Higher-risk Myelodysplastic Syndromes Pts Research Articles

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

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

Impact of Allelic State on Overall Survival in TP53-mutant Acute Myeloid Leukemia (AML) and Higher Risk Myelodysplastic Syndromes (HR-MDS)

Introduction: Mutations in TP53 confer an adverse prognosis in patients (pts) with AML and HR-MDS. There are conflicting results regarding the prognostic impact of mono-allelic vs bi-allelic and mono-hit vs multi-hit TP53 mutation status on prognosis in AML and HR-MDS. Additionally, assessment of loss-of-heterozygosity (LOH) status is not routinely available in many settings limiting the clinical implementation of TP53 mutational status. Methods: We took advantage of a large, randomized study with extensive clinical and molecular annotation to analyze 61 patients (pts) with TP53-mutated (TP53-mut) disease and to compare them to 144 TP53 wild-type pts. All pts received azacitidine and half were randomized to receive the anti-PDL1 antibody durvalumab, which did not improve clinical outcomes (Zeidan et al. Blood Advances 2022). A 38 gene-targeted myeloid mutation analysis from screening bone marrow was performed at Munich Leukemia Laboratory. Only pathogenic TP53 variants with variant allele frequency (VAF) ≥2% were included. Pts with a common SNP or VUS in the TP53 gene were classified as TP53-WT in the analysis. Multi-hit TP53 mutations were defined as previously published by the International Consensus Conference (ICC; Arber et al. Blood 2022) as ≥2 distinct TP53 mutations (VAF ≥10%) or a single TP53 mutation associated with either: 1) cytogenetic deletion involving chromosome 17p (e.g., del(17p) or monosomy 17); 2) a VAF of >50%; or 3) with any complex karyotype. We also defined multi-hit TP53 mutations as proposed by Grob et al. (Blood 2022) as (I) ≥2 TP53 gene variants irrespective of VAF, (II) ≥1 TP53 gene variant co-occurred with a cytogenetic deletion involving chromosome 17p, or (III) TP53 mutations with VAF >55%. Based on multiple prior studies (Grob et al. Blood 2022, Weinberg et al. Blood Advances 2022) patients with AML and HR-MDS with TP53 mutations were analyzed as one disease entity. Results: 37 had TP53-mut AML, 89 were TP53-WT AML, 24 had TP53-mut HR-MDS, and 55 were TP53-WT HR-MDS pts. The average VAF for TP53 mutations was 37%, and 90% had ≥10% VAF. 93% of TP53 mutations occurred in the p53 DNA-binding domain. TP53-mut pts had fewer co-occurring mutations compared with TP53-WT pts (mean number of mutations: 1.8 [SD: 0.77] for TP53-mut pts (including TP53) vs 2.9 [SD: 1.4] for TP53-WT pts; Wilcoxon P <0.001) with distinct patterns in the distribution of co-occurring mutations. In terms of TP53 allelic status, 22 (11.0%) were mono-hit and 41 (20.5%) pts were multi-hit as defined by Grob et al, while 7 (3.4%) and 56 (28.0%) pts were classified as mono-hit and multi-hit per ICC definition, respectively. In the AML cohort, TP53-mut pts were more likely to have poor-risk cytogenetics (59.5% vs 11.2%; p<0.001), therapy-related myeloid neoplasm (10.8% vs 1.1%; p=0.042), and lower bone marrow blast percentage (27.5% vs 35.5%; p=0.001) compared to TP53-WT. Among MDS pts, TP53-mut pts were more likely to have secondary MDS (20.8% vs 1.8%; p=0.013), very poor risk cytogenetics by IPSS-R (75% vs 14.6%; p<0.001), and very high risk IPSS-R score (62.5% vs 34.6%; p=0.039). There were no statistically significant differences in terms of baseline demographics and other clinical characteristics. There was no difference in overall response rate (ORR) between TP53-mut and TP53-WT pts (AML: ORR: 35.1% [95% CI: 20.7% - 52.6%] vs. 33.7% [95% CI: 24.2% - 44.6%]; p=1.000; MDS: ORR: 41.7% [95% CI: 22.8% - 63.1%] vs. 60.0% [95% CI: 45.9% - 72.7%]; p=0.208). TP53 allelic status did not influence OS using either definition (Grob et al: mono-hit: median OS 7.6 months [95% CI:5.4-10.6 months]; multi-hit 10.6 months [95% CI: 9.1-13.0 months] (Figure A); ICC definition: 8.0 months (95% CI: 6.1-20+ months) and 9.5 months [95% CI: 7.7-10.9 months], (Figure B)) and was inferior to TP53-WT (median OS: 18.9 months; 95% CI: 15.5-22.9 months). Conclusion: Outcomes of AML and MDS pts with TP53 mutations are worse compared to TP53-WT without differences between mono-hit vs multi-hit status as defined by the ICC and Grob et al. This suggests that either the negative prognostic impact of a multi-hit TP53 allelic status can be overcome by treatment with azacitidine or that a distinction by TP53 allelic status in newly diagnosed AML/HR-MDS pts treated with azacitidine does not provide additional prognostic information. Whether incorporating TP53 LOH status is necessary to further refine risk assessment warrants additional studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Updated Results of CPX-351 in Combination with Gemtuzumab Ozogamicin (GO) in Relapsed Refractory (R/R) Acute Myeloid Leukemia (AML) and Post-Hypomethylating Agent (Post-HMA) Failure High-Risk Myelodysplastic Syndrome (HR-MDS)

Background: Treatment outcomes in patients (pts) with AML and HR-MDS who progress after HMA +/- venetoclax (VEN) based regimen remains poor and warrants new therapeutic strategies. CPX-351 (Vyxeos™) is a dual liposomal formulation of cytarabine and daunorubicin, at a fixed synergistic 5:1 molar ratio, approved by US Food and Drug Administration (FDA) for the treatment of newly diagnosed therapy-related AML or AML with myelodysplastic related changes (AML MRC). GO (Mylotarg™) is a humanized IgG4 antibody directed against CD33 and conjugated to the DNA toxin calicheamicin and approved by the FDA for the treatment of newly diagnosed or R/R CD33-expressing AML. We hypothesized that the combination of CPX-351 and GO could be synergistic in this high risk pt population and have potent anti-leukemic activity. Aim: To determine the safety and efficacy of CPX-351 in combination with GO in patients with R/R AML or post-HMA failure HR-MDS. Methods: We present here the updated results of the Phase 2 single-arm pilot study (NCT03672539) of CPX-351 and GO (CPX-GO) combination therapy in pts with CD33 positive R/R AML or post-HMA failure HR-MDS. Pts received induction cycle (C) CPX-351 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) administered via intravenous (IV) infusion on days (D) 1, 3, and 5. GO was administered at a dose of 3 mg/m2 (capped at 4.5 mg) IV on D1. Pts not attaining complete remission (CR) or CR with incomplete count recovery (CRi) after C1, could receive a 2nd induction cycle of CPX at the same dose, but only on D1 and D3 with GO 3 mg/m2 on D1. Pts attaining CR/CRi could receive up to 2 consolidation cycles, after a minimum of 4 weeks from the start of the previous cycle with CPX (daunorubicin 29 mg/m2 and cytarabine 65 mg/m2) IV on D1 and D3 and GO at 3 mg/m2 on D1. GO was only administered during the second consolidation cycle if there was evidence of measurable residual disease (MRD+) as measured by flow cytometry. GO could also be administered as a single agent for maintenance treatment on D1 every 6 weeks, in case of persistent detection of MRD. CD33 genotyping to assess for GO sensitivity was available for a subset of pts. Response was denoted as per the ELN 2017 criteria for AML and IWG 2018 criteria for MDS. Results: From Nov 2018- Apr 2022, 31 pts were treated on the trial, 29 (93%) pts with AML and 2 pts (7%) with HR-MDS. Baseline disease, treatment and response characteristics are mentioned in Table 1. The median lines of prior AML therapy were 2 (range, 1-6). Eleven pts (38%) had baseline de novo AML, while 15 (52%) and 3 (10%) pts had secondary (s-AML) and therapy-related (t-AML) AML respectively. Twenty-three AML pts (79%) had prior VEN exposure. Both the prior HR-MDS patients had bone marrow (BM) blasts >15% and one pt had prior VEN exposure. Overall, 21 pts with AML (72%) were adverse risk and only 1 pt (3%) had favorable risk AML (diploid karyotype with NPM1 mutation). Four pts (all AML; 13%) had undergone a prior stem cell transplantation (SCT). The median number of cycles on trial were 1 (range, 1-6). At the time of data cutoff, none of the pts were on active study therapy and the median follow up was not reached. Sixteen pts (52%) had an overall response; 9 pts had CR/CRh/MLFS (8 AML and 1 MDS= responders), after a median of 1 cycle of therapy, and 7 pts had a partial response (all AML). CD33 genotype did not affect response rates (no response in 5 pts with C/C vs 2/6 responders in C/T genotype, p=0.45). Amongst prior VEN exposed pts, 5/24 (21%) responded versus 3/7 (43%) non VEN exposed pts (p=0.15) One pt could directly proceed to a SCT in CR after the trial therapy. For relapse free survival (RFS) analysis partial responders were grouped under non-responders. The median RFS and overall survival (OS) for the whole cohort was 6.3 and 6.8 months (mos) respectively, and median OS was 12.9 mos for responders(Fig. 1). One pt had a grade 2 infusion reaction to GO. Overall, adverse events at least possibly attributed to the trial medications were seen in 5 pts, of which 2 events were ≥ grade 3 (mucositis and seizures). No pt had hepatic veno-occlusive. Eight pts (all non-responders) (26%) died on the trial from infections/leukemia progression and there were no deaths in remission. Conclusion: In a cohort composed predominantly of heavily pre-treated and VEN exposed adverse risk AML and HR-MDS pts, CPX-GO led to overall response (CR/CRh/MLFS/PR) rates of 52% and year-long median survival in responders (CR/CRh/MLFS) with no major non-hematological adverse event. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of magrolimab treatment in combination with azacitidine on red blood cells in patients with higher-risk myelodysplastic syndrome (HR-MDS).

7054 Background: Magrolimab is a monoclonal antibody that blocks CD47, a “don’t eat me” signal expressed on cancer cells to escape immune surveillance and macrophage-mediated clearance. Prior preclinical studies have shown that CD47 is critical to RBC homeostasis, with CD47 deficiency decreasing RBC half-life. Fc-mediated opsonization also depletes RBCs, raising concerns for potential on-target anemia from anti-CD47 agents via multiple mechanisms. Notwithstanding, several clinical trials have demonstrated that magrolimab can be safely administered as a monotherapy with initial lower “priming” dose yielding transient anemia with compensatory reticulocytosis, with anemia not observed at subsequent higher maintenance doses. However, the mechanism underlying this observed protection has not been fully defined. Here we describe manageable anemia in patients (pts) with HR-MDS treated with magrolimab in combination with azacitidine (AZA) (NCT03248479) and further investigate these underlying mechanisms in preclinical models. Methods: In a multicenter prospective study, CBCs, peripheral blood, and bone marrow (BM) were collected at prespecified timepoints from HR-MDS pts (n = 57) treated with magrolimab in combination with AZA. CBCs were measured, and blood and BM samples were analyzed by flow cytometry for expression of CD47 on RBCs and WBCs. Magrolimab was initially dosed with a priming dose (1mg/kg) followed by an initial weekly maintenance dosing (30mg/kg) before transitioning to every 2 weeks maintenance dosing. AZA 75mg/m2 was administered on days 1-7 of the 28-day cycle. Preclinical modeling studies were conducted with intact and Fc-deficient anti-mouse CD47 (MIAP410) and anti-human CD47 (magrolimab) antibodies in murine models, including C57BL/6J B-hSIRPA/hCD47 mice. Results: Combination treatment of magrolimab with AZA resulted in a tolerable anemia that correlated with rapid, near complete loss of CD47 from RBCs, but not WBCs. The initial 1mg/kg priming dose was sufficient for this CD47 loss, which persisted under subsequent 30mg/kg maintenance doses. Both findings are consistent with prior clinical observations in solid tumor pts with magrolimab monotherapy and lymphoma pts in combination with rituximab. Our preclinical studies with mouse models revealed that the CD47 removal is mechanistically independent of previously described RBC antigen modulation mechanisms and cellular compartments. Instead, this CD47 loss requires anti-CD47 crosslinking between RBCs and non-RBCs. Conclusions: Overall, these results support that on-target magrolimab mediated anemia is mitigated by a near complete loss of RBC CD47. HR-MDS patients treated with magrolimab in combination with AZA exhibit a tolerable anemia through priming and maintenance doses. Clinical trial information: NCT03248479.

Immune and Epigenetic Landscape of TP53-mutated Acute Myeloid Leukemia (AML) and Higher-Risk Myelodysplastic Syndromes (HR-MDS)

Immune and Epigenetic Landscape of TP53-mutated Acute Myeloid Leukemia (AML) and Higher-Risk Myelodysplastic Syndromes (HR-MDS)

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

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

Preliminary Results from a Phase Ib Study Exploring MDM2 Inhibitor Siremadlin (HDM201) in Combination with B-Cell Lymphoma-2 (BCL-2) Inhibitor Venetoclax in Patients with Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (HR-MDS)

Preliminary Results from a Phase Ib Study Exploring MDM2 Inhibitor Siremadlin (HDM201) in Combination with B-Cell Lymphoma-2 (BCL-2) Inhibitor Venetoclax in Patients with Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (HR-MDS)

Counseling Patients (pts) with Higher-Risk Myelodysplastic Syndromes (HR-MDS) Regarding Expected Survival with Azacitidine (aza) Therapy: Are We Using Accurate Estimates?

▪Introduction:Aza is the only drug proven to prolong overall survival (OS) in pts with HR-MDS in the large randomized trial AZA-001 with a median OS of 24·5 months (mos) compared to vs. 15·0 mos for conventional care regimens (CCR) arm, with a hazard ratio of 0·58; p=0·0001 (Fenaux et al, 2009). Two-year OS probability was 51% in aza arm compared to 26% in the CCR arm (p<0·0001). These numbers are often quoted to counsel HR-MDS pts regarding expected benefits with aza therapy. However, increasing real-life and registry data suggest that the OS benefits with aza is much lower than what is suggested by AZA-001 trial. To get a more realistic estimate of OS with aza, we pooled OS data from several reported clinical trials and re-analyzed data from the AZA-001 trial.Methods: We conducted a literature search for published prospective clinical trials that had an aza monotherapy arm at the standard approved dose (75mg/m2/day for 7 days), in which OS results were presented in Kaplan-Meier (KM) methodology. GetData Graph Digitizer Version 2.26 was used to digitize the published KM curves of the aza monotherapy arms in these trials. An algorithm developed by Guyot et al. 2012 was implemented in the R statistical software to recreate individual pt level data based on the information from each KM curve, number of pts at risk, and number of events. Individual pt level data were pooled for pts receiving aza to produce overall KM estimates and estimates of median OS and 1-, 2-, and 3-year OS probabilities. Furthermore, based on the individual level pt data recreated from the AZA-001 trial, the validity of the proportional hazards assumption between the aza and CCR arms was assessed by testing the independence between Schoenfeld residuals and time. The difference (and ratio) of the Restricted Mean Survival Time (RMST) are non-parametric test which are less sensitive to assumptions than the Cox proportional hazards (CPH) ratios, and has been gaining popularity as an estimate of survival benefit in time-to-event endpoints in clinical trials (Uno et al, JCO, 2014). The hazard ratio provided in trials can significantly increase treatment effect estimates than the ratio of RMST, and the hazard ratio may seem large when the absolute effect is small. We calculated the difference (and the ratio) of the RMST in the AZA-001 trial to estimate OS benefit with aza compared to CCR, as an alternative to the hazard ratio reported in the trial, that is less sensitive to violations in the proportional hazards assumption.Results: We have found four published manuscript that fit the research criteria [Table 1]. We first assessed the proportionality of the hazard functions for each treatment arm of AZA-001 trial. While there wassome variability in the CPH model residuals for the log hazard ratio over time, the proportionality assumption is not violated based on the test of the Schoenfeld residuals (Rho = 0.085, p = 0.224). The difference in RMST between aza and CCR arms shows that OS benefit in aza arm was 5.38 months longer than CCR arm on average when pts were followed for 34 months (p < 0.001). The ratio of RMST over 34 months was 0.748, suggesting that hazard of death was reduced with aza by 25% compared to CCR (p < 0.001), in comparison to what was reported in the AZA-001 trial of hazard of death reduction of 42% based on the CPH. When KM curves for the aza arm of each of the four manuscripts were pooled [Figures 1,2], median OS was 19.2 months (95%CI 16.9, 21.8). KM estimates of OS for pooled data at 1-year was 65.4% (95%CI 60.8%, 70.3%), at 2-years 42.4% (95%CI 37.3%, 48.3%), and at 3 years 33.6% (95%CI 27.6%, 40.8%).Summary: Pooled data from clinical trials with aza monotherapy arms support the real-life observation that the median OS of 24.5 months with aza in AZA-001 trial reflects a substantial unexplained over-performance of aza in this landmark trial that is not related to the selective process of enrollment in clinical trials. While individual pts have exceptional responses with aza, such responses are uncommon and a median OS of less than 19 months (based on trial data of selected patients) and 13 to 16 months (based on real-life analyses) might be more realistic estimates for most pts with HR-MDS using aza. These observations provide rationale to strongly consider first-line enrollment into clinical trials or transplantation for HR-MDS pts rather than defaulting to the routine use of “standard-of-care” aza monotherapy, and have important implications for the design of clinical trials. [Display omitted] DisclosuresPodoltsev:CTI biopharma/Baxalta: Consultancy; Ariad: Consultancy; Alexion: Consultancy; Incyte: Consultancy. Ma:Incyte Corp.: Consultancy. Zeidan:AbbVie, Otsuka, Pfizer, Gilead, Celgene, Ariad, Incyte: Consultancy, Honoraria; Takeda: Speakers Bureau; Otsuka: Consultancy.

Validation of International Working Group response criteria in higher-risk myelodysplastic syndromes: A report on behalf of the MDS Clinical Research Consortium.

The utility of the International Working Group (IWG) 2006 response criteria for myelodysplastic syndromes (MDS) as a surrogate endpoint for outcomes is unclear. We assessed the validity of the IWG 2006 response criteria in a large cohort of higher‐risk MDS patients (pts) treated at centers from the MDS Clinical Research Consortium. The best overall response rate (ORR) by IWG 2006 criteria to first‐line therapy among 597 evaluable pts was 38% and include complete response (CR) 16%, marrow CR (mCR) 2%, partial response (PR) 10%, hematological improvement (HI) 10%, stable disease (SD) 33%, and progressive disease (PD) 24%. CR was associated with a better overall survival (OS) compared to all other response groups (P < 0.001). Among 470 pts treated with hypomethylating agent (HMA) as first‐line therapy, the overall Response Rate, defined as HI or better was 39%. The median OS from time of best response was 21 mo, 8 mo, 14 mo, 12 mo, 13 mo, and 8 mo for CR, mCR, PR, HI, SD, and PD, respectively (P < 0.001). We validated those results in a separate cohort of 539 higher‐risk MDS pts treated at Moffitt Cancer Center who received first‐line HMA therapy, particularly addressing the value of mCR and mCR+HI. mCR alone without HI, SD, and PD outcomes were inferior to CR, PR, mCR+HI, and HI. In conclusion, CR by IWG 2006 response criteria can be used as a surrogate endpoint for OS in higher‐risk MDS pts. Any response associated with restoration of effective hematopoiesis is associated with better outcome.

Azacitidine and Lenalidomide in Higher-Risk Myelodysplastic Syndromes. Long-Term Results of a Randomized Phase II Multicenter Study and Impact of Cytogenetic Scores and Mutational Status on Long-Lasting Responses

Azacitidine and Lenalidomide in Higher-Risk Myelodysplastic Syndromes. Long-Term Results of a Randomized Phase II Multicenter Study and Impact of Cytogenetic Scores and Mutational Status on Long-Lasting Responses

Feasibility and Outcomes of T-Cell Depleted Hematopoietic Stem Cell Transplantation in Patients with Relapsed or Refractory AML and High Risk MDS

Feasibility and Outcomes of T-Cell Depleted Hematopoietic Stem Cell Transplantation in Patients with Relapsed or Refractory AML and High Risk MDS

Acute Leukemia and High-Risk Myelodysplastic Syndromes in HIV-Positive Patients: 25-Years' Experience of the Rete Ematologica Lombarda (REL)

Acute Leukemia and High-Risk Myelodysplastic Syndromes in HIV-Positive Patients: 25-Years' Experience of the Rete Ematologica Lombarda (REL)

Efficacy and Safety of Azacitidine (AZA) in Combination with the Anti-PD-L1 Durvalumab (durva) for the Front-Line Treatment of Older Patients (pts) with Acute Myeloid Leukemia (AML) Who Are Unfit for Intensive Chemotherapy (IC) and Pts with Higher-Risk Myelodysplastic Syndromes (HR-MDS): Results from a Large, International, Randomized Phase 2 Study

Efficacy and Safety of Azacitidine (AZA) in Combination with the Anti-PD-L1 Durvalumab (durva) for the Front-Line Treatment of Older Patients (pts) with Acute Myeloid Leukemia (AML) Who Are Unfit for Intensive Chemotherapy (IC) and Pts with Higher-Risk Myelodysplastic Syndromes (HR-MDS): Results from a Large, International, Randomized Phase 2 Study

PD-L1 Blockade with Atezolizumab in Higher-Risk Myelodysplastic Syndrome: An Initial Safety and Efficacy Analysis

PD-L1 Blockade with Atezolizumab in Higher-Risk Myelodysplastic Syndrome: An Initial Safety and Efficacy Analysis

What Is the Optimal Time to Initiate Hypomethylating Agents (HMA) in Higher Risk Myelodysplastic Syndromes (MDS)?

What Is the Optimal Time to Initiate Hypomethylating Agents (HMA) in Higher Risk Myelodysplastic Syndromes (MDS)?

Does Trial Participation Improve Outcomes for Higher-Risk Myelodysplastic Syndromes (MDS) Patients Treated at Specialty Centers?

Background: For some rare cancers, better outcomes have been reported for patient (pts) treated at high volume or specialty centers compared to pts who did not receive such care. Greater availability of interventional clinical trials may be one of the drivers of better outcomes in specialty centers. However, not all pts referred to specialty centers are eligible or willing to participate in trials, and it is not known how outcomes compare for pts treated at specialty centers on clinical trials versus standard of care. In this study, we compared the outcomes of higher-risk MDS pts treated in and out of clinical trials at MDS specialty centers.Methods: Pts treated at MDS Clinical Research Consortium institutions (Moffitt Cancer Center, Cleveland Clinic, MD Anderson Cancer Center, Cornell University, Dana-Farber Cancer Institute, and Johns Hopkins) from 2006-2016 were included. Pts were diagnosed with MDS according to 2008 WHO criteria and identified as having “higher-risk” disease based on the revised IPSS (IPSS-R) criteria that included Intermediate, High and Very high risk categories. All pts treated outside clinical trials received hypomethylating agents (HMAs), either azacitidine (AZA) or decitabine (DAC). Trial and non-trial pts were matched 1:1 based on age, sex, number of treatment regimens prior to HMA (for non-trial pts) or experimental regimen (for trial pts) and IPSS-R categories. All non-trial pts included in the analysis received at least 4 cycles of AZA or DAC at the same institution. Transplant rates and overall survival (OS) were evaluated for association with trial participation. OS was estimated by the Kaplan-Meier method and compared using Cox proportional hazard regression with two-sided Wald test with adjustment for matching variables. The relative odds of transplant following initial treatment were estimated using logistic regression and compared with two-sided Wald test.Results: Of 774 pts in the MDS CRC database for whom complete data were available, 323 were treated in clinical trials and 451 were treated with AZA or DAC. The trial and non-trial MDS cohorts were well matched with regards to median age (68.5 vs 68.2 yrs; P=0.65), females (28.4% vs 29.9%, P=0.75), numbers of regimens (3 vs 3, P=0.77) and IPSS-R risk categories (P=0.86). Estimated median OS of pts treated in and out of clinical trials was 44.5 and 50.6 months (P=0.67), respectively. Compared to standard of care, trial participation was not associated with any survival advantage [Hazard ratio (HR), 95% CI, 0.94 (0.72-1.24), P=0.67] (Figure 1). Clinical trial participation did not significantly increase the odds of proceeding to transplant [Odds Ratio (OR) (95% CI), 1.5 (0.68, 1.61), P = 0.83)]. As shown in Table 1, in multivariate analyses, among all factors, increasing number of regimens received was significantly associated with better survival, possibly reflecting a bias towards healthier pts who survived longer to receive multiple regimens.Conclusions: In a matched-pair analysis, we found comparable survival outcomes between trial and non-trial higher-risk MDS pts treated at specialty centers. Our matched analysis failed to identify any statistical evidence to suggest that an average patient benefited from trial participation within the MDS CRC sites. Additional research is necessary to interrogate these comparisons for specific patient subpopulations by genetic alterations, co-morbidities and regimen sequence, for which trial participation may have been beneficial. Based on the population-average findings, however, we expect any improvement in survival to be modest. [Display omitted] DisclosuresKomrokji:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Roboz:Orsenix: Consultancy; Celltrion: Consultancy; Janssen Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Eisai: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; AbbVie: Consultancy; Eisai: Consultancy; Celltrion: Consultancy; Roche/Genentech: Consultancy; Aphivena Therapeutics: Consultancy; Sandoz: Consultancy; Roche/Genentech: Consultancy; Daiichi Sankyo: Consultancy; Argenx: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Celgene Corporation: Consultancy; Orsenix: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Sandoz: Consultancy; Argenx: Consultancy; Otsuka: Consultancy; Aphivena Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Cellectis: Research Funding. Nazha:MEI: Consultancy. Maciejewski:Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees.

Comparison of Two Different Therapeutic Regimens with Azacitidine and Lenalidomide (Combined versus Sequential) in Higher-Risk Myelodysplastic Syndromes. Update of Long-Term Results of a Randomized Phase II Multicenter Study

Comparison of Two Different Therapeutic Regimens with Azacitidine and Lenalidomide (Combined versus Sequential) in Higher-Risk Myelodysplastic Syndromes. Update of Long-Term Results of a Randomized Phase II Multicenter Study

A randomized, open-label, phase II study of azacitidine (AZA) in combination with durvalumab in patients (pts) with previously untreated higher-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) ineligible for hematopoietic stem cell transplantation (HSCT).

TPS7074 Background: Hypomethylating agents (HMAs) induce hematologic response in ~ 50% of higher-risk MDS pts; however, there are few treatment options for nonresponding pts at increased risk of AML progression and death. While older AML pts ineligible for HSCT have similar overall survival (OS) with AZA and chemotherapy (13.3 vs 12.2 months) (Döhner et al. Haematologica 2015;100:P566), there is an opportunity to further improve responses and OS in these pts. Blockade of the programmed cell death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway with immune checkpoint inhibitors is an emerging paradigm in anticancer therapy. PD-L1 is expressed on cells from AML and MDS pts; expression is upregulated on myeloblasts following HMA therapy (Yang et al. Leukemia 2014;28:1280) and during MDS transformation to AML (Ogata et al. Leuk Res 2012;36:1229). Durvalumab (MEDI-4736), a human anti-PD-L1 monoclonal antibody, is well tolerated and induces durable responses in pts with solid tumors (Lutzky et al. JCO 2014;32:3001). This randomized, open-label, phase 2 study evaluates efficacy and safety of subcutaneous (SC) AZA ± durvalumab in pts with higher-risk MDS and older pts with AML. Methods: Eligible MDS pts ( &lt; 20% blasts) aged ≥ 18 years, with IPSS intermediate- or high-risk MDS, and AML pts (≥ 20% blasts) aged ≥ 65 years, are randomized 1:1 to receive either AZA 75 mg/m2 SC for 7/28 days or AZA 75 mg/m2 SC for 7/28 days plus durvalumab 1500 mg IV on day 1 of 28-day cycles. Pts are stratified by cytogenetic risk: intermediate- vs poor-risk AML, and intermediate- vs poor-/very-poor-risk MDS. Primary endpoint is overall response rate per IWG 2006 criteria in MDS pts, and proportion of pts achieving complete response (CR) or CR with incomplete blood count recovery (CRi) per modified IWG 2003 criteria in AML pts. Other endpoints include safety, time to response, overall survival and PD-1/PD-L1 activity. Pts will be followed every 3 months until discontinuation. Target enrollment is 182 pts: 72 MDS pts and 110 AML pts. Enrollment began in June 2016 (ClinicalTrials.gov NCT02775903).