. The data suggest that, in addition to improving hematopoiesis and transfusion burden in MDS patients, KER-050 may reduce iron overload, a serious clinical complication impacting the survival of these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hematopoietic Stem Cells (HSC) and Granulocyte Macrophage Progenitors (GMP) are the Oxidative Stress Targets in Low/Intermediate-1 Risk Myelodysplastic Syndromes.

Myelodysplastic Syndromes (MDS) are a heterogenous group of clonal hematopoietic stem cell malignancies. Previous studies showed that Reactive Oxygen Species (ROS) play a role in the pathogenesis and clinical evolution of MDS, contributing to Hematopoietic Stem and Progenitor Cells (HSPC) genetic instability. Less is known about ROS levels in the various sub-populations of MDS HSPC and how they correlate with clinical data in MDS patients. Our study aims to analyze ROS levels in MDS Hematopoietic Stem Cells (HSC), common myeloid progenitors (CMP), Granulocyte Macrophages Progenitors (GMP) and megakaryocyte-erythrocyte progenitors (MEP); afterwards, we looked at the relationship between ROS levels and clinical data. thirty-eight MDS and 27 Normal Bone Marrow (NBM) samples were collected; ROS levels were analyzed via multicolor flow cytometry. In both NBM and MDS, HSC showed much higher ROS levels than progenitors (3 to 4 folds, p < 0.0001); HSC ROS were significantly more elevated in MDS-no excess blasts versus MDS with excess blasts and versus NBM. GMP from MDS-no excess blasts showed higher ROS compared to NBM GMP. The 3 MDS with Ringed Sideroblasts (RS) showed more elevated ROS in HSC and GMP compared to the not RS low/intermediate-1 MDS; the 2 monosomy 7 patients displayed higher ROS levels in each subpopulation compared to the normal karyotype MDS; the only del(5q) patient did not show relevant differences in ROS levels compared to the median of the normal karyotype MDS ROS. The 9 high transfusion burden patients exhibited higher ROS in HSC and GMP compared to NBM HSC and GMP. These data were not confirmed in low transfusion burden (n:2) and non-transfused patients (n:26). In low/intermediate-1 MDS, a direct correlation between ferritin values and ROS levels in progenitors, but not in HSC, was detected. Interestingly, low/intermediate-1 risk patients that are no longer responding to recombinant human erythropoietin (rh-EPO) showed higher ROS levels in GMP and HSC. Our data showed that ROS can play a role in the pathogenesis and maintenance of low and intermediate-1 risk MDS clone; ROS status can be influenced by several clinical factors as ferritin levels and rh-EPO treatment. In this scenario, high ROS levels can contribute to genetic instability and influence progression to AML. Further biological studies are needed to elucidate ROS role in MDS pathogenesis and analyze the possible benefit of antioxidant drugs added to the standard MDS treatments.

Luspatercept (Reblozyl)

&#x0D; CADTH recommends that Reblozyl should be reimbursed by public drug plans for the treatment of adult patients with very low- to intermediate-risk myelodysplastic syndromes (MDS)-associated anemia who have ring sideroblasts and require red blood cell (RBC) transfusions, if certain conditions are met.&#x0D; Reblozyl should only be covered to treat patients who have failed or are not suitable for erythropoietin-based therapy.&#x0D; Reblozyl should only be reimbursed if prescribed by a specialist in MDS and if the cost of Reblozyl is reduced. Reimbursement should only be renewed if Reblozyl shows benefit to the patient such that the patient no longer requires RBC transfusions.&#x0D;

Prognostic Factors and Clinical Considerations for Iron Chelation Therapy in Myelodysplastic Syndrome Patients.

Iron chelation therapy (ICT) is an important tool in the treatment of transfusion-dependent lower-risk myelodysplastic syndrome (MDS) patients. ICT is effective in decreasing iron overload and consequently in limiting its detrimental effects on several organs, such as the heart, liver, and endocrine glands. Besides this effect, ICT also proved to be effective in improving peripheral cytopenia in a significant number of MDS patients, thus further increasing the clinical interest of this therapeutic tool. In the first part of the review, we will analyze the toxic effect of iron overload and its mechanism. Subsequently, we will revise the clinical role of ICT in various subsets of MDS patients (low, intermediate, and high risk MDS, patients who are candidates for allogeneic stem cell transplantation).

Lenalidomide and Eltrombopag for Treatment in Low or Intermediate Risk Myelodysplastic Syndrome: Result of a Phase 2 Study Combination Clinical Trial

Lenalidomide and Eltrombopag for Treatment in Low or Intermediate Risk Myelodysplastic Syndrome: Result of a Phase 2 Study Combination Clinical Trial