Myelodysplastic Syndromes Pts Research Articles

A Phase II Study of Vibecotamab, a CD3-CD123 Bispecific T-Cell Engaging Antibody, for MDS or CMML after Hypomethylating Failure and in MRD-Positive AML

Background Leukemic stem cells have high expression of CD123 compared to normal hematopoietic stem cells and is therefore a therapeutic target in multiple leukemias including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML). Vibecotamab (formally XmAb14045) is a CD3-CD123 bispecific engaging antibody that has shown clinical activity in relapsed/refractory AML, particularly in low-blast disease. We therefore sought to evaluate vibecotamab in other low-blast states, including MDS or CMML after hypomethylating agent failure and MRD-positive AML. Methods In this two-arm, open-label, phase II study, adults with either MDS (IPSS-R intermediate or higher risk) or CMML (CMML-1 or CMML-2) after failure of hypomethylating agents or AML in first or second morphologic remission with detectable MRD at a level of ≥0.1% by flow cytometry were eligible. CD123 expression ≥20% on aberrant myeloid blasts was required for enrollment. Vibecotamab was given IV in a ramp-up dose schedule on days 1 (0.43µg/kg), 3 (0.75µg/kg), 5 (1.1µg/kg), and 8 (1.7µg/kg) in cycle 1, followed by weekly doses of vibecotamab at a dose of 1.7µg/kg. Patients (pts) received up to 4 cycles of vibecotamab in 28-day cycles. The primary endpoint of the MDS/CMML cohort was response rate (CR + mCR + PR + HI + clinical benefit) within 4 cycles. The primary endpoint of the AML MRD cohort was the MRD negativity rate within 4 cycles. Results Between May 2022 and July 2023, 23 pts were treated (11 MDS/CMML, 12 AML MRD). Baseline characteristics are shown in Table 1. In the MDS/CMML cohort, 7 pts (63%) had received two or more prior lines of therapy, 8 pts (73%) had prior venetoclax exposure, and 2 pts (18%) had prior hematopoietic stem cell transplant (HSCT). Six MDS pts (66%) were IPSS-R high or very high risk. In the AML cohort, 6 pts (50%) had received two or more lines of prior therapy, 11 pts (92%) had prior venetoclax exposure, and 5 pts (42%) had prior HSCT. Ten pts (83%) were ELN 2022 adverse risk. The baseline CD123 expression was 72% (range, 43%-99%) in the MDS/CMML cohort and 89% (range, 55%-99%) in the AML MRD cohort. The baseline MRD by flow cytometry in the AML MRD cohort was 1.1% (range, 0.1%-3.9%). Responses are shown in Table 2. In the MDS/CMML cohort, 7 pts responded (64%), with 6 pts (56%) achieving marrow complete remission (mCR) and 1 pt (9%) achieving hematologic improvement (HI) per International Working Group (IWG) 2006 criteria. Among the 9 MDS pts, 4 (44%) achieved mCR + HI (2 HI-N, 1 HI-P, and 1 HI-P + HI-N), and 1 (11%) achieved HI (HI-N + HI-P). Per revised IWG 2023 MDS response criteria, 5 of the 9 MDS pts (56%) achieved complete remission with limited count recovery (CR L). Two of 4 MDS pts (50%) with TP53 mutations achieved CR L. Both CMML pts achieved mCR, with one pt also achieving HI-N. Among 9 pts with baseline bone marrow blasts =>5% at trial enrollment, 6 (67%) achieved a mCR, with or without HI. Best response occurred after the first cycle in all pts. CD123 expression was not associated with likelihood of response. Of the 7 responders, 5 are in ongoing response (range 0.3-6.9 months), one died in CR L from non-hematologic complications (heart failure), and one relapsed 5 months after achieving CR L. Of the 12 pts in the AML MRD cohort, 3 (25%) achieved MRD negativity, all of which occurred after 1 cycle of vibecotamab. Among the 3 responders, all were ELN adverse risk and had prior venetoclax exposure, 2 had prior HSCT, and 1 had inv(3). The median MRD and CD123 expression in responders was 0.2% (range 0.1%-0.2%) and 98% (range 95%-99%) vs 1.8% (range 0.5%-3.9%) and 87% (range 66%-96%) in non-responders, respectively. At last follow-up, all 3 responders are still in MRD-negative remission (range 3.2-12.8 months). Vibecotamab was well-tolerated with no pts requiring dose reductions or being taken off study due to adverse events. Ten pts (44%) experienced grade 2 infusion reactions and 1 pt (4%) experienced a grade 3 infusion reaction. Myelosuppression was minimal, consistent with previous studies of vibecotamab. Conclusion Vibecotamab was safe and active in low-blast, high-risk myeloid diseases, with a response rate of 64% in MDS/CMML after HMA failure and 25% in MRD-positive AML. The clinical activity of vibecotamab, including in pts with prior venetoclax exposure and/or HSCT, and its lack of clinically significant myelosuppression provide rationale to combine it with other agents in AML, MDS, and CMML.

Impact of Pre-Transplant Molecular and Cytogenetic Remission on Outcomes of Allogeneic Stem Cell Transplant in Patients with Myelodysplastic Syndrome

Background: Allogeneic stem cell transplant (allo-SCT) carries a high relapse rate (~35% within 2 years) in patients (pts) with myelodysplastic syndrome (MDS). Pre-transplant measurable residual disease (MRD) increases the risk of relapse and death in acute myeloid leukemia (Thol et al, Blood 2018). However, the impact of pre-transplant MRD on post-transplant outcomes is less clear in MDS. Prior studies have compared outcomes between myeloablative (MAC) and reduced intensity conditioning (RIC) in pts with pre-transplant MRD persistence based on either cytogenetic remission alone or ultra-deep genomic sequencing with a limited 10-gene panel, suggesting reduced risk of relapse in pts receiving MAC (Festuccia et al, Biol Blood Marrow Transplant 2016; Dillon et al, JCO PO 2021). However, pre-transplant MRD assessment using a commercial next-generation sequencing (NGS) panel in addition to cytogenetic testing to assess post-transplant outcomes has not been evaluated in MDS. Methods: We conducted a multicenter retrospective review of MDS pts who underwent allo-SCT from 2015-2022. Pts with FISH/cytogenetic (FC) and/or molecular abnormalities at diagnosis and MRD assessment by commercial myeloid-panel NGS (with a variant-allele frequency detection limit up to 5%) and FC performed on peripheral blood (PB) or bone marrow (BM) aspirate within 3 months prior to transplant were included for analysis. The Kaplan-Meier method and log-rank tests were used to estimate overall survival (OS). Gray's test/cumulative incidence functions were used to estimate relapse-free survival (RFS) with non-relapse mortality (NRM) as competing risk. Results: Table 1 includes baseline pt characteristics. Of 81 pts, 69 pts (85.2%) had residual FC and/or molecular abnormalities (MRD+) at pre-transplant PB/BM assessment. Twelve (14.8%) pts were in both FC and molecular remission (MRD-) prior to transplant. With a median follow-up of 13.9 months [IQR 6.8 - 38.9], 43 (53%) died and 24 (30%) pts experienced a relapse. Twenty-three of 69 (33%) MRD+ pts had relapsed disease with a 38% cumulative incidence of relapse (CIR) at 2 years. In contrast, only 1/12 (8.3%) MRD- pts experienced a relapse after 7 years, with chromosomal loss of TP53 not present at initial diagnosis. CIR at 2 years was 33% and 41% (p=0.207) for MRD+ pts who received MAC vs RIC, respectively with NRM of 34.5% associated with MAC vs 28.2% for RIC (p=0.61). TP53 mutations were most frequently associated with relapse in 8/24 (33%) pts with a median OS of 9.8 months [8.2 - NR]. Besides the previously defined 10-gene panel (Dillon et al, JCO PO 2021), relapses were also driven by SRSF2, U2AF1, KRAS, SETBP1 and NF1 mutations present in the original clone. Six pts had DNMT3A, TET2 and/or ASXL1 (DTA) mutations only on pre-transplant NGS, with 2/6 pts relapsing without the re-emergence of DTA mutations. Median OS was not reached for MRD- pts and was 14.1 months [11.35-NR] for MRD+ pts, p = 0.061 [Fig.1]. OS probability at 2 years was 35% for MRD+ pts vs 75% for MRD- pts. Type of conditioning regimen, RIC vs MAC, did not impact OS (p= 0.6). An equal number of deaths, 35% each, were attributable to GvHD and relapse, respectively. Thirteen (30%) pts died from other causes, primarily infections and bleeding complications. NRM was 25% and 36% for MRD- and MRD+ cohorts, respectively. Pts received a median of 6 cycles [range, 2-36] of hypomethylating agent (HMA) +/- venetoclax prior to transplant with no association between the number of cycles and MRD status (p=0.80). The incidence of grade 3-4 acute GvHD and chronic GvHD requiring systemic therapy did not significantly differ, at 25% and 18.8% (p= 0.696) and 33.3% and 31.8% (p= 1.00) in MRD+ and MRD- pts, respectively. Conclusions: MRD assessment using commercially available NGS panels and cytogenetic testing that are routinely performed in MDS pts in real-world practice can predict risk of relapse. Pre-transplant MRD is associated with worse OS irrespective of the intensity of conditioning regimen. Although limited in statistical power due to a small sample size of MRD- pts in our cohort, further studies with a larger cohort are underway to better clarify the role of MRD on transplant outcomes in MDS. Our data also highlights that only a small minority of MDS pts (<15%) achieve complete molecular and cytogenetic remission at the time of transplant; strategies to eliminate the pre-transplant MDS clone are urgently needed.

Clinical, Cytogenetic and Immunophenotypic Spectra of Post-Transplant Relapse Following Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome

Introduction Allogeneic hematopoietic stem cell transplantation (HCT) is a curative therapy used to treat myelodysplastic syndrome (MDS). Relapse post-HCT confers poor outcomes and subsequent therapy is not standardized. Like acute myeloid leukemia (AML), several mechanisms are known to be involved in post-HCT relapse including clonal evolution in favor of chemotherapy-resistant clones and tumor immune escape. Systemic reviews are scarce in the MDS post-HCT relapse population. Accordingly, the present study aimed to investigate clinical, cytogenetic, and immunophenotypic (IP) spectra for MDS post-HCT relapse patients (pts), along with subsequent therapies, and clinical outcomes following post-HCT relapse. Patients and methods A retrospective study was conducted and found that 231 MDS pts received HCT between April 2010 and September 2022 at the Princess Margaret Cancer Centre (PMCC). The primary endpoint was overall survival (OS) following post-HCT relapse. Secondary endpoints explored time to relapse (TTR), relapse presentation (i.e., MDS or AML), clonal evolution (i.e., changes in cytogenetics or IP profiles), and therapeutic strategies delivered after relapse. Results Of the 231 MDS pts treated with HCT, 52 (23%) relapsed in a median of 4.5 months (range 0.9-59.8 months). Twenty-five (48%) pts relapsed with MDS (i.e., blast <20%), while 27 (52%) relapsed with AML (i.e., blast ≥20%) in the marrow. Fifteen (65%) pts showed cytogenetic changes at the time of post-HCT relapse. Eleven (48%) of which presented with more aggressive findings (i.e., additional structural abnormalities and monosomal karyotype). Ten of 17 (59%) pts presented with changes in their IP profile at post-HCT relapse, 7 (70%) of which relapsed with AML. Combined these findings give evidence of clonal evolution in favor of more aggressive malignant clones that are often responsible for post-HCT relapse. Treatment with hypomethylating agents (HMA) alone or in combination after post-HCT relapse increased OS to 5.6 months in comparison to those not receiving HMA of whom OS was 1.4 months (p=0.0003). Stratified by disease presentation cytogenetic clonal evolution was seen in 6/12 (50%) of the post-HCT MDS relapses, and 9/11 (82%) of the post-HCT AML relapses. Cytogenetic abnormalities at diagnosis and post-HCT relapse, respectively included in descending order: structural abnormalities (n=14/23, 61%; n=20/23, 87%), complex karyotype (n=12/23, 52%; 17/23, 74%), -5/del(5q) (n=11/23, 48%; n=10/23, 43%), -7/del(7q) (n=8/23, 35%; n=11/23, 48%), monosomy karyotype (n=8/23, 35%; n=11/23, 48%), -17 (n=3/23, 13%; n=5/23, 22%), der(5)/t(5;17) (n=2/23, 9%; n=5/23, 22%), -20 (n=2/23, 9%; n=3/23, 13%), and inv(3) (n=1/23, 4%, n=2/23, 9%). Seventeen pts had paired IP profiles available both prior to HCT and at post-HCT relapse, of which 10 (59%) had profile changes of at least 1 antigen. Seven of 10 (70%) pts that relapsed with AML post-HCT had IP expression changes, compared to 3/7 (42.9%) pts that relapsed with MDS post-HCT. Summarized IP findings include reduced expression of CD7 (n=2/6, 33%), altered expression of CD34 (n=3/15, 20%), altered expression of CD117 (n=3/14, 21%), and reduced expression of HLA DR (n=4/15, 27%). The presence of IP expression changes at post-HCT relapse suggests evidence of clonal evolution or immune escape as the mechanism behind the relapsed disease. Overall survival duration was 3.97 months; the 12-month OS rate was 20.0% (10.0-32.5%). Post-HCT relapse treatments included hypomethylating agents (HMA; n=13/46, 28%), HMA with donor lymphocyte infusion (DLI; n= 7/46, 15%), HMA with Venetoclax (VEN; n=7/46, 15%), chemotherapy (n=9/46, 19%), best supportive care (8/46, 17%) and second HCT (n=2/46, 4%). Patients that received HMA with or without DLI or VEN had a longer survival duration of 5.6 months (95% CI [3.4-13.2 months]) compared to those not receiving HMA 1.4 months (95% CI [0.6-0.39 months, p=0.0003]). The 12-month survival rate was also significantly in favor of pts that received HMA following post-HCT relapse (35.3% [95% CI 17.2-54.0%] vs 4.3% [95% CI 0.3-18.0%]). Conclusion Patients with MDS undergoing HCT may relapse with either MDS or AML. The relapsed disease often shows evidence of clonal evolution in its immunophenotype and/or cytogenetic profile toward a more aggressive disease. Approaches to post-HCT relapse remain heterogenous but HMA is beneficial.

Association of weight loss with risk of myelodysplastic syndromes (MDS) in adults with obesity: Insights from the SPLENDID cohort.

e18865 Background: MDS arises from pre-existing somatic mutations or clonal hematopoiesis (CH). A normal body mass index (BMI) is strongly associated with a lower prevalence of CH. We hypothesized that intentional weight loss (IWL) might be associated with lower incidence of MDS and studied this in the context of bariatric surgery (BSx) among adults with obesity. Methods: In the SPLENDID (Surgical Procedures and Long-term Effectiveness in Neoplastic Disease Incidence and Death) matched cohort study, adults with BMI ≥35Kg/m2 who had BSx (ages 18-80) during 2004-2017 were included. Each patient (pt) who underwent BSx was matched with propensity score by the nearest-neighbor method to five pts who did not undergo BSx for their obesity, resulting in a total of 30318 pts. MDS diagnosis was made using contemporary WHO criteria and myeloid sequencing mutation data were analyzed. Multivariable cox regression analysis estimated time to MDS as the primary endpoint. Results: 5053 adults with obesity had BSx while 25265 adults underwent nonsurgical (NS) care. Median age and BMI were 46 years (y) and 45kg/m2. The majority were females (77%); and had white (73%) race. Follow-up was over 17y period with median (IQR) of 6.1 (3.8-8.9)y for the entire cohort. BSx-group had 19.2% greater WL at 10-y [mean between-group difference: 24.8 (95% CI, 24.6-25.1) kg]. One patient (male) in the BSx-group vs twenty-four patients (twelve females) in the NS-group developed MDS (incidence rate: 0.03 vs 0.14, per 1000 person-years). A fully adjusted hazard ratio was 0.14 (95%CI 0.02-1.14), which did not reach conventional level of statistical significance (p = 0.066) due to small number of events. A third of MDS pts had high-risk disease per IPSS-R prognostic score (7/20 evaluable pts). 10 (of 11 NS MDS pts with available NGS data) pts had ≥1 nonsynonymous mutations and most pts (6/11) harbored multiple [Median (IQR): 2 (1-3)] high-risk mutations despite a younger median age of the cohort. Conclusions: In this large cohort of adults with obesity, we observed a lower incidence of MDS after IWL achieved with BSx. Higher prevalence of high-risk-MDS mutations in a relatively young NS-cohort with obesity warrants further investigation of effects of IWL on clonal evolution, its clinical relevance, and role of screening in halting progression of CH to MDS via early detection and targeted intervention. [Table: see text]

Abstract A062: Age-, sex-, and race-related disparities in receipt of HypomethyLating Agents (HMA) for the treatment of myelodysplastic syndrome (MDS)

Abstract Objective: Recent data suggest low use of HMAs in patients with MDS in real world. We sought to identify factors associated with HMA use. Methods: Using 2011-2014 Medicare data, we identified individuals ³65 years of age diagnosed with incident MDS during the years 2012-2013 and receiving their care exclusively through the Medicare fee-for-service system. Collected data included age, race, sex, morbidity burden based on their frailty status (robust, pre-frail, mildly frail, moderately, or severely frail), nursing home residence, presence of MDS-related clinical characteristics [cytopenia (0-1 or ³2) and transfusion dependence (independent, low, or medium/high)], area-level socioeconomic measures [percent of individuals with income 100% below the federal poverty level; percent of adults (age > 25 years) without high school diploma; rurality, based on the rural-urban continuum code; and availability of general internal medicine subspecialists per 100,000 population], and receipt of bone marrow biopsy. Among those who received HMA, we grouped patients by the number of complete cycles (1-2, 3-5, or ³6). We used multivariable logistic regression analysis to evaluate the association between demographic characteristics and receipt of HMA, adjusting for MDS-related clinical characteristics, frailty, and socioeconomic measures. Results: Of 49,154 MDS pts, only 16.1% (7,935) received HMA. This percentage ranged from a low of 7.4% among individuals ³85 years of age to a high of 23.2% among those in the 65-74 age group. Receipt of HMA was significantly higher in men than in women (19.0% vs. 12.8%), in Whites than in minoritized patients (16.7% vs. 11.6% in Blacks, and 12.7% in those of Other race), higher among those with 2-3 cytopenias vs. 0-1 cytopenia and highest among those with medium/high transfusion dependence (44.7%). Among those who underwent biopsy, receipt of HMA was at 22.9%. Patients with moderate or severe frailty, and those in a nursing home had significantly lower rates of receipt of HMA. After adjusting for MDS-related clinical variables, frailty and socioeconomic measures, older patients had significantly lower odds than their younger counterparts to receive HMA [adjusted odds ratio (aOR): 0.84, (95% confidence interval: 0.79-0.89), and aOR: 0.43 (0.40-0.47) for those in the 75-84 and ³85 age groups, respectively). Females and minoritized patients had significantly lower odds than men and White patients to receive HMA [(aOR: 0.83 (0.79-0.88) for females; aOR: 0.71 (0.63-0.81) for Blacks, and aOR: 0.78 (0.68-0.89) for patients of Other race). Among those receiving HMA, we did not observe differences in the number of completed cycles by age, race, or sex. Conclusions: In Medicare beneficiaries with MDS, older patients, women, and minoritized patients have significantly lower odds to be treated with HMAs, even after adjusting for MDS-related clinical variables, morbidity burden, and socioeconomic measures. In addition to barriers to access adequate care, these results clearly reflect biases in MDS treatment, favoring younger, White men. Citation Format: Sudipto Mukherjee, Weichuan Dong, Aaron T. Gerds, Hetty E. Carraway, Abhay Singh, Anjali S. Advani, Siran M. Koroukian. Age-, sex-, and race-related disparities in receipt of HypomethyLating Agents (HMA) for the treatment of myelodysplastic syndrome (MDS) [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A062.

International Working Group (IWG) Response Criteria and Association with Overall Survival in Patients with Myelodysplastic Syndromes Treated with Hypomethylating Agents - a Systematic Review and Meta-Analysis

* A.M.Z. and M.S. contributed equally Introduction: Response assessments in clinical trials and routine practice for patients (pts) with myelodysplastic syndromes (MDS) treated with hypomethylating agents (HMA) are based on the International Working Group (IWG) criteria proposed in 2000 and revised in 2006. However, it is not clear whether response criteria correlate with overall survival (OS). Methods: We conducted a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines with a systematic search using controlled vocabulary and free text terms for MDS and survival of Cochrane Library, Google Scholar, Ovid Embase, Ovid Medline, Pubmed, Scopus, and Web of Science Core Collection databases to find relevant articles published from inception to January 2022. The search was peer-reviewed by a second medical librarian. A targeted search of recent conference proceedings was also performed. Titles, abstracts, and full texts were reviewed for inclusion in the meta-analysis by two reviewers independently and conflicts were resolved by consensus discussion. Clinical trials and cohort studies with >100 pts reporting on the association of IWG 2000 or 2006 response criteria with OS among pts treated with HMA monotherapy or combinations were eligible for inclusion. Studies were excluded if they were (i) review or basic research articles, (ii) studies with <50% higher-risk MDS pts (inclusion of a minority of pts with MDS/MPN, oligoblastic AML, and lower-risk MDS was permitted), (iii) not published in English, and (iv) had insufficient reporting of the primary endpoint. The primary endpoint was the hazard ratio (HR) for OS for patients achieving an IWG-defined response (complete remission [CR], marrow CR, partial remission, hematologic improvement [HI]) compared to patients not achieving a response. Random-effects models were used to pool the HRs for death. Cochran Q and I2 indices were used to assess heterogeneity across included studies. Study heterogeneity was graded based on I2 indices as low (I2 <30%), moderate (I2 =30-60%), or high (I2 >60%). Comprehensive Meta-Analysis (CMA version 2.2, Biostat) was used for all analyses. Results: Our search strategy identified 7023 studies after duplicate removal. Following abstract and title review to identify clinical trials and large cohort studies reporting IWG response and OS among MDS pts treated with HMA, 195 studies were assessed for eligibility as full texts. Among these 185 studies were excluded for the following reasons: insufficient reporting of the primary outcome of OS and IWG response (n=114), duplicate publications from the same pt cohort (n=42), <50% higher-risk MDS pts (n=13), cohort studies with <100 pts (n=6), not on HMA therapy (n=4), ongoing clinical trials without published results (n=3), transplant (n=2), and review article (n=1). The final set of studies included 3896 MDS pts treated with azacitidine, decitabine, guadecitabine, or HMA-combination in 9, 4, 1, and 2 studies, respectively. Among the 5 available studies with data on the impact of CR on OS, the HR for death was 0.365 (95% CI: 0.311-0.430) for pts who achieved a CR compared to pts without a CR. Study heterogeneity was low (Cochran's Q=0.5; I2=0%; Figure A). Six studies reported the impact of HI on OS. Pts who achieved HI had favorable outcomes compared to pts without HI (HR: 0.419; 95% CI: 0.299-0.585) but with high heterogeneity across studies (Cochran's Q=14.34; I2=65.13%; Figure B). The prognostic impact of other response categories (e.g., marrow CR, partial remission) was only reported by 1 study each, precluding a meta-analysis. Conclusion: Achieving CR as defined by the IWG MDS response criteria is associated with improved OS among higher-risk MDS pts treated with HMA-based regimens. HI was also associated with OS, but with high study heterogeneity. The strong and consistent association of CR with OS supports its use as an outcome in clinical trials in MDS. The prognostic implications of other response categories as such CR with partial hematologic recovery (CRh) especially with novel combination therapies require additional studies. 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

Validation of the Molecular International Prognostic Scoring System (IPSS-M) Risk Stratification Model for Myelodysplastic Syndromes

Background The Molecular International Prognostic Scoring System (IPSS-M) is a newly developed risk stratification model for myelodysplastic syndromes (MDS) that expands on the original IPSS-R by including data on somatic oncogenic mutations across 31 gene families and weighing their impact on prognosis and outcomes. The discovery model demonstrated improved prognostic discrimination relative to the IPSS-R in regard to overall survival (OS), leukemia-free survival (LFS) and leukemic transformation, by substratifying pts into six risk categories, and led to restratification of 46% of cases. Adequate risk stratification in MDS is critical for therapeutic decision-making. Here we aimed to externally validate the findings of the original study using a large cohort of pts treated at a tertiary referral center. Methods A total of 2355 MDS pts treated at Moffitt Cancer Center with available clinical and molecular data were analyzed. For estimation of the IPSS-M score, R version 4.2.1 was used to run batch-calculation using syntax code provided by the Papaemmanuil lab at MSKCC. The mean IPSS-M score was used as reference. Correlative analysis between IPSS-R and mean IPSS-M scores and outcome predictions was performed on LFS, OS and leukemic transformation. Time-to-event analyses were estimated using the Kaplan-Meier method and groups were compared by the log-rank test. We used Cox proportional hazards models for survival endpoints. For model discrimination we used Harrell's C concordance index. Results We identified at least 4,327 driver point mutations involving up to 170 genes across 2355 pts. We identified at least one gene mutation in 83% of pts (1948). Median follow-up was 4.6 yrs (4.4-4.9). 2333 pts (99%) were classified. Table 1 shows baseline clinical and molecular characteristics between validation and discovery cohorts. Using the IPSS-M risk stratification schema, pts in the validation cohort were classified as Very Low (96, 4% vs 14% in the discovery cohort), Low (560, 24% vs 32%), Moderate Low (327, 14% vs 11%), Moderate High (258, 11% vs 11%), High (454, 19% vs 14%) and Very High (660, 28% vs 18%) (Fig. 1A). The validation cohort was comprised of sicker pts with higher risk disease per IPSS-M relative to the discovery cohort (47% vs 31%). The IPSS-M score resulted in improved discrimination relative to the IPSS-R regarding LFS, OS and leukemic transformation as evidenced by a 2.3-, 2.0- and 1.5-point increase in C-index. The IPSS-M categories showed significant separation across all examined endpoints. Median LFS and OS estimates were equivalent between validation and discovery cohorts. Median LFS was 12.3 (vs 9.7), 6.9 (6.0), 3.6 (4.1), 2.2 (2.3), 1.4 (1.7) and 0.5 (0.7) yrs from Very Low to Very High-risk categories (Fig. 1B-1C). Conversely, median OS was 11.7 (vs. 10.6), 7.1 (6.0), 4.4 (4.6), 3.1 (2.8), 2.3 (1.7) and 1.3 (1.0) yrs from VL to VH subgroups (Fig.1). A five-to-five mapping between the IPSS-R and IPSS-M risk subgroups (from combining moderate-low (ML) and moderate-high (MH) into moderate), resulted in the restratification of 45% of pts (1056), equivalent to the discovery cohort (46%). Almost 3/4 of pts classified as IPSS-R very-low (VL) were upstaged (majority to IPSS-M low and ML/MH). Almost half of pts classified as IPSS-R intermediate shifted: 39% (174) were reclassified as IPSS-M high/very high (H/VH). Similarly, about 42% of pts classified as IPSS-R high were upstaged to IPSS-M VH. Almost 20% of VH risk pts were downstaged (majority to high risk). Most significant was the reclassification of 10.5% (244) of the validation cohort from IPSS-R lower and intermediate risk categories into IPSS-M higher risk strata. Contextually, the restratification of pts from IPSS-R intermediate to higher risk strata in IPSS-M was associated with notable differences in survival outcomes which were as poor as 0.5 yrs and as high as 6.9 yrs for those reclassified as LR (relative to 1.9 yrs). Conclusion To our knowledge this is the first external validation of IPSS-M in a large cohort. Use of the IPSS-M model for the risk stratification of pts with MDS resulted in improved discrimination of LFS, OS and risk of leukemic transformation over the IPSS-R. Furthermore, it led to restratification of almost half of MDS pts and exposed important differences in survival outcomes. Generalized use of this tool will likely result in more accurate prognostic assessment and optimize therapeutic decision-making among MDS pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prevalence of Osteoporosis in Myelodysplastic Syndrome Patients and Association with Cytopenias

Background :Perturbations of the osteo-hematopoietic niche architecture disrupt tissue homeostasis and can promote malignant diseases such as myelodysplastic syndromes (MDS). Recently an increased risk of osteoporosis in patients with CHIP has been observed after adjusting on usual risk factors for osteoporosis and in mouse models DnmT3a mutation cause a reduction in bone mass. However, little is known on the clinical presentation of osteoporosis in MDS patients. Here we report the results of a prospective cohort study of bone mass evaluation in newly diagnosed MDS patients. Methods : All patients with newly-diagnosed MDS or CMML (proved by bone marrow aspirate) were prospectively enrolled since January 2020 after informed consent. Bone mass evaluation was performed by conventional radiography of dorsal and lumbar rachis and bone mineral density was measured by a HOLOGIC® device at the upper extremity of the femur and the rachis. Osteoporosis risk factor were collected by a rheumatologist. After analysis of osteoporosis biomarker and biological MDS evaluation, if the diagnosis of osteoporosis was established, specific treatment were proposed. Avaible bone marrow biopsies were analysed by RAMAN microspectrosopy and compared to healthy bone marrow analysis specimens. Results : At data cut off (06/06/2022)108 pts were enrolled and evaluable for bone mineral density. Median age was 77 years [55-99] and 45.4% were female. WHO classification included MDS-MLD, MDS-MLD, MDS-RS-SLD, MDS-RS-MLD, 5Q-, MDS-EB1, MDS-EB2, CMML and AML (with 20-30% blast) in 10.2%,16.7%, 10.7%, 5.6%, 10.2%, 14.8%, 5.6%, 23.2% and 2.6% respectively. IPSS-R was very low, low, intermediate, high and very high in 20.4%, 51%, 19.4%, 8.3%, 1% respectively. Prior to the bone assessment, 15 pts had already a diagnosis of osteoporosis and among them 10 had previously received bisphosphonates. At the time of the bone assessment, 57 additional pts (52.8%) were diagnosed with osteoporosis including 22 males et 35 females and 30 pts (27.8%) had a prevalent osteoporotic vertebral fracture. In our cohort, prevalence of osteoporosis seem to increase with R-IPSS score with 49.4 %, 57.1% and 70% in low, intermediate, and high-risk, pts respectively, near significativity (p=0.052). After univariate analysis neither age (p=0.46) , 25 OH -vitamine D (p=0.07), ferritine (p=0.53), EPO (p=0.45), nor R-IPSS score (p=0.2) were associated with osteoporosis. However osteoporotic pts had significantly lower hemoglobin levels (9.7 vs 10.3 g/dL, p=0.04) and platelet counts (215 vs 170 G/L, p=0.05). After multivariate analysis, only female gender remained statistically associated with osteoporosis (p=0.01). After initial evaluation among the 57 pts with ostoporosis, 53 pts (49% of the cohort) were treated with intravenous bisphosphonates (2 pts refused and 2 had a contraindication). Analysis of avaible bone marrow biopsies (n=8) by Raman microspectoscopy at the center of trabecula showed defects in the bone marrow matrix in MDS pts in comparison to healthy specimens (n=18) with an increase in the hydoxylation of proline suggesting degradation of collagen type I in MDS bone. (figure 1) Conclusion :We found a high prevalence of osteoporosis in 52.3% of prospective, newly diagnosed MDS pts with 27.8% of pts with osteoporotic vertebral fracture. More profound cytopenias seem to be associated with an increased risk of osteoporosis prevalence underlying the impact of the osteo-hematopoietic niche in the physiopathology of MDS. An update of this study will be presented Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effects of Autoimmune Disease on Non-High Risk MDS Outcomes: A Population Analysis

Introduction: Myelodysplastic syndromes (MDS) frequently occur in patients (pts) with autoimmune diseases (AD). Concomitant inflammatory or AD are found in 10-30% of MDS cases. Studies exploring the impact of AD on MDS outcomes show discordant results and small samples in these studies hinder definitive conclusions. We conducted a large epidemiological analysis aimed at defining the impact of concomitant AD on outcomes of non-high-risk MDS pts. Methods: Pts ≥66 years with MDS were identified from 2007 - 2017 in the Surveillance, Epidemiology, and End Results (SEER) - Medicare database. Cases were excluded if they lacked continuous Medicare A and B, were enrolled in HMOs, had MDS diagnosed solely from death certificate or autopsy, or had MDS with excess blasts. Using claims from 12 months before MDS diagnosis, pre-existing AD was identified. MDS cohorts with and without concomitant AD were compared. Covariates included age, sex, race, and MDS risk, classified into low and intermediate using the International Classification of Diseases for Oncology (ICD-O-3) codes, rurality (using Rural-Urban Continuum Codes), and Charlson Comorbidity Index (CCI). Outcomes included transformation to acute myeloid leukemia (AML) during follow-up and overall survival, calculated from MDS diagnosis to date of death or end of follow-up. Logistic regression tested the association between AD and AML transformation. Cox proportional hazards regression estimated the association of AD with survival. Risk estimates are reported as odds ratio (OR) and hazard ratios (HR), with a corresponding 95% confidence interval (CI). Results: A total of 13,344 pts diagnosed with MDS between 2007 - 2017 were analyzed, including 1,978 (14.8%) with baseline AD. Pts with concomitant AD were younger, proportion >80 years accounted for 60% vs. 65.2% in MDS cases without AD (p<0.001). They were also predominantly female (55.4% vs. 45.3%, p<0.001), non-Hispanic whites (NHW) (88.8% vs. 86.2%, p=0.045), and had a higher comorbidity burden, with CCI ≥2 accounting for 68.5% in the AD cohort compared to 51.2% (p<0.001). MDS risk distribution based on ICD-O-3 histology codes is similar between groups. In a multivariate logistic regression model adjusting for age, sex, race, MDS risk/histology, rurality, and CCI, baseline AD at MDS diagnosis was associated with 18% increased odds of AML transformation; OR = 1.18 (95% CI 1.01-1.39). Table 1 shows other covariates significantly associated with AML transformation. Increasing age, female sex, and higher CCI score were factors associated with decreased odds for AML transformation. As expected, MDS risk had the largest effect, the intermediate risk was associated with 2.3-fold increased odds of AML transformation (95% CI 1.8-2.8) compared to low risk. In a multivariate Cox-proportional hazard model adjusting for age, sex, race, MDS risk/histology, rurality, and CCI, baseline AD at MDS diagnosis was associated with a 6% decreased risk of overall death (HR 0.94, 95% CI 0.89 - 0.99). Table 2 shows other covariates significantly associated with overall survival. Non-Hispanic Black race and female sex were factors associated with decreased risk of death while rising age, rurality, and higher CCI were associated with increased hazard for death. MDS risk had the largest effect on overall survival, with the intermediate risk associated with a 52% increased risk of death (95% CI, 1.44-1.60) compared to low risk. Conclusions: In a large population-based analysis, pts with AD and non-high risk MDS were predominantly female, and Non-Hispanic Whites had a higher comorbidity burden. Concomitant AD at MDS diagnosis was associated with increased risk of AML transformation but decreased risk of mortality. These seemingly contradicting results suggest that the pathophysiologic mechanisms linking systemic inflammation with MDS and their clinical consequences remain to be fully elucidated. Inflammatory bone marrow microenvironment in AD may promote clonal evolution while neoplastic clones driven by auto-inflammation could have a less aggressive phenotype. Future studies should assess molecular mutations and clonal dynamics involved in autoimmunity and MDS to build on these epidemiologic findings. Despite the limitations of a claim-based analysis, AD prevalence among MDS pts and factors associated with MDS outcomes in our cohort were consistent with previous reports. 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

Characterization of TP53-Mutated Myelodysplastic Syndromes and Impact of Allelic Status and Concurrent Cytogenetic Abnormalities on Survival Outcomes

BackgroundTP53 mutations (TP53mt) are associated with dismal outcomes in myelodysplastic syndromes (MDS). However, clinical and biological heterogeneity among TP53mt MDS patients (pts) exists, including the prognostic relevance of mono- vs biallelic TP53mt. The newly proposed WHO 2022 and ICC 2022 classifications recognize TP53mt as a unique entity but vary in its definition. We aimed to assess the impact of TP53 allelic status and complex cytogenetics in different clinical subsets of TP53mt MDS. Methods A total of 2355 MDS pts with annotated clinical and molecular data treated at Moffitt Cancer Center were analyzed. We defined MDS with biallelic TP53 inactivation (biTP53) according to the 5th edition of the WHO classification. Biallelic status was determined by VAF ≥50%, 2 or more TP53mt and/or TP53mt with deletion 17/17p abnormalities. Pts were classified into IPSS-R lower risk (LR) and higher risk (HR) strata by merging IPSS-R VL, L and I categories, as well as H and VH groups. Results A total of 490 pts (21%) harbored a TP53mt. Of these, 78% (382) were biTP53 and 22% (108) maTP53. Median duration of follow-up was 4.7 years (4.4-4.9). Pts harboring TP53mt had significantly shorter OS relative to their TP53wt counterparts: median OS 1.2 yrs vs 4 yrs (p<.001). Median OS was worse for the biTP53 subset compared to maTP53: 1.0 yrs (0.9-1.1) vs 1.3 yrs (1.1-1.6; p<.001). Compared to those harboring TP53wt, pts with maTP53 had double the risk of death: HR 2.1 (1.8-2.5). For pts with biTP53 the risk quadrupled: HR 4.0 (3.4-4.7). Both were significant at p<.001. Patients harboring complex (CK) vs non-complex (nCK) karyotypes had inferior mOS of 1.0 yrs (0.9-1.1) vs 2.1 yrs (1.5-2.7; p<.001). Compared to TP53wt, the risk of death was higher for TP53 with CK [HR 4.7 (4.1-5.4)] than for TP53 with nCK [HR 1.5 (1.2-1.8)], both significant at p<.001. Among patients with nCK, allelic state had significant impact on outcomes: mOS for maTP53 was 2.8 yrs (2.0-3.6) vs 1.2 yrs (0.6-1.8) for biTP53 (p<.001; Figure 1). Compared to TP53wt, HR for death for maTP53 was 1.2 (0.9-1.5, p=.21) and for biTP53 was 2.7 (1.9-3.8, p<.001). There was no survival distinction between maTP53 and biTP53 among pts with CK (p=0.780; Figure 1). Both had mOS of 1 yr (0.9-1.2) and were associated with worse outcomes compared to CK TP53wt (p<0.001). Among pts with LR disease, outcomes were significantly worse for those harboring TP53mt: mOS for TP53wt was 5.2 yrs (4.7-5.7) compared to 3.3 yrs (1.6-5.0, p<.001) for maTP53 and 2.1 yrs (0-4.4, p<.001) for biTP53. There were no differences between maTP53 and biTP53 (p=.2). Allelic status remained significant in HR disease (p=.033), where mOS was worse for biTP53 compared to maTP53: 0.9 yrs (0.8-1.0) vs 1.1 yrs (1.0-1.2). Similarly, allelic state had value in pts with <5% and ≥5% blasts. Among pts with <5% blasts, TP53wt mOS was 4.8 yrs (4.3-5.4) vs 2.5 yrs (1.7-3.3) for maTP53 and 1.3 yrs (0.9-1.7) for biTP53 (p=.032). Outcomes were worse among TP53mt pts with ≥5% blasts: mOS for TP53wt was 1.7 yrs (1.6-1.9), with distinction between maTP53 and biTP53: 1.2 yrs (1.0-1.2) and 0.9 yrs (0.8-1.0) respectively (p=.005). For the <5% group, the median VAF in maTP53 was 19.5% and 40% in biTP53. For the ≥5% group, the median VAF in maTP53 was 24% (95) and 47.3% (158) in biTP53. There were no differences in outcomes using 10% blast burden as cutoff. ConclusionTP53mt MDS demarcates a heterogenous group, whose behavior is influenced by allelic status and cytogenetic architecture. TP53mt patients have poor prognosis with ≥5% blasts without distinction from a 10% cutoff. In TP53mt disease, allelic state has strong significance in pts with non-CK, and retains significance independent of IPSS-R strata and myeloblast percentage, albeit with marginal differences. Notably, CK matters independent of allelic status and is invariably associated with worse outcomes. TP53mt with CK should homogenously be considered a biallelic equivalent. This has important implications for future trial design where distinction of allelic state and CK carries relevance. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

IPSS-Molecular but Not Individual Mutations Predicts Outcomes of Patients with Myelodysplastic Syndrome (MDS) after Allogeneic Hematopoietic Cell Transplantation (Allo-HCT): A Mayo Clinic Cohort

The decision to offer Allo-HCT in MDS relies on prognostic scoring models which include clonal cytogenetic (CG) abnormalities, blood counts (cytopenias), and % of marrow blasts (i.e. revised international prognostic scoring system, IPSS-R). Recently, an updated clinical-molecular prognostic model combining genomic profiling with hematologic and CG parameters, namely IPSS-Molecular (IPSS-M), showed better prognostic discrimination across all clinical endpoints and re-stratified almost one-half of patients (pts) vs. IPSS-R. Hence, we evaluated the impact of IPSS-M, CG risk group and individual mutations on Allo-HCT outcomes. The analysis included 191 consecutive MDS pts undergoing Allo-HCT who had available next generation sequencing (NGS) analysis performed at Mayo Clinic (at diagnosis (Dx, n=164 or prior to Allo-HCT, n=162) between 11/2015 and 1/2022. Median age at Allo-HCT was 64 (18-75) yrs, and 112 (58.6%) were male. At Dx, 126 (77%) pts had at least one pathogenic genetic alteration, including (>5% incidence) ASXL1 (28.0%), TP53 (18.9%), TET2 (14.6%), SRSF2(12.2%), U2FA1 (12.2%), DNMT3A (8.5%), BCOR (7.9%), RUNX1 (6.7%), and SF3B1 5.5%; a similar mutational pattern was present at Allo-HCT: ASXL1 (28%),TET2 (15.2%) U2AF1 (13.4%), TP53 (12.2%), SRSF2 (11%), RUNX1(9.8%), DNMT3A (7.3%), SETBP1 (7.3%), SF3B1 (6.7%), BCOR (6.7%), STAG2 (5.5%), and JAK2 (5.5%). Most pts (156, 81.7%) received at least 1 line of therapy, and 45 (23.6%) had >5% marrow blasts at Allo-HCT. The majority (134, 70%) received reduced intensity conditioning. Graft versus host disease (GVHD) prophylaxis consisted of methotrexate/tacrolimus in 138 (77.5%) and post-transplant cyclophosphamide in 40 (22.5%). HCT comorbidity index was >3 in 113 (59%). IPSS-M risk group was calculated and reclassified from IPSS-R into very low (1, 0.6%), low (24, 14.7%), moderate low (34, 20.9%), moderate high (41, 25.2%), high (29, 17.8%), very high (34, 20.9%), mainly for IPSS-R intermediate and high-risk groups (Fig. 1). Median F/U after Allo-HCT was 18.8 (0.4-76.8) months. The 100-day and 1-year non-relapse mortality (NRM) were 7.9% and 18.1%, respectively. The 2-year incidence of death and relapse were 40.1% (95% confidence intervals (CI) 33.5-48%) and 21.6% (95%CI 16.4-28.4%), respectively. Cumulative incidences of grade III-IV acute GVHD was 10% and 1-year cumulative incidence of extensive chronic GVHD was 12%. In multivariable analysis, IPSS-M predicted mortality [Hazard ratio (HR) (per 1 risk category) 1.21, 95%CI 1.00-1.47, p=0.049] and relapse (HR=1.47, 95%CI 1.13-1.92, p=0.004), but not NRM (HR 0.95, 95%CI 0.74-1.22). The 1-year mortality rates for very low/low, moderate-low, moderate-high, high/very high risks were 21%, 24%, 32%, and 37%, respectively (Fig. 1). Individual mutations had minimal independent association with outcome in the multivariable model. For mortality, only ASXL1 at Dx (HR 0.48, 95%CI 0.26-0.91, p=0.024) and SF3B1 at Allo-HCT (HR 2.51, 95%CI= 1.06-5.96, p=0.037) were significant. TP53 at Dx had a borderline association (HR 0.46, 95% CI= 0.942.69, p=0.086). Also, there was no significant association of individual mutation with relapse (including TP53 at Allo-HCT, HR 1.77, p=0.085). Only SF3B1 at Allo-HCT correlated with NRM (HR 3.16, 95%CI= 1.22-8.17, p=0.018). Conversely, CG risk group remained strongly associated with mortality (p=0.007) and relapse (p=0.003), particularly poor/very poor (P/VP) risk CG (Mortality: HR 2.46, 95%CI 1.44-4.19, p=0.001; Relapse: HR 3.46, 95%CI 1.70-7.05, p=0.0006). There was no association of CG risk with NRM. We demonstrate value of IPSS-M risk stratification in predicting outcomes after Allo-HCT for MDS, re-stratifying pts into more discrete prognostic groups that predict mortality and relapse risk. Hence, IPSS-M could inform post allo-HCT decision including future maintenance strategies to prevent relapse in high/very high IPSS-M. CG risk group (esp. P/VP risk), a core component of IPSS-M, independently contributes to outcome prediction both within the model and individually. Disease risk does not predict NRM, and individual mutations have limited association with outcome, suggesting allo-HCT may mitigate the poor prognostic impact of high-risk oncogenic mutations present at Dx, including TP53 and ASXL1. An updated analysis on mutational complexity will be shown at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

Phase I Study of TQB3455, a Selective Inhibitor of IDH2 with Favorable Safety and More Potent Efficacy to IDH2-R172K Mutation, for Acute Myeloid Leukemia and Myelodysplastic Syndrome

Introduction: Approximately 15% of patients with acute myeloid leukemia (AML) and 5% of patients with myelodysplastic syndrome(MDS) harbor IDH2 mutations (mIDH2). Enasidenib (ENA), the first selective IDH2 inhibitor, was associated with impressive response rates in relapsed/refractory (R/R) AML and was approved by FDA in 2017. TQB3455, a novel selective inhibitor of IDH2, different from ENA, showed stronger inhibitory activity against IDH2-R172K in vitro, and also demonstrated potent antileukemic activity in humans. The current analysis is the first to evaluate the safety and clinical efficacy of TQB3455 monotherapy in pts with mIDH2-positive AML or MDS. Methods: This multicenter, phase 1, open-label, dose-escalation/expansion study enrolled AML or MDS pts with mIDH2, who were RR or not candidate for standard treatment, estimated survival ≥12w and ECOG performance status＜2. Prior allogeneic hematopoietic stem cell transplantation is prohibited. TQB3455 is administered continuously as oral tablets QD in 28-day cycles. Dose levels are 25mg, 50mg, 75mg, 100mg, 150mg, and 300mg.Dose escalation followed a modified 3+3 design. Once the recommended phase 2 dose (RP2D) is determined, subjects will be enrolled into expansion cohort. Primary objectives include safety, tolerability, maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Safety was assessed by treatment-emergent adverse event (TEAE) reporting and TEAEs were graded per CTCAE version 5.0. DLT was defined as any Grade ≥4 hematologic toxicity or Grade ≥3 non-hematologic toxicity（alopecia excluded）occurring within the first 28 days after initiation of treatment. Secondary objectives include pharmacokinetics (PK), preliminary efficacy per International Working Group (IWG) response criteria for AML and MDS. Fisher's exact test was used to assess the association between categorical variables. Results: As of May 31, 38 pts were enrolled in the study and had received at least one dose of TQB3455, 35 with AML and 3 with MDS. Baseline characteristics are detailed in Table 1. Pts received daily TQB3455 doses of 25mg(n=1), 50mg(n=1), 75mg(n=3), 100mg(n=3), 150mg(n=7), 300mg(n=1). When the dose escalated to 300mg, the patient experienced a DLT of pneumonia, then the dose was switched back to 150mg. The 150mg cohort was expanded to 7 evaluable patients and 1 patient experienced a DLT of differentiation syndrome. Therefore, the RP2D of TQB3455 was identified as 100 mg daily. 22 additional pts were enrolled on this dose during the expansion phase. Safety analysis was performed in all patients. The most frequent Grade 3-4 TEAEs in all regimens were 25mg(n=1, 100%), 50mg(n=1, 100%), 75mg(n=2, 66.67%), 100mg(n=13, 68.42%), 150mg(n=7, 87.50%) and 300mg(n=1, 100%). The most frequent TEAEs were pancytopenia(Table 2). 24 pts discontinued treatment, primarily due to progressive disease or relapse (n=17, 44.74%), adverse events (n=1, 2.63%), withdrawal by patient (n=3, 7.89%) or death (n=2, 5.26%). Efficacy was analyzed only in patients with AML. Three pts was not evaluable for response due to withdrawal by patients before the first efficacy evaluation. Of the 32 evaluable pts, overall response rate (ORR) was 40.63 %, including 12 pts (37.5%) in complete remission(CR) or CR with incomplete hematologic recovery (CRi), 1 pts (3.13%) in partial remission (PR). TQB3455 shows more powerful inhibitory effects on IDH2-R172K rather than IDH2-R140Q/W mutation (ORR, 66.67% vs 25.00%, p=0.03; CR, 41.67% vs 15.00%, p=0.12). The presence of FLT3 and/or RAS co-mutations at study entry was significantly associated with lack of response (ORR, 10% vs 45.46%; CR, 10% vs 31.82%). Median duration of response was 9.17 months (95% CI 7.39-not reached). After a median follow up of 5.49 months, the median overall survival (mOS) was 7.43 months (95% CI 5.55- not reached). Conclusion: TQB3455 is well-tolerated for myeloid malignancy at the R2PD of 100 mg qd. It also yield high rates of clinical response in pts with mIDH2AML. Patients with IDH2-R172K mutation fared much better than IDH2-R140Q/W with regard to response, this is in line with outcome of TQB3455 in vitro but different from previous reports of ENA. These encouraging findings have prompted further studies of TQB3455 combination therapy in patients with mIDH2 AML and MDS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Gut Microbiome, Metabolome and Immune Changes in Myelodysplastic Syndromes

Introduction. Myelodysplastic syndromes (MDS) are a group of multi-factorial disorders, in which the clonal expansion of somatically mutated hematopoietic stem and progenitor cells plays a crucial role. The influence of the bone marrow microenvironment, including inflammatory and metabolic dysbalances, on disease propagation becomes increasingly recognized. Although changes in gut microbiome have been described in various cancer types, its role in MDS has not been sufficiently elucidated yet. Due to its interconnection with carcinogenesis in solid tumours, systemic inflammation and metabolism, the gut microbiome could possibly play a role in MDS development as well. The goal of our study is to describe the composition of the gut microbiome in MDS patients (pts) and its association with inflammatory-metabolic parameters. Methods. We analysed faecal samples from 16 pts with untreated MDS or chronic myelomonocytic leukemia (median age: 66,5 years [41-81], m/f=13/3) and healthy donors (n=8, median age: 60,5 years [54-70], m/f=3/5). Exclusion criteria were antibiotic treatment within the last 4 weeks, chronic inflammatory bowel disease and other malignant disorders. Gut microbial taxonomic profiles were generated from the frozen faecal samples using 16S rRNA gene amplicon sequencing. For bioinformatic analysis, MapSeq was used. Statistical analysis included diversity analysis (observed microbial richness and Shannon index, differences assessed by Wilcoxon tests); differences in gut microbiome composition were visualized using Principal Coordinate Analysis (PCoA) in which differences were assessed by PERMANOVA. We performed flow cytometry to assess the cellular immune status including B-, T- and NK-cell populations, T/NK-subpopulations and expression of checkpoint molecules. Each parameter was analysed using Mann-Whitney U-test. Metabolite concentrations in plasma and urine were measured using NMR spectroscopy. Multivariate analysis of metabolic parameters was performed as a principal component analysis (PCA) and partial least-square discriminant analysis (PLS-DA), to evaluate the possible discrimination of the two groups. Results. Ten MDS pts were referred to the low-risk group (low and intermediate 1 according to IPSS), 5 pts - high-risk (intermediate 2 and high), in one patient information was not available. All but one patient carried at least one MDS-typical somatic mutation (median: 3 [1-6]). According to cytogenetic analysis 2 pts belong to "very good" prognostic risk, 7 - "good", 4 - "intermediate", 2 - "very bad", in 1 patient the information was not available. The median time from the diagnosis to faecal sampling was 19 months [1-205]. Microbiome composition showed statistically significant differences between MDS and healthy subjects (p<0.05, R2=0.079, PERMANOVA). Gut microbial diversity and richness (the number of genera observed per patient), was lower in MDS, although not reaching statistical significance in this small cohort. Time from MDS diagnosis until faecal sampling did not have an impact on the microbial diversity. Pts with high-risk MDS tended to have the lowest gut microbial diversity and richness compared to pts in the low-risk group, both according to IPSS and IPSS-R scores. Flow cytometry revealed that pts with MDS had reduced numbers of B-lymphocytes (CD19+: 56 vs 184/µL in MDS and healthy, accordingly, p<0.01), increased number of T effector memory cells (0.06 vs 0/µL, p<0.05) and PD-L2 expression on T-lymphocytes (MFI: 150 vs 86, p<0.01), reflecting prolonged inflammatory stimulation. In addition, we observed reduced NK-cell activity, demonstrated by the reduction of the activating receptors on NK cells (NKp30: 92.9 vs 99.05 %CD56dim, p<0.05; DNAM-1: 86.8 vs 97 %CD56bright, p<0.01). PCA applied to plasma and urine metabolites allowed us to separate MDS from healthy counterparts. Further separation was accomplished using a supervised approach with PLS-DA, which highlighted the separation of the groups due to high VIP scores of the parameters, mostly affecting lipid metabolism. Conclusions. We have demonstrated broad, statistically significant changes in microbiome, metabolome and immunome of pts with MDS. Whether these are cause or consequence of the disease development remains to be elucidated.

P770: A COMPARATIVE STUDY OF LEUKEMIC TRANSFORMATION IN THERAPY-RELATED AND DE NOVO MYELODYSPLASTIC SYNDROME AFTER HYPOMETHYLATING AGENT FAILURE

Background: Therapy-related myelodysplastic syndrome (t-MDS) is subset of myelodysplastic syndrome (MDS), known for having dismal survival outcomes. The majority of patients (pts) with t-MDS have similar clinical courses with de novo MDS patients after hypomethylating agent failure (HMA-F) that often results in transformation to acute myeloid leukemia (AML). Aims: We conducted a study to identify unique clinicopathologic features of t-AML from t-MDS compared to secondary AML (sAML) from de novo MDS after HMA-F. Methods: We identified sAML patients after HMA-F from all untreated MDS pts in a tertiary cancer center registry from 2017-2021. Clinical characteristics and pathologic data including cytogenetic (CG) and next generation sequencing (NGS) information were collected at the time of MDS diagnosis (dx), HMA-F, and AML dx. Results: 71 (48%) MDS pts with AML transformation after HMA-F were included in the study with a median follow-up time of 15.4 months (mo). At the time of MDS dx, 31 (43%) pts had t-MDS: 97%, 58% and 29% had a history of chemotherapy, radiation, and prior stem cell transplant (SCT), respectively. t-MDS patients were more likely to present with age<65 (48% vs. 28%, p=0.070) and thrombocytopenia (33,000 vs. 75,500, p=0.004) when compared to de novo MDS pts. The majority of t-MDS pts had very high risk disease by IPSS-R (67% vs. 39%, p=0.031), while de novo MDS pts frequently had high risk disease (50% vs. 20%, p=0.013). 90% of t-MDS pts had adverse CG (IPSS-R CG score 3-4) at MDS dx, compared to 46% in de novo MDS pts (p=0.004). NGS at MDS dx showed more frequent TP53 mutations in t-MDS than in de novo MDS (73% vs 36%, p=0.003). Interestingly, ASXL1 (36% vs. 1%, p=0.001), RUNX1 (9% vs. 0%, p=0.004), STAG2 (21% vs. 0%, p=0.013), TET2 (13% vs. 0%, p<0.001), and SRSF2 (18% vs. 0%, p=0.027) were more frequently found in de novo MDS (Table). t-MDS had worse overall survival (OS) from MDS dx (HR 1.82, p=0.026). The median OS from MDS dx was 19.4 mo and 14.3 mo in de novo MDS and t-MDS, respectively. The number of HMA cycles received before HMA-F was 6 (range: 1-13) in t-MDS and 5 (range: 1-23) in de novo MDS. At the time of HMA-F, t-MDS pts presented with more anemia (p=0.005) and thrombocytopenia (p=0.064). The number of CG clones were similar, but the number of CG abnormalities were higher in t-MDS pts (p=0.025). Among pts with subsequent AML transformation after HMA-F, the median time from HMA-F to AML was 1.5 mo in t-MDS to AML, compared to 4.6 mo in de novo MDS to AML. At time of AML dx, 48 (68%) pts had mutation panels available. All TP53 mutation status stayed the same in t-MDS pts at the time of MDS and AML dx. Other changes in mutations were shown in Table. Though the median OS from AML transformation was short in all pts, t-MDS pts had inferior outcomes (2.4 mo vs. 5.0 mo, HR 1.70, p=0.043). The initial response rate to salvage therapy was comparable between t-MDS and de novo MDS after AML transformation (50% and 56%, p=0.761), but more pts underwent SCT with de novo MDS compared to t-MDS (10% vs. 3%, p=0.383). Image:Summary/Conclusion: Transformation to AML after HMA-F results in poor outcomes, but pts with t-MDS have worse survival with distinct CG and mutation profiles. Further understanding of the pathogenesis of AML transformation in both t-MDS and de novo MDS after HMA-F is warranted with improved therapy options an area of unmet need.

Anti–PD-1 antibody (sintilimab) plus decitabine as first-line treatment for patients with higher-risk myelodysplastic syndrome (MDS): Preliminary results from a single-arm, open-label, phase II study.

7052 Background: Hypomethylating agents (HMAs) are the preferred treatment for untreated patients (pts) with higher-risk MDS, but the survival of pts after HMAs treatment is poor. It has been demonstrated that the PD-1/PD-L1 expression was upregulated by HMAs in MDS pts, providing a strong rationale for combining HMAs with PD-1 antibody for MDS treatment. Therefore, this single-arm, open-label, clinical trial was performed to evaluate safety and efficacy of Sintilimab plus decitabine for pts with higher-risk MDS (ChiCTR2100044393). Methods: Adult pts with higher-risk MDS by the IPSS-R were enrolled. Patients received decitabine 20mg/m2 intravenously daily for 5 days and sintilimab 200mg IV starting on the first and 22nd day of a cycle every 42 days until unacceptable toxicity, relapse, or progression, for a maximum of 8 cycles. The primary endpoint was overall response rate (CR+PR+mCR). Simon’s optimal two-stage design was employed.If five or more pts in stage I (13 pts) achieved ORR, the study would enroll 34 additional pts in stage II (47 pts). Secondary endpoints included safety, and survival outcomes. The relationship between expression levels of immune-checkpoint and efficacy of the combination therapy, as well as other potential biomarkers were also explored via genomic profiling. Results: At data cut-off (January 31, 2022), 21 pts were enrolled with a median follow-up time of 5.8 months. The median age of pts was 64 years (range 30-83), and the other characteristics are summarised in Table.The ORR was 62%,with six pts reaching complete response (CR),four pts reaching marrow CR and three pts achieved marrow CR+ hematologic improvement (HI). In addition,four pts reaching HI. The most common grade 3 TEAEs( &gt; 10%) were febrile neutropenia (76.2%) and pulmonary infection (38.1%). No grade 4 TEAEs and treatment-related deaths occurred. A total of 12 pts （57.1%）experienced immune-related adverse event, including rash (28.6%), pneumonia (9.5%), hypothyroidism (9.5%), elevated serum bilirubin (4.8%) and transpeptidase (4.8%), which were all resolved by glucocorticoid. In these 21 pts, the most frequently mutated genes are ASXL1（28.6%）, RUNX1 (14.3%) and TET2(14.3%). Updated biomarker data will be presented during the ASCO meeting. Conclusions: To the best of our knowledge, this is the first study to evaluate the efficacy and safety of sintilimab plus decitabine in pts with untreated higher-risk MDS. The preliminary results demonstrate that the combination therapy is relatively safe with anti-tumor activity. Clinical trial information: ChiCTR2100044393. [Table: see text]

Evaluation of International Working Group 2006 Response Criteria in Patients with Higher-Risk Myelodysplastic Syndromes (HR-MDS) Treated with Hypomethylating Agent Monotherapy in the Frontline Setting

▪Introduction: Monotherapy with hypomethylating agents (HMA) remains the standard of care for patients (pts) with myelodysplastic syndromes (MDS). Response in MDS is based on the modified International Working Group (IWG) 2006 criteria. Prior studies focusing on unselected MDS pts showed that achieving a complete remission (CR) was associated with favorable overall survival (OS). However, the association of other outcomes with OS was less clear and only 20% of HMA-treated MDS pts achieve a CR. For example, pts who achieved <5% bone marrow (BM) blasts are currently classified as marrow CR (mCR), which has not been associated with OS improvement. Therefore, interpreting the significance of mCR reported in various clinical trials is challenging. Clinically meaningful reduction in bleeding or infectious complications can occur at improvements in absolute neutrophil count (ANC) and platelet counts that do not meet the current thresholds used for CR (ANC ≥1.0 × 10 9/L, platelets ≥100 × 10 9/L, and Hb >11 g/dL). To avoid missing clinically meaningful benefits when studying new drugs in clinical trials, a clearly defined response criterion that is less stringent than CR but still captures clinically meaningful hematologic improvement (HI) is needed. Here we sought to evaluate the impact of current IWG 2006 response criteria as well as CRh on OS of pts with HR-MDS treated with frontline HMA monotherapy.Methods: We included all adult (≥18 years) MDS pts treated with frontline HMA (azacitidine [AZA], decitabine [DEC], or ASTX727) monotherapy between 1/1/2012 and 12/31/2020 at Yale University. We decided to use HMA monotherapy as it is the standard care for HR-MDS and to minimize the impact of therapy choice confounding the association of achieved response with OS. Pts were excluded if they received prior treatments for MDS aside from erythropoiesis-stimulating agents and if no baseline with at least one follow-up BM study were available for response assessment. We collected patient and disease characteristics (transfusion burden, IPSS/IPSS-R score, cytogenetics, molecular studies) at baseline. Best responses were assessed based on IWG 2006 criteria for MDS. We defined CRh as <5% BM blasts, platelets ≥50 × 10 9/L, ANC ≥0.5 × 10 9/L and no peripheral blood blasts. We followed pts until death or last follow-up and recorded dates of allogeneic hematopoietic cell transplant (HCT) if applicable. Date of data cut-off for survival status was 5/31/2021.We performed Kaplan-Meier analysis to estimate the duration of overall survival and we used log rank test to test the difference in OS between subgroups of pts. Multiple comparisons were adjusted using the Bonferroni method.Results: A total of 100 pts was included in this analysis (Table 1). Median age was 68 years (yrs; range, 23 - 86), 60% were males, and 79% and 18% of pts received AZA and DEC, respectively. Median number of HMA cycles was 6 (interquartile range [IQR]: 4-10), and 33 pts (33%) underwent HCT. During follow-up, 46 pts (48%) progressed to AML. At a median follow-up of 1.5 yrs (IQR: 0.9 - 2.3 yrs), median OS for the entire pt cohort was 1.9 yrs (Figure 1). OS by response category is shown in Table 2. Median OS was not reached for patients who achieved a CR (95% CI: not reached [NR] - NR) as compared to 1.9 yrs (95% CI: 1.5 yrs - NR) and 2.0 yrs (95% CI: 1.2 yrs - NR) among pts with mCR + HI and mCR without HI, respectively. Median OS among patients with stable disease (SD) was similar (2.0 yrs [95% CI: 1.5 yrs - NR]). Finally, we explored the prognostic value of CRh and found a median OS of 1.9 yrs (95% CI: 1.5 yrs - NR), which appeared comparable to mCR +/- HI or SD. Similar results were found with censoring at time of HCT (Figure 2).Discussion: In this retrospective analysis of MDS pts treated with HMA monotherapy in the frontline setting, achieving CR as best response was associated with improved OS compared with mCR +/- HI and SD. However, as the numbers were small these results should be interpreted with caution, and other clinically relevant outcomes such as freedom of transfusion, infectious or bleeding complications, and patient-reported outcomes were not captured in the current analysis. Our results also apply only to MDS pts treated with HMA monotherapy in the frontline setting. The prognostic implications of CRh need to be evaluated in larger patient cohorts. To overcome these limitations, we are currently in the process of expanding the study to a much larger multi-center, international analysis. [Display omitted] DisclosuresNeparidze: Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Research Funding. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Podoltsev: PharmaEssentia: Honoraria; Pfizer: Honoraria; CTI BioPharma: Honoraria; Blueprint Medicines: Honoraria; Incyte: Honoraria; Bristol-Myers Squib: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Brunner: GSK: Research Funding; Aprea: Research Funding; Keros Therapeutics: Consultancy; Agios: Consultancy; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Acceleron: Consultancy; Takeda: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Janssen: Research Funding. Zeidan: AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Epizyme: Consultancy; Amgen: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Acceleron: Consultancy, Research Funding; Agios: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Genentech: Consultancy; Jasper: Consultancy; ADC Therapeutics: Research Funding; Jazz: Consultancy; Astex: Research Funding; Daiichi Sankyo: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Geron: Other: Clinical Trial Committees; AstraZeneca: Consultancy; Pfizer: Other: Travel support, Research Funding; BeyondSpring: Consultancy; Ionis: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Janssen: Consultancy; Astellas: Consultancy.

Assessing the Role of Venetoclax in Combination with Hypomethylating Agents in Higher Risk Myelodysplastic Syndromes

BackgroundHypomethylating agents (HMA) remain the backbone for treating higher risk myelodysplastic syndromes (MDS) patients (pts) with less than 20% of pts achieving complete response (CR) and median overall survival (OS) of 12-18 months. Ongoing studies in higher risk MDS are assessing the role of adding venetoclax (Ven) to HMA. Preliminary data have reported promising higher response rate as first line therapy (1L) HMA/Ven) as well as activity in relapsed/refractory MDS to HMA. (R/R MDS).MethodWe analyzed all higher risk MDS pts treated at Moffitt Cancer Center defined by revised international prognostic scoring system (R-IPSS) by ≥ intermediate risk who received HMA as first line therapy after diagnosis. We compared outcomes of those pts who received single agent IL HMA, 1L HMA/Ven combination and HMA with Ven add back strategy after HMA failure (R/R MDS HMA/Ven). OS was defined from time of diagnosis.ResultsWe identified 1193 higher risk MDS pts who received HMA 1L, 1158 pts received single agent HMA (1L HMA) (1027 azacitidine (AZA) and 131 decitabine (DAC)), 35 pts received 1L HMA/Ven combination (26 AZA and 9 DAC backbone). Among pts treated with HMA alone as first line, 31 were treated subsequently with HMA/Ven combination for R/R MDS without transformation to AML. The median duration of follow up from diagnosis was 96 months (mo) for 1L HMA, 15 mo for 1L HMA/Ven and 36 mo for HMA/Ven R/R MDS.Focusing on first line therapy, 1127 received 1L HMA alone with no subsequent Ven add back and 35 pts 1L HMA/Ven. Table-1 summarizes baseline characteristics, 1L HMA/Ven pts were more likely to be MDS-EB2 and more pts harbored ASXL-1 somatic mutation (SM).The overall response rate (ORR) (HI+) was 77% for 1L HMA/Ven compared to 40% 1L HMA (p<.005). The CR/marrow CR (mCR)/PR/HI were 34%/37%/3%/3% compared to 13%/11%/1%/15% for 1L HMA/Ven and IL HMA alone respectively, p <.005. Among pts with ASXL-1 SM, The ORR was 87% (CR 44%) and 32% (CR 8%) for IL HMA/Ven and 1 L HMA alone respectively, p < .005. Among pts with TP53 SM the ORR was 75% and 44% for IL HMA/Ven and 1 L HMA alone respectively, p = .038, however CR rates were 25% versus 17%, p = .47.The rate of AML transformation was 23% and 37% for IL HMA/Ven and 1 L HMA alone respectively, p = .08. The overall survival was 21 mo (95% CI 11-32) and 20 mo (95%CI 19-22) for IL HMA/Ven and 1 L HMA alone respectively, p= .86. Among patients who proceeded to allogeneic stem transplantation (AHSCT) (n=269) 13 pts received 1L HMA/Ven, the median OS was not reached compared to 38 mo (95%CI 27-50) among who received 1L HMA alone (p=.2). The 2-year survival probability rate was 91% and 51% for IL HMA/Ven and 1 L HMA alone who proceeded to AHSCT respectively. (Figure 1 A)Among pts who received 1L HMA alone as first line, 31 pts later received HMA/Ven for R/R MDS. The median number of 1L HMA therapy alone was 6 cycles. The ORR was 61% (CR 13% and mCR 48%). The median OS from time of diagnosis for pts who received HMA/Ven for R/R MDS was 33 mo (95% CI 31-36) compared to 21 mo (95% CI 11-32) for those who had IL HMA/Ven and 20 mo (95%CI 19-22) for those who received 1L HMA alone with no subsequent Ven therapy. (p=.02). (Figure-1 B) Nine of 31 pts who received HMA/Ven R/R MDS underwent AHSCT compared to 22 who did not proceed to transplant with median OS 31 and 33 mo respectively, (p = .7).ConclusionsAmong higher risk MDS patients, 1L HMA/Ven combination yields significantly higher complete response rates including ASXL-1 mutant MDS compared to 1L HMA alone. The OS survival benefit for 1L HMA/Ven in higher risk MDS pts can only be addressed in randomized clinical trial but our data suggest promising activity among those who received 1L HMA/Ven and proceeded to AHSCT (2-year OS 91%). Ven add back strategy to HMA after 1L HMA failure has clinical activity and was associated with OS benefit. [Display omitted] DisclosuresKomrokji: Novartis: Honoraria; BMS: Honoraria, Speakers Bureau; Acceleron: Honoraria; Abbvie: Honoraria, Speakers Bureau; Agios: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; Geron: Honoraria. Padron: Taiho: Honoraria; Stemline: Honoraria; BMS: Research Funding; Blueprint: Honoraria; Kura: Research Funding; Incyte: Research Funding. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kuykendall: Protagonist: Consultancy, Research Funding; Pharmaessentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Blueprint: Honoraria; Incyte: Consultancy; Celgene/BMS: Honoraria; Abbvie: Honoraria. Lancet: AbbVie: Consultancy; Celgene/BMS: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; BerGenBio: Consultancy; Agios: Consultancy; Millenium Pharma/Takeda: Consultancy; Astellas: Consultancy; Jazz: Consultancy. Sallman: Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure:Venetoclax for treatment of myelodysplastic syndromes