Oral azacitidine (oral‐AZA) maintenance is approved for adults with acute myeloid leukemia (AML) in remission post‐intensive chemotherapy, not proceeding to hematopoietic stem cell transplantation. This study aimed to develop a population pharmacokinetic (PopPK) model to characterize oral‐AZA concentration–time profiles in patients with AML, myelodysplastic syndrome, or chronic myelomonocytic leukemia. PopPK‐estimated exposure parameters were used to evaluate exposure–response relationships in the phase III QUAZAR AML‐001 study. The PopPK dataset comprised 286 patients with 1,933 evaluable oral‐AZA concentration records. The final PopPK model was a one‐compartment model with first‐order absorption incorporating an absorption lag time and first‐order elimination. Regression analyses identified two oral‐AZA exposure parameters (area under the plasma concentration–time curve at steady state (AUC ss ); maximum plasma concentration ( C max )) as statistically significant predictors for relapse‐free survival (hazard ratio (HR) = 0.521, P < 0.001; HR = 0.630, P = 0.013; respectively), and AUC ss as a significant predictor for overall survival (HR = 0.673, P = 0.042). The probability of grade ≥ 3 neutropenia was significantly increased with increases in AUC ss (odds ratio (OR) = 5.71, 95% confidence interval (CI) = 2.73–12.62, P < 0.001), cumulative AUC through cycles 1 to 6 (OR = 2.71, 95% CI = 1.76–4.44, P < 0.001), and C max at steady‐state (OR = 2.38, 95% CI = 1.23–4.76, P = 0.012). A decreasing trend was identified between AUC ss and relapse‐related schedule extensions, vs. an increasing trend between AUC ss and event‐related dose reductions. As the majority (56.8%) of patients required no dose modifications, and the proportions requiring schedule extension (19.4%) or dose reduction (22.9%) were almost equal, oral‐AZA 300 mg once daily for 14 days is the optimal dosing schedule balancing survival benefit and safety risk.

Background: Acute myeloid leukemia (AML) is characteristically heterogeneous, with outcomes impacted by age, cytogenetics and molecular factors. Despite achieving remission with frontline intensive chemotherapy (IC), most patients (pts) eventually relapse. In the QUAZAR trial (NCT01757535), oral azacitidine (Oral-AZA) prolonged OS and RFS vs placebo (PBO) in older pts with AML in remission post IC, including pts with investigator-reported NPM1-mutant (mut) AML at diagnosis (Dx; Wei et al., N Engl J Med 2020; Döhner et al., Blood 2022). The prognostic relevance of gene variants characterized at screening, prior to Oral-AZA maintenance, and the molecular architecture at relapse after Oral-AZA has not been reported. Aims: To 1) evaluate the association between baseline (BL; post IC) gene mutations on survival outcomes after Oral-AZA vs PBO; 2) compare the gene mutation profile at relapse in the two treatment (Tx) arms. Methods: In QUAZAR, 472 pts (≥55 years) with AML with intermediate- or poor-risk cytogenetics in remission after IC were randomized 1:1 to Oral-AZA or PBO. Among pts who consented, targeted NGS was performed using 37 myeloid-related genes in DNA isolated from bone marrow (BM) mononuclear cells at BL (n=310) and relapse (n=160). Mean NGS coverage was 13K reads and the median locus-specific minimal detectable variant allele frequency (VAF) was 0.12% (range: 0.02–2.79). RFS was time from randomization until relapse (≥5% BM blasts) or death, estimated by Kaplan–Meier methods. Nominal P values were derived from log-rank tests. Results: In the NGS biomarker population (n=310), median RFS (mRFS) for Oral-AZA vs PBO was 10.2 vs 4.7 months (mo), respectively. Of these, 221 (71.3%) had detectable mutations at BL, most frequently in DNMT3A (28.4%), TP53 (15.5%), IDH2 (12.3%), TET2 (11.9%), SRSF2 (11.0%), IDH1 (6.1%) and ASXL1 (5.5%). The frequency of gene mutations detected at BL was similar between Tx arms. The presence of ≥3 mutations was associated with shorter RFS in both Tx arms (≥3 vs <3 mutations: mRFS 7.4 vs 12.9 mo [P=0.008], respectively). RFS