Trisomy 8 Defines a Distinct Subtype of Myeloproliferative Neoplasms Driven by the MYC-Alarmin Axis.

Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPNs) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for triple negative myelofibrosis (MF) patients who lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in triple negative MF, and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves numerous hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC-alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs.

Hypomethylating Agents and Venetoclax for Acute Myeloid Leukemia Relapsed After Hematopoietic Stem Cell Transplant.

BACKGROUND: Hypomethylating agent + venetoclax is an effective frontline combination for acute myeloid leukemia, but its efficacy and safety in post-allogeneic hematopoietic cell transplant (alloHCT) relapse remain underexplored. Outcomes have been poor for this population, with no standard treatment. PATIENTS AND METHODS: We retrospectively analyzed 72 Ven-naïve patients who received hypomethylating agents + venetoclax at relapse following alloHCT and aimed to evaluate the rates of complete remission with or without hematologic recovery (CR/CRi) and minimal residual disease (MRD) negativity, CR/CRi duration, and overall survival. We leveraged our larger sample to analyze the impact of cytogenetic/molecular features on the odds of CR/CRi. RESULTS: CR/CRi was achieved among 32 of 67 (48%) patients, and MRD negativity was recorded among 10 of 12. NPM1 and IDH 1 or 2 mutations increased the odds of CR/CRi, as did increasing time from alloHCT to relapse. Fourteen patients subsequently received donor lymphocyte infusions or a second alloHCT. Responses lasted a median of 17.8 months (95% CI, 7.2 months to not reached), and responders had a greater median overall survival of 19.7 months (95% CI, 7.6-51.5 months) compared to 2.9 months among nonresponders (95% CI, 1.8-4.4 months; log-rank P < .01). Treatment was well tolerated, but prolonged cytopenias were common and most patients required reduction in the number of venetoclax days per cycle. CONCLUSION: These data support the efficacy of this combination in the alloHCT relapse setting where we report responses among nearly half of patients, with possibly greater benefit for NPM1 and IDH 1/2-mutated cases. These responses can be durable and profound as evidenced by conversion to MRD negativity.

Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Unmet medical needs remain in patients with red blood cell transfusion-dependent (RBC-TD) lower-risk myelodysplastic syndromes (LR-MDS) who are not responding to or are ineligible for erythropoiesis-stimulating agents (ESAs). Imetelstat, a competitive telomerase inhibitor, showed promising results in a phase 2 trial. We aimed to compare the RBC transfusion independence (RBC-TI) rate with imetelstat versus placebo in patients with RBC-TD LR-MDS. METHODS: In phase 3 of IMerge, a double-blind, placebo-controlled trial conducted in 118 sites including university hospitals, cancer centres, and outpatient clinics in 17 countries, patients (aged ≥18 years) with ESA-relapsed, ESA-refractory, or ESA-ineligible LR-MDS (low or intermediate-1 risk disease as per International Prognostic Scoring System [IPSS] criteria) were randomly assigned via a computer-generated schedule (2:1) to receive imetelstat 7·5 mg/kg or placebo, administered as a 2-h intravenous infusion, every 4 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Randomisation was stratified by previous RBC transfusion burden and IPSS risk group. Patients, investigators, and those analysing the data were masked to group assignment. The primary endpoint was 8-week RBC-TI, defined as the proportion of patients without RBC transfusions for at least 8 consecutive weeks starting on the day of randomisation until subsequent anti-cancer therapy, if any. Primary efficacy analyses were performed in the intention-to-treat population, and safety analyses were conducted in patients who received at least one dose of trial medication or placebo. This trial is registered with ClinicalTrials.gov (NCT02598661; substudy active and recruiting). FINDINGS: Between Sept 11, 2019, and Oct 13, 2021, 178 patients were enrolled and randomly assigned (118 to imetelstat and 60 to placebo). 111 (62%) were male and 67 (38%) were female. 91 (77%) of 118 patients had discontinued treatment by data cutoff in the imetelstat group versus 45 (75%) in the placebo group; a further one patient in the placebo group did not receive treatment. Median follow-up was 19·5 months (IQR 12·0-23·4) in the imetelstat group and 17·5 months (12·1-22·7) in the placebo group. In the imetelstat group, 47 (40% [95% CI 30·9-49·3]) patients had an RBC-TI of at least 8 weeks versus nine (15% [7·1-26·6]) in the placebo group (rate difference 25% [9·9 to 36·9]; p=0·0008). Overall, 107 (91%) of 118 patients receiving imetelstat and 28 (47%) of 59 patients receiving placebo had grade 3-4 treatment-emergent adverse events. The most common treatment-emergent grade 3-4 adverse events in patients taking imetelstat were neutropenia (80 [68%] patients who received imetelstat vs two [3%] who received placebo) and thrombocytopenia (73 [62%] vs five [8%]). No treatment-related deaths were reported. INTERPRETATION: Imetelstat offers a novel mechanism of action with durable transfusion independence (approximately 1 year) and disease-modifying activity for heavily transfused patients with LR-MDS who are not responding to or are ineligible for ESAs. FUNDING: Janssen Research & Development before April 18, 2019, and Geron Corporation thereafter.

Drivers of deep molecular response and long-term outcomes in patients with core binding factor acute myeloid leukemia.

A swimmer plot on clinical course of patients undergoing allogeneic stem cell transplant for core binding factor acute myeloid leukemia.

Standardising acute myeloid leukaemia classification systems: a perspective from a panel of international experts.

The existence of two acute myeloid leukaemia classification systems-one put forth by WHO and one by the International Consensus Classification in 2022-is concerning. Although both systems appropriately move towards genomic disease definitions and reduced emphasis on blast enumeration, there are consequential disagreements between the two systems on what constitutes a diagnosis of acute myeloid leukaemia. This fundamental problem threatens the ability of heath-care providers to diagnose acute myeloid leukaemia, communicate with patients and other health-care providers, and deliver appropriate and consistent management strategies for patients with the condition. Clinical trial eligibility, standardised response assessments, and eventual drug development and regulatory pathways might also be negatively affected by the discrepancies. In this Viewpoint, we review the merits and limitations of both classification systems and illustrate how the coexistence, as well as application of both systems is an undue challenge to patients, clinicians, hematopathologists, sponsors of research, and regulators. Lastly, we emphasise the urgency and propose a roadmap, by which the two divergent classification systems can be harmonised.

Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are the standard-of-care treatment for anaemia in most patients with lower-risk myelodysplastic syndromes but responses are limited and transient. Luspatercept promotes late-stage erythroid maturation and has shown durable clinical efficacy in patients with lower-risk myelodysplastic syndromes. In this study, we report the results of a prespecified interim analysis of luspatercept versus epoetin alfa for the treatment of anaemia due to lower-risk myelodysplastic syndromes in the phase 3 COMMANDS trial. METHODS: The phase 3, open-label, randomised controlled COMMANDS trial is being conducted at 142 sites in 26 countries. Eligible patients were aged 18 years or older, had a diagnosis of myelodysplastic syndromes of very low risk, low risk, or intermediate risk (per the Revised International Prognostic Scoring System), were ESA-naive, and required red blood cell transfusions (2-6 packed red blood cell units per 8 weeks for ≥8 weeks immediately before randomisation). Integrated response technology was used to randomly assign patients (1:1, block size 4) to luspatercept or epoetin alfa, stratified by baseline red blood cell transfusion burden (<4 units per 8 weeks vs ≥4 units per 8 weeks), endogenous serum erythropoietin concentration (≤200 U/L vs >200 to <500 U/L), and ring sideroblast status (positive vs negative). Luspatercept was administered subcutaneously once every 3 weeks starting at 1·0 mg/kg body weight with possible titration up to 1·75 mg/kg. Epoetin alfa was administered subcutaneously once a week starting at 450 IU/kg body weight with possible titration up to 1050 IU/kg (maximum permitted total dose of 80 000 IU). The primary endpoint was red blood cell transfusion independence for at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), assessed in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The COMMANDS trial was registered with ClinicalTrials.gov, NCT03682536 (active, not recruiting). FINDINGS: Between Jan 2, 2019 and Aug 31, 2022, 356 patients were randomly assigned to receive luspatercept (178 patients) or epoetin alfa (178 patients), comprising 198 (56%) men and 158 (44%) women (median age 74 years [IQR 69-80]). The interim efficacy analysis was done for 301 patients (147 in the luspatercept group and 154 in the epoetin alfa group) who completed 24 weeks of treatment or discontinued earlier. 86 (59%) of 147 patients in the luspatercept group and 48 (31%) of 154 patients in the epoetin alfa group reached the primary endpoint (common risk difference on response rate 26·6; 95% CI 15·8-37·4; p<0·0001). Median treatment exposure was longer for patients receiving luspatercept (42 weeks [IQR 20-73]) versus epoetin alfa (27 weeks [19-55]). The most frequently reported grade 3 or 4 treatment-emergent adverse events with luspatercept (≥3% patients) were hypertension, anaemia, dyspnoea, neutropenia, thrombocytopenia, pneumonia, COVID-19, myelodysplastic syndromes, and syncope; and with epoetin alfa were anaemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19 pneumonia, and myelodysplastic syndromes. The most common suspected treatment-related adverse events in the luspatercept group (≥3% patients, with the most common event occurring in 5% patients) were fatigue, asthenia, nausea, dyspnoea, hypertension, and headache; and none (≥3% patients) in the epoetin alfa group. One death after diagnosis of acute myeloid leukaemia was considered to be related to luspatercept treatment (44 days on treatment). INTERPRETATION: In this interim analysis, luspatercept improved the rate at which red blood cell transfusion independence and increased haemoglobin were achieved compared with epoetin alfa in ESA-naive patients with lower-risk myelodysplastic syndromes. Long-term follow-up and additional data will be needed to confirm these results and further refine findings in other subgroups of patients with lower-risk myelodysplastic syndromes, including non-mutated SF3B1 or ring sideroblast-negative subgroups. FUNDING: Celgene and Acceleron Pharma.

Assessment and validation of the molecular international prognostic scoring system for myelodysplastic syndromes.

The Molecular International Prognostic Scoring System (IPSS-M) is a novel risk stratification model for myelodysplastic syndromes (MDS) that builds on the IPSS and IPSS-R by incorporating mutational data. The model showed improved prognostic accuracy over the IPSS-R across three endpoints: overall survival (OS), leukemia-free survival (LFS) and leukemic transformation. This study aimed to validate the findings of the original in a large cohort of MDS patients, as well as assess its validity in therapy-related and hypoplastic MDS. We retrospectively reviewed clinical, cytogenetic and molecular data for 2355 MDS patients treated at the Moffitt Cancer Center. Correlative analysis between IPSS-R and mean IPSS-M scores and outcome predictions was performed on LFS, OS and leukemic transformation. Using the IPSS-M, patients were classified as Very Low (4%), Low (24%), Moderate-Low (14%), Moderate-High (11%), High (19%) and Very-High risk (28%). Median OS was 11.7, 7.1, 4.4, 3.1, 2.3, and 1.3 years from VL to VH risk subgroups. Median LFS was 12.3, 6.9, 3.6, 2.2, 1.4, and 0.5 years respectively. For patients with t-MDS and h-MDS the model retained its prognostic accuracy. Generalized use of this tool will likely result in more accurate prognostic assessment and optimize therapeutic decision-making in MDS.

Updates in Risk Stratification in Myelodysplastic Syndromes.

ABSTRACT: Risk stratification plays an essential role in treatment planning in myelodysplastic syndromes. For decades, the International Prognostic Scoring System and its revised version have provided unified consensus for clinical trial enrollment and design. These models relied on laboratory and cytogenetic data to estimate prognosis and dictate treatment paradigms. Critical developments in DNA sequencing techniques in recent years, as well as our growing understanding of the clonal dynamics of myelodysplastic syndromes and the role that specific mutations have in shaping disease-specific phenotypes and treatment susceptibilities, have made it possible to identify molecular markers that carry critical diagnostic and therapeutic relevance and remained unaccounted for in the older models. The Molecular International Prognostic Scoring System is a novel risk stratification model that integrates clinical, cytogenetic, and molecular data to devise a more refined prognostic tool that builds on the accuracy of the traditional models.

Telomerase-targeted therapies in myeloid malignancies.

Human telomeres are tandem arrays that are predominantly composed of 5'-TTAGGG-3' nucleotide sequences at the terminal ends of chromosomes. These sequences serve 2 primary functions: they preserve genomic integrity by protecting the ends of chromosomes, preventing inappropriate degradation by DNA repair mechanisms, and they prevent loss of genetic information during cellular division. When telomeres shorten to reach a critical length, termed the Hayflick limit, cell senescence or death is triggered. Telomerase is a key enzyme involved in synthesizing and maintaining the length of telomeres within rapidly dividing cells and is upregulated across nearly all malignant cells. Accordingly, targeting telomerase to inhibit uncontrolled cell growth has been an area of great interest for decades. In this review, we summarize telomere and telomerase biology because it relates to both physiologic and malignant cells. We discuss the development of telomere- and telomerase-targeted therapeutic candidates within the realm of myeloid malignancies. We overview all mechanisms of targeting telomerase that are currently in development, with a particular focus on imetelstat, an oligonucleotide with direct telomerase inhibitory properties that has advanced the furthest in clinical development and has demonstrated promising data in multiple myeloid malignancies.

Transplantation Referral Patterns for Patients with Newly Diagnosed Higher-Risk Myelodysplastic Syndromes and Acute Myeloid Leukemia at Academic and Community Sites in the Connect® Myeloid Disease Registry: Potential Barriers to Care.

Hematopoietic stem cell transplantation (HCT) is indicated for patients with higher-risk (HR) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Age, performance status, patient frailty, comorbidities, and nonclinical factors (eg, cost, distance to site) are all recognized as important clinical factors that can influence HCT referral patterns and patient outcomes; however, the proportion of eligible patients referred for HCT in routine clinical practice is largely unknown. This study aimed to assess patterns of consideration for HCT among patients with HR-MDS and AML enrolled in the Connect® Myeloid Disease Registry at community/government (CO/GOV)- or academic (AC)-based sites, as well as to identify factors associated with rates of transplantation referral. We assessed patterns of consideration for and completion of HCT in patients with HR-MDS and AML enrolled between December 12, 2013, and March 6, 2020, in the Connect Myeloid Disease Registry at 164 CO/GOV and AC sites. Registry sites recorded whether patients were considered for transplantation at baseline and at each follow-up visit. The following answers were possible: "considered potentially eligible," "not considered potentially eligible," or "not assessed." Sites also recorded whether patients subsequently underwent HCT at each follow-up visit. Rates of consideration for HCT between CO/GOV and AC sites were compared using multivariable logistic regression analysis with covariates for age and comorbidity. Among the 778 patients with HR-MDS or AML enrolled in the Connect Myeloid Disease Registry, patients at CO/GOV sites were less likely to be considered potentially eligible for HCT than patients at AC sites (27.9% versus 43.9%; P < .0001). Multivariable logistic regression analysis with factors for age (<65 versus ≥65 years) and ACE-27 comorbidity grade (<2 versus ≥2) showed that patients at CO/GOV sites were significantly less likely than those at AC sites to be considered potentially eligible for HCT (odds ratio, 1.6, 95% confidence interval, 1.1 to 2.4; P = .0155). Among patients considered eligible for HCT, 45.1% (65 of 144) of those at CO/GOV sites and 35.7% (41 of 115) of those at AC sites underwent transplantation (P = .12). Approximately one-half of all patients at CO/GOV (50.1%) and AC (45.4%) sites were not considered potentially eligible for HCT; the most common reasons were age at CO/GOV sites (71.5%) and comorbidities at AC sites (52.1%). Across all sites, 17.4% of patients were reported as not assessed (and thus not considered) for HCT by their treating physician (20.7% at CO/GOV sites and 10.7% at AC sites; P = .0005). These findings suggest that many patients with HR-MDS and AML who may be candidates for HCT are not receiving assessment or consideration for transplantation in clinical practice. In addition, treatment at CO/GOV sites and age remain significant barriers to ensuring that all potentially eligible patients are assessed for HCT.

Sex Disparities in Myelodysplastic Syndromes: Genotype, Phenotype, and Outcomes.

Introduction/Background The impact of biological sex on the clinical phenotype, genotype, and outcomes among patients with MDS is not well characterized. Materials and Methods We retrospectively reviewed the clinical and genomic data from male and female patients included in our institutional MDS database at Moffitt Cancer Center. Results Among 4580 patients with MDS, 2922 (66%) were men and 1658 (34%) were women. Women were younger (mean age 66.5 vs. 69 years for men, P < .001) at diagnosis. There were more Hispanic/black women than men (9% vs. 5%, P =<.001). Women had lower hemoglobin and higher platelet counts than men. More women had del 5q/monosomy 5 abnormalities compared to men (P =<.001). Therapy related MDS were more common in women than men (25% vs.17%, P=<.001). On assessment of molecular profile, SRSF2, U2AF1, ASXL1, and RUNX1 mutations were more frequent in men. The median overall survival (mOS) was 37.5 months (mo) for females compared to 35 monthsfor males, (P = .002). The mOS was significantly prolonged for women in lower-risk MDS, but not in higher-risk MDS. Women were more likely to respond to immunosuppression with ATG/CSA than men (38% vs. 19%, P= 0.04).Conclusion Ongoing research is needed for understanding the impact of sex on phenotype, genotype, and outcomes in patients diagnosed with MDS.

Improved benefit of continuing luspatercept therapy: sub-analysis of patients with lower-risk MDS in the MEDALIST study.

Red blood cell transfusion independence (RBC-TI) is an important goal in treating lower-risk myelodysplastic syndromes with ring sideroblasts. In the phase 3 MEDALIST study, RBC-TI of ≥ 8 weeks was achieved by significantly more luspatercept- versus placebo-treated patients in the first 24 weeks of treatment. In this post hoc analysis, we evaluated RBC transfusion units and visits based on patients' baseline transfusion burden level and the clinical benefit of luspatercept treatment beyond week 25 in initial luspatercept nonresponders (patients who did not achieve RBC-TI ≥ 8 weeks by week 25) but continued luspatercept up to 144 weeks. RBC transfusion burden, erythroid response, serum ferritin levels, and hemoglobin levels relative to baseline were evaluated. Through week 25, fewer RBC transfusion units and visits were observed in luspatercept-treated patients versus placebo, regardless of baseline transfusion burden. This continued through 144 weeks of luspatercept treatment, particularly in patients with low baseline transfusion burden. Sixty-eight patients were initial nonresponders at week 25 but continued treatment; most (81%) received the maximum dose of luspatercept (1.75 mg/kg). Sixteen percent achieved RBC-TI for ≥ 8 weeks during weeks 25-48, 26% had reduced RBC transfusion burden, 10% achieved an erythroid response, 44% had reduced serum ferritin, and hemoglobin levels increased an average of 1.3 g/dL from baseline. These data have implications for clinical practice, as transfusion units and visits are less in luspatercept-treated patients through week 25 regardless of baseline transfusion burden, and continuing luspatercept beyond week 25 can potentially provide additional clinical benefits for initial nonresponders. Trial registration: NCT02631070.

SOHO State of the Art Updates and Next Questions: Treatment of Lower Risk Myelodysplastic Syndromes.

MDS is a clonal stem cell neoplasm with a spectrum from lower risk disease to short term life threatening higher risk disease. The disease risk is dictated by clinical and molecular features. Majority of MDS patients including lower risk disease unfortunately succumb from disease related complications namely cytopenia. While cytopenias may be mild early upon diagnosis and can be surveilled, ultimately treatment is required. Anemia is the hall mark of disease and most common indication to treat in lower risk MDS. Erythroid stimulating agents are used in the first line setting. Treatment can be a personalized approach as in select patient such as patients with del(5q) and those with ringed sideroblasts, lenalidomide, and luspatercept can be extremely effective respectively at improving cytopenias. Younger patients and hypoplastic MDS have also shown and improved response to immunosuppressive therapy. Hypomethylating agents can be option for patients with higher risk features or thrombocytopenia/neutropenia. Refractory cytopenias still poses frustration as options are limited and there is need to add more treatments to our armamentarium.

Considerations for Drug Development in Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) have historically been challenging diseases for drug development due to their biology, preclinical modeling, and the affected patient population. In April 2022, the FDA convened a panel of regulators and academic experts in MDS to discuss approaches to improve MDS drug development. The panel reviewed challenges in MDS clinical trial design and endpoints and outlined considerations for future trial design in MDS to facilitate drug development to meaningfully meet patient needs. Challenges for defining clinical benefit in patients with MDS include cumbersome response criteria, standardized transfusion thresholds, and application and validation of patient reported outcome instruments. Clinical trials should reflect the biology of disease evolution, the advanced age of patients with MDS, and how patients are treated in real-world settings to maximize the likelihood of identifying active drugs. In patients with lower-risk disease, response criteria for anemic patients should be based on baseline transfusion dependency, improvement in symptoms, and quality of life. For higher-risk patients with MDS, trials should include guidance to prevent dose reductions or delays that could limit efficacy, specify minimal durations of treatment (in the absence of toxicity or progression), and have endpoints focused on overall survival and durable responses. MDS trials should be designed from the outset to allow the practicable application of new therapies in this high-needs population, with drugs that can be administered and tolerated in community settings, and with endpoints that meaningfully improve patients' lives over existing therapies.

Clinical characteristics and outcomes of EZH2-mutant myelodysplastic syndrome: A large single institution analysis of 1774 patients.

EZH2 mutations in myeloid neoplasms are loss of function type, and have been linked to poor overall survival (OS) in patients with myelodysplastic syndrome (MDS). However, the specific determinants of outcomes in EZH2-mutant (mut) MDS are not well characterized. In this single-center retrospective study, clinical and genomic data were collected on 1774 patients with MDS treated at Moffitt Cancer Center. In our cohort, 83 (4.7%) patients had a pathogenic EZH2 mutation. Patients with EZH2mut MDS were older than EZH2-wild type (wt) group (median age- 72 vs. 69 years, p = 0.010). The most common co-occurring mutation in EZH2mut MDS was ASXL1, with a significantly higher frequency than EZH2wt (54% vs. 19%, p < 0.001). Patients with EZH2mut MDS had lower response rates to hypomethylating agents compared to EZH2wt MDS (26% vs. 39%; p = 0.050). Median OS of patients with EZH2mut MDS was 30.8 months, with a significantly worse OS than EZH2wt group (35.5 vs. 61.2 months, p = 0.003) in the lower-risk IPSS-R categories. Among patients with EZH2mut MDS, co-presence of ASXL1 or RUNX1 mutations was associated with inferior median OS compared to their wt counterparts (26.8 vs. 48.7 months, p = 0.031). Concurrent chromosome 7 abnormalities (12%) were also associated with significantly worse OS (median OS- 20.8 vs. 35.5 months, p = 0.002) in EZH2mut MDS. Future clinical trials should explore the potential role of novel targeted therapies in improving outcomes in patients with EZH2mut MDS.