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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.

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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.

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.

7014 Background: Demographic and disease factors influence outcomes for patients (pts) with AML. In the phase 3 QUAZAR AML-001 trial, Oral-AZA significantly prolonged OS and RFS vs. placebo (PBO) for pts with AML in first remission after IC (Wei, NEJM, 2020). Univariate analyses showed OS and RFS benefits with Oral-AZA vs. PBO across pt subgroups defined by baseline (BL) characteristics. MV analyses were performed to identify BL characteristics independently predictive of OS/RFS in QUAZAR AML-001, and to assess Tx effects of Oral-AZA vs. PBO on survival when adjusted for BL factors. Methods: Pts were aged ≥55 yrs with AML in complete remission (CR) or CR with incomplete count recovery (CRi) after induction ± consolidation. Within 4 months of CR/CRi, pts were randomized 1:1 to receive Oral-AZA 300 mg or PBO for 14d/28d cycle. Cox proportional hazards models were used to estimate Tx effects of Oral-AZA vs. PBO on OS and RFS, adjusting for BL age, sex, ECOG PS score, cytogenetic risk at diagnosis (Dx), prior MDS, geographic region, CR/CRi after induction (per investigator) and at BL (per sponsor), MRD status, receipt of consolidation, number of consolidation cycles, platelet count, and ANC. In a stepwise procedure, randomized Tx and BL variables were selected incrementally into a Cox model if P ≤ 0.25. After each addition, the contribution of the covariate adjusted for other covariates in the model was evaluated and retained in the model if P ≤ 0.15. Results : Oral-AZA Tx remained a significant independent predictor of improved OS (HR 0.70) and RFS (HR 0.57) vs. PBO after controlling for BL characteristics (Table). MRD status, cytogenetic risk, and pt age were each also independently predictive of OS and RFS. Response after induction (CR vs. CRi) and BL ANC were predictive of OS but not RFS, whereas prior MDS, CR/CRi at BL, and number of consolidation cycles were only predictive of RFS. Conclusions: Tx with Oral-AZA reduced the risk of death by 30% and risk of relapse by 43% vs. PBO independent of BL characteristics. Cytogenetic risk at Dx, MRD status, and pt age also independently predicted survival outcomes. Clinical trial information: NCT01757535. [Table: see text]

7513 Background: A goal of AML maintenance therapy is to decrease the risk of relapse by suppressing growth of residual leukemic cells post-induction. CC-486 is an oral hypomethylating agent that allows for extended dosing schedules ( >7 days [d]/28d cycle) to sustain therapeutic activity. In the QUAZAR AML-001 trial (NCT01757535), CC-486 maintenance treatment (Tx) significantly prolonged overall (OS) and relapse-free survival vs. placebo (PBO) in pts with AML in first remission following induction chemotherapy (IC), who were not candidates for hematopoietic stem cell transplant (HSCT). Pts initially received CC-486 or PBO for 14d/cycle, but pts who relapsed with 5–15% blasts could receive escalated 21d/cycle dosing. We review outcomes of pts who received 21d dosing in QUAZAR AML-001. Methods: Pts were aged ≥ 55 years, with intermediate- or poor-risk cytogenetics and ECOG PS ≤ 3, and had achieved first CR/CRi after IC ± consolidation. Within 4 mo of CR/CRi, pts were randomized 1:1 to CC-486 300 mg or PBO QD on d 1–14 of 28d Tx cycles. CR/CRi status was assessed every 3 cycles. Pts relapsing with 5%–15% blasts in blood or bone marrow could receive study drug for 21d/cycle at the investigator’s discretion. Tx could continue until > 15% blasts, unacceptable toxicity, or HSCT. Results: 91 patients (CC-486, 51/238 [21%]; PBO, 40/234 [17%]) were assigned to ≥ 1 21d/cycle dosing schedule. Median time to dose escalation was 9.2 mo (range 1.0-52.7) for CC-486 and 6.0 mo (0.5-19.3) for PBO. Median number of 21d dosing cycles was 2.0 (range 1-45) in the CC-486 arm and 2.0 (1-16) in the PBO arm; 43% and 18% of pts, respectively, received > 3 cycles of 21d dosing. Among 78 evaluable pts, 10/43 (23%) CC-486 pts and 4/35 (11%) PBO pts regained CR/CRi (central review) during dose escalation. Median OS from randomization was 22.8 mo vs. 14.6 mo with CC-486 vs. PBO, respectively (HR 0.66 [95%CI 0.42, 1.0]; P = 0.073), and 1-year survival rates were 80.4% vs. 59.5% (+20.9% [95%CI 2.1%, 39.7%]). The most common AEs with first onset during 21d dosing were febrile neutropenia (CC-486 24%, PBO 3%), thrombocytopenia (22%, 23%), anemia (22%, 20%), and neutropenia (20%, 10%). Conclusions: Escalated 21d CC-486 dosing was well tolerated and resulted in prolongation of OS and restoration of remission in approximately one-fourth of pts. Hematologic AEs first reported during escalated dosing in both Tx arms may be due in part to disease relapse. A 21d dosing schedule should be considered for pts receiving CC-486 who experience relapse with 5–15% blasts. Clinical trial information: NCT01757535 .

7530 Background: About 40-50% of older patients (pts) with AML attain complete remission (CR) with induction chemotherapy (IC) but relapse is common.Effective, well-tolerated maintenance treatment (Tx) is needed for older pts in remission who are not eligible for hematopoietic stem cell transplant (HSCT). CC-486 is an oral hypomethylating agent that allows for extended dosing schedules ( >7 days [d]/cycle) to sustain therapeutic activity. In the phase III placebo (PBO)-controlled QUAZAR AML-001 trial (NCT01757535), CC-486 maintenance therapy in pts with AML in first remission following IC produced significant improvements in overall and relapse-free survival. Here we report safety and tolerability findings among pt subgroups defined by age at study entry. Methods: Eligible pts were ≥ 55 yrs of age, with de novo or secondary AML, intermediate or poor risk cytogenetics, and ECOG PS ≤ 3; had achieved first CR or CRi after IC ± consolidation; and were not candidates for HSCT. Within 4 mo of CR/CRi, pts were randomized 1:1 to CC-486 300 mg or PBO QD on d 1–14 of repeated 28d Tx cycles. Safety was assessed across 3 age subgroups (≥ 55 to < 65, ≥ 65 to < 75, and ≥ 75 yrs) in pts who received ≥ 1 dose of study drug. Adverse events (AEs) were coded using MedDRA v. 22.0 and graded by NCI-CTCAE v. 4.0. Results: 469 pts ( >99% of all enrolled pts) were evaluable for safety (CC-486 n = 236; PBO n = 233). Median age was 68 yrs (range 55-86). Age distribution was similar between the two Tx arms (Table). Between Tx arms, AE rates within each age stratum were similar to rates in the overall study population. The most common AEs (any grade) with CC-486 were GI events, which were more frequent than in the PBO arm across age groups. Within the CC-486 arm, AE rates were generally consistent across age groups, except for constipation, which was > 20% more frequent in pts aged ≥ 75 yrs, and thrombocytopenia, which was ≥ 20% less frequent in this group (Table). Overall, 13% and 4% of pts in the CC-486 and PBO groups discontinued Tx due to AEs. Conclusions: In QUAZAR AML-001, CC-486 was generally well tolerated in all age groups, including elderly pts aged ≥ 75 yrs. Clinical trial information: NCT01757535 . [Table: see text]

7533 Background: Effective AML maintenance treatment (Tx) should decrease the risk of relapse and prolong survival without compromising HRQoL. In the placebo (PBO)-controlled phase III QUAZAR AML-001 trial (NCT01757535), CC-486, an oral hypomethylating agent, provided significant improvements in overall (OS) and relapse-free survival (RFS) in patients (pts) with AML in first remission following IC. Here we present pt-reported HRQoL outcomes from that study. Methods: Eligible pts were ≥ 55 yrs of age with intermediate- or poor-risk cytogenetics and ECOG PS ≤ 3, and in CR/CRi after IC ± consolidation. Pts were randomized 1:1 to CC-486 300 mg or PBO QD on days (d) 1–14 of 28d Tx cycles. HRQoL was assessed by FACIT-Fatigue scale and EQ-5D-3L health utility index, completed on d1 of each cycle and at end of Tx (EOT). Endpoints include Tx differences in mean changes from baseline (BL), and proportions of pts with clinically meaningful change from BL (improvement, no change, deterioration). Evaluable pts had an HRQoL assessment at BL and ≥ 1 post-BL visit. Stratified ANCOVA models included Tx and BL scores as covariates. Results: In all, 225/238 pts (95%) in the CC-486 arm were evaluable for FACIT-Fatigue and EQ-5D-3L, and 219/234 pts (94%) in the PBO arm were evaluable for FACIT-Fatigue and 217 (93%) for EQ-5D-3L. Pt characteristics were comparable between Tx arms. Most pts (61%) were 65-74 yrs of age. Median number of CC-486 Tx cycles was 12 and PBO cycles was 7. Compliance rates were > 95% at BL and remained high ( > 85%) at all post-BL visits except for EOT. At BL, pts in both Tx arms had comparable low levels of fatigue and generally good HRQoL relative to an age-matched general population. There were no meaningful differences between CC-486 and PBO in mean changes from BL in FACIT-Fatigue or EQ-5D-3L scores at any post-BL visit. There was no statistically significant difference between Tx arms in proportion of pts with a clinically meaningful deterioration in FACIT-Fatigue score at any post-BL visit except at cycle 29 (likely due to chance; no adjustment made for multiple testing), or in EQ-5D-3L at any visit. Median time to deterioration was not significantly different between CC-486 and PBO on the FACIT-Fatigue scale (41 vs 44 weeks, respectively; P = 0.70) or the EQ-5D-3L (200 vs 164 weeks; P = 0.63). Conclusions: HRQoL and low levels of fatigue were preserved with CC-486 maintenance Tx. CC-486 significantly improved OS and RFS while maintaining HRQoL comparable to PBO. Clinical trial information: NCT01757535 .

Parenteral azacitidine improves overall survival in higher-risk myelodysplastic syndromes. An oral azacitidine formulation would allow extended dosing schedules, potentially improving safety and/or efficacy. Two Phase 1 studies evaluated the pharmacokinetics (PK) of oral azacitidine in subjects with hematologic malignancies. Study 1 evaluated different oral formulations (immediate release tablet [IRT], enteric-coated tablet, and capsule; N = 16). Study 2 assessed the effect of food (Part 1; N = 17) and gastric pH modulation with omeprazole (Part 2; N = 14) on oral azacitidine PK. Azacitidine plasma concentration-time profiles for IRT and capsule formulations were similar, with more rapid time to maximum plasma concentration (Tmax ) than the enteric-coated tablet. Study 2 evaluated only IRT formulations of oral azacitidine. Under fed condition, Tmax was delayed ∼1.5 hours but area under the concentration-time curve (AUC∞ ) and maximum plasma concentrations (Cmax ) were comparable under fed and fasted conditions. Mean azacitidine AUC∞ and Cmax increased upon omeprazole co-administration (18.3% and 13.2%, respectively, vs. oral azacitidine alone), but not to a clinically meaningful extent. High inter-subject variability in AUC∞ and Cmax (%CV range 46.4-68.9%) was observed. Oral azacitidine is rapidly absorbed with little or no effect of food on PK parameters, and does not require dose adjustments when taking a proton-pump inhibitor.

6606 Background: Inactivation of tumor-suppressor genes by DNA hypermethylation of CpG islands in gene promoter regions occurs frequently in MDS. We explored the relationship between methylation in...