favored Oral-AZA in pts with low mutational burden at BL (<3 mutations: mRFS 12.9 vs 4.9 mo [P<0.001]; n=143 vs 128 [PBO]), but there was no significant difference between Tx arms in pts with higher mutational burden (≥3 mutations: mRFS 7.4 vs 1.9 mo [P=0.12]; n=22 vs 17 [PBO]). Analysis of BL gene variants showed RFS benefit for Oral-AZA (n=51) vs PBO (n=37) among pts with DNMT3A mutations (Figure). To determine if this effect was related to concurrent NPM1 mutations at Dx, we compared RFS between Tx arms in pts who had either single DNMT3Amut or co-mutated DNMT3Amut/NPM1mut AML (23.7% of the NPM1mut cohort). In pts with DNMT3Amut/NPM1mut AML, mRFS was not reached vs 6.2 mo for Oral-AZA vs PBO, respectively (HR [CI]: 0.04 [0.008, 0.235]; P<0.001). In pts with DNMT3Amut/NPM1wildtype AML, mRFS was 10.0 vs 4.6 mo for Oral-AZA vs PBO, respectively (HR [CI]: 0.40 [0.225, 0.724]; P=0.002; Figure). At relapse, the frequency of mutations was comparable between Tx arms (not shown). Summary/Conclusion: In pts with AML in remission post IC, post hoc analyses showed that Oral-AZA improved RFS vs PBO in pts with lower mutational burden at BL. RFS was improved by Oral-AZA in pts with DNMT3A mutations independent of NPM1 status at Dx. As DNMT3A mutations at BL could either be preleukemic or related to clonal hematopoiesis, factors responsible for improved outcome after Oral-AZA independent of NPM1 mutations remain to be determined. The spectrum of mutations at relapse was similar between Tx arms. Figure. RFS according to gene mutation status at BLKeywords: Acute myeloid leukemia, Genomics, AML, Clinical trial

Book Citations: Authors, Title, HemaSphere, 2023;7(S3):pages. The individual abstract DOIs can be found at https://journals.lww.com/hemasphere/pages/default.aspx. Disclaimer: Articles published in the journal HemaSphere exclusively reflect the opinions of the authors. The authors are responsible for all content in their abstracts including accuracy of the facts, statements, citing resources, etc. 762 At all cycles, NPM1 PCR and MFC MRD were generally concordant (Spearman r=0.5, P<0.0001); NPM1mut+/MFC MRD+ 25.4% (61/240) and NPM1mut–/MFC MRD– 44.2% (106/240). In outlier analyses, 17.5% of cases were NPM1mut+ by PCR (42/240) and MRD– by MFC (NPM1:ABL % 0.24 vs 44.3 for NPM1mut+/MRD+, n=61), whereas 12.9% (31/240) were NPM1mut–/MFC MRD+. Post IC, both MRD+ and – segments (n=15/80 vs 34/80) aligned with inferior or favorable RFS, respectively. Discordant MRD +/– and –/+ segments (n=16/80 vs 15/80) were not clearly associated with RFS. With Oral-AZA, 57% (8/14) of NPM1mut+ pts converted to NPM1mut– status or achieved log reduction in NPM1 (at C6/C12) vs 30% (3/10) with PBO. Of 44 paired NPM1mut– samples available at screening and relapse, 20.5% (9/44) remained NPM1mut– at relapse by PCR (no difference between Tx arms) and were characterized by other mutations detected by NGS including EZH2 (3 cases) and TET2, TP53 and PHF6 (2 cases). After adjusting for prognostic variables post IC, Oral-AZA remained independently associated with favorable RFS, while NPM1mut+ status by PCR post IC was associated with inferior RFS (Table). Summary/Conclusion: For pts with NPM1mut AML at Dx, NPM1 PCR was positive in 38.3% at screening. NPM1mut was not detected in 20.5% of cases at morphologic relapse. For pts with NPM1mut AML at Dx, PCR is informative and concordant with MFC MRD. NPM1 monitoring has prognostic value in AML and, importantly, achievement of NPM1 negativity post IC is associated with better clinical outcomes with Oral-AZA. Table. Multivariable analysis of NPM1+ pts HemaSphere | 2023;7(S3) EHA2023 Hybrid Congress Copyright Information: (Online) ISSN: 2572-9241 © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association. This is an open access Abstract Book distributed under the Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) which allows third parties to download the articles and share them with others as long as they credit the author and the Abstract Book, but they cannot change the content in any way or use them commercially. Abstract Book Citations: Authors, Title, HemaSphere, 2023;7(S3):pages. The individual abstract DOIs can be found at https://journals.lww.com/hemasphere/pages/default.aspx.Book Citations: Authors, Title, HemaSphere, 2023;7(S3):pages. The individual abstract DOIs can be found at https://journals.lww.com/hemasphere/pages/default.aspx. Disclaimer: Articles published in the journal HemaSphere exclusively reflect the opinions of the authors. The authors are responsible for all content in their abstracts including accuracy of the facts, statements, citing resources, etc. 763

Oral azacitidine (Oral-AZA) maintenance therapy improved relapse-free (RFS) and overall survival (OS) significantly versus placebo for AML patients in remission after intensive chemotherapy (IC) in the phase 3 QUAZAR AML-001 study. Immune profiling was performed on the bone marrow (BM) at remission and on-treatment in a subset of patients with the aim of identifying prognostic immune features and evaluating associations of on-treatment immune effects by Oral-AZA with clinical outcomes. Post-IC, increased levels of lymphocytes, monocytes, T cells and CD34 + CD117+ BM cells were prognostically favourable for RFS. CD3+ T-cell counts were significantly prognostic for RFS in both treatment arms. At baseline, high expression of the PD-L1 checkpoint marker was identified on a subset of CD34 + CD117+ BM cells; many of which were PD-L2+. High co-expression of T-cell exhaustion markers PD-1 and TIM-3 was associated with inferior outcomes. Oral-AZA augmented T-cell numbers during early treatment, increased CD4+:CD8+ ratios and reversed T-cell exhaustion. Unsupervised clustering analysis identified two patient subsets defined by T-cell content and expression of T-cell exhaustion markers that were enriched for MRD negativity. These results indicate that Oral-AZA modulates T-cell activity in the maintenance setting of AML, and these immune-mediated responses are associated with clinical outcomes.

Background: Acute myeloid leukemia (AML) is a genetically heterogeneous disease and despite some patients (pts) achieving remission with frontline intensive chemotherapy (IC), most eventually relapse. In the QUAZAR trial (NCT01757535), oral azacitidine (Oral-AZA) prolonged overall survival and relapse-free survival (RFS) vs placebo (PBO) in older pts with AML in remission post IC (Wei et al, N Engl J Med 2020). Here, we studied the molecular landscape and clonal dynamics of pts treated with Oral-AZA/PBO in the QUAZAR study. The mutational landscape for older patients with AML in remission after IC may be confounded by persistence of pre-leukemic (PL) or age-related clonal hematopoietic (CH) variants. The implications of these residual mutations on disease relapse and treatment (Tx) outcome are largely unknown. Aims: 1) characterize the mutational landscape from remission bone marrow at baseline (BL) prior to Oral-AZA maintenance (i.e., in remission post-IC); 2) determine the fate of variants over time and at relapse in the Oral-AZA vs PBO arms; 3) examine associations between mutational landscape and relapse risk between Tx arms. Methods: In QUAZAR, 472 pts (≥55 years) with AML with intermediate- or poor-risk cytogenetics in remission after IC (BL) were randomized 1:1 to Oral-AZA or PBO. Among pts who consented to biomarker analyses (n=310), targeted NGS (37 myeloid genes) was performed on bone marrow DNA at BL (Oral-AZA/PBO: n=165/145), cycle 6 (n=107/79) and relapse (n=83/77). Mean NGS coverage was 13K reads and median minimal detectable variant allele frequency (VAF) was 0.12% (range: 0.02-2.79). Clonal variants were categorized by the longitudinal association between VAF and blast percentage (slope of leukemic variants >0.1; PL/CHIP <0.1). RFS was computed from time of randomization to relapse (≥5% BM blasts) or death, estimated by Kaplan-Meier methods. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained from Cox regression models. Nominal P values were derived from log-rank tests. Results: In the NGS cohort (n=310), median RFS (mRFS) for Oral-AZA vs PBO was 10.2 vs 4.7 months (mo), respectively. At BL, prior to maintenance Tx, 221 (71.3%) had detectable mutations, the most frequently occurring mutations (>5% of pts) were in DNMT3A (28.4%), TP53 (15.5%), IDH2 (12.3%), TET2 (11.9%), SRSF2 (11.0%), IDH1 (6.1%) and ASXL1 (5.5%). At BL, 110/310 (35.5%) pts had VAF >5%, potentially representing persistence of PL/CH variants in remission. Comparative analysis of all gene variants at BL and relapse revealed that some VAFs increased with blast frequency, while other variants remained largely static. Applying a variant classification algorithm, 97/258 pts had potential leukemic variants detected at BL. These involved DNMT3A (16.1%), SRSF2 (7.1%), TP53 (7.1%) and IDH2 (5.7%). PL/CH variants included DNMT3A (17.5%), TP53 (8%), IDH2 (5.7%) or TET2 (5.7%). TP53 was detected in 19.4% PL/CH variants (mean VAF 1.7%; range 0.2-13.4). Notably, when analyses were limited to potential leukemic variants at BL (<5% VAF), their presence was correlated with worse RFS (PBO: mRFS for 0, 1 or 2+ mutations was 6.1, 4.7 or 1.9 mo, respectively). The presence of ≥2 leukemic mutations was associated with shorter RFS only in PBO arm (mRFS vs <2 mutations: 1.9 vs 5.7 mo, P=0.02; Oral-AZA: 10.2 vs 10.2 mo). RFS favored Oral-AZA in pts with low mutational burden at BL (<2 mutations: mRFS 10.2 vs 5.7 mo [ P=0.003]; n=145 vs 122 [PBO]), and in a small subset of pts with higher mutational burden (≥2 mutations: mRFS 10.2 vs 1.9 mo [ P=0.008]; n=14 vs 13 [PBO]). Oral-AZA prolonged RFS vs PBO in pts across most mutational subtypes, when assessed for mutations that were deemed potentially leukemic (Figure). At relapse, the frequency of mutations, hotspots variants and co-mutations were comparable between Tx arms. Mutation-based pathway analysis indicated Ras pathway genes were enriched at relapse in PBO (28.6%) vs Oral-AZA arm (14.5%, P=0.03). Summary: In pts with AML in remission post IC, post-hoc analyses showed that Oral-AZA improved RFS vs PBO regardless of the mutational landscape at baseline. The spectrum of mutations at relapse was similar between Tx arms, suggesting that Oral-AZA maintenance prolongs remission without altering mutational heterogeneity.

Epigenetic dysregulation leads to aberrant DNA hypermethylation and is common in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). A large number of clinical trials in AML, MDS, and other hematologic malignancies have assessed hypomethylating agents (HMAs), used alone or in combination with other drugs, in the frontline, maintenance, relapsed/refractory, and peritransplant settings. Effective maintenance therapy has long been a goal for patients with AML in remission. Previous large, randomized clinical trials of maintenance with HMAs or other agents had not shown meaningful improvement in overall survival. Oral azacitidine (Oral-AZA [CC-486]) is approved in the United States, Canada, and European Union for treatment of adult patients with AML in first complete remission (CR) or CR with incomplete blood count recovery (CRi) following intensive induction chemotherapy who are ineligible for hematopoietic cell transplant. Regulatory approvals of Oral-AZA were based on outcomes from the randomized, phase III QUAZAR AML-001 trial, which showed a median overall survival advantage of 9.9 months with Oral-AZA versus placebo. Oral-AZA allows convenient extended AZA dosing for 14 days per 28-day treatment cycle, which is not feasible with injectable AZA. Focusing on AML and MDS, this report reviews the rationale for the use of orally bioavailable AZA and its potential use in all-oral combination therapy regimens; the unique pharmacokinetic and pharmacodynamic profile of Oral-AZA compared with injectable AZA; the clinical safety and efficacy of Oral-AZA maintenance therapy in patients with AML in first remission and for treatment of patients with active MDS; and ongoing Oral-AZA clinical trials.

BackgroundFor patients with lower-risk (LR) myelodysplastic syndromes (MDS), overall survival (OS) is rarely a primary clinical trial endpoint. Treatments such as lenalidomide can reduce red blood cell (RBC) transfusion burden (TB) and serum ferritin, but the long-term impact on OS remains undetermined.Patients and MethodsData from 3 trials evaluating lenalidomide in patients with LR-MDS (the phase 2 MDS-003 and phase 3 MDS-004 trials in del[5q]; the phase 3 trial MDS-005 in non-del[5q] patients) were pooled. Predictors of OS were assessed by multivariate analysis using time-dependent models for TB and RBC transfusion independence (RBC-TI), and a landmark analysis of RBC-TI at 17 weeks. Separate analyses using MDS-004 and MDS-005 data determined the relationship between OS and serum ferritin.ResultsMedian follow-up for MDS-003, MDS-004, and MDS-005 was 3.2, 3.0, and 1.7 years, respectively. In multivariate analyses, transfusion of ≥6 RBC units over 8 weeks was a significant predictor of shorter OS vs. 0 units in the time-dependent TB model (hazard ratio [HR] 4.65; 95% confidence interval [CI] 3.32-6.52; P < .0001). RBC-TI achievement was associated with prolonged OS in the time-dependent (HR 0.48; 95% CI 0.37-0.62; P < .0001) and landmark model (HR 0.57; 95% CI 0.44-0.75; P < .0001). Increased serum ferritin was associated with shorter OS (P < .0001).ConclusionThis analysis of prospective trial data in patients with LR-MDS confirms lenalidomide may improve OS by reducing TB and serum ferritin. OS should be considered as an endpoint in future lower risk MDS clinical trials.

Measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy is predictive of early relapse and poor survival. Postremission maintenance therapy that prolongs MRD negativity or converts MRD+ patients to MRD- status may delay or prevent relapse and improve overall survival (OS). In the phase 3 QUAZAR AML-001 trial, oral azacitidine (oral-AZA; formerly CC-486), a hypomethylating agent, significantly prolonged OS and relapse-free survival (RFS) compared with placebo in patients aged ≥55 years with AML in first remission after intensive chemotherapy who were not candidates for hematopoietic stem cell transplantation. In this trial, MRD (≥0.1% leukemic cells in bone marrow) was assessed by multiparameter flow cytometry in serial samples collected at baseline and on day 1 of every 3 cycles. As expected, baseline MRD status was significantly associated with both OS and RFS. Multivariate analyses showed oral-AZA significantly improved OS and RFS vs placebo independent of baseline MRD status. Oral-AZA treatment also extended the duration of MRD negativity by 6 months vs placebo and resulted in a higher rate of conversion from MRD+ at baseline to MRD- during treatment: 37% vs 19%, respectively. In the oral-AZA arm, 24% of MRD responders achieved MRD negativity >6 months after treatment initiation. Although presence or absence of MRD was a strong prognostic indicator of OS and RFS, there were added survival benefits with oral-AZA maintenance therapy compared with placebo, independent of patients' MRD status at baseline. Registered at clinicaltrials.gov as #NCT01757535.

At LT follow-up, median OS was unchanged, but at later time-points the tails of the Oral-AZA and placebo OS curves showed greater separation, indicating sustained LT OS benefit with Oral-AZA. Intermediate-risk cytogenetics and NPM1 at diagnosis, and absence of post-IC MRD, were associated with LT survival.

The randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial (ClinicalTrials.gov identifier: NCT01757535) evaluated oral azacitidine (Oral-AZA) in patients with acute myeloid leukemia (AML) in first remission after intensive chemotherapy (IC) who were not candidates for hematopoietic stem cell transplantation. Eligible patients were randomized 1:1 to Oral-AZA 300 mg or placebo for 14 days per 28-day cycle. We evaluated relapse-free survival (RFS) and overall survival (OS) in patient subgroups defined by NPM1 and FLT3 mutational status at AML diagnosis and whether survival outcomes in these subgroups were influenced by presence of post-IC measurable residual disease (MRD). Gene mutations at diagnosis were collected from patient case report forms; MRD was determined centrally by multiparameter flow cytometry. Overall, 469 of 472 randomized patients (99.4%) had available mutational data; 137 patients (29.2%) had NPM1 mutations (NPM1mut), 66 patients (14.1%) had FLT3 mutations (FLT3mut; with internal tandem duplications [ITD], tyrosine kinase domain mutations [TKDmut], or both), and 30 patients (6.4%) had NPM1mut and FLT3-ITD at diagnosis. Among patients with NPM1mut, OS and RFS were improved with Oral-AZA by 37% (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.41-0.98) and 45% (HR, 0.55; 95% CI, 0.35-0.84), respectively, vs placebo. Median OS was improved numerically with Oral-AZA among patients with NPM1mut whether without MRD (48.6 months vs 31.4 months with placebo) or with MRD (46.1 months vs 10.0 months with placebo) post-IC. Among patients with FLT3mut, Oral-AZA improved OS and RFS by 37% (HR, 0.63; 95% CI, 0.35-1.12) and 49% (HR, 0.51; 95% CI, 0.27-0.95), respectively, vs placebo. Median OS with Oral-AZA vs placebo was 28.2 months vs 16.2 months, respectively, for patients with FLT3mut and without MRD and 24.0 months vs 8.0 months for patients with FLT3mut and MRD. In multivariate analyses, Oral-AZA significantly improved survival independent of NPM1 or FLT3 mutational status, cytogenetic risk, or post-IC MRD status.

Azacitidine-mediated hypomethylation promotes tumor cell immune recognition but may increase the expression of inhibitory immune checkpoint molecules. We conducted the first randomized phase 2 study of azacitidine plus the immune checkpoint inhibitor durvalumab vs azacitidine monotherapy as first-line treatment for higher-risk myelodysplastic syndromes (HR-MDS). In all, 84 patients received 75 mg/m2 subcutaneous azacitidine (days 1-7 every 4 weeks) combined with 1500 mg intravenous durvalumab on day 1 every 4 weeks (Arm A) for at least 6 cycles or 75 mg/m² subcutaneous azacitidine alone (days 1-7 every 4 weeks) for at least 6 cycles (Arm B). After a median follow-up of 15.25 months, 8 patients in Arm A and 6 in Arm B remained on treatment. Patients in Arm A received a median of 7.9 treatment cycles and those in Arm B received a median of 7.0 treatment cycles with 73.7% and 65.9%, respectively, completing ≥4 cycles. The overall response rate (primary end point) was 61.9% in Arm A (26 of 42) and 47.6% in Arm B (20 of 42; P = .18), and median overall survival was 11.6 months (95% confidence interval, 9.5 months to not evaluable) vs 16.7 months (95% confidence interval, 9.8-23.5 months; P = .74). Durvalumab-related adverse events (AEs) were reported by 71.1% of patients; azacitidine-related AEs were reported by 82% (Arm A) and 81% (Arm B). Grade 3 or 4 hematologic AEs were reported in 89.5% (Arm A) vs 68.3% (Arm B) of patients. Patients with TP53 mutations tended to have a worse response than patients without these mutations. Azacitidine increased programmed cell death ligand 1 (PD-L1 [CD274]) surface expression on bone marrow granulocytes and monocytes, but not blasts, in both arms. In summary, combining azacitidine with durvalumab in patients with HR-MDS was feasible but with more toxicities and without significant improvement in clinical outcomes over azacitidine alone. This trial was registered at www.clinicaltrials.gov as #NCT02775903.

Evidence suggests that combining immunotherapy with hypomethylating agents may enhance antitumor activity. This phase 2 study investigated the activity and safety of durvalumab, a programmed death-ligand 1 (PD-L1) inhibitor, combined with azacitidine for patients aged ≥65 years with acute myeloid leukemia (AML), including analyses to identify biomarkers of treatment response. Patients were randomized to first-line therapy with azacitidine 75 mg/m2 on days 1 through 7 with (Arm A, n = 64) or without (Arm B, n = 65) durvalumab 1500 mg on day 1 every 4 weeks. Overall response rate (complete response [CR] + CR with incomplete blood recovery) was similar in both arms (Arm A, 31.3%; Arm B, 35.4%), as were overall survival (Arm A, 13.0 months; Arm B, 14.4 months) and duration of response (Arm A, 24.6 weeks; Arm B, 51.7 weeks; P = .0765). No new safety signals emerged with combination treatment. The most frequently reported treatment-emergent adverse events were constipation (Arm A, 57.8%; Arm B, 53.2%) and thrombocytopenia (Arm A, 42.2%; Arm B, 45.2%). DNA methylation, mutational status, and PD-L1 expression were not associated with response to treatment. In this study, first-line combination therapy with durvalumab and azacitidine in older patients with AML was feasible but did not improve clinical efficacy compared with azacitidine alone. ClinicalTrials.gov: NCT02775903.

PURPOSE Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion–dependent anemia and thrombocytopenia. METHODS Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI). RESULTS Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 109/L, and absolute neutrophil count was 1.3 × 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI ( P = .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 109/L. CONCLUSION CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed.

BACKGROUND: Current guidelines for AML ascribe disease-risk partly based on NPM1 and FLT3 mutational status. NPM1 mutations (mut) occur in 25%-30% of patients (pts) with AML and are associated with favorable prognosis in the absence of co-occurring FLT3-ITD. FLT3-ITD alterations are observed in ~15-30% of AML pts and confer poor prognosis, whereas the prognostic implication of FLT3-TKD point mutations (~7% of pts) is less clear. Post-IC, absence of MRD is associated with favorable relapse-free and overall survival (RFS/OS). In the randomized, phase 3 QUAZAR AML-001 trial, Oral-AZA (CC-486) significantly prolonged OS and RFS vs placebo (PBO) in older pts with AML in first remission after IC (Wei, NEJM 2020). It is of high interest to understand the effects of Oral-AZA in pts with NPM1 and/or FLT3 mutations, and whether their outcomes are influenced by post-IC MRD status.

Abstract Background AML may be initiated by cytogenetic alterations or mutations in genes encoding epigenetic regulators. Epigenetic dysregulation influences the transformation of hematopoietic stem cells or their downstream progenitors into self-renewing leukemic stem cells (LSCs), which contribute to AML pathogenesis and tumor growth. Residual chemoresistant LSCs are implicated in relapsed and/or refractory (R/R) AML, a life-threatening disease with limited treatment options. The epigenetic eraser LSD1 demethylates histone lysine residues to alter gene expression, is essential for hematopoiesis, and is often overexpressed in LSCs in AML. CC-90011 is a potent, selective, and reversible oral inhibitor of LSD1 that has shown antitumor effects in solid-tumor and AML cell-line models. CC-90011 monotherapy had a favorable safety profile and showed evidence of antitumor activity in patients with advanced solid tumors and R/R non-Hodgkin lymphoma (Hollebecque et al. ESMO TAT 2021. Abstract 7O). CC-90011 combined with etoposide plus carboplatin or cisplatin was well tolerated in patients with extensive-stage small cell lung cancer (Ponce at al. ELCC 2021. Abstract 50P). VEN plus AZA has emerged as standard therapy for elderly patients with AML. Adding CC-90011 to VEN and AZA may inhibit the aberrant LSD1 activity associated with AML pathogenesis and LSC propagation, increase sensitization to VEN and AZA, and produce deeper and more durable responses than VEN plus AZA alone. Study Design and Methods CC-90011-AML-002 (NCT04748848) is a phase 1/2, open-label, multicenter study to evaluate the safety, tolerability, and preliminary efficacy of CC-90011 plus concurrent VEN and AZA in adult patients with R/R AML or in patients with newly diagnosed AML (ndAML) who are ≥ 75 years of age or are 18-74 years of age and ineligible for intensive induction chemotherapy. The study has 2 dose-escalation parts in patients with R/R AML (part 1) or ndAML (part 2), and a randomized dose-expansion part in patients with ndAML (part 3). Part 3 will use a 2:1 randomized design with Bayesian informative prior to calculate the posterior probability that the complete remission (CR) rate in the treatment arm is higher than in the control arm. Enrolled patients must have a projected life expectancy of ≥ 12 weeks, ECOG performance status of 0-2, white blood cell count ≤ 25 × 10 9/L, and adequate organ function. Patients will be excluded if they are candidates for FLT3 inhibitor therapy or have suspected or proven acute promyelocytic leukemia, favorable-risk cytogenetics, or central nervous system involvement. In parts 1 and 2, patients will receive CC-90011 20, 40, or 60 mg plus VEN and AZA (3-6 patients per treatment arm). In part 3, patients will receive VEN plus AZA with or without CC-90011 administered at the recommended phase 2 dose (RP2D) determined in part 2 (approximately 64 and 32 patients, respectively), with an interim analysis for futility once 50% of patients have been randomized and completed 3 treatment cycles. In all parts, CC-90011 will be administered orally on days 1, 8, and 15 of each 28-day cycle, AZA 75 mg/m 2 will be administered intravenously or subcutaneously on days 1-7 of each cycle, and oral VEN 400 mg will be administered on days 1-28 of each cycle, with a dose ramp-up on days 1 and 2 of cycle 1. VEN will be given ≥ 6 hours after CC-90011 to minimize drug-drug interactions. For clinical outcome evaluation, patients should be treated for ≥ 3 cycles but can discontinue sooner due to disease progression, unacceptable adverse events, intercurrent illness, or investigator's decision. Primary objectives are to evaluate the safety and tolerability of CC-90011 plus VEN and AZA, and to determine the maximum tolerated dose and/or RP2D of CC-90011. Secondary objectives are to assess the preliminary efficacy of CC-90011 plus VEN and AZA in parts 1-3, and to evaluate the minimal residual disease (MRD) response and conversion rates by multicolor flow cytometry and/or next-generation sequencing in parts 2 and 3. Preliminary efficacy will be determined using CR rate, rate of CR with partial or incomplete hematologic recovery, overall response rate, and duration of response in parts 1-3, and event-free and overall survival in part 3. Because CC-90011 is expected to target LSCs, its addition to VEN plus AZA is predicted to increase the depth and durability of response by MRD evaluation compared with control, rather than increase remission rates. Figure 1 Figure 1. Disclosures DiNardo: AbbVie: Consultancy, Research Funding; Novartis: Honoraria; Foghorn: Honoraria, Research Funding; Takeda: Honoraria; ImmuneOnc: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Forma: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Agios/Servier: Consultancy, Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; GSK: Consultancy; Astex: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees. Erba: AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau; AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee; AbbVie Inc: Other: Independent review committee. Mawad: Abbvie: Speakers Bureau. Kremyanskaya: Protagonist Therapeutics: Consultancy, Research Funding; Incyte: Research Funding; Constellation: Research Funding; Astellas: Research Funding; Bristol Myers Squibb: Research Funding; Chimerix: Research Funding; Astex: Research Funding. Blachly: AstraZeneca: Consultancy, Honoraria; KITE: Consultancy, Honoraria; INNATE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Carraway: Celgene, a Bristol Myers Squibb company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Other: Independent review committee; AbbVie: Other: Independent review committee; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astex: Other: Independent review committee; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Youn: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Garzon: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lopes de Menezes: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Martin-Regueira: Bristol Myers Squibb: Current Employment, Current holder of individual stocks in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Beach: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Watts: Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Rafael Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding.