High-risk Myelodysplastic Syndrome Research Articles

15-Days Duration of Venetoclax Combined with Azacitidine in the Treatment of Relapsed/Refractory High-Risk Myelodysplastic Syndromes: A Retrospective Single-Center Study

The treatment of patients with refractory and/or relapsed (R/R) high-risk myelodysplastic syndrome (HR-MDS) remains a daunting clinical challenge. Venetoclax is a selective BCL-2 inhibitor, which combined with hypomethylating agents (HMAs), increased responses and prolonged survival in unfit and previously untreated AML. We performed a retrospective study of patients with R/R HR-MDS receiving combination azacytidine (AZA) plus 15-days duration of Venetoclax (VEN-15d) in order to determine their efficacy and toxicity in this context. We showed that the overall response rate (ORR) was 57.2% (20/35) and the median over survival (OS) was 14 months in R/R MDS. The most common treatment-emergent adverse events were peripheral blood cytopenias and infectious complications. Our retrospective study showed that the real-world experience of treating R/R MDS with AZA plus VEN-15d highlights an encouraging response rate with myelosuppression being the major toxicity. Of note, VEN-15d with AZA may salvage patients failing to respond optimally to HMAs and reduce the disease-burden for subsequent allo-SCT in our analysis. These data of combination AZA plus VEN-15d in R/R MDS warrant further prospective evaluation in clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical and Genetic Characteristics of STAG2 Mutations in Myeloid Neoplasms

Introduction: Stromal Antigen 2 (STAG2), located on chromosome Xq25, is the most mutated cohesin complex (CC) gene in myeloid neoplasms (MN), mostly MDS and AML. Somatic STAG2 mutations (STAG2m) are described as "secondary-type", specific for secondary AML (sAML). With mixed existing data regarding response to therapy and its impact on survival, we did a single institutional retrospective study on impact of STAG2 mutations in MN. Methods: After IRB approval, we retrospectively screened 3635 patients (pts) who had next generation sequencing (NGS) performed at Mayo Clinic between 2018-2021. Pts harboring STAG2m were identified (n=91/3635 [2.5%]), and their records reviewed for clinical information. Pts were included at time of in-house NGS. BlueSky Software V7.40 was used for statistical analysis. Results:Characteristics: Majority of pts were males (78%), with median age of 72 years. Diagnosis included MDS (55%), AML (29%), MDS/MPN (10%) and MPN (3%). Two CCUS and 1 aplastic anemia (AA) case were included. Therapy-related MN (tMN) was identified in 15%. Of MDS cases, 72% were MDS-EB and 46% were IPSS-R high/very high risk. Of AML cases, 38% were sAML. An abnormal karyotype was found in 28 pts (31%), with trisomy 8 being the most common. MN diagnosis was made in 47 pts (52%) prior to NGS.STAG2m: Median variant allele frequency (mVAF) was 50% (range 5-100%) and was higher in males (p<.001). VAF did not differ between diagnostic groups, MDS subtypes/risk groups or de novo (dn) and tMN. There was no correlation between VAF and blast count. STAG2m were nonsense (54%), frameshift (36%) and splice site (10%). The STAG domain had 6 (p.Arg259) and 4 (p.Arg216) nonsense mutations.Co-mutations: Median number of co-mutations was 3 (range 0-6) and did not correlate with MN classification. ASXL1 (65%), TET2 (36%), SRSF2 (36%), RUNX1 (30%) and BCOR (20%) were the most common co-mutations. High risk MDS pts had more BCORm (p=.01) and RUNX1m (p=.2) than lower risk pts. None of the co-mutation predicted progression to AML. Co-mutational pattern did not differ in dnAML vs sAML and dnMN vs tMN. Six pts had isolated STAG2m and were clinically like co-mutated pts.Therapy outcome and AML progression: Therapy was given to 63 pts (69%) including 30, 16 and 6 who received HMA, HMA + venetoclax (VEN) and intensive chemotherapy (IC), respectively. Hematopoietic stem cell transplantation (HSCT) was done in 25 pts. Response rate was 46%, 63% and 83% for HMA, HMA+VEN and IC, respectively. There was no difference in response rate based on therapy regimen. Median overall survival (mOS) did not differ between HMA responders and non-responders. Relapse occurred in 54% of AML and 19% of MDS pts. Therapy regimen, cytogenetics and VAF did not impact relapse. Progression to AML occurred in 18% of MDS and 22% of MDS/MPN pts. Higher risk MDS were more likely to progress than lower risk (p=.04) and median number of co-mutations was 4.Survival and molecular dynamics: mOS among 88 pts (excluding CCUS and AA) was 19.9 months. There was no difference in survival based on gender (p=.2), cytogenetics (p=.08), MN classification (p=.3), MDS risk grouping (p=.6) or between dnAML vs sAML (p=.2). mOS was lower in tMN compared to dnMN (9.9 vs 20.5 months, p=.03), STAG2m VAF≥ 75% compared to <75% (8.2 vs 21.4 months, p=.002), and circulating blasts ≥5% compared to <5% (10.1 vs 21.4 months, p=.01). HSCT improved mOS (not reached vs 15.6 months, p=.007). All remained significant on multivariate analysis (HR=2.6, p= .03; HR=2.6, p= .005; HR=2.9, p= .002 and HR=.3, p= .008, respectively). Of 91 pts, 31 had subsequent NGS. STAG2m persisted in 16 (52%), and the number and pattern of co-mutations did not change. mOS was lower among those with persistent STAG2m (p=.03). Conclusion:STAG2m was most common in elderly males and MDS. It was associated with high risk MDS and increasing genetic instability on AML progression. Isolated STAG2m were uncommon while common co-mutations were ASXL1, TET2, SRSF2, RUNX1 and BCOR. This implies a role of STAG2m in MN progression. STAG2m independently predicted poor prognosis, regardless of MN classification, especially in tMN and with circulating blasts ≥5%. HSCT had a favorable impact on STAG2m pts. Our study is limited by the small sample size and retrospective nature. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venetoclax Plus Intensive Chemotherapy in AML and Advanced MDS: Assessment of Leukemia Stem Cell Eradication By High-Resolution MRD Assay

Background: For the past five decades the standard of care for fit patients with acute myeloid leukemia (AML) has been induction with the "7+3" regimen, using a combination of cytarabine (AraC) and anthracycline (daunorubicin, idarubicin) followed by consolidation high-dose AraC (HiDAC). With this approach, approximately 70% of younger (≤60 years of age) and 60% of older (>60 yrs) fit patients achieve a complete remission, with 30-50% of those patients attaining measurable residual disease (MRD) negative state by multiparameter flow cytometry (MFC). However, even patients with MRD-negative remissions relapse due to remaining chemotherapy-resistant pre-leukemic and leukemic stem cells (LSCs). Eradication of residual disease at the LSC level is therefore the ultimate goal to achieve durable remissions and cure. The combination of Venetoclax (Ven) with chemotherapy can have a synergistic effect; by reducing the apoptotic threshold, Ven can facilitate increased apoptosis induced by genotoxic agents, while at the same time chemotherapy can downregulate MCL-1 that drives Ven resistance. Ven in combination with hypomethylating agents has shown to not only eradicate AML blasts but also target and eliminate LSCs. Early phase trials combining Ven with intensive chemotherapy (IC) have shown encouraging safety and efficacy signals. However, the optimal dose and schedule of Ven that can best synergize with IC to eradicate LSCs remain unknown. Here we present a phase 1b study evaluating the safety and tolerability of Ven in combination with daunorubicin (dauno)/AraC) induction followed by HiDAC consolidation in patients with newly diagnosed AML or high-risk myelodysplastic syndrome (MDS). Objective: The primary objectives of this study are to evaluate the safety, tolerability, and to determine the maximum tolerated dose (MTD) of the combination of Ven plus dauno & AraC, as well as HiDAC IC. Secondary objectives are response per 2017 ELN and revised IWG criteria, survival, event-free survival and duration of response. A key exploratory objective is to comprehensively analyze LSC and assess rates of LSC eradication by means of MFC and single cell sequencing ("high-resolution MRD assay"). Design: This is a Phase 1b, open-label, dose-escalation study, evaluating Ven in combination with IC in previously untreated, adult patients with AML and high-risk MDS (NCT05342584). In Part 1, we are utilizing a 3+3 design to evaluate the safety and tolerability of different Ven doses in combination with IC. In Part 2, we will evaluate the safety and clinical activity in additional 12 patients at the dose determined in Part 1. To evaluate for LSC MRD, bone marrow aspirates obtained at the time of each disease evaluation will be analyzed by high-resolution MRD assays. Specifically, we will perform multicolor flow cytometry assays optimized for primary samples and able to distinguish, quantify, and sort pre-LSCs and LSCs. Furthermore, we will combine this assay with ultra-deep sequencing (1Million x) to detect very low levels of mutant cells, importantly within the LSC compartment. Eligible patients must have a new diagnosis of AML or high-risk MDS (blasts>10% AND R-IPSS>3.5%), be 18-75 yrs of age and deemed fit for intensive chemotherapy. During induction, escalating Ven doses (400 mg x8 -> 11 -> 14 days) will be combined with AraC 100mg/m2 and 2 doses of dauno (60 and 90mg/m2) in patients aged 60yrs or younger, whereas dauno 60 will be used for all patients older than 60yrs. During consolidation, the Ven dose will be escalated (200 -> 400mg) in a similar 3+3 design at a fixed 7-day duration in combination with age-adjusted high dose AraC regimen (1.5g/m2 in ≤60yrs and 1g/m2 in >60yrs, every 12hrs on days 1,3,5). Conclusion: This study will evaluate the optimal dosing of Venetoclax and daunorubicin as part of the Ven plus "7+3" induction regimen. It will also evaluate the optimal dose of Venetoclax in combination with HiDAC consolidation chemotherapy. This trial will utilize a novel highly-sensitive LSC MRD assay to test the efficacy of Venetoclax in eliminating LSCs when combined with conventional chemotherapy.

Disease Characteristics and International Prognostic Scoring Systems (IPSS, IPSS-R, IPSS-M) in Adult Patients with Higher-Risk Myelodysplastic Syndromes (MDS) Participating in Two Randomized, Double-Blind, Placebo-Controlled Studies with Intravenous Sabatolimab Added to Hypomethylating Agents (HMA) (STIMULUS-MDS1 and MDS2)

Background: Patients (pts) with higher-risk MDS have poor outcomes. Sabatolimab (MBG453) is a novel immunotherapy targeting T-cell immunoglobulin domain and mucin domain-3 (TIM-3), an immuno-myeloid regulator expressed on both immune and leukemic stem cells. Sabatolimab+HMA delivered durable responses in a Phase (Ph) Ib study in pts with high-risk/very high risk (HR/vHR)-MDS (Brunner AM, ASH 2021). We report disease characteristics from 2 ongoing randomized, double-blind, placebo-controlled studies of sabatolimab+HMA in higher-risk MDS (Ph II STIMULUS-MDS1 [NCT03946670] and Ph III STIMULUS-MDS2 [NCT04266301]) and compare different scoring systems (International Prognostic Scoring System [IPSS], revised IPSS [IPSS-R] and molecular IPSS [IPSS-M]) in this overall population. Methods: We enrolled pts ≥18 years old with intermediate-risk (IR)/HR/vHR-MDS per IPSS-R not eligible for stem cell transplant or intensive chemotherapy. In STIMULUS-MDS1 (MDS1) only, pts with IR-MDS had to have ≥5% bone marrow (BM) blasts at baseline. Pts with chronic myelomonocytic leukemia-2 (CMML-2) were only eligible in STIMULUS-MDS2 (MDS2). Pts were randomized 1:1 to sabatolimab+HMA (azacitidine [AZA] or decitabine) or placebo+HMA in MDS1, and to sabatolimab+AZA or placebo+AZA in MDS2. Baseline mutations were evaluated by a targeted 37-gene next-generation sequencing panel on genomic DNA from BM mononuclear cells and/or peripheral blood (2% variant allele frequency sensitivity). No data were collected for del17/17p, TP53 loss-of-heterozygosity (LOH), BCORL1, GNB1, NF1, PPM1D, PRPF8, and MLL-PTD. IPSS-M was derived based on Bernard et al, 2022 (R package from https://github.com/papaemmelab/ipssm) using available clinical, cytogenetic, and mutation data. Given low prevalence of MLL-PTD, this alteration was considered nonmutated for all pts. Results: In total, 657 pts were enrolled (MDS1, n=127; MDS2, n=530: MDS, n=492 and CMML-2, n=38). Further analyses focused on the 619 pts with MDS in MDS1 and MDS2. Of these, respectively, 87.4% and 76.8% were ≥65 years old; 67.7% and 65.2% were males. In MDS1, de novo disease was reported in 89.8% and secondary disease in 10.2% of pts; in MDS2 <1% had secondary disease. In MDS1, cytogenetic risk categories were very good/good in 40.9%, intermediate in 18.9%, and very poor/poor in 40.2% of pts; respective categories in MDS2 were 45.9%, 24.4%, and 29.7%. BM blast counts <10% were reported in 48.0% of pts in MDS1 and 58.1% in MDS2. Of pts enrolled in MDS1, 16.5%, 37.8%, and 45.7% were IR, HR, and vHR MDS per IPSS-R, respectively, and in MDS2 were 29.3%, 36.0% and 34.8%. The top 5 mutated genes in 118 pts with mutation testing in MDS1 were TP53 (34.7%), ASXL1 (33.9%), DNMT3A (27.1%), TET2 (25.4%), and RUNX1 (25.4%). The most frequently mutated genes in 403 pts with mutation testing in MDS2 were ASXL1 (38.7%), TET2 (28.3%), and RUNX1 (28.5%); a lower proportion of MDS2 pts vs MDS1 had mutations in TP53 (26.1%) and DNMT3A (17.4%). In MDS1, preliminary IPSS-M scores based on available data were low/moderate-low/moderate-high in 9.3%, high in 22.0%, and very high in 58.5% of pts (10.2% not available [uncertainty]). Respective IPSS-M scores for MDS2 were 15.6%, 18.6%, and 55.3% (10.4%). BM blasts 10-20% were associated with higher-risk categories, the majority being vHR IPSS-R and IPSS-M although these risk groups also included pts with <10% blasts (Figure 1A). Upstaging was observed from derived former IPSS criteria to IPSS-R. Furthermore, when comparing IPSS-R and IPSS-M, we observed that of pts with IR IPSS-R 22.2% and 21.5% were upstaged to HR and vHR IPSS-M respectively; 51.2% of pts with HR IPSS-R were upstaged to vHR IPSS-M; and 86.5% of pts with vHR IPSS-R remained vHR and 7.6% were downstaged to HR IPSS-M (Figure 1B). Conclusions: Pts in MDS1 had poorer prognosis features (baseline blasts, cytogenetics and higher IPSS-R) compared with MDS2 study. This preliminary analysis is among the first in large, well-controlled trials to assess IPSS-M and shows higher-risk categories compared with IPSS-R. Until molecular testing is routine globally, pt selection for clinical trials is still dependent on IPSS-R. However, these results demonstrate that complete molecular and cytogenetic assessment at baseline will improve evaluation in clinical trials and provide useful information for treatment decisions. Further analyses are planned in the STIMULUS clinical trial program of sabatolimab. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Genomic Correlates of Outcome in a Randomised Comparison of CPX-351 and FLAG-Ida in High-Risk Acute Myeloid Leukaemia and Myelodysplastic Syndrome: Results from the UK NCRI AML19 Trial

Background Liposomal daunorubicin and cytarabine (CPX-351) improves survival compared to 3+7 chemotherapy in patients aged 60 years with secondary AML defined by clinical or cytogenetic criteria (Lancet JE, JCO 2018). It is increasingly recognised that secondary AML may be better defined by mutational profile than clinical history (Döhner, Blood 2022; Khoury, Leukemia 2022), however patients with molecularly defined secondary AML were not specifically included in previous studies. Moreover, no randomised data for CPX-351 in patients aged <60y were available prior to this study. Previous UK NCRI trials established the FLAG-Ida regimen as a preferred regimen in patients aged <60y with high-risk and secondary AML (Burnett AK, Leukemia 2018). The UK NCRI AML19 trial randomised patients with AML or high grade MDS between induction therapy with CPX-351 and FLAG-Ida. Initial results reporting similar event-free and overall survival (OS) have been previously presented (Russell NH, HemaSphere 2022). Here we present an exploratory analysis of outcomes stratified by genomic, cytogenetic and clinical definitions of secondary AML. Methods AML19 (ISRCTN78449203) enrolled patients with previously untreated AML, MDS-EB2, or MDS-EB1 with IPSS score >3.5, predominantly aged <60 years. Patients known to have an adverse karyotype at diagnosis according to MRC criteria were randomised between CPX-351 and FLAG-Ida. Treatment consisted of up to 4 courses of CPX-351 or 2 courses of FLAG-Ida followed by MACE/MidAC consolidation with allogeneic transplant recommended after 2 cycles if feasible. Of note, patients could also enter the FLAG-IDA vs CPX randomisation if they became high risk at other defined points after induction, the results of which will be reported separately. Cytogenetic testing was performed in local laboratories with results reviewed and coded centrally. Complex karyotype was defined as ≥4 unrelated abnormalities. Following the completion of the trial, banked diagnostic DNA was analysed for variants in 41 recurrently mutated myeloid genes, including the entire coding regions of all myelodysplasia-related genes according to 2022 WHO and ELN criteria (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) (Döhner, Blood 2022; Khoury, Leukemia 2022). Libraries were prepared using the Agilent SureSelect XT HS2 platform and sequenced on an Illumina NextSeq2000 to a depth of >1000x. Results In total, 195 patients entered were randomised at trial entry, and NGS was performed on 173. Of the whole cohort, 49% were classified by clinical features as de novo AML, 20% as secondary AML and 31% as high-risk MDS. Myelodysplasia-related cytogenetic abnormalities were present in 70% of patients, with a complex karyotype in 51%. TP53 was the most commonly mutated gene in 43% of patients, followed by DNMT3A in 19% and ASXL1 in 18% (Figure A). A mutation in at least one myelodysplasia-related gene was present in 75 (43%) patients, of whom 60 (35%) were categorised as secondary AML by mutational status, which by ELN 2022 criteria requires the absence of TP53 variants. As previously reported, OS did not differ between the two randomisation arms (Hazard Ratio [HR] for CPX-351 0.84, 95% confidence interval [95CI] 0.59 - 1.20). In patients with clinically defined secondary AML, there was no OS benefit for CPX-351 (HR 1.1, 95CI 0.53 - 2.30), while high-risk MDS had a trend to benefit (HR 0.54, 95CI 0.28 - 1.00) (Figure B). When secondary disease was defined by the presence of myelodysplasia-related cytogenetic abnormalities, CPX-351 did not provide benefit (HR 1.04, 95CI 0.77 - 1.55). However, in patients with mutationally defined secondary AML, there was an OS benefit from CPX-351 (HR 0.42, 95CI 0.21 - 0.84, p value for heterogeneity 0.05) (Figure B). Patients with TP53 mutations had an adverse prognosis, with median OS of 7 months compared to 28 months in those with wild-type TP53. CPX-351 did not provide benefit compared to FLAG-Ida in this group (HR 0.92, 95CI 0.57 - 1.49). Conclusion In this exploratory subgroup analysis, CPX-351 had a significant survival benefit over FLAG-Ida in young high-risk patients with secondary AML/MDS as defined by the presence of myelodysplasia-related gene mutations, but not by clinical criteria. We observed no significant difference in patients with TP53 mutations. Acknowledgements This study received research support from Cancer Research UK and a research grant from Jazz Pharma Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase I/II Study of Combination of Azacitidine, Venetoclax and Pevonedistat in Patients with Newly-Diagnosed Secondary Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) with Hypomethylating Agent (HMA) Failure

Background: Pevonedistat (PEV) is an inhibitor of NEDD8-activating enzyme (NAE) which is critical for degradation of several cellular proteins essential for tumor growth and survival. The combination of azacitidine (AZA) and venetoclax (VEN) is approved for patients (pts) with newly diagnosed (ND) AML who are unsuitable for intensive chemotherapy, and clinical studies show preliminary efficacy with AZA+VEN in higher risk MDS pts. We evaluate the efficacy and safety of the combination of AZA, VEN, and PEV in ND secondary AML (s-AML) and in MDS after HMA failure. Methods: This phase 1/2 trial enrolled pts with ND s-AML, including therapy-related AML (t-AML), AML from prior MDS or chronic myelomonocytic leukemia (CMML) or myeloproliferative neoplasm (MPN), or AML with dysplasia in ≥50% cells in ≥2 myeloid lineages (MRC). A second arm enrolled pts with MDS or CMML that had progressed on prior HMA therapy. Pts had to have a performance status ≤2, total bilirubin ≤1.5 x upper limit of normal (ULN), ALT/AST ≤2.5 x ULN, and creatinine clearance ≥30 mL/min. Pts in AML arm may have received prior HMA for preceding hematologic malignancy. In both AML and MDS/CMML cohorts, pts received AZA 75 mg/m2 SC/IV on days 1-7 and PEV 20 mg/m2 IV on days 1, 3 and 5 on every 28 day-cycle. In AML cohort, VEN was given on days 1-28 in cycle 1 and days 1-21 on cycle 2+. In MDS/CMML cohort, VEN was given on days 3-14 in cycle 1 and days 1-14 on cycle 2+. In initial phase 1 portion of the study (AML cohort only), VEN at max dose 200 mg and 400 mg were explored. Results: Between 3/2019 and 8/2021, 32 pts with AML (10 t-AML, 22 AML from MDS/CMML/MPN, 4 MRC) and 8 pts with MDS/CMML post-HMA failure (6 with MDS, 2 with CMML) were treated (Table). In the AML cohort, the median age was 74 years, with 14 pts (44%) ≥75 years of age. Cytogenetics was adverse in 21 pts (66%), and adverse risk mutations, including TP53, RUNX1, and ASXL1 were present in 34%, 31%, and 22%, respectively. 17 pts (53%) had treated secondary AML (ts-AML; i.e. prior exposure to HMA or chemotherapy for preceding myeloid neoplasm). The overall response rate (ORR, defined as CR+CRi+MLFS) was 75%, with CR in 15 pts (47%), CRi in 6 pts (19%), and MLFS in 3 pts (9%). One pt achieved PR (3%). 78% of pts achieved best response after 1 cycle of therapy (range, 1-4 cycles to best response). Among 21 pts with CR/CRi, 10 pts (48%) achieved MRD negativity by flow cytometry. 14/21 pts (67%) with poor-risk cytogenetics responded, compared to 10/11 pts (91%) with non-poor cytogenetics. 9/11 pts (82%) with TP53-mutated AML responded. 11/17 pts (65%) with ts-AML responded, compared with 13/15 pts (87%) who did not have ts-AML. With median follow up of 20 months (mos) for the AML cohort, the median OS was 8.2 mos and median relapse-free survival (RFS) was 7.4 mos. 5 pts proceeded to transplant in first remission. The median OS for pts with adverse cytogenetics was 6.8 mos and was not reached in pts without adverse cytogenetics (1-year OS of 70%). The median OS for pts with TP53-mutated AML (n=11) was 8.1 mos, pts with inv(3) (n=4) was 3.8 mos, and pts without TP53 mutation or inv(3) (n=17) was 18 mos (Figure). In MDS/CMML HMA failure cohort, the median age was 73 years. Most pts had adverse cytogenetics (50%) and were high to very high-risk by IPSS-R (87%). Overall response rate (CR+marrow CR [mCR]+HI) was 75%, with CR in 3 pts (37%), mCR in 2 pts (25%), and HI in 1 pts (13%). With a median follow up of 11 mos, the median OS was 9.9 mos. Transformation to AML occurred in 1 pt (after 11 mos). No DLTs were observed in the phase 1 portion, and VEN 400 mg daily was the recommended phase 2 dose. Myelosuppression was similar to expectations with AZA+VEN alone. Grade 3/4 non-hematologic adverse events occurring in ≥10% pts were febrile neutropenia or other infection in 75%, hypophosphatemia in 22%, and hyperbilirubinemia in 10%. The 4-week and 8-week mortality rates were 9% and 25% in AML cohort and 0% and 13% in MDS/CMML cohort, respectively. Conclusion: AZA, VEN, and PEV combination is active and well-tolerated in both ND s-AML and MDS/CMML after HMA failure. This population was enriched with very poor risk features, including a majority of pts in the AML cohort with prior HMA or chemotherapy exposure for an antecedent myeloid malignancy and 1/3 of pts with a TP53 mutation. Response rates were high across disease subgroups, although duration of responses and survival were modest in pts with historically poor risk features, including those with adverse risk cytogenetics and TP53 mutations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase 1 Results of the First-in-Class CXCR1/2 Inhibitor SX-682 in Patients with Hypomethylating Agent Failure Myelodysplastic Syndromes

Background: SX-682 is an oral dual allosteric inhibitor of the CXCR1 and CXCR2 (CXCR1/2) chemokine receptors, a signaling pathway involved in the recruitment of immunosuppressive MDSCs and autocrine growth of disease-initiating leukemic stem cells (LSCs) in AML and myelodysplastic syndromes (MDS). CXCR2 overexpression is predictive of transfusion dependence in MDS. CXCR2 inhibition reduces proliferation of leukemic cell lines and primary MDS/AML patient (pt) samples in vitro and impairs leukemic growth in an in vivo AML animal model. CXCR2 is also involved in normal neutrophil egress from the bone marrow and thus absolute neutrophil count (ANC) serves as a pharmacodynamic (PD) marker for CXCR1/2 inhibition by SX-682. In pts with normal bone marrow, 25-400 mg SX-682 twice-daily (BID) dose-dependently reduces ANC, with maximum ANC reduction (-66% of baseline) obtained at >150 mg BID, consistent with maximum CXCR1/2 inhibition above this dose. ANC rapidly (24 hrs) normalizes with dose-holding. This NHLBI funded trial (HL142389, NCT04245397) explored the safety and efficacy of SX-682 monotherapy in pts with hypomethylating agent (HMA) failure MDS. Methods: This Phase 1 dose-escalation with expansion study treated five cohorts of HMA failure MDS pts with escalating 25-400 mg BID doses of SX-682 in six continuous 28-day cycles with responding pts continuing treatment. Steady-state pharmacokinetics (PK) were obtained. Response assessment was at the end of cycles 1, 3 and 6 and every third cycle thereafter using IWG criteria (Cheson 2006). This interim analysis after dose-escalation to select the expansion dose was pre-specified. Results:17 MDS pts received SX-682 (median 1 prior therapies; range 1-4) with 6 pts in the 200 mg cohort, 3 pts in each of the 25, 50 and 100 cohorts and 2 pts in the 400 mg cohort (Table). Median age was 76, and pts were low (n=1), intermediate-1 (n=10), intermediate-2 (n=5) and high (n=1) risk by the International Prognostic Scoring System (IPSS). All pts were transfusion-dependent and all had failed prior HMA and 24% lenalidomide. Steady-state PK exhibits increasing drug plasma concentration with dose comparable to pts with solid tumors. The ANC PD marker exhibited a dose-dependent decrease from baseline (ΔANC) that plateaued in the 200 and 400 mg dose cohorts consistent with maximum receptor inhibition (Table). Marrow MDSCs and LSCs were reduced after initiation of SX-682. SX-682 was well-tolerated with no maximally tolerated dose and no pt discontinued treatment for adverse events. Treatment-emergent adverse events > grade 3 were most common in the 200 and 400 mg dose cohorts, and those related to neutrophils are consistent with being related to SX-682. Effects on neutrophils reversed on cessation of drug dosing. There was a dose-dependent increase in overall response rate (ORR) from 0% at 25 mg BID to 50% at 200 mg BID consistent with the observed clinical benefit being related to CXCR1/2 inhibition by SX-682 (Table). Four of the five responders had mutant genes (MGs) involving splicing factors (60% of responders; SF3B1, SRSF2) and/or epigenetic regulation (60% of responders; TET2, ASXL1, IDH2). Across all dose cohorts, 8 of 17 (47%) pts had a reduction in marrow blasts after initiating SX-682 (Figure). The 200 mg dose yielded the most rapid and deep reduction in blasts with 2 of 6 pts (33%) achieving a marrow complete remission (mCR) in keeping with this dose providing maximum receptor inhibition. There was hematologic improvement (HI) in 3 pts with one having a durable near-CR response (on SX-682 >500 days) consisting of trilineage HI (hemoglobin > 10 g/dL) and transfusion independence for over 4 months (pt required 16 transfusions in the 7 weeks before starting SX-682 therapy). Based on ANC PD, ORR and marrow blast responses, the 200 mg BID dose was selected for the expansion phase of the trial. Conclusions: SX-682 is a novel therapy in HMA failure MDS with dual activity against LSCs and MDSCs. SX-682 was well tolerated with encouraging efficacy with a biologically effective oral dose selected at 200 mg BID. An expansion cohort in both lower and higher risk MDS pts is ongoing and will additionally include HMA naïve patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase I Trial of CD8-Depleted Human Leukocyte Antigen (HLA) Mismatched Unrelated Donor Lymphocyte Infusion (DLI) to Achieve Remissions in Myelodysplastic Syndrome (MDS) and Secondary Acute Myeloid Leukemia (sAML)

Background Hypomethylating agents (HMAs) are the standard of care in higher risk MDS, yielding a median survival of 12-18 months. After HMA failure or progression to sAML. median survival is only 4-6 months. We developed a novel cellular therapy using HLA mismatched, unrelated, CD8-depleted, CD4+ DLI to induce remission in patients with MDS and sAML who have not previously undergone allogeneic hematopoietic cell transplant (HCT). The DLI is intentionally class II HLA mismatched to activate donor CD4+ T cells which then provide immunologic "help" to reverse recipient immune exhaustion and, thus, promote a potent antitumor response (Symons. BBMT. 2008). Further, HLA mismatched donors are easily identified and allow the potential for an "off the shelf" product. By depleting CD8+ T cells, it is intended that the DLI does not engraft, thus negating the risk of graft-versus-host disease (GVHD). Instead, this therapy is intended to induce remission as a bridge to curative allogeneic HCT. Methods This completed phase I trial enrolled patients with MDS refractory to at least 4 cycles of HMA or sAML at the Moffitt Cancer Center from 2020-2022. Patients who received prior allogeneic HCT were excluded. DLI donors were selected from a pre-existing pool of unrelated donors at the New York Blood Center (NYBC) on the basis of class II HLA mismatch, CMV compatibility, and ABO compatibility. Patients were treated with induction chemotherapy as chosen by their primary physician. In parallel, donors underwent leukapheresis at the NYBC and the cell product was shipped to the Moffitt Cancer Center. The DLI was depleted of CD8+ T cells using the CliniMACS® system with CliniMACS® CD8 reagent in the Moffitt Cell Therapy Laboratory. HLA-mismatched CD4+ DLI was infused fresh within 24-36 hours after completing induction chemotherapy. The trial followed a 3+3 design to determine the recommended phase II dose (RP2D) of DLI where dose level (DL) 1 was 1x106 CD4 cells/kg, DL2 was 1x107 CD4 cells/kg, and DL3 was 5x107 CD4 cells/kg. Dose limiting toxicities (DLTs) were defined as grade 2-4 acute GVHD, grade 3-4 cytokine release syndrome (CRS), grade 2-4 infusion reactions, aplasia beyond 56 days in the presence of detectable donor chimerism, or grade 4 organ toxicity by CTCAE 5.0. Mechanistic studies were pursued to evaluate markers of immune tolerance, cytokine profiles, and confirm the DLI did not engraft. Results Nine patients (8 sAML, 1 MDS) were treated. All patients had progressed through at least one prior line of therapy (Table 1). The median age was 66. All AML patients had adverse risk disease by ELN risk stratification including 4 patients with TP53 mutation and complex cytogenetics. The MDS patient had very high-risk disease by R-IPSS. A suitable donor was identified for all patients despite a donor pool of only 30 donors. Cell collections, shipments, and processing for all patients were successful with all products achieving <3% CD8+ T cells and >70% cell viability. No patients experienced DLTs at any dose level. One patient at DL3 experienced grade 2 CRS that resolved with tocilizumab. There were no cases of grade 3-4 CRS nor GVHD (Table 2). Complete remission (CR) was achieved in 2/3 (66%) patients at DL3, 1/3 (33%) patients at DL2, and 0/3 (0%) patients at DL1. All 3 patients who reached CR proceeded to allogeneic HCT. At the time of marrow recovery post-treatment, donor DNA in the blood and marrow was no longer detectable in any of the patients. Patients who achieved CR (n=3) had significantly higher levels of IL6 on day +1 (p=0.01) and a trend towards higher levels of IL2, IL15, IFN-gamma, and TNF-alpha in the first 7 days after DLI compared to patients who did not achieve CR. Conclusions Induction chemotherapy followed by CD8-depleted HLA mismatched, unrelated donor DLI was feasible and well tolerated with no DLTs, confirming the RP2D of 5x107 CD4 cells/kg. At DL3, 2 of 3 patients achieved CR, including one with TP53 mutation and complex cytogenetics, which is generally resistant to induction chemotherapy and compares favorably to 20-30% historical CR rates with chemotherapy alone in those pts. Mechanistic studies correlated increased post-treatment cytokine levels with depth of remission. Assessment of markers of immune tolerance are pending and will be presented at the conference. Based on these promising results, this novel cellular therapy is being investigated now in a phase II clinical trial at the Moffitt Cancer Center. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase I/II Study of Seclidemstat, an LSD1 Inhibitor, and Azacitidine for Patients with Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

INTRODUCTION: Hypomethylating agents (HMA) remain the standard of care for myelodysplastic syndromes (MDS) but responses remain transient with loss of response being associated with dismal outcomes. Lysine specific demethylase 1 (LSD1) is a histone demethylase implicated in the maintenance of pluripotency and proliferation genes which is overexpressed in MDS. Given the importance of epigenetic deregulation in MDS and chronic myelomonocytic leukemia (CMML) we hypothesized that LSD1 inhibition, in combination with HMAs, may be synergistic and lead to enhanced antileukemic and pro-differentiation potential in MDS/CMML. METHODS: To study this we designed an open label phase I/II clinical trial of seclidemstat, a selective LSD1 inhibitor, in combination with azacytidine for patients with MDS or CMML with intermediate-1 or higher risk by International Prognostic Scoring System (IPSS) and progression or no response to 6 prior cycles of HMA. Study design includes an initial phase I dose escalation phase evaluating 6 dose levels of seclidemstat (150mg, 300mg, 450mg, 600mg, 900mg and 1200mg administered orally bid on days 1-28 of each 28 day cycle) in combination with azacytidine 75mg/m2 daily on days 1-7 of each 28 day cycle. Following the completion of phase I dose escalation the study will include a dose expansion phase (n=20) to gain further experience at the selected phase 2 recommended dose of seclidemstat. Study primary endpoint is to determine the safety, tolerability and maximum tolerated dose of seclidemstat in combination with azacytidine. Other study objectives include overall response rate and survival outcomes. Responses to therapy will be assessed following 2006 IWG response criteria. The study includes futility and safety stopping rules. This study is registered at clinicaltrials.gov (NCT04734990). RESULTS: To date, a total of 6 patients (3 in dose level 1 of seclidemstat 150mg po bid, and 3 in dose level 2 of 300mg po bid) have been treated on study as of July 2022: 5 with MDS and 1 with CMML. Patient characteristics are shown in Table 1. A total of 4 (67%) patients had higher risk MDS with complex karyotype and/or TP53 mutations after failure to HMA. Median number of prior therapies was 2 (range 1-3). Only 5 patients are evaluable for toxicity and response at the time of data cut off. To date, no DLTs have been observed. All evaluable patients experienced treatment emergent adverse events (AEs) with no treatment-related grade 3 AEs. The most frequently observed AE was transient grade 1 (n=2) and 2 (n=1) creatinine elevation which was observed during the first week of therapy and subsequently reverted to baseline levels. One patient developed QTC prolongation in the context of a right ventricular bundle branch block which was unrelated to study treatment. Dose interruptions were required only in 1 patient due to grade 2 creatinine elevation, and treatment could be resumed after normalization of creatinine levels. With a median follow up of 4.3 months (95% CI 2.0-6.6) and a median of 3 (range 2-4) cycles of therapy, response to therapy was observed in 2 patients including 1 mCR+HI with partial cytogenetic response, who transitioned to allogeneic stem-cell transplant after 3 cycles of therapy, and 1 mCR. Two patients remain on study at the 300mg po bid dose level. CONCLUSIONS: The combination of seclidemstat with azacitidine seems safe at the current dose levels and shows initial signs of potential activity. Further enrollment and follow up continues to further explore this combination. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Safety and Tolerability of AZD0466 As Monotherapy for Patients with Advanced Hematological Malignancies. Preliminary Results from an Ongoing Phase I/II Trial

Background: Anti-apoptotic proteins of the BcL-2 family such as Bcl-2 and Bcl-xL are critical to tumor survival and are associated with resistance to anticancer therapy. Specific Bcl-2 inhibition using venetoclax is beneficial in patients with acute myeloid leukemia (AML), but resistance often develops due to upregulation of anti-apoptotic proteins such as Bcl-xL and Mcl-1. Dual inhibition of Bcl-2 and Bcl-xL therefore has potential for broader activity than is observed with Bcl-2-specific inhibitors such as venetoclax. AZD0466 is a drug-dendrimer conjugate in which the Bcl-2/xL dual inhibitor AZD4320 is covalently conjugated to a pegylated poly-L-lysine dendrimer and gradually released by hydrolysis. Release of AZD4320 results in lower peak plasma levels compared to direct infusion of AZD4320 at similar concentrations, reducing the potential for the on-target toxicity associated with Bcl-xL inhibition (Balachander et al. Clin Cancer Res 2020; Patterson et al. Commun Biol 2021). AZD0466 has shown preclinical efficacy in solid (Arulananda et al. Cell Death Discov 2021) and hematological malignancies (Balachander et al. Clin Cancer Res 2020; Patterson et al. Commun Biol 2021). Preliminary results from the first-in-human study (NCT04214093) in advanced solid malignancies indicated that AZD0466 is well tolerated; no dose-limiting toxicities (DLTs) were reported. Here, we present preliminary data from an ongoing phase I trial of AZD0466 in patients with advanced hematological malignancies (NCT04865419). Methods: NIMBLE (drug deNdrIMer targeting BCL2/xL in acute LEukemias) is a modular, non-randomized phase I/II trial. Module 1 is evaluating the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of AZD0466 as monotherapy in adults with relapsed/refractory AML, acute lymphocytic leukemia (ALL), or higher risk myelodysplastic syndrome who have received ≥1 prior line of therapy, have no standard-of-care treatment available, and have no active CNS involvement. No minimum platelet count at study entry was specified and transfusions were permitted as part of supportive care. Module 1, Part A is a dose escalation study evaluating the safety and tolerability of AZD0466 monotherapy. The selected starting dose is AZD0466 300 mg IV; decisions on escalation and de-escalation are based on a mTPI-2 design (Guo et al. Contemp Clin Trials 2017;58:23-33). AZD0466 administration starts with a dose ramp-up with administration on days 1, 4, and 8 of cycle 1, followed by weekly IV administration at the target dose. The duration of Cycle 1 is 35 days, while subsequent cycles of 28 days. All patients are treated until progressive disease, unacceptable toxicity, or withdrawal of consent. The primary objectives of Module 1A are DLT (according to predefined criteria and occurring during cycle 1), maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). Secondary objectives include assessment of PK parameters for total and released plasma AZD4320. Results: As of May 31, 2022, 9 patients had been treated (55% male; median age, 70 years). Patients received AZD0466 at target doses of 300 mg (n=4), 600 mg (n=4), or 1200 mg (n=1). The safety analysis set consists of 9 patients and the DLT-evaluable set of 7 patients. No DLTs have been observed. All patients experienced at least one adverse event (AE). Five patients experienced AEs possibly related to treatment (grade 3 febrile neutropenia event, n=1; grade 3 gamma-glutamyltransferase increase, n=1; grade 2 sinus tachycardia, n=1; grade 1 aspartate aminotransferase increase, n=3; grade 1 alanine aminotransferase increase, n=2; grade 1 abnormal coagulation test, lactate dehydrogenase increase and alkaline phosphatase increase, all n=1). Four serious AEs occurred, none of which was treatment related. No AZD0466 discontinuations due to AEs have been observed. There were no thrombocytopenia events considered related to AZD0466 at the doses given. Following IV infusion, released AZD4320 exhibited a dose-proportional increase in area under the concentration time curve (AUC) and maximum serum concentration (Cmax), moderate PK variability (≈50% coefficient of variation), and a half-life of ≈18 hours. Conclusions: AZD0466 has been well tolerated, with no DLTs to date and no discontinuations due to treatment-related AEs. The trial continues to enroll, further dose escalation is planned, and updated data will be presented.

Phase 1/1b Safety Study of Prgn-3006 Ultracar-T in Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes

Phase 1/1b Safety Study of Prgn-3006 Ultracar-T in Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes

Maintenance Therapy with Venetoclax/Azacitidine Can be Safely Given after Venetoclax/FluBu2 RIC Allogeneic Transplantation for the Treatment of High Risk MDS/AML: Results of a Phase 1 Study

Background: Relapse is the main cause of transplant failure. We previously reported safety and durable remissions with venetoclax (Ven) added to fludarabine/busulfan (FluBu2) reduced intensity conditioning allogeneic hematopoietic cell transplantation (HCT) without planned maintenance therapy in patients (pts) with high risk myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) (Garcia, Blood Advances, 2021). Detectable measurable residual disease (MRD) at day +100 frequently resulted in relapse after transplant. To address relapse risk after VenFluBu2 transplant in this high risk population, we assessed the safety and activity of Ven/Azacitidine (VenAza) maintenance therapy. Methods: In a Phase 1 trial (NCT03613532), pts with an 8/8 HLA-matched donor and diagnosis of AML with <5% blasts (ELN adverse, secondary, or flow MRD positive) or MDS/MPN or MDS with ≥10% blasts (secondary, IPSS higher risk, or TP53mut or RAS pathway mutations) received VenFluBu2 (Ven 400 mg on D-8 to D-2; fludarabine 30 mg/m2/d on D-5 to D-2; IV busulfan 0.8 mg/kg bid on D-5 to D-2), followed by PBSC infusion (D0) and tacrolimus/methotrexate GVHD prophylaxis. Between D42-D90, VenAza maintenance therapy (Ven 400 mg on D1-D14 and Aza 36 mg/m2 IV on D1-D5) was initiated in pts who engrafted and had no evidence of morphologic relapse or uncontrolled GVHD in 42-day (dose level 1) or 28-day (dose level 2) cycles for up to 1 year. DLT was defined as Gr 4 neutropenia/thrombocytopenia >2 wks. Clinical NGS (sensitivity 1-3%) was performed before and after HCT (+28, +100). BH3 profiling analysis was performed on 11 paired blood samples before/after cycle 1 of VenAza. Results: As of 6/2022, 27 pts were enrolled and had the following disease status at time of HCT: 10 AML pts (8 CR, 2 CRi); 16 MDS pts (1 CR, 5 marrow CR (mCR) with hematologic improvement (HI), 5 mCR without HI, 1 HI-erythroid alone, and 4 active disease (5-10% blasts)); and 1 MDS/MPN pt in CR. Pts had a median age of 67y (range 47,78), co-morbidities (52% HCT-CI≥4), 44% were flow MRD negative, and 56% had Ven exposure prior to HCT. Baseline TP53mut was present in 59% (16/27). After VenFluBu2 RIC HCT, 22 of 27 pts received VenAza maintenance therapy (n=11 per dose level); remaining 5 of 27 pts did not (3 relapsed early, 2 withdrew). No DLTs were observed. The most common grade 3-4 treatment emergent adverse events (AE) during maintenance were anemia (45%), neutropenia (95%) and thrombocytopenia (91%), which were mainly transient. Cycle 1 nadir occurred on D29 for ANC (median 1.2 K/µL, range 0,3.7) and on D15 for platelet (median 119 K/µL, range 70,169). Infection during maintenance was reported in only 1 pt (n=1 BK viruria). Serious AEs were reported in 2 (1 rash; 1 BK case). Median of 4 VenAza cycles were received in DL1 (range 1,8); DL2 on-going. Cumulative incidence of grade ≥2 acute GVHD at 6 mo was 22% (95% CI: 9,39) and chronic GVHD at 1y was 23% (95% CI: 8,42). With a median 12 mo follow up (range 4-21), regardless of maintenance status, 1y OS, PFS, NRM and relapse were 70% (95% CI: 46,85), 57% (95% CI: 36,74), 0% and 43% (95% CI: 28,57), respectively. To date, 12 of 27 pts have relapsed (4 before, 7 during, and 1 after maintenance on D523). Ven use prior to HCT did not impact outcome. Pre-transplant flow MRD negativity was associated with improved 1y OS (88% vs 50%, p=0.03) and 1y PFS (81% vs 39%, p=0.08). Flow MRD was positive in 17% (4/24) at D28 and in 44% (11/25) at D100. At time of HCT, NGS was positive in 89% (24/27), but this reduced to 42% (10/24) at D28 and 58% (14/24) at D100 (Figure 1). PFS was similar for those with or without TP53mut at HCT (p=0.14). Among 22 pts that received VenAza maintenance therapy, 1y PFS and 1y OS were 65% (95% CI: 40,82) and 79% (95% CI: 52,92), respectively. BH3 profiling did not reveal any significant changes in baseline apoptotic priming in CD3+, CD3+CD4+, CD3+CD8+ T cells, and CD3+CD4+CD127-CD25+ Treg cells, suggesting VenAza was not cytotoxic to T cells. Flow cytometry to assess for immune recovery is in process. Conclusions: VenAza maintenance therapy after VenFluBu2 RIC alloHCT appears to be safe with low infection rate and no excessive GVHD. This Ven-based peri-transplant strategy for high risk MDS/AML pts has encouraging activity though relapses still occurred. A cohort assessing all oral maintenance (Ven plus decitabine/cedazuridine) is enrolling. A randomized trial will be required to evaluate the benefit of Ven with conditioning chemotherapy or with maintenance therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Molecular Biomarker Analyses for Exploring the Therapeutic Mechanism of Lemzoparlimab and Azacitidine (AZA) in Newly Diagnosed Higher Risk Myelodysplastic Syndrome (HR-MDS)

Molecular Biomarker Analyses for Exploring the Therapeutic Mechanism of Lemzoparlimab and Azacitidine (AZA) in Newly Diagnosed Higher Risk Myelodysplastic Syndrome (HR-MDS)

Novel First-in-Class Drug ONC201 As a Post-Transplant Maintenance for AML and MDS: A Phase I Trial in Progress

Background: Relapses of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic hematopoietic cell transplantation represent an area of significant unmet clinical need and a research priority identified by the National Cancer Institute. For patients with high-risk AML and MDS, post-transplant relapses remain the principal cause of mortality. The role of chemotherapy agents outside of FLT3 inhibitors or TKIs, and post-transplant cellular therapy to prevent relapse of leukemia are not well established. However, chemotherapy agents are frequently utilized off-label in clinical practice, thus signifying an urgent need to develop effective therapeutic strategies. ONC201 is a novel first-in-class small molecule imipridone, that antagonizes G protein-coupled receptor, DRD2 resulting in AKT/ERK inactivation. ONC201 is also an allosteric agonist of mitochondrial caseinolytic protease P that activates an integrated stress responses. In preclinical studies, leukemia cells demonstrate sensitivity to ONC201 regardless of their genetic and mutation profiles. Leukemia cells with genetic and mutation changes such as TP53 mutation and complex karyotype that confer resistance to conventional therapy are sensitive to ONC201. ONC201 is also toxic to leukemia stem cells while sparing normal bone marrow cells [Sci Signal. 2016 Feb 16;9(415):ra17]. Several clinical trials in solid and hematologic malignancies have demonstrated that oral ONC201 has a low toxicity profile and is well tolerated. The profile of ONC201 is well suited for further development to prevent post-transplant relapses of AML and MDS. Here, we report the design of the first trial to use ONC201 as post-transplant maintenance (ClinicalTrials.gov ID: NCT03932643). Study Design and Methods: The study will follow a 3+3 phase 1 trial design. The primary objective is to determine the rate of dose-limiting toxicities (DLT) during the first cycle and grade ≥3 toxicities during the first 3 cycles. Key inclusion criteria include adult recipients of allogeneic hematopoietic stem cell transplant within 6-20 weeks for a history of high-risk AML or MDS; <5% bone marrow blasts; Karnofsky Performance Status of ≥70; absolute neutrophil count (ANC) greater than 1000/μL, and platelet count ³50,000/µL. Key exclusion criteria include a history of acute graft-versus-host disease (GVHD) grade III/IV; initiation of any new systemic immunosuppressive agent for GVHD within 4 weeks of enrollment, current use of prednisone at a dose of ≥0.25 mg/kg/day; uncontrolled serious infection; active ischemic heart disease, heart failure or arrhythmia; severe chronic obstructive pulmonary disease; resting O2 saturation <90%; aspartate transaminase, alanine transaminase or bilirubin >2 times the upper limit of normal; and creatinine clearance <30 mL/min. Patients will receive oral weekly ONC201 at a starting dose of 250 mg and dose escalation by 125 mg up to a maximum dose of 625 mg weekly, in the absence of DLT. Patients will be monitored for toxicities (using Common Terminology Criteria for Adverse Events, CTCAE version 5.0), quality of life (QOL) (Functional Assessment of Cancer Therapy-Bone Marrow Transplant, FACT-BMT), changes in functional status (KPS, instrumental activities of daily living and short physical performance battery), rates of disease relapse and mortality (See Study Schema). We will enroll a total of 20 patients; the first 6-9 patients are expected to receive escalating doses of ONC 201, and the remaining patients will receive the maximum tolerated doses. Clinical studies in solid malignancies have indicated that ONC201 can expand and activate NK cells in peripheral blood, or recruit CD8+ T-cells to the tumor. Hence, the study will assess expansion and activation of NK and T cell populations in peripheral blood and utilize transcriptomic analyses of NK and T cells to explore the mechanisms behind the immunologic changes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prognostic Role of Cleaved Caspase-3 Reflecting Apoptosis in MDS Patients

Background: Myelodysplastic syndrome (MDS) is a heterogenous, clonal disorder in hematopoiesis. Pathophysiology of MDS is not clear yet, but there is growing interest in association with cellular proliferation and apoptosis. We hypothesized that Ki-67 and cleaved caspase-3 could be prognostic markers representative of proliferation and apoptosis in MDS patients. Methods: We performed retrospective study using bone marrow samples from 76 MDS patients who was diagnosed between 2004 and 2014 at Seoul National University Hospital. We compared Ki-67 and cleaved caspase-3 to evaluate cellular proliferative and apoptotic activities using immunohistochemical testing (IHC). And we additionally analyzed Ki-67 and cleaved caspase-3 between patients with MDS, idiopathic cytopenia of undetermined significance (ICUS) and health controls (HCs) based on data previously studied. And we also compared difference according to MDS risk scoring system. Results: Cleaved caspase-3 was highest in MDS patients, followed by ICUS patients and HCs (2.70, 95% CI: 2.56-2.85 vs. 2.19, 95% CI: 1.85-2.54 vs. 1.45, 95% CI: 1.17-1.73, p < 0.001). Similarly, the mean Ki-67 grade was also highest in MDS patients, followed by ICUS patients and HCs (1.72, 95% CI: 1.55-1.90 vs. 1.58, 95% CI: 1.30-1.86 vs 1.05, 95% CI: 0.95-1.16, p = 0.001) (Figure). Higher cleaved caspase-3 grade was significantly associated with lower IPSS-R score (p = 0.020), whereas Ki-67 was not. Interestingly, TET2 mutation was associated with decreased cleaved caspase-3 levels (p = 0.030). In terms of survival, there is no significant difference according to cleaved caspase-3 or Ki-67. In addition, we divided patients with MDS into four groups: lower-risk MDS patients with lower caspase-3 levels (A group : n = 32), lower-risk MDS patients with higher caspase-3 levels (B group : n = 13), higher-risk MDS patients with lower caspase-3 levels (C group : n = 28), and higher-risk MDS patients with higher caspase-3 levels (D group : n= 2). We compared PFS and OS between the four groups and found that high-risk MDS patients with lower caspase-3 showed significantly worse PFS than the other groups (p < 0.001; A vs B, p = 0.655; B vs C, p = 0.018; A vs C, p < 0.001) Conclusion: Our results suggest that apoptotic activity gradually increases from HCs, patients with ICUS to patients with MDS. Therefore, we could predict apoptotic activity from cleaved caspase-3. In addition, higher apoptotic activity was associated with better MDS patient prognostic scores and survival outcomes. Further studies are needed to reveal the the differences in apoptotic activity between lower- and higher-risk MDS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Myelodysplastic Syndromes without Detectable Mutations: Analysis of Clinical Presentation and Outcome

Introduction: The majority of patients with myelodysplastic syndromes (MDS) present with somatic mutations detectable by next generation sequencing (NGS). Recently, several reports (Bernard E. et al, NEJM Evid 2022) have highlighted the importance of the mutational profile to predict prognosis in MDS. However, its accepted that a fraction of patients with MDS do not have detectable mutations at presentation. The biology and clinical behavior of this subset of patients remains unclear. We consequently investigated the characteristics and clinical outcome of patients with untreated MDS without detectable mutations referred to a single institution. Methods: We retrospectively evaluated patients with untreated MDS diagnosed between 2017-2022. Patient characteristics and bone marrow data, including cytogenetic and NGS information, were assessed. Genomic DNA was extracted from whole bone marrow aspirate samples and subject to 81-gene target PCR-based sequencing using a next generation sequencing (NGS) platform. Follow-up and dynamic variables such as type of treatment, response, acute myeloid leukemia (AML) transformation and survival were also assessed. Response assessment used IWG 2006 criteria. Overall survival (OS) was calculated from diagnosis do death with the Kaplan-Meier method, using log-rank test for group comparison. Results: Of 805 patients in the database, a total of 65 patients had no mutations detected (8%). Among them, 45 (69%) patients were male. Median age at diagnosis was 65 years old (range 23-83). Main characteristics are detailed in Table 1. Of note, 23 patients (35%) had a therapy-related MDS (t-MDS). Regarding cytogenetics, a total of 31 patients (48%) had a normal karyotype, 8 patients (12%) had a complex karyotype and 10 patients (15%) had non-complex -7 or chromosome 7 abnormality. Patients with t-MDS had a higher proportion of karyotypes with either complexity or chromosome 7 abnormality (47% vs 27% for tMDS and non-tMDS, respectively, p=0.01). MDS with excess of blasts was diagnosed in 17% (26%). By R-IPSS risk score: 49% had a low or very low score, 20% had an intermediate score, and 28% had a high or very high score. By IPSS-M (with the caveat that KMT2A-PTD was not assessed): 58% had a low or very low score, 15% a moderate-low score, 8% a moderate-high score, and 15% had a high or very high score. With a median follow-up of 27 months, 45 patients (69%) required any treatment including 34 of them treated with frontline hypomethylating agent-based therapy (HMA) and two patients treated with an intensive AML-like therapy. Among these patients treated either with HMA or intensive treatment, the overall response rate (ORR) was 62% (21 patients out of 34 with evaluable response). AlloSCT was performed in 14 patients (22%), and 4 patients transformed to AML. Median overall survival (OS) was 66.7 months for all patients, with a 2 and 5-year OS of 77% and 56%, respectively. Patients with higher-risk MDS (R-IPSS >4.5) had a lower 2-year OS, compared to those with low or intermediate R-IPSS scores, although not reaching statistical significance (60% vs 87%, respectively, p=0.09). Patients with t-MDS had a worse OS, compared to those with non-tMDS (92% vs 52%, p=0.001) (Figure 1). This last finding can be explained, in part, by a higher proportion of high-risk karyotypes as well as active neoplasms besides t-MDS. Conclusions: Around 10% of patients with MDS lack NGS-detectable mutations by current methods. These patients have different risk categories according to classical classifications, and there is an significant percentage of patients with tMDS, which also present with worse prognosis. The biological pathways altered in this subset of patients needs to be understood. Other alterations such as chromosomal abnormalities, epigenetic modifications and/or mutations in infrequent genes could explain this phenomenon. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment Patterns and Characteristics Among Patients with Myelodysplastic Syndromes Initiating Oral Decitabine and Cedazuridine or Intravenous/Subcutaneous Hypomethylating Agents in a Real-World Setting

Introduction: Hypomethylating agents (HMAs) are recommended as standard of care treatment for patients with higher-risk myelodysplastic syndromes (MDS); however, intravenous (IV) and subcutaneous (SC) administration of HMA therapy has been associated with additional patient burden. In July 2020, the HMA oral decitabine and cedazuridine (DEC-C) was approved by the US Food and Drug Administration (FDA) for the treatment of MDS, as an alternative to IV or SC HMAs. This study reports initial results evaluating DEC-C and IV/SC HMA treatment patterns and population characteristics among MDS patients in a real-world setting. Methods: This retrospective observational study utilized the IQVIA PharMetrics® Plus database which comprises adjudicated claims for more than 190 million unique patients across the US. Adults with ≥1 claim for HMAs between July 1, 2020 and November 30, 2021, and continuous enrollment for 6-months prior to and ≥1-month following the index date were included. Patients newly initiating HMA therapy were identified, where index was the date of the first claim for DEC-C (DEC-C-new cohort) or IV/SC HMA therapy (IV/SC-new cohort), and patients had no claims for HMA therapy in the prior 6 months; a third cohort including all patients initiating DEC-C as either new HMA therapy or switching from IV/SC HMAs was also identified, where index was the date of first claim for DEC-C (DEC-C-all cohort). Patients in the IV/SC-new cohort also had to have ≥1 diagnosis codes for high-grade MDS lesions and/or refractory anemia with excess blasts. Patients had a variable follow-up period of up to 1-year post-index and were followed through December 31, 2021. Demographic/clinical characteristics and treatment patterns were evaluated across the 3 cohorts according to HMA therapy. Results: Of 208 patients meeting inclusion criteria, 90 initiated DEC-C (DEC-C-all) and 118 initiated IV/SC HMAs (IV/SC-new) during the study period; 59 patients newly initiated HMA therapy with DEC-C (DEC-C-new). Demographic and clinical characteristics were similar across the 3 cohorts (Table), with no statistically significant differences observed between the DEC-C and IV/SC cohorts newly initiating HMA therapy. Overall, the proportion of males was higher (vs females) across the DEC-C-all, DEC-C-new, and IV/SC-new cohorts (61.1%, 62.7%, and 53.4%, respectively), and most patients were aged ≥55 years (93.4%, 91.5%, and 80.4%; median age 65, 67, and 64 years, respectively). All 3 groups had high levels of comorbidity, with mean Charlson Comorbidity Index (CCI) scores of 3.4, 3.3, and 3.1, respectively, and 27.8%, 27.1%, and 24.6% having CCI scores ≥5. Across the DEC-C-all, DEC-C-new, and IV/SC-new groups, common comorbidities included malignancy (58.9%, 55.9%, and 46.6%, respectively), chronic pulmonary disease (25.6%, 27.1%, and 22.9%) and congestive heart failure (20.0%, 15.3%, and 17.8%). In all groups, some patients had a diagnosis of acute myeloid leukemia (AML) during the pre-index period (20.0%, 10.2%, and 21.2%, respectively), and a small proportion received hematopoietic stem cell transplantation (HSCT) pre-index (6.7%, 1.7%, and 1.7%). Red blood cell transfusions were reported in 57.8%, 54.2%, and 53.4%, and platelet transfusions in 28.9%, 25.4%, and 22.9%, for the DEC-C-all, DEC-C-new, and IV/SC-new groups, respectively. Among patients with ≥6-months continuous enrollment post-index, mean number of HMA cycles of therapy (based on number of claims) over the 6-months post-index were similar (4.1, 4.1, and 4.2 cycles in the DEC-C-all, DEC-C-new, and IV/SC-new cohorts, respectively). Conclusions: To our knowledge, this study provides the first real-world data on treatment patterns and characteristics among MDS patients initiating oral DEC-C. Characteristics were similar among patients initiating DEC-C and IV/SC HMAs; data also suggest ongoing off-label use of HMAs post-HSCT transplant and in AML. The similar number of HMA claims between groups suggests comparable compliance with oral therapy at home vs IV/SC treatment in the clinical setting, with a possible advantage of DEC-C in reducing the treatment burden associated with existing IV/SC HMA therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Primary Results of Stimulus-MDS1: A Randomized, Double-Blind, Placebo-Controlled Phase II Study of TIM-3 Inhibition with Sabatolimab Added to Hypomethylating Agents (HMAs) in Adult Patients with Higher-Risk Myelodysplastic Syndromes (MDS)

Primary Results of Stimulus-MDS1: A Randomized, Double-Blind, Placebo-Controlled Phase II Study of TIM-3 Inhibition with Sabatolimab Added to Hypomethylating Agents (HMAs) in Adult Patients with Higher-Risk Myelodysplastic Syndromes (MDS)

Fried's Frailty Phenotype Predicts Mortality and Survival for Newly Diagnosed Older Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Fried's Frailty Phenotype Predicts Mortality and Survival for Newly Diagnosed Older Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

AZURE: A Phase 1/2 Study of Blu-263 As Monotherapy and in Combination with Azacitidine in Patients with Advanced Systemic Mastocytosis

Background: Systemic mastocytosis (SM) is a clonal hematologic neoplasm, which leads to proliferation and accumulation of mast cells (MCs) in multiple body organs (the skin, bone marrow [BM], spleen, liver, and gastrointestinal tract) causing end organ damage. The KIT D816V mutation is identified in up to 95% of patients and is therefore a major therapeutic target in advanced SM (AdvSM) which consists of aggressive SM, mast cell leukemia, and SM with an associated hematologic neoplasm (SM-AHN). SM-AHN is associated with a high degree of genetic heterogeneity and some patients with high risk AHNs require the use of AHN-directed therapy, such as hypomethylating agents (HMAs). The combination of a highly selective KIT D816V inhibitor with an HMA represents an opportunity to improve response by inhibiting both MC and AHN clones in high-risk patients. AZURE, an international phase 1/2, open-label, 2-arm study, will evaluate the safety and efficacy of BLU-263, an orally administered and selective inhibitor of KIT D816V in patients with AdvSM, both as monotherapy as well as in combination with azacitidine. Study design and methods: Approximately 18 patients will initially be treated with escalating BLU-263 monotherapy doses to determine the recommended dose (RD) of BLU-263 (RDmono). This will be followed by dose expansion with an additional 13 patients to further characterize the safety and preliminary efficacy of BLU-263 in AdvSM. Once an initial BLU-263 monotherapy dose has been demonstrated to be safe, patients may begin enrollment in the combination arm, where approximately 18 patients will receive standard azacitidine at doses of 75 mg/m2/day on days 1-7 of each 28-day cycle, and BLU-263 starting at 50% of the monotherapy dose to determine the RDcombo. After RDcombo determination, approximately 10 additional patients will be enrolled into a safety expansion cohort. Dose escalation of monotherapy and combination therapy will follow the rules of Bayesian optimal interval design. Key eligibility criteria include age ≥18 years and Eastern Cooperative Oncology Group performance status 0-3. Eligible patients must have a centrally confirmed pathologic diagnosis of AdvSM per World Health Organization criteria. Patients eligible for the combination therapy include those with chronic myelomonocytic leukemia-2; high- or very high-risk myelodysplastic syndrome (MDS) per International Prognostic Scoring System for Myelodysplastic Syndromes-Revised (IPSS-R); accelerated phase myeloproliferative neoplasm; MDS with excessive blasts-2; complex karyotype/mutational profile; or patients with a hematologic neoplasm and strong rationale for combination treatment following consultation with the sponsor and response assessment committee where needed. Primary endpoints include determination of the RD and safety profile of BLU-263 monotherapy and BLU-263 + azacitidine combination therapy, as well as efficacy according to established response criteria in AdvSM. Secondary endpoints include pharmacokinetic parameters of BLU-263 and BLU-263 + azacitidine, overall response rate, time to response, duration of response, progression-free survival, and the proportion of patients pursuing allogeneic hematopoietic stem cell transplantation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal