Oral Azacitidine Research Articles

POSTER: AML-068 Survival Differences in Patients With Acute Myeloid Leukemia (AML) Treated With Oral Azacitidine (Oral-AZA) as Maintenance and Those Eligible but Not Treated in a US Electronic Health Record (EHR) Database

POSTER: AML-068 Survival Differences in Patients With Acute Myeloid Leukemia (AML) Treated With Oral Azacitidine (Oral-AZA) as Maintenance and Those Eligible but Not Treated in a US Electronic Health Record (EHR) Database

MDS-367 A Phase II/III Trial of Oral Azacitidine (Oral-AZA) in Patients With Low- or Intermediate-Risk Myelodysplastic Syndromes (MDS)

MDS-367 A Phase II/III Trial of Oral Azacitidine (Oral-AZA) in Patients With Low- or Intermediate-Risk Myelodysplastic Syndromes (MDS)

POSTER: AML-370 Phase IB OMNIVERSE Trial: Safety and Tolerability of Oral Azacitidine (Oral-AZA) in Combination With Venetoclax (VEN) for Treatment of Acute Myeloid Leukemia (AML)

POSTER: AML-370 Phase IB OMNIVERSE Trial: Safety and Tolerability of Oral Azacitidine (Oral-AZA) in Combination With Venetoclax (VEN) for Treatment of Acute Myeloid Leukemia (AML)

AML-370 Phase IB OMNIVERSE Trial: Safety and Tolerability of Oral Azacitidine (Oral-AZA) in Combination With Venetoclax (VEN) for Treatment of Acute Myeloid Leukemia (AML)

AML-370 Phase IB OMNIVERSE Trial: Safety and Tolerability of Oral Azacitidine (Oral-AZA) in Combination With Venetoclax (VEN) for Treatment of Acute Myeloid Leukemia (AML)

Survival benefit of maintenance therapy in AML patients after complete remission in northeast Iran oncology centers with limited access to oral azacitidine.

123 Background: Acute myeloid leukemia (AML) is associated with high relapse rates even in patients who achieve a complete remission with initial treatment. Maintenance therapy with cytotoxic agents has been considered a strategy to prolong disease-free survival (DFS) and overall survival (OS). The lack of availability of oral Azacitidine in some countries limits its use. This study aimed to compare the DFS and OS rates of AML patients with and without maintenance therapy using subcutaneous cytarabine or oral thioguanine. Methods: This retrospective cohort study reviewed the charts of non-m3 AML patients treated in oncology centers in northeast Iran from February 2015 to February 2021. The study included patients aged 15-60 who experienced complete remission following induction and then consolidation chemotherapy and did not receive Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT). Patients were categorized based on receiving maintenance therapy (MT) after the first-line treatment and those who were only followed up (FU). Patients’ demographic information, pathology and lab findings, date of relapse and/or death, and first-line and maintenance treatments regimens were extracted. For each of the MT and FU groups, the frequency of main outcomes (death and/or relapse) was calculated, and the Median (95%CI) of DFS and OS was estimated. The log-rank test was used to compare the DFS and OS between groups. Results: A total of 100 patients (50 MT and 50 FU) met the study inclusion criteria. There were no significant differences between the two groups regarding patients’ demographic characteristics, pathology and lab findings, and ELN’s risk category. The relapse rate in the FU and MT groups was 76% (n=38) and 60% (n=30) respectively (p=0.09). 39 individuals (78%) in the FU group and 26 individuals (54.2%) in the MT group died between complete remission and Feb 2022(p=0.01). The Median (95% CI) of DFS in FU and MT groups were 11 (8.6-13.3) and 18 (7.3 -28.6) months respectively (P=0.03). The median OS (95% CI) was 16 (10.8 - 21.1) months in the FU group and 23 (10.8 - 35) months in the MT group (P=0.04). Further comparisons between patients who received subcutaneous cytarabine and oral thioguanine revealed no significant differences regarding DFS and OS. Conclusions: The study results suggest that maintenance therapy with subcutaneous cytarabine or oral thioguanine after complete remission in non-m3 AML patients is associated with improved DFS and OS. Further randomized controlled trials and cost-utility studies are recommended to consider these available cytotoxic agents as maintenance therapy alternatives in regions where Azacitidine is not available.

Population Pharmacokinetics of Oral Azacitidine, and Exposure-Response Analysis in Acute Myeloid Leukemia.

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 (AUCss ); maximum plasma concentration (Cmax )) as statistically significant predictors for relapse-free survival (hazard ratio (HR) = 0.521, P < 0.001; HR = 0.630, P = 0.013; respectively), and AUCss 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 AUCss (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 Cmax at steady-state (OR = 2.38, 95% CI = 1.23-4.76, P = 0.012). A decreasing trend was identified between AUCss and relapse-related schedule extensions, vs. an increasing trend between AUCss 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.

Management of Patients with Lower-Risk Myelodysplastic Neoplasms (MDS).

Myelodysplastic neoplasms (MDS) are a heterogenous group of clonal hematologic disorders characterized by morphologic dysplasia, ineffective hematopoiesis, and cytopenia. In the past year, the classification of MDS has been updated in the 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours and the International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemia with incorporation of morphologic, clinical, and genomic data. Furthermore, the more comprehensive International Prognostic Scoring System-Molecular (IPSS-M) allows for improved risk stratification and prognostication. These three developments allow for more tailored therapeutic decision-making in view of the expanding treatment options in MDS. For patients with lower risk MDS, treatment is aimed at improving cytopenias, usually anemia. The recent approval of luspatercept and decitabine/cedazuridine have added on to the current armamentarium of erythropoietic stimulating agents and lenalidomide (for MDS with isolated deletion 5q). Several newer agents are being evaluated in phase 3 clinical trials for this group of patients, such as imetelstat and oral azacitidine. This review provides a summary of the classification systems, the prognostic scores and clinical management of patients with lower risk MDS.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Diffuse large B cell lymphoma (DLBCL) is an aggressive but potentially curable malignancy. Nearly one-third of patients are >75 y, and advanced age is an adverse prognostic variable. R-miniCHOP, a dose attenuated version of standard R-CHOP, offers a 2-year progression-free survival (PFS) of 47% based on phase II data (Peyrade F et al, 2011). For comparison, patients age 60-80 have about a 75% 2-year overall survival (OS) with R-CHOP chemotherapy (Coiffier B et al., 2002). A key dilemma is identifying which older patients with DLBCL should be considered for curative intent chemoimmunotherapy. The FIL (Fondazione Italiana Linfomi; Italian Lymphoma Foundation) has developed a tool accounting for age, comorbidities, and ability to perform daily and instrumental activities to classify patients as fit, unfit, or frail (Tucci A et al, 2015), with a key observation being improved survival when curative intent chemoimmunotherapy was delivered to fit and unfit patients. (Merli F et al., 2021). However, there is no prospective validation of frailty assessment and treatment outcomes. Epigenetic deregulation is a feature of DLBCL in older patients. Pre-clinical models show that pre-treatment with hypomethylating agents improves the anti-tumor effect of the agents contained in R-CHOP (Clozel T et al., 2013). Early studies of azacitidine with R-CHOP showed promising efficacy and acceptable toxicity (Martin P et al., 2022). The availability of oral azacitidine is appealing, reduces the infusion burden of treatment, and is agnostic to cell-of-origin. Methods: S1918 is a randomized trial of R-miniCHOP ± oral azacitidine in patients >75 y with newly diagnosed aggressive B-cell non Hodgkin lymphomas (NCT04799275). This is the first randomized study in this population conducted in North America by the National Clinical Trials Network (NCTN) and will enroll 384 patients. Patients receive prephase therapy with prednisone 60–100 mg × 4–7 days to improve performance status and decrease early treatment-related mortality (Owens CN et al., 2015; Pfreundschuh M et al., 2008). A safety run-in has been completed. The phase II objective is to determine if oral azacitidine + R-miniCHOP should be tested further against R-miniCHOP based on estimates of 1-year PFS. The phase III objective is to compare OS at 2 years between arms. S1918 incorporates the FIL Tool for baseline frailty assessment and a serial comprehensive geriatric assessment to evaluate effects of therapy on quality of life and functional status. Key correlative tests include circulating tumor DNA (ctDNA) assays to explore if ctDNA quantity and methylation patterns correlate with response. S1918 has potential to impact future trial design and change the standard of care for patients > 75 y with aggressive lymphoma with its randomized design, incorporation of baseline frailty and geriatric assessments, and utilization of ctDNA correlatives. The research was funded by: NIH/NCI grants U10CA180888, U10CA180819, U10CA180820, and U10CA180821; and in part by Celgene Corporation (now part of Bristol-Myers Squibb). Keywords: aggressive B-cell non-Hodgkin lymphoma, combination therapies, ongoing trials Conflicts of interests pertinent to the abstract. E. A. Brem Consultant or advisory role Bayer, TG Therapeutics, Astra Zeneca, BeiGene Honoraria: Astra Zeneca, BeiGene, SeaGen, Morphosys/Incyte, Pharmacyclics/Janssen P. Caimi Research funding: Abbvie, ADC Therapeutics, Genentech, Consultancy: Abbvie, ADC Therapeutics, Beigene, BMS, Genentech, Incyte, Kite, Lilly, MEI Pharma, Novartis, Takeda R. L. Olin Consultant or advisory role Actinium, Servier Research funding: Cellectis B. Kahl Consultant or advisory role Genentech, BMS J. P. Leonard Consultant or advisory role Roche/Genentech, BMS/Celgene

A phase 2/3 trial of oral azacitidine (Oral-AZA) in patients (pts) with low- or intermediate-risk myelodysplastic syndromes (MDS).

TPS7083 Background: MDS, a heterogeneous group of clonal myeloid malignancies, are characterized by ineffective hematopoiesis and peripheral blood cytopenias, which can often lead to red blood cell (RBC) transfusion dependence and a risk of progression to acute myeloid leukemia (AML). In early clinical trials, 14- and 21-day (d) dosing regimens of the hypomethylating agent Oral-AZA were well tolerated and induced hematologic improvement (HI) in pts with lower-risk (LR) MDS. In a phase 3 trial, Oral-AZA 300 mg QD for 21d per 28d cycle significantly improved the rate of RBC transfusion independence (TI) and induced durable HI versus placebo (PBO) in patients (pts) with LR-MDS with RBC-transfusion-dependent anemia and thrombocytopenia (Garcia-Manero, et al. J Clin Oncol 2021). Grade 3/4 cytopenias were common in the Oral-AZA arm. Given the substantial clinical benefit of Oral-AZA observed in this setting, a new phase 2/3 trial is ongoing to further evaluate the 14d Oral-AZA regimen in pts with International Prognostic Scoring System Revised (IPSS-R)-defined low or intermediate (int)-risk MDS. Methods: This ongoing, multicenter, randomized, phase 2/3 trial (CA055-026; NCT05469737) will evaluate the safety and efficacy of Oral-AZA in pts with IPSS-R low- or int-risk MDS. Key eligibility criteria include ≥ 18 years, ECOG performance status score ≤ 2, and ≥ 1 cytopenia (anemia, thrombocytopenia, or neutropenia). Pts with an absolute neutrophil count &lt; 0.5 × 109/L within a week of randomization will be excluded. Informed consent will be obtained from all participants. The phase 2 portion will enroll and randomize ~42 pts 1:1 to receive open-label Oral-AZA 200 or 300 mg QD for 14d per 28d cycle, plus best supportive care (BSC), to determine the recommended phase 3 dose (RP3D). The primary endpoints are safety and rate of complete remission (CR) within 6 Tx cycles. The secondary endpoints are overall response rate (ORR), and packed (p) RBC-TI and platelet-TI sustained for 84d in ≤ 6 Tx cycles. ORR includes CR, partial remission (PR), marrow CR, and any HI, per IWG 2006 response criteria. In the phase 3 portion, ~188 additional pts will be enrolled and randomized 1:1 to Oral-AZA at the RP3D or PBO for 14d per 28d cycle, plus BSC. Pts in the PBO arm with stable disease at Tx cycle 6 disease assessment or with documented disease progression after ≥ 3 Tx cycles will have the option to cross over into the Oral-AZA arm. The primary endpoint is CR in ≤ 6 Tx cycles. The key secondary endpoint is 84d pRBC-TI. Other secondary endpoints include those described in the phase 2 portion plus overall survival, event-free survival, time to AML progression, iron parameters, health-related quality of life, healthcare resource utilization, and safety parameters. Pts who benefit from Oral-AZA in phase 2 or 3 may continue to receive Tx in an extension phase. Trial recruitment began in December 2022 and is ongoing. Clinical trial information: NCT05469737 .

Phase 1b OMNIVERSE trial: Safety and tolerability of oral azacitidine (Oral-AZA) in combination with venetoclax (VEN) for treatment of acute myeloid leukemia.

e19011 Background: Safer and more effective lower-intensity treatment (Tx) options are needed for patients (pts) with acute myeloid leukemia (AML) ineligible for intensive chemotherapy (IC). The combination of VEN, an oral BCL-2 inhibitor, and injectable AZA (Inj AZA), a hypomethylating agent, is indicated in IC-ineligible pts with newly diagnosed (ND) AML and has shown significantly improved response and survival rates vs. Inj AZA alone (DiNardo et al., N Engl J Med 2020). Oral-AZA allows for extended dosing schedules vs. Inj AZA. Methods: OMNIVERSE (NCT04887857) is an ongoing, phase 1b, multicenter, open-label, dose-determination study evaluating Oral-AZA + VEN in pts with relapsed/refractory (R/R; part 1) and ND AML (part 2). This abstract presents data from part 1. Eligible pts are adults with R/R AML (WHO 2016 criteria) not eligible for further IC, with an ECOG performance status of ≤ 2. The Oral-AZA starting dose is 300 mg QD × 14 days (d) per 28d cycle (dose level [DL] −1), which can be de-escalated to 200 mg QD × 14d depending on dose-limiting toxicities (DLTs); VEN 400 mg QD is taken continuously (or 21d per cycle; DL −2). Dosing decisions are guided by a modified toxicity probability interval 2 (mTPI-2) design. The primary endpoint is to evaluate safety/tolerability and establish the maximum tolerated dose (MTD) of Oral-AZA + VEN in R/R AML (starting dose for part 2). Secondary endpoints are to assess preliminary investigator-determined response rates per ELN 2017 AML response criteria (Döhner et al., Blood 2017) for complete remission (CR), CR with partial hematologic recovery, CR with incomplete blood count recovery (CRi), morphologic leukemia-free state, overall response, and measurable residual disease (plus conversion rate). Results: Pt enrollment began in December 2021 and is ongoing; data from part 1 are available for 5 pts (3 female; aged 51–80 years). 3 pts had 1 prior line of Tx and 2 pts had 2. Oral-AZA + VEN was given for 1–12 cycles. Of the 5 pts, 3 reported ≥ 1 any grade (Gr) drug-related adverse event, the most common of which were Gr 1–3 diarrhea (2 pts) and Gr 1–2 nausea (2 pts). Gr 3 febrile neutropenia, which was not deemed drug related, was reported in 4 pts (6 episodes total). In 1 pt, Oral-AZA was reduced to 200 mg QD x 14d from cycle 4 due to Gr 1 diarrhea and VEN to 70 mg QD x 28d from cycle 3 due to co-Tx with a strong CYP3A inhibitor (per protocol). 3 pts died after Tx discontinuation. No DLTs were observed and MTD of Oral-AZA + VEN was determined to be Oral-AZA 300 mg QD x 14d + VEN 400 mg QD x 28d. As of January 2023, 2 pts remained on Tx and best response achieved was CRi in 2 pts and stable disease in 3 pts. Conclusions: These results indicate that a MTD of Oral-AZA 300 mg QD x 14d + VEN 400 mg QD x 28d has a manageable safety profile consistent with known profiles of the 2 agents. Further evaluation in AML is warranted. Clinical trial information: NCT04887857 .

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: TFH lymphomas (TFHL) commonly harbor mutations in TET2, RHOA, DNMT3A and IDH2. While RHOA and IDH2 appear restricted to the neoplastic cells, TET2 and DNMT3A mutations occur in a significant proportion of cases in a hematopoietic progenitor cell and can also be detected in B or myeloid cells. Cell-free DNA (cfDNA) sequencing allows the detection of circulating tumor DNA in solid cancers or B-cell lymphomas, with predictive value, but few data exist on cfDNA sequencing in TFHL. Methods: In the frame of the ORACLE study, a phase 3 trial comparing oral azacitidine to investigator choice treatment in relapsed or refractory TFHL patients, we collected tumor biopsies and plasma in streck tube at inclusion, after 3 cycles, and at progression. Tumour and cfDNA were sequenced by NGS using 9 genes, amplicon-based libraries. Median sequencing depth was 2386X in tumor and 3519X in cfDNA. Results: Among patients with confirmed TFHL treated in LYSA centers, we collected 45 samples at inclusion, 16 after cycle 3, and 14 at progression. The median cfDNA concentration at each time point was respectively 7507 (IQR 3418–19414), 5182 (3438–12429), and 15750 (7316–26953) hEG/mL. Results of cfDNA at inclusion and tumor sequencing were compared in 43 patients. Common TET2 mutations were detected in the tumor of 36/43 (84%) and in cfDNA of 33/43 (77%) patients, with a median variant allele frequency (VAF) of 17.75% vs. 9.8% respectively. RHOAG17V was detected in 29/43 (67%, VAF 10%) and in 24/43 (59%, VAF 4.4%), DNMT3A in 13/43 (30%, VAF 17.9%) and 15/73 (35%, VAF 17.9%), and IDH2 in 12/43 (28%, VAF 5.9%) and 8/43 (19%, VAF 5.4%) of tumor biopsies and cfDNA samples respectively. Only one patient had detectable TET2, DNMT3A, IDH2, and RHOA mutations in the cfDNA and not in the tumor biopsy, corresponding to a tumor with low neoplastic cell content. By contrast, 3 patients had DNMT3A mutations, not affecting the R882 residue, detected in the cfDNA but not in the tumor likely corresponding to clonal hematopoiesis not related to the TFHL. We also compared 25 paired cfDNA samples collected at inclusion and after cycle 3 (including progression sample if occurring at cycle 3 or before). In all but one patient, we observed the persistence of TET2 and DNMT3A mutations, even in responding patients, confirming that these mutations are not restricted to neoplastic cells, and suggesting that treatment, especially with 5-azacitidine, does not affect the clonal hematopoiesis. By contrast, among the 14/25 patients with a detectable RHOA mutation in cfDNA at inclusion, progression-free survival was longer in the 4 patients with the disappearance of the RHOA mutations in cfDNA at cycle 3 than in the 10 others (median 29 vs. 3 months, p = 0.01). The research was funded by: BMS Force Hémato Keywords: Aggressive T-cell non-Hodgkin lymphoma, Liquid biopsy, Minimal residual disease No conflicts of interests pertinent to the abstract.

Oral Azacitidine for Maintenance Treatment of Acute Myeloid Leukaemia After Induction Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Celgene) of oral azacitidine (ONUREG), as part of the Single Technology Appraisal (STA) process, to submit evidence for the clinical effectiveness and cost-effectiveness of oral azacitidine for maintenance treatment of acute myeloid leukaemia (AML) after induction therapy compared with watch-and-wait plus best supportive care (BSC) and midostaurin. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review on the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations and describes the development of the NICE guidance by the Appraisal Committee. In the QUAZAR AML-001 trial, oral azacitidine significantly improved overall survival (OS) versus placebo: median OS gain of 9.9months (24.7months versus 14.8months; hazard ratio (HR) 0.69 (95% CI 0.55-0.86), p < 0.001). The median time to relapse was also better for oral azacitidine, and the incidences of TEAEs were similar for the two arms. The company excluded two of the comparators listed in the scope, low-dose cytarabine and subcutaneous azacitidine, informed only by clinical expert opinion, leaving only best supportive care (BSC) and midostaurin for the FLT3-ITD and/or FLT3-TKD (FLT3 mutation)-positive subgroup. An ITC comparing oral azacitidine to midostaurin as maintenance therapy in the appropriate subgroup demonstrated that the OS and relapse-free survival (RFS) HRs were favourable for oral azacitidine when compared with midostaurin. However, in the only available trial of midostaurin as maintenance treatment in AML that was used for this ITC, subjects were not randomised at the maintenance phase, but at induction, which posed a substantial risk of bias. The revised and final probabilistic incremental cost-effectiveness ratio (ICER) presented by the company, including a commercial arrangement, was £32,480 per quality-adjusted life year (QALY) gained for oral azacitidine versus watch-and-wait plus BSC. Oral azacitidine was dominant versus midostaurin in the FLT-3 subgroup. The ERG's concerns included the approach of modelling haematopoietic stem cell transplantation (HSCT), the generalisability of the population and the number of cycles of consolidation therapy pre-treatment in the QUAZAR AML-001 trial to UK clinical practice, and uncertainty in the relapse utility. The revised and final ERG base case resulted in a similar probabilistic ICER of £33,830 per QALY gained versus watch-and-wait plus BSC, but with remaining uncertainty. Oral azacitidine remained dominant versus midostaurin in the FLT-3 subgroup. After the second NICE appraisal committee meeting, the NICE Appraisal Committee recommended oral azacitidine (according to the commercial arrangement), within its marketing authorisation, as an option for maintenance treatment for AML in adults who are in complete remission, or complete remission with incomplete blood count recovery, after induction therapy with or without consolidation treatment, and cannot have or do not want HSCT.

Oral azacitidine modulates the bone marrow microenvironment in patients with acute myeloid leukaemia in remission: A subanalysis from the QUAZAR AML-001 trial.

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.

Multicenter phase 2 study of oral azacitidine (CC-486) plus CHOP as initial treatment for PTCL

AbstractPeripheral T-cell lymphomas (PTCL) with T-follicular helper phenotype (PTCL-TFH) has recurrent mutations affecting epigenetic regulators, which may contribute to aberrant DNA methylation and chemoresistance. This phase 2 study evaluated oral azacitidine (CC-486) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as initial treatment for PTCL. CC-486 at 300 mg daily was administered for 7 days before C1 of CHOP, and for 14 days before CHOP C2-6. The primary end point was end-of-treatment complete response (CR). Secondary end points included safety and survival. Correlative studies assessed mutations, gene expression, and methylation in tumor samples. Grade 3 to 4 hematologic toxicities were mostly neutropenia (71%), with febrile neutropenia uncommon (14%). Nonhematologic toxicities included fatigue (14%) and gastrointestinal symptoms (5%). In 20 evaluable patients, CR was 75%, including 88.2% for PTCL-TFH (n = 17). The 2-year progression-free survival (PFS) was 65.8% for all and 69.2% for PTCL-TFH, whereas 2-year overall survival (OS) was 68.4% for all and 76.1% for PTCL-TFH. The frequencies of the TET2, RHOA, DNMT3A, and IDH2 mutations were 76.5%, 41.1%, 23.5%, and 23.5%, respectively, with TET2 mutations significantly associated with CR (P = .007), favorable PFS (P = .004) and OS (P = .015), and DNMT3A mutations associated with adverse PFS (P = .016). CC-486 priming contributed to the reprograming of the tumor microenvironment by upregulation of genes related to apoptosis (P < .01) and inflammation (P < .01). DNA methylation did not show significant shift. This safe and active regimen is being further evaluated in the ALLIANCE randomized study A051902 in CD30-negative PTCL. This trial was registered at www.clinicaltrials.gov as #NCT03542266.

Indirect treatment comparison of oral versus injectable azacitidine as maintenance therapy for acute myeloid leukemia.

Aim: Evaluate the relative efficacy of oral versus injectable azacitidine (AZA) maintenance therapy in acute myeloid leukemia (AML) after complete remission. Materials & methods: Systematic literature review identified QUAZAR AML-001, HOVON 97 AML, UK NCRI AML16and QoLESS-AZA-AMLE (sensitivity analysis) trials. Network meta-analysis and matching-adjusted indirect comparisonsassessed survival outcomes. Results: In the network meta-analysis, combining the HOVON 97 and UK NCRI trials, oral AZA (QUAZAR) was associated with significantly improved overall survival (OS) versus injectable AZA (hazard ratio: 0.744; 95% credible interval: 0.557-0.998). After matching-adjusted indirect comparisons, to address differences in patient characteristics across trials, OS improvements were maintained with oral versus injectable AZA (hazard ratio: 0.753; credible interval: 0.563-0.998). Conclusion: In AML, maintenance therapy with oral AZA was associated with improved OS versus injectable AZA.

A randomized, phase II trial of oral azacitidine (CC-486) in patients with resected pancreatic adenocarcinoma at high risk for recurrence

BackgroundOf the only 20% of patients with resectable pancreatic ductal adenocarcinoma (rPDA), cancer recurs in 80% of cases. Epigenetic dysregulation is an early hallmark of cancer cells acquiring metastatic potential, and epigenetic modulators may reactivate tumor suppressor genes, delay recurrence, and sensitize PDA to future chemotherapy.MethodsThis was a randomized phase II study (NCT01845805) of CC-486 (oral DNA methyltransferase inhibitor azacitidine) vs. observation (OBS) in rPDA patients harboring high-risk features (stage pN1-2, R1 margins, or elevated CA 19–9 level) with no evidence of disease following standard adjuvant therapy. Patients were randomized to oral CC-486 treatment (300 mg daily on days 1–21 on a 28-day cycle) or OBS for up to 12 cycles or until disease relapse/unacceptable toxicities. Following recurrence, records of next-line therapies, imaging, and survival were obtained. The primary endpoint was progression-free survival (PFS)—time from randomization to recurrence (imaging/biopsy confirmed or death). Secondary endpoints included OS and PFS and ORR and metastatic PFS with subsequent next-line systemic therapy in metastatic setting.ResultsForty-nine patients (24 in CC-486 arm, 25 in OBS arm) were randomized: median age 66 (range 36–81), 53% male, 73% node positive, 49% elevated CA 19–9, 20% R1 resection, 63% and 100% received perioperative concurrent chemoradiation and chemotherapy, respectively. Median time from surgery to randomization was 9.6 mo (range 2.9–36.8). For the CC-486 arm, median treatment duration was 5.6 mo (range 1.3 to 12.8) with 14 treatment-related grade 3 or 4 AEs among 5 patients (22%) resulting in dose-reduction. Four patients (17%) discontinued therapy due to AEs. With median follow-up of 20.3mo (IQR 12.8, 41.4), 38 (79%) of evaluable patients recurred (34 imaging-confirmed, 4 clinically). Median PFS in imagining-confirmed cases was 9.2 and 8.9mo (HR 0.94, 95% CI 0.46–1.87, p = 0.85) for CC-486 and OBS patients, respectively. Median OS (2-yr OS%) was 33.8 (50%) and 26.4 mo (61%) in CC-486 and OBS patients, respectively. (HR 0.98, 95% CI 0.46–2.05, p = 0.96). ORR with subsequent chemotherapy in the metastatic setting was minimal in both arms.ConclusionsTreatment with CC-486 following adjuvant therapy did not prolong time-to-relapse in patients with high-risk rPDA or improve disease response on 1st-line metastatic therapy.

Treatment with Oral Azacitidine in Elderly Patients with Higher Risk Myelodysplastic Syndromes after Response to Subcutaneous Azacitidine

Background Hypomethylating agents (HMAs) are the standard of care for (elderly) IPSS-R higher risk MDS (HR-MDS) patients, but HMA treatment for those patients who are not eligible for hematopoietic stem cell transplant has to be continued for very long time to maintain efficacy. This prolonged continuous treatment renders patients dependent on hospital and on caregivers, and as a result, decreases QoL and too often provokes premature interruption of therapy. Oral azacitidine is approved for maintenance therapy of acute myeloid leukemia patients in complete remission after intensive chemotherapy, and it has shown activity in lower risk MDS. Oral decitabine has been recently approved by FDA for treatment of MDS. There are no data regarding maintenance of response achieved by sc azacitidine in HR MDS by switching to the oral formulation. Aim The primary objective of the study is to explore the feasibility of replacing subcutaneous (sc) azacitidine by the oral formulation, in patients with HR-MDS and responding to sc azacitidine as well as the maintenance or improvement of the achieved hematological response (time to relapse/progression).Methods A monocentric, pilot phase 2 study (ClinicalTrials.gov: NCT04806906) was planned to enroll 10 subjects with confirmed diagnosis of MDS or dysplastic non proliferative CMML, IPSS-R higher risks, aged ≥ 65 years, in CR/CRi, PR or SD with HI stable for additional 2 cycles after response at 4-6 cycles of azacitidine therapy, hence a total of at minimum 6 to 8 cycles of sc azacitidine. At screening, morphological MDS diagnosis, cytogenetic analysis, IWG response assessment, bone marrow and peripheral blood sampling for flow cytometric analysis, NGS evaluation of somatic mutations, DNA methylation analysis and HRQoL are performed. During treatment, subjects are assessed for safety, tolerability and efficacy of oral azacitidine. Assessments during treatment include monitoring for AEs, monitoring for loss of response and SPMs, physical examination, vital signs and weight measurement, ECOG performance status, hematology and serum chemistry, serum ferritin level, concomitant medications, therapies and procedures, review of bone marrow aspirate or biopsy. Patients receive 300 mg oral azacitidine for the first 14 days of each 28-day treatment cycle until no longer receiving the benefit or until progression. Dose of oral azacitidine can be de-escalated based on toxicity. Besides feasibility of treatment with oral azacitidine, we evaluate safety/tolerability, time to treatment discontinuation, and patient-reported outcomes, utilizing the EQ-5D, and measures of healthcare resource utilization. DNA methylation pattern of bone marrow CD34 positive cells at diagnosis, after response to sc azacitidine, and after 2 and 4 cycles of oral azacitidine is also determined by ERRBS for all patients. Results As per August 1, 2022, with a follow up ranging from 1-10 months, 5 HR MDS patients have been enrolled in the study. Median age is 81 yrs (79-86). Male/female ratio: 4/1. At start of therapy with sc azacitidine IPSS-R risk was high 3/5, very high 2/5. Median number of cycles of sc azacitidine is 25 (7-56), median number of cycles of oral azacitidine is 4 (1-9). The dose of 300mg/day was maintained for all patients. Pattern of DNA methylation determined by ERRBS is available for all treated patients and confirms the activity of oral azacitidine. Two patients evolved to AML after 9 and 4 cycles of oral azacitidine, with progression free survival (PFS) from onset of therapy of 17 and 12 months respectively. None of those 2 patients had adverse events during therapy. Treatment was interrupted after 2 cycles in 1 patient following a GI event grade 3 and following patient decision; 2 patients are still ongoing without report of hematological or non-hematological toxicity. At present 1/5 patients died with AML. Conclusions. The patients included in this study were HR MDS, particularly frail, not eligible to investigational studies because of poor compliance and very old median age. The administration of oral azacitidine in patients who responded to sc azacitidine is feasible, the treatment is very well tolerated with no AEs different from those observed in sc azacitidine treatment. Two of five treated patients experienced progressive disease after >12 months of HMA therapy from diagnosis. Oral azacitidine may allow prolonged and continuous treatment in frail HR MDS, optimizing outcome.

A Real World Experience of Combined Treatment with Romidepsin and Azacitidine in Patients with Peripheral T-Cell Lymphoma - a Bridge to Transplant and an Effective Salvage for the Unfit

Introduction Patients with peripheral T cell lymphoma (PTCL) lack good treatment options, particularly in the relapsed and refractory setting (Mak V et al. J Clin Oncol 2013). The development of the targeted therapies in PTCL has been lagging behind those developed for B cell lymphomas. Our work suggested that combination of epigenetic therapies could be a safe and effective approach in PTCL, particularly in T cell lymphomas with follicular helper phenotype (Marchi E et al. Br. J Haematol 2015; O'Connor AO et al; Blood 2019; Falchi L et al. Blood 2020). This could be explained by the presence of recurrent mutations in epigenetic factors, including Ten-Eleven Translocation-2 (TET2), DNA methyl transferase-3A (DNMT3A), and isocitrate dehydrogenase-2 (IDH2). that specifically clusters in PTCL (Couronné L. et al. N Eng J Med 2012; Lemonnier F et al. Blood 2012). Despite these observations, a direct link between presence of the mutations and sensitivity to treatment remain to be established. Objectives To evaluate the merits of romidepsin plus azacitidine in patients with PTCL when administered in a 'real-world’ scenario (both subcutaneous and oral azacytidine). Our phase 2 study of oral azacitidine in combination with romidepsin showed remarkable results and we wanted to evaluate the efficacy of these two drugs in patients who were not enrolled on a clinical study for following reasons: 1) Rarity of PTCL prevents wide availability of clinical studies for this patient population; 2) Enrollment criteria, including performance status, prevent enrollment of all patients who are too frail but could possibly benefit from this treatment; 3) Second synchronous or recent malignancies. Methods We retrospectively identified PTCL patients that were treated with azacitidine and romidepsin outside of a clinical trial based upon queries regarding off study use. The study was reviewed and approved by each Medical Center Institutional Review Board. We have identified 26 patients world-wide and these patients were treated using 4 different schedules: Schedule A: azacitidine 75mg/m2 s.c. on days 1-7, romidepsin 14 mg/m2 on day 1, 8 and 15 of a 28 day cycle (total of 7 patients); Schedule B: azacitidine 75mg/m2 s.c. on days 1-5, romidepsin 14 mg/m2 on day 8, 15 and 22 of a 35 day cycle; Schedule C (6 patients): azacitidine 75mg/m2 s.c. on days 1-7, romidepsin 12-14 mg/m2 on day 8, 15 and 22 of a 28 day cycle (6 patients); and Schedule D (as per Falchi L. et al. Blood 2020, 7 patients). Results In our retrospective analysis we have identified 18 patients who had angioimmunoblastic lymphoma (AITL), 2 with adult T-cell leukemia/lymphoma (ATLL), 3 with TFH PTCL, 1 with PTCL-NOS and 2 with composite lymphoma (TFH PTCL with diffuse large B cell lymphoma and ALK- ALCL with FL). Twelve of the 26 patients had next generation sequencing performed. Most common mutations found were those of TET2 (8 pts), RHOA (4pts), IDH2 (3pts) and DNMT3A (2 pts). Among these 26 patients, overall response rate (ORR) was 73% and the complete response rate (CR) was 53%. Median number of cycles was 3.5 (range 1-12). Treatment was well tolerated and notable adverse effects included nausea, fatigue, rash, neutropenia and thrombocytopenia. One patient experienced febrile neutropenia while another had pulmonary infiltrates (drug toxicity vs. infection). Thrombocytopenia was the most common reason for dose reduction of romidepsin (to 12mg/m2) or its omission on day 8, 15 or 22. Median OS and PFS were not reached and 13.3 months respectively (Figure 1). Median DOR was not reached. In 8 patients, azacitidine and romidepsin were used to achieve remission prior to stem cell transplant (1 auto, 7 allo), with all 7 patients were in CR at their last disease assessment. One patient died of transplant related mortality 8 months after his allogeneic stem cell transplant. Conclusion Subcutaneous azacitidine and romidepsin administered in a 'real-world’ situation is highly effective in patients with relapsed PTCL with tolerable toxicity, and can be used to successfully bridge patients to stem cell transplant and to treat frail patients that would not be candidate for enrollment in clinical trials.. Notably, the efficacy was similar to the one reported on a clinical study with oral azacitidine and romidepsin. A randomized phase 2B trial of romidepsin and oral azacitidine versus investigator's choice in patients with R/R PTCL is currently ongoing and open to enrollment (NCT04747236). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Survival Outcomes for Patients in the QUAZAR AML-001 Trial Who Received Subsequent Therapy for Acute Myeloid Leukemia (AML) after Discontinuing Oral Azacitidine or Placebo

Introduction: While many older patients (pts) with AML attain complete remission (CR) after treatment (Tx) with intensive chemotherapy (IC), most will relapse and overall survival (OS) is poor, especially for pts who are not candidates for hematopoietic stem cell transplant (HSCT). In the randomized phase 3 QUAZAR AML-001 trial (NCT01757535), oral azacitidine (Oral-AZA), a hypomethylating agent (HMA), significantly prolonged OS (24.7 months [mo] vs 14.8 mo with placebo [PBO], P < 0.001) and relapse-free survival (10.2 vs 4.8 mo, respectively, P < 0.001) vs PBO in pts with AML in first remission after IC who were not candidates for HSCT (Wei AH, et al. N Engl J Med 2020;383:2526-2537). After discontinuing study drug, pts in QUAZAR AML-001 continued to be monitored for OS even if they received subsequent AML Tx. Given the high rate of relapse in older pts and the limited Tx options for relapsed/refractory AML, it is important to evaluate the impact of Oral-AZA maintenance Tx on the clinical outcomes for pts who received subsequent AML Tx after relapse. Methods: Eligible pts were aged ≥ 55 years, had AML with intermediate- or poor-risk cytogenetics at diagnosis, Eastern Cooperative Oncology Group performance status score ≤ 3, and had achieved a first CR or CR with incomplete blood count recovery (CRi) after IC ± consolidation Tx. Within 4 mo of achieving CR/CRi, pts were randomized 1:1 to receive Oral-AZA 300 mg or PBO once daily for 14 days per 28-day cycle. Randomized Tx could continue until pts developed relapse with > 15% blasts, unacceptable toxicity, or HSCT. These post hoc analyses assessed Kaplan-Meier (KM)-estimated OS and 1- and 2-year survival rates for pts who received subsequent AML Tx after relapse, both from the time of study randomization and from the time of receipt of first subsequent Tx, until death by any cause. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models stratified by age, cytogenetic risk, and receipt of consolidation Tx. These analyses were not prospectively powered to detect statistically significant differences between Tx arms. Results: At data cutoff (September 2020), 137/238 pts (58%) in the Oral-AZA arm and 172/234 pts (74%) in the PBO arm received subsequent AML Tx after discontinuing study drug. Demographic and disease characteristics at baseline in this subgroup were similar between the Oral-AZA and PBO arms and comparable to those for all pts in the trial (Wei AH, et al. N Engl J Med 2020;383:2526-2537). Pts from both Tx arms received similar classes of first-line subsequent Tx; 43% of pts in the Oral-AZA arm vs 45% in the PBO arm received IC, 50% vs 46% received lower-intensity therapies (including 25% vs 31% injectable HMAs), and in both arms 6% received supportive care and 1% received other Tx. In the Oral-AZA arm, 13 pts (9%) went on to receive HSCT, compared with 31 (18%) in the PBO arm. At a median follow-up of 51.7 mo, OS from the time of randomization for pts who received subsequent Tx was nominally prolonged with Oral-AZA vs PBO (median, 17.9 vs 12.5 mo, respectively; HR, 0.79 [95% CI, 0.62-1.0]) (Figure A). KM-estimated 1-year survival rates were 67% for Oral-AZA, compared with 51% for PBO, and 2-year rates were 41% and 29%, respectively. Median OS from the time of first subsequent Tx was similar in the Oral-AZA and PBO arms: 5.3 and 5.8 mo, respectively (HR, 1.1 [95% CI, 0.85-1.4]) (Figure B). Estimated 1-year survival rates from first subsequent Tx were 25% in the Oral-AZA arm and 31% in the PBO arm, and at 2 years, survival rates were 17% and 18%, respectively. Conclusions: Pts who received Oral-AZA during first remission, followed by subsequent Tx, showed a trend for improved OS from the time of study randomization compared with pts who initially received PBO. Survival outcomes from the start of first subsequent Tx were not meaningfully different between Oral-AZA and PBO. This suggests that Oral-AZA maintenance Tx can extend the duration of remission without influencing the clinical benefit of subsequent AML Tx. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase II Study of Azacitidine Plus Venetoclax As Maintenance Therapy in Acute Myeloid Leukemia: Durable Responses with Longer Term Follow-up

Background: Relapse is the major cause of treatment failure in acute myeloid leukemia (AML). Patients with AML who are ineligible for allogeneic stem cell transplantation (SCT) have limited options to delay or prevent relapse once they have completed their initial therapy. Oral azacitidine (CC-486) has been shown to improve relapse-free survival (RFS) and overall survival (OS) in patients with AML who have achieved first complete remission (CR) after intensive chemotherapy, and is currently the only agent approved as maintenance therapy in AML. The combination of azacitidine (AZA) and venetoclax (VEN) is synergistic and highly effective in AML. To further improve outcomes in the post-remission setting, we studied the combination of low-dose IV/SQ AZA plus VEN as maintenance therapy in AML. Methods: This phase II study enrolled patients with AML ≥ 18 years, not immediately eligible for SCT, and who had achieved a first CR/CRi (regardless of measurable residual disease [MRD] status) following at least 2 cycles of intensive chemotherapy (defined as intermediate or higher dose cytarabine; cohort 1) or low-intensity therapy (defined as hypomethylating agent or low-dose cytarabine-based; cohort 2). Patients in CR2 or beyond were also eligible if positive for MRD. Patients were treated with AZA 50 mg/m2 IV/SQ on days 1-5 plus VEN 400 mg PO on days 1-14, every 28 days for up to 24 cycles. VEN duration could be reduced to 7 days in patients at high risk for cytopenias. VEN dosing was adjusted for concomitant azole antifungal use. The primary outcome was RFS (defined as enrollment to relapse or death, whichever occurred first). Secondary outcomes included OS, MRD clearance rates, and safety/toxicity. Patients becoming eligible for SCT could be taken off protocol to undergo the procedure and were censored at the time of SCT. This study was registered on ClinicalTrials.gov (NCT04062266). Results: As of July 14th, 2022, 34 patients have been enrolled (25 in cohort 1, 9 in cohort 2). The median follow-up time is 13.3 months (IQR 8.6-21.6). The baseline patient characteristics are shown in table 1. Nineteen (76%) patients had been previously exposed to VEN as part of their induction regimen. During cycle 1, 21 (62%) patients received 7 days of VEN and 13 (38%) received 14 days of VEN. The median number of cycles given is 9.5 (range 1-24). The median RFS is not reached (NR) in cohort 1 (70% at 12 months) and NR in cohort 2 (58% at 12 months). The median OS is NR in cohort 1 (95% at 12 months) and NR in cohort 2 (63% at 12 months). When stratified by ELN 2017, median RFS is NR (85% at 12 months), NR (70% at 12 months), and 4 months (23% at 12 months) for ELN favorable, intermediate, and adverse, respectively (figure 1). Eight patients have gone off protocol to receive SCT. There was no significant effect of prior venetoclax exposure on RFS or OS. Of the 7 MRD-positive patients at enrollment, 2 (29%) converted to MRD-negative while on maintenance therapy. The MRD-positive patients in our study had a high incidence of adverse prognostic factors (5/7 ELN adverse, 3/7 complex karyotypes). Of these MRD-positive patients, 3 went off study to receive SCT and remain in remission. The 4 remaining MRD-positive patients have relapsed after 1.9, 2.5, 4.0, and 6.0 months. The most common grade 3/4 adverse events were thrombocytopenia (21%), infections (21%), neutropenia (18%), and neutropenic fever (6%). Four patients (12%) required VEN dose reductions at cycle 2 for cytopenias. Seven (21%) patients died, all following relapse of AML or from SCT complications. Conclusions: With over 13 months of follow up, this is the first experience demonstrating the tolerability and feasibility of low-dose AZA plus VEN as maintenance therapy in AML. RFS and OS are encouraging, especially in the non-adverse risk ELN categories (favorable or intermediate). Further studies are needed to improve maintenance strategies in patients with ELN adverse or MRD-positive disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal