Study Of Azacitidine Research Articles

Phase 1 study of azacitidine in combination with quizartinib in patients with FLT3 or CBL mutated MDS and MDS/MPN

We conducted a phase 1 study evaluating 3 dose levels of quizartinib (30 mg, 40 mg or 60 mg) in combination with azacitidine for HMA-naïve or relapsed/refractory MDS or MDS/MPN with FLT3 or CBL mutations. Overall, 12 patients (HMA naïve: n=9, HMA failure: n=3) were enrolled; 7 (58 %) patients had FLT3 mutations and 5 (42 %) had CBL mutations. The maximum tolerated dose was not reached. Most common grade 3–4 treatment-emergent adverse events were thrombocytopenia (n=5, 42 %), anemia (n=4, 33 %), lung infection (n=2, 17 %), skin infection (n=2, 17 %), hyponatremia (n=2, 17 %) and sepsis (n=2, 17 %). The overall response rate was 83 % with median relapse-free and overall survivals of 15.1 months (95 % CI 0.0–38.4 months) and 17.5 months (95 % CI NC-NC), respectively. FLT3 mutation clearance was observed in 57 % (n=4) patients. These data suggest quizartinib is safe and shows encouraging activity in FLT3-mutated MDS and MDS/MPN. This study is registered at Clinicaltrials.gov as NCT04493138.

Abstract CT060: Phase 1 study of azacitidine in combination with evorpacept for higher-risk myelodysplastic syndrome (MDS)

Abstract Background:Evorpacept (EVO) is a high affinity CD47-blocking fusion protein with an inactive human immunoglobulin Fc region designed to enhance the activity of other anti-neoplastic therapies with minimal additional toxicity. Here, we present final phase 1 results from the ASPEN-02 study. Methods:ASPEN-02 is an open-label, multicenter phase 1/2 study designed to evaluate the safety and activity of EVO in combination with azacitidine (AZA) in subjects with newly diagnosed (ND) higher-risk (HR) or relapsed/refractory (R/R) MDS. Adult subjects with ND HR (IPSS-R > 3.5) or R/R MDS were enrolled into phase 1 cohorts receiving escalating doses of EVO (20 mg/kg Q2W, 30 mg/kg Q2W, and 60 mg/kg Q4W) combined with AZA (75 mg/m2 IV/SC x 7d) in a 28-day treatment cycle. A phase 1 dose expansion portion enrolled adults with ND HR MDS into two dosing cohorts determined to be safe at EVO 40 mg/kg Q4W and 60 mg/kg Q4W. This clinical trial is registered at clinicaltrials.gov: NCT04417517. Results: As of June 2, 2023, 65 subjects were treated in the phase 1 portion, including 13 subjects with R/R MDS [EVO doses of 20 mg/kg Q2W (n=1) or 60 mg/kg Q4W (n=12)], and 52 subjects with ND HR MDS [EVO doses of 40 mg/kg Q4W (n=23) and 60 mg/kg Q4W (n=29)]. Of 52 ND HRMDS subjects, 9 (17.3%) had therapy-related MDS. Multi-hit TP53 mutations were present at baseline in 2/13 (15.4%) R/R MDS and 3/52 (5.8%) ND HR MDS patients. 13/13 (100%) R/R MDS patients had received prior hypomethylating agents or cytotoxic chemotherapy. Median age was 70 (range 24 - 88) years, and baseline ECOG scores were 0 (n=27, 41.5%), 1 (n=31, 47.7%), or 2 (n=7, 10.8%). No dose-limiting toxicity was observed, and a maximum tolerated dose (MTD) was not reached. Treatment-emergent AEs and treatment-related AEs for EVO were reported in 65/65 (100%) and 35/65 (53.8%) subjects respectively; discontinuation, however, was infrequent. Seven (10.8%) subjects experienced a serious adverse event related to EVO. There were no EVO-related deaths on study. Preliminary PK indicated dose-proportional pharmacokinetics consistent with prior studies. Objective response [complete remission (CR), partial remission (PR), marrow CR (mCR), hematologic improvement (HI)], per modified International Working Group 2006 criteria, was observed in 19/52 (36.5%) ND HR [CR=8, mCR=9, HI=2] and 2/13 (15.4%) R/R [mCR=2] MDS subjects. Conclusion:The myeloid checkpoint inhibitor EVO was well tolerated in combination with AZA with an initial safety and activity profile comparable to that of historical AZA monotherapy. Additional updated data will be provided at the time of presentation. Citation Format: Guillermo Garcia-Manero, Bart L. Scott, Ashwin Kishtagari, Srinivasa R. Sanikommu, Aref Al-Kali, Je-Hwan Lee, Juan M. Bergua Burgues, Maria Diez-Campelo, Harry P. Erba, Carmen Garcia-Hernandez, Guillermo Sanz Santillana, Casey O'Connell, Jun-Ho Jang, Dong-Yeop Shin, Hamid Sayar, Mayank Rao, Richard S. Schwartz, Grace An, Feng Jin, Alison J. Forgie, Athanasios C. Tsiatis, Jessica K. Altman. Phase 1 study of azacitidine in combination with evorpacept for higher-risk myelodysplastic syndrome (MDS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT060.

Tumor Lysis Syndrome in Patients with AML Initiated on Venetoclax-Based Treatment without a Dose Ramp-up

Introduction Treatment with the combination of a hypomethylating agent (HMA) and venetoclax (VEN) is the standard of care for older patients (pts) with acute myeloid leukemia (AML). Venetoclax, an oral BCL-2 inhibitor, was initially approved for the treatment of chronic lymphocytic leukemia (CLL). In the early, pivotal studies assessing VEN safety, tumor lysis syndrome (TLS) was found to be a dose-limiting, potentially fatal toxicity. Dosing modifications were made to allow for safer initiation of the drug and, ultimately, a dose ramp-up was included in the dosing recommendation for CLL. Given the risk for TLS with VEN initiation for CLL, it was hypothesized that the risk would be the same, or potentially greater, when treating pts with AML. Therefore, studies of VEN in AML have included a dose ramp-up. Although reported rates of tumor lysis syndrome in these studies have been much lower than expected, a dose ramp-up for pts with AML is included in the package insert for VEN and continues to be utilized in clinical trials. Methods We conducted a retrospective analysis of pts ≥18 years of age with newly diagnosed or relapsed/refractory AML treated with a standard dose hypomethylating agent (HMA), either azacitidine or decitabine, and VEN without a dose ramp-up (initiated at 400mg daily or 100mg daily if on concomitant voriconazole or posaconazole) at Thomas Jefferson University Hospital from January 1, 2018- August 1, 2021. The primary objective of this study was to determine the rate of laboratory and clinical TLS within 72 hours after chemotherapy initiation, as defined by the Cairo-Bishop criteria (Table 1). The secondary objectives were (1) to identify clinical and laboratory risk factors for the development of TLS in pts with AML who were treated with HMA-VEN without a VEN dose ramp-up and (2) to compare rates of TLS in pts with AML who were treated with HMA-VEN without a VEN dose ramp-up to historical rates of TLS in pts who underwent a VEN dose ramp-up. In the Phase 3 study of azacitidine and venetoclax the rate of TLS during the VEN dose ramp-up period (days 1-3 of treatment) was 1% (DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629.). Results Ninety pts were included in the analysis. Seventy-one pts had newly diagnosed AML and 19 had relapsed/refractory disease. The majority of pts (58/90, 64%) had adverse risk disease by 2017 European LeukemiaNet Criteria. Median baseline white blood cell count at the time of therapy initiation was 3.25 (range 0.5-161.4). Sixty-one pts (68%) were receiving allopurinol prophylaxis at the time of HMA-VEN administration. Eighteen pts (20%) had a history of underlying renal disease. Fifteen pts (17%) were on medications, such as thiazide diuretics, aspirin, or levodopa, that can increase the risk of TLS at the time of treatment. Zero pts met the defined criteria for laboratory or clinical TLS. One pt developed acute kidney injury and one pt developed a cardiac arrhythmia (atrial fibrillation) but neither had concomitant evidence of laboratory TLS. Discussion In this retrospective study of 90 pts with newly diagnosed or relapsed/refractory AML who were treated with HMA-VEN without a VEN dose ramp-up no pts developed clinical or laboratory tumor lysis syndrome. This is comparable to the rate of TLS (1%) seen in the registration trial of HMA-VEN where pts were treated with VEN 100 mg on day 1, 200 mg on day 2, and 400 mg on day 3 and thereafter. Starting pts with AML on full dose VEN on day 1, regardless of white blood cell count, renal function, or concomitant medications, appears safe and could be implemented in clinical practice and clinical trials moving forward. This would simplify dosing for pts, pharmacists, and providers and allow for easier initiation of therapy.

Results of Phase I/II Study of Azacitidine in Combination with Quizartinib for Patients with Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms with FLT3 or CBL Mutations

Introduction: FMS-like tyrosine kinase 3 ( FLT3) mutations occur in approximately 1% of patients (pts) with newly diagnosed myelodysplastic syndrome (MDS) and up to 19% of pts at time of failure to hypomethylating agents (HMA). In addition, mutations in the Casitas B-lineage Lymphoma gene ( CBL) are observed in 10% of pts with MDS/MPN and up to 15% of pts with CMML. Preclinical studies suggest that CBL-mutant cells are dependent on FLT3 signaling. Here we present results of a phase I-II study of the FLT3 inhibitor quizartinib in combination with azacitidine for pts with FLT3 and CBL mutant MDS and MDS/MPN. Methods: We conducted a phase I/II clinical trial of azacitidine in combination with quizartinib for pts with MDS and MDS/MPN with detectable FLT3 and/or CBL mutations and with/without prior failure to HMA (HMA-F). The study included an initial phase I dose-escalation portion, following a 3+3 design, followed by a phase II dose expansion portion. Dose escalation included 3 dose levels of quizartinib: 30, 40 and 60 mg administered p.o daily on days 1-28 of each 28 day cycle. Therapy consisted on quizartinib (at corresponding dose level) in combination with azacitidine 75 mg/m 2/day i.v os s.c on days 1-5. The primary endpoint was to evaluate safety, tolerability and maximum tolerated dose of quizartinib. Responses were evaluated following 2006 IWG criteria. The Kaplan-Meier product-limit method was used to estimate median survival. Results: Between July 2020 and June 2023 a total of 16 pts have been treated: 12 in the phase I portion and 4 in the phase II. A total of 4 pts had MDS with excess blasts, 2 had MDS/MPN with neutrophilia and 10 had CMML. Eight (50%) pts had FLT3-ITD mutations and 8 (50%) had CBL mutations. Four (25%) pts had HMA-F one of which had received 4 lines of therapy including hematopoietic stem-cell transplant (HSCT) prior to enrollment. Based on the Molecular IPSS, 8 (50%), 3 (19%) and 5 (31%) pts had very high, high and moderate high risk disease. Among CMML pts, 3 (30%) pts had high and 7 (70%) had intermediate-2 risk by CPSS-Molecular score. In the phase I portion, 3 pts received quizartinib at dose level 1, 3 at dose level 2 and 6 at dose level 3. No dose limiting toxicities were detected during the 28-day DLT evaluation window. Dose level 2 was selected as the P2RD. Most common adverse events (AEs) were constipation (56%), fatigue (50%), insomnia (44%), anorexia (38%), cough (38%), diarrhea (38%) and arthralgia (31%). Most common grade 3-4 AEs were anemia (31%), thrombocytopenia (31%), lung infection (13%), skin infection (13%), hyponatremia (13%) and sepsis (13%). Arrythmias were observed 5 pts: atrial fibrillation (grade 2, n=2; grade 3, n=1), Mobitz type II atrioventricular block (grade 3, n=1), atrial flutter (grade 2, n=1), QTC prolongation (grade 2, n=1). The 4-week and 8-week cumulative incidences of mortality were 0%. Median number of days to cycle 2 was 30 (range 27-51). Median number of days to cycle 2 of therapy by dose level were: 30, 30 and 37 days for dose levels 1, 2 and 3, respectively (p=0.301). Dose reductions due to myelosuppression were required in 5 (31%) pts including dose reductions of azacitidine in 3 pts and of quizartinib in 3 pts. Median number of cycles was 4 (range 1-17). Median cycles to to best response was 1 (range 1-6). The overall response rate was 69% (n=11): CR in 1 (6%), mCR with HI in 2 (13%), mCR in 8 (50%) pts. FLT3 mutant pts were more likely to respond to therapy (100% vs 50%, p=0.038). Clearance (n=6, 75%) or allelic burden reductions (n=2, 25%) of FLT3-ITD mutations were observed in all FLT3 mutant pts. No clearance of CBL mutations were observed. Dynamics of absolute neutrophil count, platelets and hemoglobin during cycle 1 are shown in Figure 1A. Median response duration was 3.5 months (range 0-22 moths). With a median follow up of 19.1 months (95% CI 2.6-35.6), the median event-free survival has not been reached and the median overall survival is 17.5 months (NR vs 10.1 months in FLT3 vs CBL mutant pts, p=0.084, Figure 1B) Five (31%) pts discontinued study to proceed with HSCT at time of best response, 3 (19%) due to transformation to AML, 2 (12%) due to pt choice, 1 (6%) due to treating physician choice and 1 (6%) due to relapse. Four (25%) pts remain on study. Conclusion: Therapy with azacitidine in combination with quizartinib for pts with higher-risk MDS and MDS/MPN with FLT3 or CBL mutations has acceptable toxicity profile and is associated with promising responses mainly among FLT3-mutant pts.

Phase I/II Study of Azacitidine (AZA) with Venetoclax (VEN) and Magrolimab (Magro) in Patients (pts) with Newly Diagnosed (ND) Older/Unfit or High-Risk Acute Myeloid Leukemia (AML) and Relapsed/Refractory (R/R) AML

Phase I/II Study of Azacitidine (AZA) with Venetoclax (VEN) and Magrolimab (Magro) in Patients (pts) with Newly Diagnosed (ND) Older/Unfit or High-Risk Acute Myeloid Leukemia (AML) and Relapsed/Refractory (R/R) AML

Phase 2 study of azacitidine (AZA) and venetoclax (VEN) as maintenance therapy for acute myeloid leukemia (AML) patients in remission.

e19018 Background: Most patients (pts) with AML achieve remission with current therapies but rates of relapse are high. Maintenance with oral AZA (CC-486) has been shown to prolong overall survival (OS) and relapse-free survival (RFS) in SCT-ineligible patients with AML in remission. The addition of VEN to maintenance regimens should be explored. Methods: We designed a phase 2, single-center, single-arm study to evaluate the efficacy and tolerability of AZA + VEN maintenance in AML. Pts ≥ 18 years in first remission (CR1) after induction and 1+ consolidations not immediately eligible for SCT were treated with AZA 50 mg/m2 IV/SQ on D1-5 and VEN 400 mg on D1-14 (or D1-7 at physician discretion) every 28 days, up to 24 cycles. Pts in CR2 and beyond were eligible if positive for minimal residual disease (MRD). Both intensive (INT; int/high dose cytarabine-based) and low-intensity (LOW; HMA/LDAC-based) induction regimens were permitted, including prior VEN. The primary outcome was modified RFS (mRFS; enrollment to relapse or death). Key secondary objectives were OS (enrollment to death), safety, and MRD clearance. Results: As of Feb 10 2022, 33 pts have been enrolled (characteristics in Table). The median number of cycles given is 6 (range 1-23). 20 pts (61%) received 7 days and 13 (39%) received 14 days of VEN. To date, 8 relapses and 6 deaths (all after relapse or SCT) have occurred. 5 pts (15%) have gone off protocol for SCT (censored at time of SCT). Median mRFS is not reached (NR) in both the INT and LOW cohorts (1-yr mRFS 73.9% and 58.3%, respectively). When stratified by ELN 2017, mRFS was NR, NR, and 4 mo for favorable, intermediate, and adverse risk, respectively (6-mo mRFS 92.3%, 90%, and 44.4%). Median OS is NR in both the INT and LOW cohorts (1-yr OS 93.8% and 53.3%, respectively). mRFS was numerically higher in pts with VEN exposure as part of their induction regimen (1-yr mRFS 79.1% vs 55.6% in non-VEN-exposed pts, p=0.067). Of the 7 MRD(+) pts at enrollment, 2 (29%) cleared their MRD on AZA/VEN maintenance. MRD(+) pts had a median mRFS of only 4 mo compared to NR in the MRD(-) pts (p=0.001). The MRD(+) pts in our study were very high risk (5/7 ELN adverse, 3/7 complex karyotype). The most common grade 3/4 AEs were infections (18%), thrombocytopenia (15%), neutropenia (12%), and neutropenic fever (6%). 4/33 pts (12%) required C2 VEN dose reduction for cytopenias. Conclusions: AZA/VEN maintenance is effective and tolerable in AML pts not immediately eligible for SCT after intensive or low-intensity induction. The regimen yields encouraging mRFS and OS durations. Longer follow-up and comparative studies are needed to confirm these initial results. Clinical trial information: NCT04062266. [Table: see text]

Phase 2 study of azacitidine (AZA) plus pembrolizumab (pembro) as second-line treatment in patients with advanced pancreatic ductal adenocarcinoma.

4158 Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death with a 5-year survival rate of 10%. Novel strategies for advanced PDAC are a critical need. A DNA hypomethylating agent (HMA) increased tumor-infiltrating effector T cells and significantly prolonged survival in combination with immune checkpoint blockade (ICB) in a PDAC mouse model (Gonda et al 2020). We hypothesized that combining HMA with ICB will lead to therapeutic benefit in pts with advanced PDAC. Methods: This is an open-label, single-arm, single-center, Phase 2 trial of AZA plus pembro in pts with unresectable or metastatic PDAC. Pts were treated with AZA 50 mg/m2 subcutaneous daily for 5 days Q4W beginning week 1 day 1 followed by pembro 200 mg IV Q3W starting week 3 day 1. Key eligibility criteria included documented progression on or following first-line systemic treatment, ECOG PS 0-1, and adequate organ function. The primary objective was progression-free survival (PFS). Thirty-one evaluable pts were required to detect an improvement in PFS from 2 mo to 4 mo with a one-sided p-value of 0.05 and 80% power. Secondary endpoints included safety and tolerability, overall response rate (ORR), disease control rate (DCR), and overall survival (OS). Data cutoff was February 10, 2022. Results: Between Oct 2017 and Sept 2021, 36 pts were enrolled (median age 62.5, 75% white, 72% male). At data cutoff, 34 and 31 pts received at least 1 dose of AZA and pembro, respectively. Median PFS for ≥1 dose of AZA was 1.48 mo (95% CI: 1.35, 1.74) and for ≥1 dose of pembro was 1.51 mo (95% CI, 1.38, 3.42). The median OS was 4.67 months. Among the 34 pts, 3 (8.8%) experienced a partial response (PR) by RECIST with a DCR of 32.4%. Of the 3 pts with PR, 2 received 35 doses of pembro and continued beyond 2 years with an ongoing PR. One pt remains on pembro 20 months after study completion. None of the pts with a PR were microsatellite instability-high or tumor mutation burden high, and next-generation sequencing of the 3 cancers identified a BRCA1 variant and POLE variant. Treatment-related AEs (TRAEs) occurred in 20/34 pts (59%), the most common of which were diarrhea and fatigue. Grade ≥3 occurred in 7/34 (21%) including 1 immune-related grade 5 event (encephalitis). Conclusions: AZA plus pembro demonstrated a tolerable safety profile but no PFS benefit compared to historical controls. Our data suggests combined epigenetic therapy and ICB may expand therapeutic options in a subset of pts with PDAC. Further investigation is needed to identify biomarkers to predict response and elucidate effective timing, sequencing, and combination of epigenetic agents. Follow-up for OS is ongoing. Correlative analysis of epigenetic effects and characterization of the tumor immune microenvironment will be reported. Clinical trial information: NCT03264404.

A randomized phase 2 trial of azacitidine with or without durvalumab as first-line therapy for higher-risk myelodysplastic syndromes

AbstractAzacitidine-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.

Phase I/II Study of Azacitidine (AZA) with Venetoclax (VEN) and Magrolimab (Magro) in Patients (pts) with Newly Diagnosed Older/Unfit or High-Risk Acute Myeloid Leukemia (AML) and Relapsed/Refractory (R/R) AML

Phase I/II Study of Azacitidine (AZA) with Venetoclax (VEN) and Magrolimab (Magro) in Patients (pts) with Newly Diagnosed Older/Unfit or High-Risk Acute Myeloid Leukemia (AML) and Relapsed/Refractory (R/R) AML

Initial Results of Phase I/II Study of Azacitidine in Combination with Quizartinib for Patients with Myelodysplastic Syndrome and Myelodysplastic/Myeloproliferative Neoplasm with FLT3 or CBL Mutations

Initial Results of Phase I/II Study of Azacitidine in Combination with Quizartinib for Patients with Myelodysplastic Syndrome and Myelodysplastic/Myeloproliferative Neoplasm with FLT3 or CBL Mutations

A phase II study of azacitidine in combination with granulocyte-macrophage colony-stimulating factor as maintenance treatment, after allogeneic blood or marrow transplantation in patients with poor-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)

Relapse is the most common cause of treatment failure following allogeneic blood or marrow transplantation (alloBMT) for AML or MDS. Post-transplant maintenance therapies may prevent relapse. We conducted a phase II trial combining azacitidine (AZA) with GM-CSF in non-relapsed, post-transplant patients with AML or MDS. Patients received escalating doses of AZA to a maximum of 75 mg/m2 for 5 days per cycle for up to 12 cycles. GM-CSF was given on days 1–10 of each cycle. Eighteen patients were treated following non-myeloablative (17) and myeloablative (1) alloBMT for AML (61.1%), MDS (27.7%), or therapy-related myeloid neoplasm (11.1%). The majority of patients (72%) received their graft from an HLA-haploidentical donor. The treatment was well-tolerated with rare grade 3–4 hematologic toxicities. One patient suffered an exacerbation of GVHD. The 24-month relapse-free and overall survivals were 47 and 57%, respectively, with a median of 18.6 and 29 months.

Acute Myeloid Leukemia and Myelodysplasia Related Changes: Trends in Survival between 2000 and 2013

Background:Acute Myeloid Leukemia with myelodysplasia-related changes (AML-MRC), formerly known as the Acute myeloid leukemia with multilineage dysplasia is a distinct hematological disorder characterized by the presence of more than 20% blasts in peripheral blood or bone marrow and dysplasia in 50% or more of the cells in two or more myeloid cell lineages in the absence of recurrent cytogenetic abnormalities seen in AML and with no prior history of cytotoxic treatment for an unrelated disease (2). The presence of myelodysplasia was considered an independent prognostic factor in the past until it was disputed in a study by Wandt et al in 2008 (4). This heterogeneous disorder is associated with poor prognosis only when associated with Myelodysplastic syndrome (MDS) related cytogenetic abnormalities and are preceded by MDS, which is the majority(3). Induction chemotherapy is the treatment of choice in young healthy patients and hypomethylating agents (HMA) such as azacitadine and decitabine have been used in elderly patients who are unfit to receive induction chemotherapy if they are treatment naive(1). No significant advancements have been made in the treatment of this category of AML in the elderly patients with previous history of MDS treated with HMA. Our objective is to evaluate the survival trends of this entity over the last decade.Methods:We utilized National Cancer Institute Surveillance, Epidemiology, and End Results (SEER-18) database to identify adult patients with Acute Myeloid Leukemia (AML) with myelodysplastic related features. Several cohorts were categorized by race, gender and age were categorized. We grouped patients into three different time periods as: 2000-2004, 2005-2009 and 2010-2013. 1-year and median overall survival (OS) were computed using Kaplan Meier Curve and log rank test. Cox proportional hazard model was used for multivariate analysis.Results:The database comprised of 1733 patients from 2000-2013. Majority of the patients were male Caucasians, aged 60- 79 years. Median overall survival among the different year of diagnosis cohort was found to be comparable by KM curve (6 months, 6 months and 7 months for 2000-2004, 2005-2009 and 2010-2013 respectively) with p value of 0.112 by log rank test. On multivariate analysis using cox PH model, after adjusting for age, sex, race, income and area of residence, survival among patients in 2010 to 2013 was found to be significantly better compared to 2000 to 2004 (HR of 0.84, 95% confidence interval of 0.73 to 0.97, P 0.015). The one year OS rate was 35.7 % ±2, 30.3 % ±1.8, 31.7 % ±2.3 for 2010-2013, 2005-2009 and 2000-2004 cohorts respectively.Conclusion:Survival for patients with AML-MRC has improved over the decade, most likely attributable to improved supportive care since there hasn't been any major breakthrough in treatment of these patients.References1) Dombret, H., Seymour, J. F., Butrym, A., Wierzbowska, A., Selleslag, D., Jang, J. H., Kumar, R., Cavenagh, J., Schuh, A. C., Candoni, A., Récher, C., Sandhu, I., Bernal del Castillo, T., Al-Ali, H. K., Martinelli, G., Falantes, J., Noppeney, R., Stone, R. M., Minden, M. D., McIntyre, H., Songer, S., Lucy, L. M., Beach, C. L., & Döhner, H. (2015). International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood, 126(3), 291-299. Accessed August 02, 2017.2) Brunning RD, Matutes E, Harris NL, et al. Acute myeloid leukemia with multilineage dysplasia. In: Jaffe E, Harris NL, Stein H, et al, eds. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. 3rd ed. Lyon, France: IARC; 2001:88-89.3) Huck A, Pozdnyakova O, Brunner A, Higgins JM, Fathi AT, Hasserjian RP. Prior cytopenia predicts worse clinical outcome in acute myeloid leukemia. Leuk Res. 2015 Oct. 39 (10):1034-40.4) Wandt H, Schakel U, Kroschinsky F, et al. MLD according to the WHO classification in AML has no correlation with age and no independent prognostic relevance as analyzed in 1766 patients. Blood. 2008;111:1855- 1861. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

DNA Methylation Analysis before and during Treatment with Azacitidine Plus Pevonedistat or Azacitidine Alone in Patients with MDS, CMML, and AML Previously Untreated with Hypomethylating Agents

Background: Clinical responses to hypomethylating agents (HMA) occur in the minority of patients with myelodysplastic syndromes (MDS) and related disorders and require months of treatment. Robust biomarkers of HMA response would have great clinical utility but remain elusive. Combinations of HMA and novel agents may improve response rates and latency and be associated with distinct biomarkers. Predictive baseline DNA methylation (DNAm) profiles have yet to be identified in MDS, although responders show more global hypomethylation after response occurs. DNAm changes shortly after treatment may add predictive power as they reflect additional factors including effective cellular exposure and the rate of DNAm recovery between treatment cycles. To determine if DNAm profiling at baseline and early during treatment can improve our ability to predict response, we examined targeted DNAm profiles in samples from patients with higher-risk MDS (HR-MDS), chronic myelomonocytic leukemia (CMML), and low-blast count acute myeloid leukemia (LB-AML), previously untreated with HMA who were enrolled in the Pevonedistat-2001 (P-2001) Phase 2 study of azacitidine (AZA) with or without pevonedistat (PEV). Methods: Targeted DNAm was quantified using bisulfite padlock probes (BSPP) at ~141,000 unique regions known to contain differentially methylated CpG sites. BSPP sequencing was performed on 130 genetically and clinically annotated bone marrow mononuclear cell DNA samples collected at screening and Cycle 2 Day 22±3 (C2D22). Data from 15 samples were removed due to low CpG coverage resulting in 115 samples with >10X coverage of 322,387 CpGs each. There were 27 patients with paired samples, 30 with screening only, and 31 with C2D22 only (Table 1, Figure 1A). Responses for HR-MDS and CMML were categorized according to the IWG-2006 modified criteria and for LB-AML according to the IWG-2003 criteria. Differentially methylated CpGs were identified using the R package 'DSS' v2.35.0. Non-negative matrix factorization-based unsupervised clustering was performed using the Onco-GPS method within the Python 'ccal' package. Statistical analyses were carried out using R version 3.6.2. Results: Differential DNAm analysis between screening and C2D22 for the 27 paired samples shows global demethylation after treatment in nearly all cases but is more pronounced in responders (mean change in global DNAm: response = -5.5%; non-response = -2.0%; t-test p < 0.001). There was no significant difference in demethylation between AZA and AZA+PEV treated groups (AZA: -5.3%; AZA+PEV: -4.1%; t-test p = 0.32). Patients who attained a complete response (CR) in the AZA+PEV arm tended to have more demethylated CpGs than those with a CR in the AZA arm (Figure 1B. Mean number of demethylated CpGs in complete responders: AZA = 16,459; AZA+PEV = 24,731; t-test p = 0.396). In general, responding patients strictly defined by CR or partial response had steeper declines in mean DNAm levels (Figure 1C) than patients with other types of responses, but did not show an association between demethylation and time to response (TTR). Unsupervised clustering of the top 3% most variably methylated CpGs using Onco-GPS did not identify clusters associated with response at screening, but did resolve a cluster highly enriched for responders assessed at C2D22 (Figure 1D. Cluster B, Fisher's exact test p = 0.011; odds-ratio 95% CI = 1.52-Inf). Analysis of the CpG sites that define Cluster B and creation of a formalized statistical predictor of response based on DNAm patterns is ongoing. Conclusions: DNAm patterns early in the course of HMA treatment correlate with eventual response, with CRs associated with the greatest degree of demethylation. Responders are more likely to have greater demethylation that may reflect greater effective AZA exposure or slower remethylation dynamics. Addition of PEV may intensify site-specific demethylation in responders and increase the proportion of responding patients. With a median TTR of 3-4 months in the P-2001 study, depth of demethylation at the C2D22 timepoint may help predict eventual response. Strategies to augment demethylation with adjunctive agents or HMA dose escalation in patients with early inadequate demethylation should be investigated. Ongoing work will incorporate mutation status and focus on refining DNAm signatures that can predict eventual response. Disclosures Luger: Arcturus Therapeutics: Current Employment. Zhao:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Fram:Takeda, Bristol Myers, Gilead, Pfizer, Baxter, Teva: Current equity holder in publicly-traded company; BeyondSpring Pharmaceuticals Inc.: Consultancy; Takeda Pharmaceuticals Intl. Co.: Current Employment; Vertex Pharmaceuticals: Patents & Royalties: No Royalties; Patent 10/728,114 (Vertex Pharmaceuticals). Dash:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment, Other: Stockholder. Bejar:Forty-Seven/Gilead: Honoraria; Genoptix/NeoGenomics: Honoraria; Daiichi-Sankyo: Honoraria; Takeda: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Astex/Otsuka: Honoraria; AbbVie/Genentech: Honoraria; Aptose Biosciences: Current Employment.

Long-Term Outcome of Low-Dose Hypomethylating Agents in Lower-Risk Myelodysplastic Syndromes: A Randomized Phase 2 Study

Long-Term Outcome of Low-Dose Hypomethylating Agents in Lower-Risk Myelodysplastic Syndromes: A Randomized Phase 2 Study

A phase 1 study of azacitidine with high-dose cytarabine and mitoxantrone in high-risk acute myeloid leukemia

AbstractIn this phase 1 study, azacitidine (AZA) was given before high-dose cytarabine (HiDAC) and mitoxantrone (mito) based on the hypothesis that epigenetic priming with a hypomethylating agent before cytotoxic chemotherapy would improve response rates in patients with high-risk acute myeloid leukemia (AML), including relapsed/refractory disease. The primary objective was to establish the recommended phase 2 dose of AZA given before standard HiDAC/mito. In a dose escalation scheme, 46 patients (median age, 66 years) received AZA at 37.5, 50, or 75 mg/m2 subcutaneously or IV once daily on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10 (the HiDAC/mito dose was reduced 33% in elderly subjects). Two dose-limiting toxicities occurred (both in the same patient): acute liver failure and kidney injury at the 50 mg/m2 dose. The 30-day induction death rate was 2.2% (1 of 46). The overall response rate, including complete remission and complete remission with incomplete count recovery, was 61% (28 of 46). Previously untreated patients aged ≥60 years with therapy-related AML and de novo AML were more likely to respond than untreated patients with AML progressing from an antecedent hematologic disorder (myelodysplastic syndrome and chronic myelomonocytic leukemia). Patients with favorable European Leukemia Network risk (P = .008), NPM1 mutations (P = .007), or IDH2 mutations (P = .03) were more likely to respond, and those with TP53 mutations (P = .03) were less likely to respond. The recommended phase 2 dose of AZA is 75 mg/m2 per day on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10. This trial was registered at www.clinicaltrials.gov as #NCT01839240.

Long-Term Follow up of a Randomized Phase 2 Study of Low-Dose Decitabine Versus Low-Dose Azacitidine in Lower-Risk Myelodysplastic Syndromes

Long-Term Follow up of a Randomized Phase 2 Study of Low-Dose Decitabine Versus Low-Dose Azacitidine in Lower-Risk Myelodysplastic Syndromes

APR-246 Combined with Azacitidine (AZA) in TP53 Mutated Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). a Phase 2 Study By the Groupe Francophone Des Myélodysplasies (GFM)

APR-246 Combined with Azacitidine (AZA) in TP53 Mutated Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). a Phase 2 Study By the Groupe Francophone Des Myélodysplasies (GFM)

A Study of Azacitidine for Patients With Int/High -Risk MDS and AML-MRC

A Study of Azacitidine for Patients With Int/High -Risk MDS and AML-MRC

Sequential azacitidine and lenalidomide for patients with relapsed and refractory acute myeloid leukemia: Clinical results and predictive modeling using computational analysis

BackgroundPatients with relapsed and refractory (R/R) acute myeloid leukemia (AML) have limited treatment options. Genomically-defined personalized therapies are only applicable for a minority of patients. Therapies without identifiable targets can be effective but patient selection is challenging. The sequential combination of azacitidine with high-dose lenalidomide has shown activity; we aimed to determine the efficacy of this genomically-agnostic regimen in patients with R/R AML, with the intention of applying sophisticated methods to predict responders. MethodsThirty-seven R/R AML/myelodysplastic syndrome patients were enrolled in a phase 2 study of azacitidine with lenalidomide. The primary endpoint was complete remission (CR) and CR with incomplete blood count recovery (CRi) rate. A computational biological modeling (CBM) approach was applied retrospectively to predict outcomes based on the understood mechanisms of azacitidine and lenalidomide in the setting of each patients’ disease. FindingsFour of 37 patients (11%) had a CR/CRi; the study failed to meet the alternative hypothesis. Significant toxicity was observed in some cases, with three treatment-related deaths and a 30-day mortality rate of 14%. However, the CBM method predicted responses in 83% of evaluable patients, with a positive and negative predictive value of 80% and 89%, respectively. InterpretationSequential azacitidine and high-dose lenalidomide is effective in a minority of R/R AML patients; it may be possible to predict responders at the time of diagnosis using a CBM approach. More efforts to predict responses in non-targeted therapies should be made, to spare toxicity in patients unlikely to respond and maximize treatments for those with limited options.

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

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