Risk Myelodysplastic Syndromes Research Articles

Secondary haematological dysplasia after CAR-T-cell therapy foracute lymphoblastic leukaemia in children.

The use of CAR-T is becoming more widespread in the treatment of haematological malignancies. In adults, secondary myelodysplastic syndromes (MDS) after CAR-T have been described. However, there are currently no data on the risk of MDS following CAR-T in children treated for acute lymphoblastic leukaemia (ALL). We studied all children treated with CAR-T cells at Hospital Sant Joan de Déu in Barcelona and those with persistent cytopenias were evaluated at the cytological, cytogenetic, and molecular levels to look for MDS. A total of 106 patients received CAR-T for ALL. Among 40 patients without early relapse or subsequent therapy after CAR-T, four fulfilled the WHO criteria for myelodysplasia. These four patients had received a haematopoietic stem cell transplantation (HSCT) prior to CAR-T and presented cytopenias with severe dysplastic changes in bone marrow after CAR-T. One patient had clonal MDS with high-risk cytogenetics arising from the host cells requiring a HSCT. Three patients had non-progressive dysplasia arising from the donor cells. Two are alive in complete remission with stable cytopenias and one succumbed to ALL relapse. This is the first description of post-CAR-T MDS and haematological dysplasia in children and highlights the need to monitor children with persistent post-CAR-T cytopenias.

Expression levels of genes implicated in the working mechanism of lenalidomide predict treatment response in lower risk myelodysplastic syndrome patients.

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443 (PB431): A Sub Analysis of Clinical Study of Tomaralimab, a Toll-like Receptor 2 (TLR-2) Antibody, in Patients with Lower Risk Myelodysplastic Syndromes (MDS) That Have Received Prior Hypomethylating Agent (HMA) Therapy

443 (PB431): A Sub Analysis of Clinical Study of Tomaralimab, a Toll-like Receptor 2 (TLR-2) Antibody, in Patients with Lower Risk Myelodysplastic Syndromes (MDS) That Have Received Prior Hypomethylating Agent (HMA) Therapy

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).

Genetic predisposition to myelodysplastic syndrome: Genetic counseling and transplant implications

The development of myelodysplastic syndromes (MDS) is influenced by various genetic predispositions. Several important genes contribute to disease susceptibility. This paper explores common genetic predisposition genes in MDS, including DDX41, CEBPA, and SAMD9/SAMD9L, which are linked to hereditary conditions presenting diagnostic and clinical challenges. It delves into hereditary conditions that affect platelet production and count, such as RUNX1, ETV6, and ANKRD26, detailing their clinical features and how they contribute to an increased risk of MDS. The discussion extends to additional genetic syndromes like GATA2 deficiency, telomere biology disorders, Fanconi anemia, and Li-Fraumeni syndrome, along with new findings on genes like ERG that offer new insights into disease etiology. The importance of genetic counseling in MDS is underscored, outlining its goals, methods for evaluating family history, risk assessment, and the ethical considerations involved. Furthermore, the role of hematopoietic cell transplantation in managing MDS, particularly in patients with germline syndromes, is reviewed, emphasizing the need for optimal donor selection and personalized treatment approaches. This comprehensive overview illustrates the critical role of genetic factors in MDS and highlights the need for continued research and tailored clinical practices to improve patient outcomes.

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.

Safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of KT-253, a targeted protein degrader of MDM2, in patients with relapsed/refractory (R/R) solid tumors, lymphoma, high grade myeloid malignancies and acute lymphoblastic leukemia (ALL).

3084 Background: The tumor suppressor p53 is mutated in approximately 50% of cancers. In those cancers with wild-type p53, its activity is controlled by mouse double minute 2 (MDM2), an E3 ligase that tags p53 for degradation. KT-253 is a novel, highly potent heterobifunctional MDM2 degrader that upregulates p53 activity and overcomes the p53-MDM2 feedback loop, resulting in >200-fold higher potency compared to MDM2 inhibitors. In preclinical PDX models of sensitive p53WT solid tumors, AML and ALL, KT-253 robustly activates p53, induces apoptosis, and results in tumor regressions with every 3-week dosing. The ability to rapidly induce an acute apoptotic response and dose intermittently may result in a therapeutic index that has eluded previous MDM2 targeting agents. Methods: The ongoing open-label Phase 1 study evaluates safety, PK, PD and preliminary efficacy of IV KT-253 administered on Day 1 of 21-day cycles. Patients (pts) with advanced (≥2 prior therapies) solid tumors (ST)/lymphomas (Arm A) and relapsed/refractory (R/R) high grade myeloid malignancies (AML, high/very-high risk myelodysplastic syndrome (MDS), MDS/myeloproliferative neoplasms) and ALL (Arm B) are eligible. Blood samples are collected for KT-253 PK/PD analyses. Results: As of 26 January 2024, 18 pts have been treated, 13 in Arm A dose levels (A: DL) 1-4 and 5 in Arm B dose levels (B: DL) 1-2, with mean number of 3 and 2 doses, respectively. The most common solid tumor types were Merkel cell carcinoma ((MCC) n=3), adenoid cystic carcinoma ((ACC) n=2) and uveal melanoma (n=2). Arm B included 5 pts with R/R AML. The median age was 61 years (yrs) (range 42, 81) in Arm A and 66 yrs (range 57, 70) in Arm B. The most common adverse events (AEs) in > 20% of pts included nausea, fatigue, headache, and vomiting. There was 1 DLT of AEs leading to discontinuation that included Grade (G) 2 nausea and fatigue in A: DL4. There were no neutropenia or thrombocytopenia AEs in either arm. KT-253 related SAEs included G3 hypotension in a pt with decreased oral intake (A: DL1). Overall best response: 1 CR (B: DL2, AML); 2 PRs (A: DL1, MCC; B: DL1, AML); 3 SD (A: DL1, fibromyxoid sarcoma; DL2, ACC; DL3, renal cell cancer). PD data from A: DL1-4 and B: DL1-2 demonstrated rapid upregulation of plasma GDF-15 protein and upregulation of CDKN1A and PHLDA3 mRNA levels in blood. KT-253 demonstrated dose-dependent increase in plasma exposure with levels approximating efficacious doses. Conclusions: KT-253 results in potent upregulation of p53-dependent biomarkers and has demonstrated early signs of anti-tumor activity including objective responses in MCC and AML at doses that are well tolerated. Dose escalation is ongoing at DL4 in Arm A and at DL2 in Arm B and analyses from additional pts will be presented at the meeting. Clinical trial information: NCT05775406 .

Preliminary safety and efficacy of oral azacitidine (Oral-AZA) in patients (pts) with low-/Intermediate (Int)-risk myelodysplastic syndromes (MDS): Phase 2 results from the ASTREON trial.

6509 Background: There is an unmet need for new treatment (tx) options in lower-risk MDS (LR-MDS) to address cytopenias and prevent progression to higher-risk MDS and acute myeloid leukemia. Here, we report safety and preliminary efficacy data from phase 2 of the ASTREON study, which evaluated 14-day Oral-AZA regimens in pts with Low-/Int-risk MDS. Methods: ASTREON is a phase 2/3, multicenter study evaluating safety and efficacy of Oral-AZA plus best supportive care (BSC) in pts with Low-/Int-risk MDS (NCT05469737). Phase 2 is an open-label, dose optimization study to determine the recommended phase 3 Oral-AZA dose. Eligible pts (≥ 18 years of age with Revised International Prognostic Scoring System [IPSS-R] Low-/Int-risk MDS and ≥ 1 cytopenia) were randomized 1:1 to receive Oral-AZA 200 mg or 300 mg QD for 14 d per 28-d cycle plus BSC. Primary endpoints are rates of adverse events (AEs) and complete remission (CR) within 6 cycles per International Working Group (IWG) 2006 criteria. Secondary endpoints include achievement of overall response (OR) (including CR, partial remission, marrow CR, hematologic improvement-erythroid response [HI-E], HI-platelet response, and HI-neutrophil response per IWG 2006 criteria); best OR; and OR duration. HI rates within 6 cycles were calculated by investigator assessment per IWG 2006 criteria for pts who received ≥ 75% of the cycle 1 dose and had ≥ 1 post-baseline (BL) efficacy assessment (modified intent-to-treat [mITT] population). Results: As of December 4, 2023, 47 pts were randomized and received ≥ 1 Oral-AZA dose (200 mg, n = 24; 300 mg, n = 23); 6 and 5 pts discontinued tx in the 200 mg and 300 mg arms. The median (range) tx durations were 24.1 (12.1–34.1) and 24.7 (7.7–39.1) wk for the 200 mg and 300 mg arms, respectively. IPSS-R scores and RBC transfusion burden at BL were balanced between tx arms. Most pts (42/47 [89.4%]) had prior MDS tx, including but not limited to erythropoiesis-stimulating agents, lenalidomide, luspatercept, and imetelstat. AE rates were similar between arms: 11/24 (45.8%) vs 12/23 (52.2%) pts in the 200 mg vs 300 mg arms reported ≥ 1 tx-related grade 3 or 4 tx-emergent AE. The most common tx-related AEs in both arms were hematologic and gastrointestinal. Tx-related serious AEs occurred in 1/24 and 3/23 pts in the 200 mg and 300 mg arms, respectively. One death occurred in the 300 mg arm and was considered tx-related. In the mITT population, 8/22 and 7/21 pts achieved any HI in the 200 mg and 300 mg arms, respectively. Six pts in each dose group achieved HI-E. Among mITT pts with anemia at BL, 6/19 (31.6%) pts in the 200 mg and 5/18 (27.8%) pts in the 300 mg arm achieved HI-E. Updated results will be presented. Conclusions: The safety of Oral-AZA 200 mg and 300 mg was consistent with the known Oral-AZA safety profile. Preliminary efficacy data support continued evaluation of Oral-AZA in LR-MDS. Clinical trial information: NCT05469737 .

Latest results of a phase 2 study of IMM01 combined with azacitidine (AZA) as the first-line treatment in adults with higher risk myelodysplastic syndromes (MDS).

6510 Background: Patients diagnosed with higher-risk myelodysplastic syndrome (MDS) have poor prognosis. Azacitidine (Aza) has been shown to prolong survival in patients with treatment-naive, higher-risk MDS compared to a menu of standard of care options. IMM01 is a fusion protein comprising a recombinant signal regulatory protein α (SIRPα) and IgG1, exerting anti-tumor effects by inhibiting the "Don't eat me" signal and activating the "Eat me" signal, leading to robust antibody-dependent cellular phagocytosis (ADCP). Methods: This is an open-label, multi-center, phase 2 study (NCT05140811) that evaluated safety and efficacy of IMM01 in combination with AZA as the first-line treatment for patients with untreated higher-risk MDS. Enrolled patients were aged ≥18 years with intermediate to very high risk MDS, as defined by the Revised International Prognostic Scoring System (IPSS-R) score >3.5, and were not eligible for stem cell transplant or intensive chemotherapy. Patients were received intravenous IMM01 at a dosage of 2.0mg/kg/week and subcutaneous AZA at a dosage of 75 mg/m2 on days1-7 per 28-day cycle. Results: By the cutoff-day of Dec 22, 2023, 57 patients were enrolled in the study. The median age was 64 (30-83) years, with 41 (71.9%) being male, and 55 (96.5%) having an ECOG of ≥1. Based on risk classification per IPSS-R, 43.9% were high risk (HR) and 31.6% were very high risk (vHR). At baseline, the median levels of blood counts were 69 (35-136)g/L for hemoglobin, 43 (2-409)×109/L for platelets and 0.8 (0.1-8.6)×109/L for neutrophils. The median duration of follow-up was 12.8 months (95%CI:9.7-15.3). Among the 51 efficacy evaluable patients, overall response rate (ORR) was 64.7%, including 29.4% complete response (CR) rate, 15.7% marrow CR (mCR) with hematologic improvement (HI), 5.9% HI and 13.7% mCR alone. The median time to response (TTR) was 1.9 months (95%CI:1.8-2.8) and the median duration of response (DoR) was not reached(NR). The median of progression-free survival (PFS) was not reached, with an estimated 12-month PFS of 54.4% (95% CI, 31.4-72.6). NGS analysis identified common mutations in DNMT3A, ASXL1, U2AF1 and RUNX1. Notably, NPM1 mutations significantly correlate with treatment response, particularly achieving CR. The most common ≥G3 treatment related adverse events (TRAEs) (≥10%) included leukopenia (78.9%), thrombocytopenia (66.7%), neutropenia (66.7%), lymphopenia (56.1%), anemia (43.9%), infection (15.8%) and pneumonia (10.5%). Without using of a low priming dose, the Grade ≥3 hemolysis was rare (only 1.8%). Conclusions: IMM01 (without low-dose priming) combined with AZA were well tolerated and showed exciting efficacy results in patients with treatment-naive higher-risk MDS. Clinical trial information: NCT05140811 .

Effects of immune cells in mediating the relationship between gut microbiota and myelodysplastic syndrome: a bidirectional two-sample, two-step Mendelian randomization study

BackgroundThe definitive establishment of a causal relationship between gut microbiota and myelodysplastic syndrome (MDS) has not been achieved. Furthermore, the involvement of immune cells in mediating the connection between gut microbiota and MDS is presently unclear.MethodsTo elucidate the bidirectional correlation between gut microbiota and MDS, as well as to investigate the mediating role of immune cells, a bidirectional two-sample, two-step Mendelian randomization (MR) study was conducted. Summary statistics were obtained from genome-wide association studies (GWAS), including MDS (456,348 individuals), gut microbiota (18,340 individuals), and 731 immune cells signatures (3757 individuals).ResultsGenetically predicted eight gut microbiota traits were significantly associated with MDS risk, but not vice versa. Through biological annotation of host-microbiome shared genes, we found that immune regulation may mediate the impact of gut microbiota on MDS. Subsequently, twenty-three immunophenotypes that exhibited significant associations with MDS risk and five of these immunophenotypes were under the causal influence of gut microbiota. Importantly, the causal effects of gut microbiota on MDS were significantly mediated by five immunophenotypes, including CD4 +T cell %leukocyte, CD127 on CD45RA − CD4 not regulatory T cell, CD45 on CD33 + HLA DR + WHR, CD33 on basophil, and Monocyte AC.ConclusionsGut microbiota was causally associated with MDS risk, and five specific immunophenotypes served as potential causal mediators of the effect of gut microbiota on MDS. Understanding the causality among gut microbiota, immune cells and MDS is critical in identifying potential targets for diagnosis and treatment.

Inflammatory profile of lower risk myelodysplastic syndromes.

The precise link between inflammation and pathogenesis of myelodysplastic syndrome (MDS) is yet to be fully established. We developed a novel method to measure ASC/NLRP3 protein specks which are specific for the NLRP3 inflammasome only. We combined this with cytokine profiling to characterise various inflammatory markers in a large cohort of patients with lower risk MDS in comparison to healthy controls and patients with defined autoinflammatory disorders (AIDs). The ASC/NLRP3 specks were significantly elevated in MDS patients compared to healthy controls (p < 0.001) and these levels were comparable to those found in patients with AIDs. The distribution of protein specks positive only for ASC was different to ASC/NLRP3 ones suggesting that other ASC-containing inflammasome complexes might be important in the pathogenesis of MDS. Patients with MDS-SLD had the lowest levels of interleukin (IL)-1β, tumour necrosis factor (TNF), IL-23, IL-33, interferon (IFN) γ and IFN-α2, compared to other diagnostic categories. We also found that inflammatory cytokine TNF was positively associated with MDS progression to a more aggressive form of disease and IL-6 and IL-1β with time to first red blood cell transfusion. Our study shows that there is value in analysing inflammatory biomarkers in MDS, but their diagnostic and prognostic utility is yet to be fully validated.

Patterns of lower risk myelodysplastic syndrome progression: factors predicting progression to high-risk myelodysplastic syndrome and acute myeloid leukemia.

The patterns of low-risk myelodysplastic syndrome (MDS) progression and the clinical and molecular features of those patterns have not been well described. We divided our low-risk (LR) MDS patients (N=1,914) into 4 cohorts: 1) patients who remained LR-MDS (LR-LR; N=1,300; 68%), 2) patients who progressed from LR to high-risk (HR) MDS (LR-HR) without transformation into acute myeloid leukemia (AML) (N=317; 16.5%), 3) patients who progressed from LR to HR MDS and then AML (LR-HR-AML; N=124; 6.5%), and 4) patients who progressed from LR MDS directly to AML (LR-AML; N=173; 9%). Risk factors for progression included: male gender, low absolute neutrophil count (ANC), low platelet count, high bone marrow (BM) blasts, ferritin >1000 mcg/L, albumin <3.5 g/dL, multi-lineage dysplasia (MLD), and lack of ring sideroblasts. Among patients with marked BM fibrosis (N=49), 18% progressed directly to AML. Somatic mutations (SM) associated with an increased risk of direct or indirect AML progression included SRSF2 and NRAS. SM in IDH1, IDH2 and NPM1 were more common in patients with direct AML transformation. SM associated with progression to higher risk disease only, without AML transformation, were ASXL1, TP53, RUNX1, and CBL. SF3B1 mutation was associated with less progression. About 171 patients (13.1% of all LR-LR patients) died within two years of diagnosis of LR-MDS without disease progression. Among the 61 cases with documented cause of death, 18 patients (29.5%) died from cytopenia and MDS-related complications. Identifying patterns of disease progression of LR MDS patients and their predictive factors will be crucial to be able to tailor therapy accordingly.

Effects of Black Raspberry Supplementation on Methylation Pathways in Vav-creAsxl1fl/flTet2fl/fl Double Knockout Mice with Early-stage Myelodysplastic Syndrome.

Myelodysplastic syndromes (MDS) are a subset of myeloid malignancies defined by clonality of immature hematopoietic stem cells that leads to faulty blood cell development. These syndromes can lead to an increased risk of infection and may transform into acute myeloid leukemia, making it critical to determine effective treatments for the condition. While hypomethylating agents such as azacitidine and decitabine, as well as stem cell transplants, have been delineated as favored treatments for MDS, not all patients are physiologically receptive to these treatments. However, black raspberries (BRBs) have been shown to exert hypomethylating effects in various malignancies, with minimal adverse effects and thus a broader range of potential candidacies. This study aimed to investigate the potential of BRBs to exert such effects on MDS using Addition of Sex Combs Like/Tet Methylcytosine Dioxygenase 2 (Asxl1/Tet2) double knockout mice (Vav-cre Asxl1fl/fl Tet2fl/fl), which typically manifest symptoms around 25 weeks of age, mirroring genetic mutations found in humans with MDS. Following a 12-week dietary supplementation of Vav-cre Asxl1fl/fl Tet2fl/fl mice with 5% BRBs, we observed both hyper- and hypomethylation at multiple transcription start sites and intragenic locations linked to critical pathways, including hematopoiesis. This methylation profile may have implications for delaying the onset of MDS, prompting a need for in-depth investigation. Our results emphasize the importance of exploring whether an extended BRB intervention can effectively alter MDS risk and elucidate the relationship between BRB-induced methylation changes, thus further unlocking the potential benefits of BRBs for MDS patients.

The Effect of Oral Iron Chelator Deferiprone on Iron Overload and Oxidative Stress in Patients with Myelodysplastic Syndromes: A Study by the Israeli MDS Working Group

Background: Most patients with lower risk myelodysplastic neoplasms or syndromes (MDSs) become RBC transfusion-dependent, resulting in iron overload, which is associated with an increased oxidative stress state. Iron-chelation therapy is applied to attenuate the toxic effects of this state. Deferiprone (DFP) is an oral iron chelator, which is not commonly used in this patient population, due to safety concerns, mainly agranulocytosis. The purpose of this study was to assess the effect of DFP, on oxidative stress parameters in iron-overloaded RBC transfusion-dependent patients with lower risk MDSs. Methods: Adult lower risk MDS patients with a cumulative transfusion burden of >20 red blood cell units and evidence of iron overload (serum ferritin >1,000 ng/mL) were included in this study. DFP was administered (100 mg/kg/day) for 4 months. Blood samples for oxidative stress parameters and iron overload parameters were done at baseline and monthly: reactive oxygen species (ROS), phosphatidylserine, reduced glutathione, membrane lipid peroxidation, serum ferritin, and cellular labile iron pool. The primary efficacy variable was ROS. Tolerability and side effects were recorded as well. A paired t test was applied for statistical analyses. Results: Eighteen patients were treated with DFP. ROS significantly decreased in all cell lineages: median decrease of 58.6% in RBC, 33.3% in PMN, and 39.8% in platelets (p < 0.01 for all). Other oxidative stress markers improved: phosphatidylserine decreased by 57.95%, lipid peroxidase decreased by 141.3%, and reduced gluthathione increased by 72.8% (p < 0.01 for all). The iron-overload marker and cellular labile iron pool decreased by 35% in RBCs, 44.3% in PMN, and 46.3% in platelets (p < 0.01 for all). No significant changes were observed in SF levels. There were no events of agranulocytosis. All AEs were grades 1–2. Conclusions: Herein, we showed preliminary evidence that DFP decreases iron-induced oxidative stress in MDS patients with a good tolerability profile (albeit a short follow-up period). No cases of severe neutropenia or agranulocytosis were reported. The future challenge is to prove that reduction in iron toxicity will eventually be translated into a clinically meaningful improvement.

Risk of Myelodysplastic Syndromes (MDS) in Adolescents and Young Adults with Cancers Treated with Chemotherapy with or without Radiotherapy

Introduction The risk of MDS among adolescents and young adults (AYA) with cancer treated with chemotherapy with or without radiotherapy in the US is not well understood. Method We interrogated NCI's Surveillance, Epidemiology and End Result (SEER)-17 registries to identify patients (pts) between the ages of 15-39 years (AYA) diagnosed with MDS at least one year after diagnosis of a primary unrelated cancer treated with chemotherapy and or radiotherapy over a twenty-year period (January 2000 to December 2020). All cancers, including MDS, were identified using ICD-O-3/WHO-2008 histology codes. We excluded all leukemia and MDS entities from index cancer sites. The risk of MDS was estimated by standardized incidence ratio (SIR), defined as the ratio of observed MDS cases in the AYA pts treated for first cancers to the expected number of MDS cases in the general US population during this period. A referent rate file for MDS incidence in age, gender, race and calendar-year matched US population available in SEER*Stat software (version 8.4.0) was used for SIR calculation. We calculated exact, 2-sided Poisson-based 95% confidence intervals (CIs) about the SIRs. We stratified the risk using 5- calendar year periods, and latency after index cancer diagnosis. SIR and time to MDS development was calculated for six most common index cancers using R(v4.2.2)-software. Result Of a total of 168,078 AYA pts eligible for analysis, with 1,290,803-person years at risk during 2000 to 2020, 66 pts developed MDS during this period. The median age at diagnosis of index cancer and MDS were 34 years (yrs) (interquartile range (IQR), 27-37 yrs) and 38 yrs (IQR, 32-44 yrs), respectively. There were 680% more cases of MDS in the AYA cohort compared to that expected in the matched general US population [SIR (95% CI): 7.80 (6.03-9.92), p&amp;lt;0.05)]. A higher SIR was observed for males (12.19) compared to females (5.82) and among all race/ethnicity, highest among black males [(SIR (95%CI): 18.99 (6.17-44.32), p&amp;lt;0.05]. We analyzed SIR for top-six index cancer sites that contributed to most MDS cases. Lymphomas [Non-Hodgkin (NHL) and Hodgkin (HL)] and breast accounted for 54.5% of all MDS cases. SIR for MDS in pts with NHL was 22.07 (95% CI: 12.61-35.84), in HL pts was 10.75 (95% CI: 4.64-21.18), and in breast cancer pts was 2.79 (95% CI:2.22-7.51). Even though the absolute number of cases was low, pts with brain, as well as bone and joint cancers had highest SIRs for MDS. When stratified by 5-calendar year periods, the SIR of MDS was elevated compared to general population through all periods and was highest during 2000-2005 (27.44; 95% CI: 11.03-56.53), and declined for the subsequent time periods. When analyzed by latency period, the SIR for MDS was highest at 1-3 years after index cancer diagnosis (21.46: 95% CI 13.45-32.50) and then showed a steady decline with increasing latency over a period of 15-20 years but never reached the rates observed in general population (Figure 1). Among the six most common index sites, pts with bone and joint cancer had earliest time to occurrence of MDS, whereas the longest latency to developing MDS was observed in pts with testicular cancer (Figure 2). Conclusion AYA cancer cohort treated with chemotherapy or radiotherapy have nearly 8-fold higher risk of future development of MDS compared to the same age matched general US population. This risk is highest during the initial 1-3 years of diagnosis of index cancer, declines over time, but never reaches the rates in the general population. These findings warrant further investigation to understand the biology behind this observation and have potential treatment and surveillance implications.

Metabolic Syndrome Among Patients with Myelodysplastic Syndrome: A Population Analysis

Introduction: Metabolic syndrome (MS) comprises a cluster of cardiovascular risk factors, including central obesity, dysglycemia, elevated blood pressure (BP), increased triglyceride levels (HyperTG), and low HDL cholesterol levels. Epidemiologic and clinical data suggest that MS may be an important etiologic factor in the progression of certain cancer types. These studies have excluded patients with myelodysplastic syndromes (MDS), but MS may be relevant in these patients owing to the link between cardiovascular disease and MDS derived from clonal hematopoiesis. We conducted a population-based analysis to define the prevalence of MS and its components among patients with MDS and explore the effect of MS on MDS outcomes. Methods: We identified patients aged 66 and older diagnosed with MDS between 2007 and 2017 using the SEER-Medicare database. Preexisting MS was identified using ICD-9/10 codes in claims from at least 12 months before MDS diagnosis. MS was defined as the presence of 3 or more of the 5 MS components. MDS histologic risk was defined based on ICD-O-3 morphology codes. Transfusion dependence, defined as 2 or more transfusions within 8 weeks of MDS diagnosis date, and therapy with hypomethylating agents (HMA), lenalidomide and erythropoietin stimulating agents (ESA) were defined from HCPCS codes and prescription records. Other variables defined included age, sex, race/ethnicity, rurality (using RUCC codes), marital status, and socioeconomic status [SES] (using the Yost index). Descriptive statistics were used to define the frequency of MS and its components. MDS outcomes of interest were transformation to acute myeloid leukemia (AML), defined from ICD-9/10 codes for AML, and overall survival (OS), defined as the time between MDS diagnosis and death from any cause. Cox proportional hazards regression was used to determine the association between MS and AML transformation and OS, through adjusted hazard ratios (HR). Results: A total of 15,227 cases diagnosed with MDS between 2007 and 2017 were analyzed, including 3,402 (22.3%) with baseline MS. High BP was present in 72.2%, HyperTG in 47.8%, dysglycemia in 35.5%, central obesity in 4.6% and 0.5% had low HDL cholesterol. The prevalence of MS and the distribution of its components did not significantly differ based on MDS histologic risk (Table 1). The prevalence of hyperTG was notably higher in patients with MDS, especially in the high histologic risk category (50.4%). Compared to other MDS patients, those with preexisting MS were predominantly male (55.5% vs 53.3%, p=0.03) of non-White race (6.7% vs 4.8% non-Hispanic Black, p&amp;lt;0.01, and 2.1% vs 1.5% Hispanic, p&amp;lt;0.01), from urban/metropolitan areas (87.7% vs 86%, p=0.01) and lower SES quintiles 1 and 2 (34.2% vs 31.5%, p&amp;lt;0.01). In a model adjusting for age, sex, race/ethnicity, rurality, marital status, SES, MDS risk, transfusion dependence and MDS therapies (HMA, lenalidomide and ESA), baseline MS at the time of MDS diagnosis was not associated with a significant effect on the risk of AML transformation (HR=1.0, 95%CI 0.9-1.2) or the risk of death from any cause (HR=1.0, 95%CI 0.9-1.1) (Table 2). In models assessing the effect of MS subcomponents on MDS outcomes, high BP (HR=1.0, 95CI% 1.0-1.1) and obesity (HR=1.1, 95CI% 1.0-1.2) were associated with an increased risk of mortality. Obesity was also associated with an increased risk of transformation to AML (HR=1.3, 95CI% 1.0-1.6). Conclusions: The overall prevalence of MS among patients with MDS appears similar to that reported in the general population and does not differ based on the histologic risk category. The observed prevalence of HyperTG was higher than expected, particularly in high-risk MDS patients. Older males of non-White race from urban/metropolitan areas of lower SES are more likely affected across all groups. Though preexisting MS is present in an important proportion of MDS patients, it was not significantly associated with an increased risk of mortality or AML transformation after adjusting for confounders. Obesity was associated with higher mortality and linked to increased transformation to AML. Given recent data suggesting that statins may improve survival and decrease AML transformation in MDS, future studies should investigate the potential association between other metabolic parameters and MDS outcomes.

Mutational Profile and Dynamics of PPM1D-Mutant Clones in the Spectrum of Myeloid Disorders

Introduction Mutations in PPM1D a regulator of DNA damage response, are enriched in patients with clonal hematopoiesis (CH) exposed to cytotoxic treatment or with therapy-related myeloid neoplasm. However, their role in leukemic transformation is unclear. Here, we describe a large cohort of patients with PPM1D mutations from CH to acute myeloid leukemia (AML) to understand the molecular landscape of mutant PPM1D related disease and the longitudinal dynamics of CH under treatment. Methods We included, in a non-sequential cohort, 96 PPM1D mutated patients treated at Gustave Roussy with CH, clonal cytopenia of unknown significance (CCUS), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN) or AML. A 77 gene panel NGS analysis was performed. An additional 16 PPM1D mutated AML patients from ALFA trials (1200, 0701,0702) were included. 10 patients with ovarian cancer from this cohort had sequential blood samples (OvBIOMark trial) available prior to hematologic evaluation, from the diagnosis or first relapse of their cancer through the course of therapy. Those samples were analyzed with a UMI based 18 gene panel (HaloplexHS, Agilent). Overall survival (OS) analyses were performed with the Kaplan-Meier method from the time of diagnosis until death from any cause. Results Among the 112 patients with PPM1D mutations, 23 (21%) had CH, 36 (32%) CCUS, 19 (17%) MDS, 25 (22%) AML (including 4 relapses), and 9 (8%) MPN. Median age was 65 [range, 21-88] years with 67% of females. Only 18% of the patients had no previous cancer history. Most frequent primary cancers were gynecological cancer (27%), lymphoid malignancies (22%), and breast cancer (17%). Median time between primary cancer diagnosis and hematologic assessment was 5.3 [range, 1.2-8.5] years. Eighty six percent of patients had one PPM1D mutation, 9% had 2, and 5% had 3 or more (restricted to CH and CCUS). Median variant allele frequency (VAF) was 3% [0.2-38], 3% [1-31], 2.4% [1-41], 23% [1-50], and 4% [1-42] in CH, CCUS, MDS, AML and MPN, respectively. Among CH/CCUS patients, PPM1D was the sole detected somatic mutation in 39% (23/59), compared to 9% (5/53) in MDS/AML/MPN patients (odds ratio=6, p=0.0004); 3/5 of the latter had complex karyotype. The most frequently co-mutated genes were DNMT3A (29%) and TP53 (25%), uniformly across all conditions ( Fig 1A). MDS-related gene mutations, RUNX1 (7%), ASXL1 (4%), SF3B1 (4%), SRSF2 (4%), U2AF1 (4%), were specific to AML/MDS/MPN. Among 28 patients with both PPM1D and TP53 mutations, PPM1D mutations were dominant or co-dominant in 64% (18/28), and secondary in 36% (10/28). IPSS-M risk of evaluable MDS was high/very high in 54% (7/13) of patients. ELN 2022 classification of AML was adverse in 68% (17/25) of patients. AML treatment options included best supportive care for 8% of patients (2), 5-Azacytidine for 32% (8), intensive chemotherapy for 60% (15). With a median follow up of 2.4 years, the median OS was 4.6 (CI95%; 4.1-NA), 1.31 (CI95%; 0.53-NA), 1.27 (0.43-NA), 0.66 (CI95%; 0.42-1.26) and 20.4 (CI95%; 20.4-NA) years for CH, CCUS, MDS, AML and MPN, respectively. TP53 mutation status did not stratify OS. Four ovarian cancer patients with CH/CCUS transformed to MDS/AML with a median of 5.3 [1-12] years. At transformation, 3/4 had a stable PPM1D mutation, 1/4 an increase in PPM1D VAF (2 to 28%), and 3/4 had TP53 mutations before and at transformation. We analyzed 67 timepoints from 10 ovarian cancer patients during therapy (median 7 per patient). 10/10 received alkylating agents and 5/10 PARPi. The median number of mutations per patient was 4 and 6 at baseline and last follow-up, respectively. PPM1D-mutated clone size increased from 0.4% [0.1-3] at baseline to 7% [2-30] at last follow-up. Beyond clonal expansion, PPM1D VAF dynamics showed non-linear changes related to alkylating agents exposure: 2/10 patients had a continuous expansion, 2/10 had expansion then contraction (GR-1/3, Fig 1B), and 6/10 had expansion then stabilization (GR-2, Fig 1B). Conclusion We described a large cohort of PPM1D mutated patients from CH to AML. Their prognosis was poor independently of TP53 mutation at AML/MDS stage. PPM1D mutations were frequently part of the dominant clone. To confirm the clonal architecture, single cell sequencing analysis in 8 AML/MDS patients are ongoing. Trajectory of PPM1D mutations in ovarian cancer patients revealed a non-linear alkylating agent dependency which warrants further investigation.

Results of a Phase II Study of Cladribine, Low Dose Cytarabine and Venetoclax, Alternating with Azacitidine and Venetoclax in Patients with Higher Risk Chronic Myelomonocytic Leukemia or Myelodysplastic Syndromes

INTRODUCTION: Clinical responses to hypomethylating agents (HMAs) in patients (pts) with higher-risk myelodysplastic syndromes (HR-MDS) and myeloproliferative chronic myelomonocytic leukemia (CMML) remain short-lived, with high risk of transformation to acute myeloid leukemia (AML). Prior data suggests use of the purine analogue cladribine can induce monocyte apoptosis and is active in AML, particularly in combination with low dose cytarabine (LDAC) and venetoclax. We aimed to evaluate the safety and activity of cladribine, LDAC and venetoclax in HR-MDS and CMML. METHODS: We designed a phase II basket clinical trial of cladribine combined with LDAC and venetoclax alternating with azacitidine and venetoclax for pts with HR-MDS or CMML. Pts were divided into 4 cohorts: cohort A: MDS with int-1 to high risk by IPSS and &amp;gt;5% blasts with prior HMA-failure (HMA-F); cohort B: CMML-1/CMML-2 with prior HMA-F; cohort C: previously untreated MDS with Int-2 or High risk by IPSS and &amp;gt;10% bone marrow (BM) blasts; cohort D: previously untreated CMML-2 or CMML-1 with at least one high-risk feature (extramedullary disease, splenomegaly of &amp;gt;5cm below costal margin, platelets &amp;lt;100x10 9/L, Hgb level &amp;lt;10g/dL, WBC &amp;gt;13x10 9/L, clonal cytogenetic abnormality [other than monosomy Y]). HMA-F was defined as no response after 6 cycles of therapy with HMA or relapse/progression after any number of cycles. Induction consisted of cladribine 5mg/m 2 daily IV on days 1-3, cytarabine 20mg s.c bid days 1-5 and venetoclax 400mg daily days 1-5. Re-induction was allowed in pts not achieving response after induction. Consolidations consisted of azacitidine 75mg/m 2 daily days 1-7 with venetoclax 400mg daily days 1-7 alternating with cladribine 5mg/m 2 days 1-3, cytarabine 20mg s.c bid days 1-5 and venetoclax 400mg days 1-5 every two 28-day cycles. The primary end point was to evaluate safety, efficacy, and tolerability of the combination. Responses were evaluated following 2006 IWG criteria. The Kaplan-Meir product-limit method was used to estimate median survival. RESULTS: Between October 2022 and June 2023, 20 pts have been treated: 10, 5, 3 and 2 in cohorts A, B, C and D, respectively. Thirteen pts had MDS, and 7 had CMML. Median age was 74 years (range 52-83). Among MDS pts, 8 (62%) had int-2 and 5 (38%) had high risk by IPSS. By the Molecular IPSS, 10 (79%) had very high, 1 (8%) had high, 1 (8%) had moderate high and 1 (8%) had low risk. Among CMML pts, 4 (57%) had high, 2 (29%) had intermediate-2 and 1 (14%) had intermediate-1 risk by the CPSS Molecular score. Among HMA-F cohorts, median number of prior therapies was 1 (range 1-4), median cycles of prior HMA was 6 (range 2-63) and 4 (27%) pts had failure to prior venetoclax therapy. Most common adverse events (AEs) were hypoalbuminemia (40%), nausea (40%), sinus bradycardia (40%), alanine aminotransferase increase (35%), constipation (35%), lower extremity edema (35%), fatigue (35%) and hypocalcemia (35%) Most common grade 3-4 AEs were leukopenia (20%) and febrile neutropenia (15%). The 4-week and 8-week cumulative incidences of mortality were 0%. Median number of cycles was 2 (range 1-6). Median cycles to best response was 1 (range 1-3). Among HMA naïve pts (cohorts C and D), the ORR was 80% (n=4): CR in 2 (40%), mCR in 2 (40%). Based on 2023 IWG response criteria, responses in cohort C (n=3) included: CR in 2 (67%) and CR bilineage (CRbi) in 1 (33%). Based on 2015 IWG MDS/MPN criteria, responses in cohort D (n=2) included optimal marrow response and clinical benefit in 1 (50%) and 1 (50%) pts, respectively. Among HMA-F pts (cohorts A and B) the ORR was 20%: 1 CR (10%) and 1 (10%) mCR with HI. Median follow up is 5.3 months (95% CI 2.4-81). Median EFS is 2.1 months in cohorts A and B and not reached in C and D (Fig 1A). Median OS has not been reached for all cohorts (Fig 1B). At the time of data cut-off, all pts in cohorts C and D discontinued study to proceed with hematopoietic stem-cell transplantation (HSCT). Among cohorts A and B, 2 pts (13%) discontinued study to proceed with HSCT, 5 (33%) due to transformation to AML, 2 (13%) due to no response, 2 (13%) due to physician choice, 1 (7%) due to patient choice and 2 (13%) pts remain on study. CONCLUSIONS: Preliminary data suggests the use of cladribine, LDAC and venetoclax can be safely administered in pts with very high risk MDS and CMML with early promising results in pts with de novo disease.

Phase 1/2 Multicenter, Open-Label Study of CTX-712 in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes

Background and Significance Dysregulation of alternative splicing, caused by abnormal expression or mutation of splicing factors, has been identified as an important contributor to the genesis and progression of cancer, and suggested as a novel target for anticancer treatment. CDC2-like kinases (CLK) represent a family of dual-specificity tyrosine and serine-threonine kinases that are involved in the regulation of splicing by phosphorylation of serine/arginine-rich splicing factors (SRSFs) which play a central role in exon recognition. CTX-712 is an orally available, potent, selective, and a first-in-class pan-CLK inhibitor (CLK 1-4), that inhibits phosphorylation of SRSFs resulting in significant antitumor activity in vitro and multiple xenograft models in vivo. CTX-712 formulated in capsules is currently being evaluated in an ongoing first-in-man study in Japan, evaluating tolerability and early efficacy in patients with solid tumors or hematologic malignancies (JapicCTI-184188). Preliminary data from the Japanese study were presented during ASCO 2022 and ASH 2022, and showed an acceptable safety profile (doses up to 175 mg (MTD 140 mg) twice a week in 28-day cycles, observed DLTs included dehydration, decreased platelets, hypokalemia, and pneumonia) with early signs of clinical antitumor activity (2 partial responses / 26 treated solid tumor patients, 5 complete remissions and complete remission with incomplete hematologic recovery/ 8 treated patients with AML or MDS), warranting further clinical investigations.. (J Clin Oncol (2022) 40(16_suppl):3080. Blood (2022) 140(Supplement 1):6211-2.). This abstract details a second study with CTX-712 that has just been initiated. Study Design and Methods A new film-coated tablet formulation will be evaluated in this phase 1/2 multicenter, open-label study of CTX-712 in patients with (mutated or wild type spliceosomes genes) relapsed/refractory AML, higher risk MDS (IPSS-R intermediate, high, or very high), or high marrow blast (≥5 %) MDS/MPN (including CMML). The phase 1 part of the study will be conducted at 4 US sites, and all sites are currently open for enrolment. The study allows patients with performance status 0, 1, or 2, adequate organ function, and up to four prior lines of therapy. Due to potential risk of interactions (in vitro studies suggest CYP3A4 as main metabolic pathway for CTX-712), concomitant use of strong CYP3A4 inhibitors is prohibited. Use of azole antifungals that are not strong CYP3A4 inhibitors (e.g., isavuconazole) is permitted. The phase 1 part of the study consists of dose-escalation (sequential standard 3 + 3 design), where cohorts of 3 (or 6) patients will receive ascending doses of CTX-712 once weekly in a 28-day cycle with continuous monitoring of emerging clinical PK, PD, safety, and efficacy data, to determine the recommended phase 2 dose (RP2D) based on the suggestion by the Safety Review Committee (SRC). The protocol defines five different dose levels (20-140 mg, once weekly) but also authorizes the SRC to suggest up to two interim dose levels or alternate schedules (e.g., dosing two times a week) if supported by emerging data. The suggested RP2D will be used in a confirmatory phase 1 expansion cohort where an additional 10 patients (total n = 16; 8 patients with AML and 8 patients with MDS) will be treated to gain further confidence in the selected dose level. The phase 2 part of the study will commence after the RP2D has been identified and confirmed and aims at evaluating therapeutic activity in R/R AML (Cohort 2a) or R/R HR-MDS (Cohort 2b), in addition to confirmation of the safety profile. Clinical trial registry number: NCT05732103

Single-Cell Multiomics Analysis Reveals Potential Drivers of Response to the Anti-TIM3 Inhibitor Sabatolimab Combined with Azacitidine in MDS and CMML

Background The median survival for patients with newly diagnosed (ND) higher risk myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) remains poor. The potential curability of MDS and CMML with allogeneic hematopoietic stem cell transplantation supports the concept of anti-tumor immunity and has led to interest in evaluating immune-based therapeutic approaches in myeloid neoplasms. The immune checkpoint molecule TIM-3 (encoded by the gene HAVCR2) is a target of interest in myeloid neoplasms given its expression on leukemic stem cells as well as several subsets of immune cells including T cells, monocytes, dendritic cells and NK cells. Sabatolimab (MBG453) is an investigational IgG4 anti-TIM-3 antibody currently under evaluation for myeloid neoplasms. In this exploratory study, we sought to characterize the effects of sabatolimab combined with the hypomethylating agent (HMA), azacitidine, on the immune landscape using single cell sequencing of samples from subjects with MDS and CMML treated with the combination from a previously reported phase 1b study (NCT03066648; Brunner et al 2022). Methods Following IRB approval, single-cell RNA sequencing (scRNA-seq) and associated proteomic cellular indexing of transcriptomes and epitopes sequencing (CITE-seq) was performed on both blood (BLD) and bone-marrow (BM) derived samples from subjects with: 1) MDS (n=3) or CMML (n=2) treated with HMA therapy alone as part of standard care; 2) ND MDS (n=5) or CMML (n=3) treated with azacitidine combined with sabatolimab; and 3) relapsed/refractory MDS (n=3) treated with sabatolimab alone. Paired BLD and BM samples as well as samples from serial treatment time points were selected whenever feasible (Fig 1). A total of 206,183 cells from BM and 172,421 cells from BLD post-quality control filtering were analyzed. Further, scRNAseq data from normal BLD(200,000 cells) and BM(240,650 cells) generated as part of the human cell atlas (https://data.humancellatlas.org/explore/projects/cc95ff89-2e68-4a08-a234-480eca21ce79) were integrated with this dataset to assist with immune cell subset characterization, enable downstream comparisons to healthy hematopoietic cells, and to help define cell subsets associated with disease states. Results In baseline samples from subjects with MDS treated with azacitidine-sabatolimab, we found that an increased baseline abundance of interferon-responsive CD8 T cells in both the BM and BLD (FDR&amp;lt;0.1) was associated with response to therapy. An increased baseline abundance of plasmacytoid dendritic cells and a granulocyte population also suggested an association with response to therapy. Differential gene expression analysis of baseline samples from responding versus non-responding subjects with MDS treated with azacitidine-sabatolimab showed a higher baseline expression of TNF and IFNG in BM CD8 T cells and up-regulated expression of MHC-II machinery ( HLA-DRB1, HLA-DPA1, CD74) in myeloid cell subsets in responding subjects (FDR &amp;lt;0.1), suggesting that pre-treatment ability of these cells to be involved in antigen-presentation may play a role in response. In subjects with CMML treated with azacitidine-sabatolimab, we observed dynamic changes in cellular abundances and gene expression when comparing baseline to post-therapy timepoints. Specifically, BM CD8 T cell subsets showed an up-regulation of cytotoxicity genes ( GZMA), interferon response genes ( IFIT2, IFITM1, IFITM2) and IL32 cytokine post-therapy (FDR &amp;lt;0.1). When evaluating myelomonocytic cell populations, we observed an increase in CD16 monocytes post-treatment. Additionally, dendritic cells and monocytes showed an up-regulation of interferon response genes ( IFIT1, OAS1, IFI27). Conversely, we observed a down-regulation of metallothionein genes ( MT1E, MT1G, MT2A) as well as a collection of transcription factors ( NR4A1, FOSL2, JUN, CEBPB, CEBPD), NF-κB inhibitors ( NFKBIZ, NFKBIA) and CXCL8 in the post-treatment samples (FDR &amp;lt;0.1). Conclusions Our study provides one of the most comprehensive evaluations of the cellular dynamics of anti-TIM3 immunotherapy in patients to date, allowing for the nomination of novel putative predictive biomarkers of response and identification of potential immunomodulatory mechanisms induced by the combination of sabatolimab with azacitidine in MDS and CMML for further future analysis.