Cycles Of Azacitidine Research Articles

Abstract PO-007: A phase 1 study of romidepsin, azacitidine, dexamethasone, and lenalidomide (RAdR) for relapsed/refractory T-cell malignancies

Abstract Romidepsin, azacitidine and lenalidomide are all active in T-cell malignancies (TCM) demonstrating single agent objective response rates (ORR) of 20 to 30% (Coiffier 2012; Morschhauser 2013; Dupuis 2022). Combinations of these targeted agents improves the rates of complete response (CR) but have significant toxicity due to indefinite schedules. We hypothesized that use of a multi-targeted therapy regimen such as RAdR given in fixed duration cycles would be safe and effective. We tested escalating doses of lenalidomide (5-20mg) with fixed doses of romidepsin, azacitidine and dexamethasone in a phase 1 study. Patients (pts) first received a 7-day window of lenalidomide for cytokine correlative research followed by six cycles of romidepsin (12mg/m2; days 1 and 10), azacitidine (300mg; days 1-10), dexamethasone (40mg; days 1 and 10), and lenalidomide (5-20mg; days 1-10) in 21-day cycles for up to 6 cycles. The primary endpoint was the maximum tolerated dose (MTD) of lenalidomide and the primary objective was the overall safety of the regimen. A 3+3 design was used with an additional 9 pts treated at the MTD. 26 pts were enrolled with a median age of 61 years (range, 28-80) including 31% over 65. Eight (31%) pts had PTCL, NOS, 6 (23%) had mycosis fungoides (MF), 5 (19%) had angioimmunoblastic T-cell lymphoma, and 4 (15%) ATLL. Median prior lines of therapy were 2 (range, 1-8), 31% had received >3 prior lines and 2 patients had received prior allogeneic transplantation. The median number of cycles was 4 (range, <1-6). The most frequent reasons for stopping therapy were progressive disease (38%), completion of planned therapy (27%) and adverse events (23%). The most frequent grade 1-2 non-hematologic adverse events were vomiting (52%), diarrhea (48%) and dysgeusia (48%), and AE grade 3+ included infection (16%) and hypokalemia (16%). Grade 3+ neutropenia occurred in 24% of cycles and both grade 3+ anemia and thrombocytopenia in 12% of cycles. Two DLTs were observed, grade 4 thrombocytopenia at dose level 1 and grade 3 abdominal pain at dose level 2. The MTD of lenalidomide was determined to be 20mg. In evaluable pts (N=21) the ORR was 66% and CR rate was 14%. After a median follow-up of 23 months. Median progression free survival (PFS) and overall survival (OS) were 4 months and not reached, respectively. 2-year OS was 53%. Two pts (PTCL, NOS and MF) completed the planned 6 cycles of therapy and remain in remission without consolidation at 30 months. Five pts were successfully bridged to SCT, all of whom remain alive and without progression. In pts treated at the MTD, the ORR was 89% and the CR rate was 22%. The multi-targeted therapy regimen RAdR is safe and can achieve CR after fixed duration in patients with relapsed refractory TCM. Toxicity is predominantly gastrointestinal and hematologic. Most patients do not achieve durable CR with RAdR alone, but it may be effective bridging therapy to consolidation. This study was supported by the Intramural Research Program of the NIH and was registered at Clinicaltrials.gov [NCT04447027]. Citation Format: Max Gordon, Milos Miljkovic, Samuel Ng, Rahul Lakhotia, Christopher Melani, Kevin Conlon, James Phelan, Bonita Bryant, Stefania Pittaluga, Elaine Jaffe, Louis Staudt, Wyndham Wilson, Mark Roschewski. A phase 1 study of romidepsin, azacitidine, dexamethasone, and lenalidomide (RAdR) for relapsed/refractory T-cell malignancies [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-007.

Overexposure to venetoclax is associated with prolonged-duration of neutropenia during venetoclax and azacitidine therapy in Japanese patients with acute myeloid leukemia.

An observational study was conducted to evaluate the pharmacokinetics of venetoclax and its impact on the efficacy and safety for Japanese patients with acute myeloid leukemia (AML) treated with venetoclax and azacitidine therapy. The association between the plasma concentration, after the first cycle of azacitidine and venetoclax therapy, and the efficacy and safety was evaluated in 33 patients with untreated or relapsed/refractory AML. Full dose of venetoclax was administered to all patients. Venetoclax treatment was 28day long in 82% of patients; the relative dose intensity of azacitidine was 82%. Trough concentration was significantly higher among patients with complete remission (CR) and CR with incomplete hematologic recovery (CRi) than those with the morphologic leukemia-free state and partial remission, and no response groups (P = 0.01). Median duration of grade 3 neutropenia was 28 days (range 8-46 days). Area under the concentration-time curve (AUC0-24) was significantly higher among patients with protracted grade 3 neutropenia (≥ 28 days) than those with a shorter duration (< 28 days) (P = 0.03); multivariate analysis revealed that a higher AUC0-24 was a significant predictor of a longer duration of neutropenia (odds ratio 54.3, P = 0.007). Plasma concentrations of venetoclax were variable in Japanese patients with AML. Higher plasma concentrations were associated with CR/CRi and protracted grade 3 neutropenia. Therefore, it is essential to adjust the duration of venetoclax administration based on individual pharmacokinetic data to limit total drug exposure, reduce severe neutropenia, and achieve higher efficacy.

Real-world study of the use of azacitidine in myelodysplasia in Australia.

Hypomethylating agents are the most widely used upfront therapy for patients with myelodysplastic syndrome (MDS) who are not suitable for hematopoietic stem cell transplantation. In Australia, azacitidine was, until recently, the only approved and subsidized treatment for patients with intermediate-2 and high-risk MDS, chronic myelomonocytic leukemia, and low blast acute myeloid leukemia. We analyzed prescription data to evaluate the real-world persistence and overall survival (OS) of patients prescribed azacitidine for the first time in Australia. A retrospective cohort analysis of patients who had been prescribed Pharmaceutical Benefits Scheme (PBS)-listed azacitidine for the first time, between January 2016 and April 2021, was conducted using the PBS 10% dataset. Treatment persistence and OS were estimated using Kaplan-Meier methods. The impact of the number of treatment cycles and treatment adherence on OS was also estimated. There were 351 patients in the PBS 10% dataset who initiated treatment with azacitidine. The average age (standard deviation [SD]) at azacitidine initiation was 71.9 (11.1) years and the average number (SD) of azacitidine prescriptions was 5.6 (0.2). The median persistence on azacitidine was 15.6 months, and the OS was 13.4 months. The median OS for patients who had six or more cycles of azacitidine treatment was greater compared to patients who had five or less cycles of treatment. The data from this real-world study illustrate the unmet medical needs of patients with MDS treated with azacitidine in Australia. The majority of patients are not treated with the optimal number of cycles of azacitidine, which is negatively correlated with patient outcomes.

Successful treatment with venetoclax and azacitidine for extramedullary relapse of acute myeloid leukemia after cord blood transplantation

A 33-year-old man was diagnosed with acute myeloid leukemia (AML). He was treated with daunorubicin and cytarabine and achieved complete remission. He underwent consolidation therapy with three cycles of venetoclax and azacitidine (VEN+AZA). He received cord blood transplantation following a reduced-intensity conditioning (RIC) regimen. After 19 months, an extramedullary mass appeared in the paranasal sinuses along with vision loss, and relapsed AML was diagnosed based on a biopsy. Palliative irradiation was performed because the patient did not wish to receive a second transplantation. A painful extramedullary mass was found in the inguinal area, and radiation therapy was performed. Subsequently, extramedullary masses appeared in the submandibular region, but radiation therapy was not feasible because the irradiation field overlapped with that of the previous therapy. The extramedullary masses decreased after two cycles of VEN+AZA therapy. This is a rare report of VEN+AZA therapy for an extramedullary relapse of AML.

Clinical impacts of severe thrombocytopenia in the first cycle of azacitidine monotherapy and cytogenetics in patients with myelodysplastic syndrome: The Kyoto Conditional Survival Scoring System.

Azacitidine (AZA) has been one of the standard treatments for transplantation-ineligible patients with myelodysplastic syndrome (MDS); however, hematological toxicities frequently cause treatment interruption in the early phase of the therapy. The present study conducted a multicenter retrospective study to investigate the prognostic impacts of various factors, including factors included in the Revised International Prognostic Scoring System (IPSS-R) and severe cytopenia in the early phase of AZA monotherapy in 212 patients with MDS. Severe cytopenia was evaluated after the initiation of therapy by absolute neutrophil counts on the 29th day after AZA (ANC29) initiation, and red cell concentrates (RCC) and platelet concentrate (PC) transfusion units required within 28 days from the start of AZA, designated in the present study as RCC28 and PC28, respectively. The survival period was determined from the 29th day of AZA treatment to death from any cause as the conditional survival period after the first cycle of AZA (CS-AZA1). Multivariate analysis demonstrated that severe thrombocytopenia defined by >30 units of PC28 and very poor risk cytogenetics according to IPSS-R were independent prognostic factors for CS-AZA1. The Kyoto Conditional Survival Scoring System was subsequently developed by incorporating severe thrombocytopenia defined by PC28 and very poor risk cytogenetics, which successfully stratified the risks of the patients in CS-AZA1. In conclusion, extreme PC transfusion dependency during the first cycle of AZA and very poor risk cytogenetics are important prognostic factors in AZA monotherapy for MDS.

Phase I/II Clinical Trial Evaluating Azacitidine + Venetoclax + Donor Lymphocyte Infusion in Post-Transplant Relapse Myelodysplastic Syndromes and Acute Myeloid Leukemia: Preliminary Results of Ventograft, a GFM Study

Background: Azacitidine (AZA) is approved for the treatment of patients with high-risk MDS and in combination to Venetoclax (VEN) in AML. Beyond direct cytotoxic/epigenetic effects of AZA and ability to induce remissions even in patients refractory to chemotherapy, AZA has been shown to increase the immunogenicity of AML blasts by reexpression of key antigens [ Schroeder et al. Leukemia 2013]. Moreover, VEN imparts distinct cell death sensitivity and adaptivity patterns in T cells ( Ludwig et al. Cell Death Dis 2021). DLI have shown efficacy to treat or prevent relapse of AML or MDS following allogeneic stem cell transplantation (allo-SCT) in 20-40% of the cases [ Castagna et al. Transfusion and Apheresis 2016]. A german retrospective study showed an overall response rate (ORR) of 33% (including 27% CR and 6% PR), to AZA and DLI following relapse after allo-SCT in AML and MDS [ Schroeder et al. BBMT 2015], a regimen used since in many centers. We present here preliminary results of a phase I/II evaluating the combination of AZA/VEN/DLI in relapse MDS/AML. Patients and Methods: In this open label multicenter phase I/II study, MDS and AML patients relapsing post allo-SCT, without active graft versus host disease (GVHD) and active infections, are treated with VEN during 14 days in combination with AZA at 75 mg/m²/day for 5 days for each cycle (or 50 mg/m²/day for 5 days each cycle if relapse occurs less than 4 months after allo- SCT), and VEN orally at escalating dose (step 1: VEN 100mg/d; step 2: VEN 200mg/d and step 3: VEN 400mg/d) in the phase I part and at maximal tolerated dose (MTD) on days 1-14 of each cycle in the phase II part. Cycles are administered every 28 day (or delayed until day 42 in case of hematological toxicity). DLI are started at least 8 weeks after immunosuppressive therapy discontinuation, if chimerism in &amp;lt;90% recipient, and administered on day 15 every two cycles (C2, C4, C6, C8) in the absence of GVHD. Patients receive at least 8 cycles of AZA/VEN + DLI unless progression occurs. Response is assessed after 4, 6 and 8 cycles. Patients achieving a response receive 12 cycles of AZA + VEN followed by cycles of AZA alone. In the absence of response after 8 cycles, patients stop treatment. Results: From November 2022 to June 2023, 9 patients were included in part 1 of VENTOGRAFT. M/F was 8/1. Median age 57 years (range 18-71). Two patients had MDS and 7 patients had AML at diagnosis. Five patients had MDS (IPSS-R was low (1), intermediate (2) and very high (2)), and 3 patients had AML (ELN2017 was intermediate (1) and unfavorable (2) and molecular relapse (1)) at the time of relapse. Median interval between allo-SCT and relapse was 44 months (range 2-181). At data cut-off, 3 patients had been treated in step 1, 3 patients in step 2 and 3 patients in step 3 (AZA + VEN 400mg/d D1-14)). Median number of AZA + VEN cycles was 3 (range 1-8) and median number of DLI infused was 1 (range 0-3). One dose limiting toxicity (No ANC recovery on D42 and one patient still neutropenic at D28) was observed in step 3 leading to inclusion 3 more patients on this step. Other adverse events observed were grade 1/2 nausea (2 patients), grade 1 skin lesions (1 patient), ALAT increase grade 3 (1 patient), febrile neutropenia grade 3 (2 patients), grade 3 abdominal pain (1 patient) and grade 3 gastrointestinal bleeding (2 patients). GVHD was seen in 1/9 (11%) patients). CMV and EBV reactivation were observed in 0 and 2 patients, respectively. Overall response rate was 6/9 (67%) patients 67% including 22% complete remission (CR), 22% of CR with incomplete recovery (CRi) and 33% of morphologic leukemia-free state (MLFS). Full donor chimerism was obtained in all patients obtaining a response. Conclusion: The combination of AZA at 75mg/m²/d D1-5 and VEN at 100 to 400mg/d D1-D14 (400mg/d ongoing) was safe, showed a promising ORR of 67%. Final results of the phase 1 and first patients treated in this phase 2 will presented at the ASH meeting.

Selinexor in Combination with Azacitidine (AZA) in Patients with Myelodysplastic Syndrome (MDS): A Real-World Retrospective Study

Background: Patients with higher-risk MDS face limited treatment options and poor outcomes. While HMAs are approved as frontline therapy for higher-risk MDS, primary failure occurs in 50% of HMA-treated patients, and most responders progress within 2 years. There is an unmet need to improve the efficacy of AZA frontline therapy while maintaining a tolerable safety profile. Preclinical studies have demonstrated that the combination of selinexor and azacitidine synergistically inhibits MDS cell proliferation and arrests the cell cycle at the G2/M phase (Yixuan Guo, 2022). The combination of selinexor and azacitidine may be a promising approach for treating MDS. Here, we present this single-center, real-world evidence supporting the use of selinexor in combination with AZA in MDS patients. Methods: Medical records of 19 patients with MDS receiving selinexor in combination with AZA at the First Affiliated Hospital of Soochow University between Jan 2022 and March 2023 were reviewed. Inclusion criteria were a pathologically confirmed diagnosis of MDS, and receipt of ≥1 cycle of azacitidine in combination with selinexor. HMA-naïve patients and those previously treated with HMAs were included. Patients with a diagnosis other than MDS or progression to AML before treatment with selinexor + AZA were excluded. Patients received selinexor 40-60 mg QW orally and AZA 75 mg/m 2 intravenously or subcutaneously on days 1-5 or 7 of each 28-day cycle. Responses were evaluated per the International Working Group criteria. Results: A total of 19 pts (median age, 54 y [range, 13-68 y]) were treated (Table 1). IPSS-R risk was high or very high in 15.8% and 68.4% of pts, respectively. IPSS-M risk was high or very high in 10.5% and 78.9% of pts, respectively. 57.9% of pts were previously treated with HMA. 63.2% had myelofibrosis, 42.1% had hepatosplenomegaly, 31.6% had a TP53 mutation, and 63.2% had poor or very poor-risk cytogenetics. As of Jun 10, 2023 at a median follow-up of 5.9 months (range 1.5-17.4 months), eight pts died (42.1%) due to disease progression. For the total cohort, the overall response rate (ORR) was 73%. In pts with worse survival prognosis, such as relapse and refractory, high and very high in IPSS-R, high and very high in IPSS-M, myelofibrosis and TP53 mut, the ORR was 64%, 81%, 76%, 75% and 83%, respectively (Figure 1). In seven pts with splenomegaly, six pts had reduced spleen volume, and one pt had no significant change by abdominal palpation or imaging examination. The 6-month overall survival (OS) was 74.7% in total pts, and 70.0% in pts previously exposed to HMA (Figure 2a, 2b). Selinexor + AZA therapy improved survival of patients with poor prognosis, such as TP53 mut (0.099), MF (+) (0.613), ≥high in IPSS-R (0.938) (Figure 2c, 2d, 2e). The survival of six pts who received transplantation after combination therapy was significantly prolonged, with 6-month OS was 83.3% (Figure 2f). Conclusion: Selinexor + AZA combination therapy was well tolerated with promising efficacy in patients with untreated or relapse/refractory MDS, including those with TP53 mutation, myelofibrosis, and higher risk in IPSS-R.

Lenzilumab in Addition to Azacitidine Improves Complete Response Rates in Chronic Myelomonocytic Leukemia

Introduction: Chronic myelomonocytic leukemia (CMML) is a rare cancer orchestrated by granulocyte-macrophage colony-stimulating factor (GM-CSF), a pro-inflammatory cytokine that drives leukemic monocyte proliferation. Standard of care (SOC) for CMML treatment includes azacitidine (AZA), with a complete response (CR) rate of 16-21% 1,2. The PREcision Approach to CHronic Myelomonocytic Leukemia (PREACH-M; ACTRN12621000223831) trial investigates novel CMML therapies directed by molecular profiling. Lenzilumab (LENZ; Humanigen, Inc., Short Hills, NJ) a proprietary Humaneered® first-in-class monoclonal antibody with best-in-class off-rate and affinity that neutralizes GM-CSF. PREACH-M interim results show that LENZ/AZA improves hematologic parameters, decreases spleen size, and dampens pro-inflammatory responses in CMML with RAS-pathway mutations. This report details the objective clinical responses from an interim analysis of the first 11 subjects who completed at least three months LENZ/AZA treatment. Methods: PREACH-M is a Phase 2/3 non-randomized, uncontrolled, open-label trial in 72 adults aged at least 18 years, newly diagnosed with WHO 2016 criteria for CMML. Key exclusion criteria include prior treatment with investigational agents; radiotherapy within 28 days before treatment; treatment with G-CSF within 7 days of screening; GM-CSF within 28 days of screening; and uncontrolled medical conditions. Subjects exhibiting RAS-pathway mutations ( NRAS, KRAS, CBL) receive 24 cycles (every 28 days) of AZA (SC; 75 mg/m2 for 7 days) and LENZ (IV; 552 mg; d1 &amp; d15 of cycle 1 and d1 only for all subsequent cycles); while those with only TET2 mutations receive the same AZA regimen and sodium ascorbate (IV; 30 g for 7 days [15 g for 1st dose only, 30 g thereafter if no evidence of tumor lysis syndrome]; PO; 1.1g on all other days). Subjects who complete 24 cycles of treatment are followed every 6 months for an additional 24 months. The primary endpoint is the frequency of complete response (CR) or partial response (PR) during the first 12 cycles according to Savona Criteria. Secondary endpoints include responses according to modified 2006 International Working Group criteria, 2 year overall survival, and symptom improvement. Results: As of July 2023, 15 subjects were enrolled in the LENZ/AZA arm (8 females, 7 males with mean age 69; mean white cell count 21x10 9/L, mean Hb 121 g/L; mean platelet count, 74x10 9/L, mean blast count, 10.1%). Mutations included; CBL (47% of subjects), NRAS (27%), KRAS (47%), NRAS and KRAS (13%), and TET2 (93%). Subjects exhibited CPSS-MOL scores, of intermediate risk 1 (n=1), intermediate risk 2-3 (n=8), and high risk 4-6 (n=6). All the 11 evaluable subjects at 3 months responded to LENZ/AZA. CR was achieved within 3 cycles in 55% of subjects. Six of the subjects demonstrated CR including 2 with a high risk CPSS-MOL profile and 8 achieved either CR or complete marrow response (blasts&amp;lt;5%) within 12 months. One subject had a platelet response, 1 subject each had PR and stable disease with blasts &amp;lt;5%. CMML progression was absent and 1 subject became eligible for allogeneic transplant. These findings exceed historical CR rates for hypomethylating agents (16%; 95%CI, 12-21% 1 and 21%;13-29% 2). Self-reported symptom scores from the standardized MPN-SAFFS improved from baseline (mean of 22 vs 12, P=0.06). Fifteen grade 3 and 9 grade 4 adverse events were reported of which 2 were “probably” ascribed to both LENZ/AZA and 7 were “possibly” ascribed to LENZ. No unexpected adverse events were observed. Conclusion: Interim analysis of the PREACH-M trial demonstrated that GM-CSF neutralization with LENZ/AZA, for the treatment of CMML with RAS-pathway mutations resulted in 55% CR, achieved early in treatment, durability up to 18 months, thus far, and no unexpected serious adverse events. These data suggest CMML is driven by a non-redundant cytokine that responds to immunotherapy. 1. Xu Y, Guo R, Miao M, Zhang G, Lan J, Jin J. Real-world data on efficacy and safety of azacitidine therapy in chronic myelomonocytic leukemia in China: results from a multicenter, retrospective study. Invest New Drugs 2022;40(5):1117-1124. DOI: 10.1007/s10637-022-01283-x. 2. Zheng X, Lv L, Li X, Jiang E. Efficacy and Safety of Hypomethylating Agents in Chronic Myelomonocytic Leukemia: A Single-Arm Meta-analysis. Glob Med Genet 2022;9(2):141-151. DOI: 10.1055/s-0042-1744157.

Survival and Prognosis Among 301 Patients with Newly-Diagnosed Acute Myeloid Leukemia Following Venetoclax Plus Hypomethylating Agent Therapy

Background: Venetoclax (Ven) in combination with hypomethylating agent (HMA) is the preferred treatment for elderly/unfit patients with newly-diagnosed acute myeloid leukemia (AML). Current prognostication for AML is based on European LeukemiaNet (ELN) genetic risk stratification which has limited applicability in patients treated with Ven-HMA ( Blood, 2022). Accordingly, our primary objective was to determine predictors of treatment response and survival outcomes in treatment-naïve AML patients receiving Ven-HMA. Methods: Our study population was recruited from Mayo Clinic (MN, FL, AZ), after institutional review board approval and based on documentation of newly-diagnosed AML treated with Ven-HMA outside of clinical trials between November 2018 and April 2023. Cytogenetic and molecular studies were performed by conventional karyotype, and next-generation sequencing, respectively. Response was assessed according to the 2022 ELN criteria Results: Patient characteristics A total of 301 newly-diagnosed AML patients (median age 73 years, 66% male, 62% de novo) received a median of 3 cycles (range 1-48) of azacitidine 75 mg/m2 days 1-7 ( n=100) or decitabine 20 mg/m2 days 1-5 ( n=201) with Ven. ELN 2022 cytogenetic risk included favorable (1%, n=4), intermediate (61%, n=184) or adverse (38%, n=113). Mutations involved TP53 in 77/301 (25%), ASXL1 in 54/279 (19%), RUNX1 in 54/296 (18%), NPM1 in 44/299 (15%), DNMT3A in 40/296 (13%), K/NRAS in 41/296 (14%), IDH1 in 20/301 (6%), IDH2 in 30/301 (10%), FLT3-ITD in 25/301 (8%) and DDX41 in 9/247 (4%) of informative cases. Predictors of response Complete remission, with (CR) or without (CRi), count recovery, was documented in 182 (60%) patients, including CR in 36% and measurable residual disease (MRD) negative by flow cytometry in 77% of 105 informative cases that achieved CR/CRi. Median time to CR/CRi was 1.4 months. In univariate analysis, CR/CRi was more likely to occur in the presence of NPM1 mutation, (86% vs. 56%; p &amp;lt; .01), IDH2 mutation, (80% vs. 58%; p = .02), DNMT3A mutation, (78% vs. 57%; p = .01), or DDX41 mutation, (100% vs. 58%; p &amp;lt;.01), and in the absence of adverse karyotype, (71% vs. 42%; p &amp;lt; .01), TP53 mutation, (67% vs. 40%; p &amp;lt;.01), FLT3-ITD mutation, (63% vs. 36%; p = .01), or RUNX1 mutation, (64% vs. 44%; p = .01); in multivariable analysis, adverse karyotype, ( p &amp;lt; .01), FLT3-ITD ( p &amp;lt; .01), RUNX1 ( p &amp;lt; .01), NPM1 ( p = .03), IDH2 ( p = .04), and DDX41, ( p = .01) mutations remained significant. Predictors of survival After a median follow-up of 8.5 months (range 0.5-56), 13.2 months for living patients, 174 (58%) deaths, 73 relapses (40% of those achieving CR/CRi), and 41 (14%; including 35 in CR/CRi) allogeneic hematopoietic stem cell tranplants (AHSCT) were documented. In univariate analysis of pre-treatment variables, thrombocytopenia &amp;lt; 100 x 10 9/l, (HR 1.5, 95% CI 1.03-2.2; p = .03), adverse karyotype, (HR 2.8, 95% CI 2.1-3.8; p &amp;lt; .01) TP53 mutation, (HR 2.5, 95% CI 1.8-3.5; p &amp;lt; .01), or absence of IDH2 mutation, (HR 3.5, 95% CI 1.7-7.6; p &amp;lt; .01) predicted inferior survival. Failure to achieve CR/CRi (HR 4.5, 95% CI 3.3-6.1; p &amp;lt; .01) was also associated with inferior survival and in multivariable analysis, failure to achieve CR/CRi, (HR 3.4, 95% CI 2.5-4.8; p&amp;lt; .01), presence of adverse karyotype, (HR 1.6, 95% CI 1.1-2.6; p = .02), TP53 mutation, (HR 1.6, 95% CI 1.002-2.4; p = .04), and absence of IDH2 mutation (HR 2.2, 95% CI 1.004-4.7; p = .04) were identified as risk factors for survival. Subsequent HR-weighted scoring resulted in three-tiered risk stratification: low (0-1 point; n= 130), intermediate (2-3 points; n= 105), and high (4-5 points; n= 66), with respective median survival (3-year rate) of 28.9 (48%), 9.6 (6%), and 3.1 (0%) months ( p &amp;lt; .01) (Figure). AHSCT had an independent favorable impact on survival (HR 0.3, 95% CI 0.1-0.6; p &amp;lt; .01), most apparent in low ( p =0.04), and intermediate ( p &amp;lt;.01), as opposed to high ( p = .06) risk. Conclusions: In the current single institutional series of Ven-HMA treated newly-diagnosed AML, response to Ven-HMA was the foremost predictor of survival. Additional risk factors for survival included adverse karyotype, presence of TP53 and absence of IDH2 mutations. These observations allowed for a three-tiered genetics-enhanced survival model with CR/CRi as a backbone, and also confirmed survival advantage from AHSCT, regardless of risk category.

ELN 2022 Favorable Genetic Risk Acute Myeloid Leukemia Treated with Venetoclax Plus Hypomethylating Agent: Predictors of Response and Survival

Background: The 2022 European LeukemiaNet (ELN) genetic-risk stratification for acute myeloid leukemia (AML), assigns favorable prognosis to t(8;21)(q22;q22.1)/ RUNX1:: RUNX1T1, inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/ CBFB:: MYH1, NPM1 mutations without FLT3-ITD or adverse karyotype, and bZIP in-frame CEBPA mutations (Döhner , Blood, 2022 ). This risk stratification was derived from intensively treated patients; accordingly, prognostication in ELN favorable genetic risk AML, following venetoclax and hypomethylating agent (VEN-HMA) therapy, remains unclear and was the subject of the current study. Methods: Under an institutional review board approved minimum risk protocol, the Mayo Clinic database was searched to identify AML patients with favorable genetic risk, who received treatment with VEN-HMA in the frontline setting. All patients received at least one cycle of either azacitidine 75 mg/m 2 days 1-7 or decitabine 20 mg/m 2 days 1-5 with VEN dose adjusted based on azole antifungal prophylaxis. Genetic risk stratification and treatment response were assessed according to the 2022 ELN criteria. Survival was estimated from the time of VEN-HMA treatment start to last follow-up or death. Results: Patient characteristics A total of 46 newly-diagnosed AML patients with ELN 2022 favorable genetic risk [ NPM1 mutation, n=36 (78%), CEPBA bZIP mutation, n=7 (15%) and t(8;21)(q22;q22.1)/ inv(16)(p13.1q22), n=4 (9%)] received a median of 4 cycles (range 1-32) of VEN-HMA. Median age was 71 years, with 63% males, and 87% de novo AML. Additional mutations frequently involved TET2 in 17/43 (40%), DNMT3A in 14/45 (31%), SRSF2 in 10/43 (23%), K/NRAS in 10/45 (22%), IDH1 in 8/46 (17%), FLT3-TKD in 7/46 (15%), ASXL1 in 6/43 (14%) and IDH2 in 6/46 (13%),of informative cases.Myelodysplasia (MDS)-related gene mutations ( ASXL1, RUNX1, BCOR, EZH2, SRSF2, U2AF1, SF3B1, STAG2, and/or ZRSR2) were present in 15 of 40 (38%) of patients (93% males). Predictors of response Of the 39 (85%) patients that achieved complete remission, with (CR) ( n=24; 52%), or without count recovery (CRi) ( n=15; 33%); CR/CRi rates were not significantly higher in patients with NPM1 mutations (89%), t(8;21)(q22;q22.1)/ inv(16)(p13.1q22) (75%), or CEPBA bZIP mutations (67%) ( p=0.37). Among patients achieving CR/CRi, measurable residual disease by multiparametric flow cytometry was negative in 15 of 16 (94%) of evaluable cases after cycles 1 or 2. In addition, NPM1 qPCR was negative in 15 of 24 (63%) informative patients. Median time to response was 1.2 months with median response duration of 9.4 months. CR/CRi rates were significantly higher in females vs males (100% vs 76%, p=0.01), and in the absence vs presence of MDS-related gene mutations (96% vs 60%, p=0.004). Multivariable analysis confirmed superior response in the absence of MDS-related gene mutations ( p=0.04). Predictors of survival At a median follow-up of 10.6 months (range; 1.1-51 months), 21 patients (46%) have died, 9 relapsed (23% of those achieving CR/CRi), and 6 (13%) underwent allogeneic hematopoietic stem cell transplant. Median overall survival was 21 months with 1/2/3-year survival rates of 65%/41%/41% (Figure 1a); median relapse-free survival (RFS) was not reached; 1/2/3-year RFS rates were 81%/66%/57% (Figure 1b). Overall survival was superior in patients achieving CR/CRi (23 months vs 5.6 months; p&amp;lt;0.01), in females vs males (not reached vs 9.7 months; p&amp;lt;0.01), and in the absence of MDS-related gene mutations (not reached vs 5.6 months; p=0.01) (Figure 1c). Subsequent multivariable analysis identified female gender ( p=0.01), and absence of MDS-related mutations ( p=0.17) as independent predictors of superior survival. Similar results were obtained when analysis was restricted to NPM1 mutated patients. Conclusions: In the current retrospective study, VEN-HMA therapy in elderly/unfit AML patients with ELN 2022 favorable genetic risk, resulted in response rates that were comparable to those previously appreciated from published reports of patients receiving intensive induction therapy; however, follow-up in the current study was too short to accurately assess long-term overall and relapse-free survival impact. Our study also highlights the adverse prognosis retained by MDS-related gene mutations.

Lymphoid Malignancies in Shwachman-Diamond Syndrome: Incidence, Clinical Features, and Outcomes from the North American SDS Registry

Introduction: Many marrow failure conditions are associated with myeloid malignancy predisposition and a subset carry an increased risk of both myeloid and lymphoid malignancies. The increased risk of myeloid malignancy is known in Shwachman-Diamond syndrome (SDS), however, the risk of lymphoid malignancy in SDS has not been previously reported. Through the North American SDS Registry (SDSR), we identified patients with SDS diagnosed with lymphoma. We report the clinical features and outcomes in these patients as well as the incidence rates of lymphoma, MDS, and AML in this cohort. Methods: Patients with biallelic SBDS mutations enrolled on the SDSR were included for analysis. Age- and sex-specific incidence rates from the SEER Program (2016-2020) were multiplied by person-years of observation to obtain expected numbers of events. The crude rate per 100,000 (100,000*observed number of malignancies/person-years of follow-up) and the standardized incidence ratio (SIR) were calculated. Results: Out of a total of 217 patients with SDS with biallelic SBDS mutations in the SDSR, we identified 3 subjects who developed lymphoma. Case 1: A male patient with biallelic SBDS mutations (c.258 + 2T&amp;gt;C; c.653G&amp;gt;A, p.Arg218Gln) presented with dyspnea and was diagnosed with primary mediastinal B-cell lymphoma at age 16 years. Bone marrow exam was negative for lymphoma but revealed a new del20q clone. He received 6 cycles of R-CHOP. His course was complicated by febrile neutropenia, pleural effusion, deep vein thrombosis, and decreased cardiac ejection fraction requiring subsequent omission of doxorubicin and carvedilol initiation. He is in remission &amp;gt;3 years from diagnosis. Case 2: A male patient with biallelic SBDS mutations (c.258 + 2T&amp;gt;C; c.183_184TA&amp;gt;CT, p.Lys62*) was diagnosed at age 23 years with diffuse large B-cell lymphoma (DLBCL) of the distal stomach and duodenal bulb. Bone marrow exam was negative for malignancy but demonstrated an abnormal karyotype: 46,XY,t(11;16)(q23;q24), del(20)(q11.2q13.3)[9]/46,XY[11]. He received 5 cycles of R-CHOP therapy, which was complicated by febrile neutropenia and S. aureus sepsis. Four years later, he was diagnosed with relapsed DLBCL of the distal ileum and concurrent AML with 5q deletion. He achieved complete remission of both malignancies after 2 cycles of cyclophosphamide, vincristine, prednisone, obinutuzumab, azacitidine, and venetoclax. Therapy was complicated by B. cereus bacteremia with brain abscesses and endocarditis and C. difficile infection. He underwent a matched unrelated donor hematopoietic stem cell transplant and is in remission &amp;gt;180 days from transplant. Case 3: A male patient with biallelic SBDS mutations (c.258 + 2T&amp;gt;C; c.183_184TA&amp;gt;CT, p.Lys62*) was diagnosed with Stage IVB classical Hodgkin lymphoma at age 12 years after presenting with mediastinal syndrome. Bone marrow biopsy was negative for findings suggestive of MDS or malignancy, however, the initial PET-CT was consistent with medullary involvement. He initiated therapy with steroids, doxorubicin, vinblastine, dacarbazine, and brentuximab vedotin and received focal radiation. His course was complicated by recurrent febrile neutropenia, C. difficile colitis, and cellulitis. Due to infectious complications and delayed count recovery after 2 cycles, despite chemotherapy dose reductions, he was transitioned to brentuximab and nivolumab. He demonstrated complete response by Deauville criteria prior to cycle 5 of brentuximab and nivolumab. Among 217 patients with biallelic SBDS mutations in the SDSR, the median age was 12.8 years (range: 0.3 - 52.8). The observed number, rates, and SIR for lymphoma, MDS, and AML are given in Table 1. A high SIR indicates a higher incidence in the SDSR relative to the SEER population in 2016-2020. The observed rate of lymphoma was 28.5 times higher in SDS than the expected rate in the general population. Conclusions: The incidence of lymphoma among patients with SDS is increased relative to the general population but is lower than the incidence of MDS or AML. Increased toxicity with standard therapies was observed in these patients. Given the increased risk of MDS/AML in SDS, which may be further increased by antecedent chemotherapy, non-genotoxic therapies should be investigated for lymphoma in SDS. Our results show that SDS should be added to the list of marrow failure conditions predisposing to both myeloid and lymphoid malignancies.

NIMG-51. RADIOGRAPHIC IMPROVEMENT IN A PATIENT WITH OLIGODENDROGLIOMA UNDERGOING TREATMENT FOR ACUTE MYELOID LEUKEMIA

Abstract INTRODUCTION: The standard chemotherapy for treating oligodendroglioma consists of a combination of procarbazine, lomustine, and vincristine (PCV). The combination of hypomethylating agents, like azacitidine, and BCL2 inhibitors like venetoclax have not been formally studied in the treatment of glial tumors. The combination of these two drugs is commonly used to treat acute myeloid leukemia, with IDH mutant disease being a particularly sensitive subtype. CASE REPORT: A 48-year-old man was diagnosed with a left frontal, grade II oligodendroglioma following multiple episodes of speech arrest and right-hand numbness. He was subsequently treated with six cycles of PCV with a minor response. After slow progression over eight years, the tumor started displaying contrast enhancement. While planning for radiation therapy, he presented to the Emergency Department with severe fatigue and shortness of breath. Workup led to a diagnosis of pure erythroid leukemia, with molecular and cytogenetic studies suggesting a neoplasm related to prior exposure to cytotoxic chemotherapy. He was treated with three cycles of venetoclax and azacitidine, but unfortunately, the erythroleukemia progressed after a transient response to this treatment. On the other hand, however, a re-staging MRI brain showed a remarkable reduction of his tumor size of approximately 40% per RANO criteria. The patient was off steroids and remained neurologically asymptomatic during this time. Discussion: The use of azacitidine for the treatment of IDH mutant gliomas has been reported in the literature, with mixed results that might suggest at least some benefit in a subtype of patients. Other studies have also suggested that the BCL2 gene is associated with treatment resistance and tumor recurrence in gliomas. Our case presents an interesting observation that combining a hypomethylating agent with a BCL2 inhibitor might convey clinical and radiographic benefits for patients with relapsed IDH mutant gliomas.

Maintenance therapy with a combination of azacitidine, danazol, and thalidomide after intensive chemotherapy in patients with acute myeloid leukemia

ABSTRACTObjectiveThis study aimed to evaluate the efficacy of azacitidine (AZA) combined with danazol (DNZ) and thalidomide (THD) maintenance therapy after intensive chemotherapy (IC) in patients with acute myeloid leukemia (AML).Methodswe retrospectively analyzed the clinical data of 11 patients treated with AZA combined with DNZ and THD as maintenance therapy after IC at the Baiyun Hospital were between February 2017 and March 2021. The patients' clinical features, relapse-free survival (RFS), and overall survival (OS) were analyzed.ResultsEleven cases fulfilled the AML criteria per the 2016 World Health Organization classification. Of the 11 patients, five were females, and six were males, with a median age of 45 years (range, 23-65 years). Ten patients were in the first complete remission (CR1), and one patient was in the second complete remission (CR2). All patients received AZA combined with DNZ and THD maintenance therapy after IC. The median number of AZA cycles received was 7 (6-12). Until June 2022, the median follow-up period was 37 (14-63) months; one patient had a relapse, and three died. RFS at 1 year and 3 years was 100% and 71.1%, respectively, and OS at 3 years was 100%.ConclusionAZA combined with DNZ and THD maintenance therapy is effective for patients with AML who are ineligible for allogeneic hematopoietic stem cell transplantation. Further studies with large sample sizes and randomized are needed to verify these findings.

Azacitidine as a rare cause of reactive arthritis in a patient with acute myeloid leukemia.

Azacitidine (AZA), a demethylating agent, is one of the mainstay treatments for patients with myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) who are ineligible for curative allogeneic stem-cell transplantation and is recommended as first-line treatment in multiple countries. While arthralgia and myalgia have been commonly reported as side effects, the incidence of drug-induced reactive arthritis has only been reported twice so far. We present a retrospective overview of a clinical case of a 71-year-old patient that developed new cytopenias on a background of Chronic Lymphocytic Leukaemia and was diagnosed with therapy-associated AML. His treatment included an indefinite course of AZA to induce remission and optimise long-term survival which resulted in a satisfactory haematological response. However, after his ninth AZA cycle, he presented to the emergency department with knee swelling and erythema and conjunctivitis. Arthrocentesis of the knee revealed reactive arthritis with no crystal or organism growth. His symptoms were managed effectively with conservative management including NSAIDs, analgesia and temporary immobilization for joint rest. The adverse drug reaction probability score in our study was calculated as six and adverse drug reaction was thus assigned to the "probable" category. We report a case that points to AZA as a probable cause of arthritis flares in MDS patients. The current limitation of this study is the lack of available data, future reviews and research will aid in providing stronger evidence of a correlation between arthritis and AZA treatment.

Abstract 3269: Reappraisal of immunologic mechanisms of hypomethylating agents in treatment of high-risk myelodysplastic syndrome and acute myeloid leukemia

Abstract Hypomethylating agents (HMA) have been used for the treatment of high-risk myelodysplastic syndrome (HR-MDS) and acute myeloid leukemia (AML) of the elderly. In addition to direct cytotoxic effect of HMA on MDS/AML, HMA upregulates effector T-cell function by demethylating T-cell exhaustion-associated genes (Hazem, Cell 2017) and promoting effector T-cells trafficking to tumor microenvironment by Th1-type chemokines reactivation (Peng, Nature 2019). To elucidate dynamic changes of immune cells profile and gene expression after HMA treatment in MDS/AML, we conducted single cell RNA sequencing of three sequential bone marrow (BM) samples from one HR-MDS patient treated with azacitidine. In BM samples at diagnosis (‘diagnosis’), after 2 cycles of azacitidine (BM blasts increased from 6 to 11%; ‘progression’), and after 3 additional cycles of azacitidine (BM blasts decreased to 3.5% with trilineage hematopoiesis; ‘response’), cell clusters were identified according to immune cell types. The relative proportion of the NK-cell cluster showed the most significant increase up to response (1.3% at ‘diagnosis’, 4.3% at ‘progression’, and 11.8% at ‘response’). By contrast, the CD8 T-cells cluster showed modest increase of proportion at the 3 timepoints (2.7%, 3.9%, and 7%, respectively). Differentially Expressed Gene (DEG) analysis showed CXCR4 was overexpressed in the BM NK-cell cluster at the ‘response’ time point. To determine whether the NK cells can be trafficked to BM by HMA treatment in mouse MDS/AML models, mouse myeloid leukemia cells (C1498 cells) were transplanted into the tail vein of 6-to-8-week aged syngeneic C57/BL6 mice. C1498 bearing mice were intraperitoneally treated with HMA (decitabine) or vehicle for 5 consecutive days. While HMA inhibited in vivo AML proliferation, the quantity of NK cells (NK1.1+) was significantly increased in BM of HMA-treated mice than vehicle controls. In addition, CXCR4 expression in NK1.1+ cells from BM of HMA-treated mice were significantly up-regulated, compared with vehicle controls. The NK depletion in HMA-treated AML mice decreased anti-leukemic effect, suggesting that NK cells may be one of immune cell subsets responsible for HMA induced anti-leukemia effect. Taken together, recruitment of NK cells into MDS/AML BM through CXCR4 overexpression and anti-leukemic cytotoxicity exerted by NK cells can be one of the important immunologic mechanisms of HMA in MDS/AML. Treatment strategy of recruiting more NK cells BM by HMA and maximizing cytotoxicity of NK cells should be further investigated. Citation Format: Junshik Hong, Suji Min, Jihyun Park, Carly M. Fielder, Qianni Hu, Sung-Soo Yoon, Tae Kon Kim. Reappraisal of immunologic mechanisms of hypomethylating agents in treatment of high-risk myelodysplastic syndrome and acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3269.

Successful Bridging to Allogeneic Hematopoietic Stem Cell Transplantation by Azacitidine and Venetoclax in a Case of Acute Myeloid Leukemia With t(3;3)(q21.3;q26.2) Developed Early After Orthotopic Heart Transplantation

A 48-year-old male patient developed acute myeloid leukemia (AML) with t(3;3)(q21.3;q26.2) chromosomal mutation 8 months after orthotopic heart transplantation from a human leukocyte antigen-unmatched brain-dead donor for cardiac sarcoidosis. He had sequelae of stroke and chronic renal failure at the time of AML diagnosis. He received 3 cycles of azacitidine and venetoclax induction therapy and achieved complete hematological remission with incomplete count recovery without causing severe complications, including infection. He sequentially underwent allogeneic peripheral blood stem cell transplantation from a HLA-8/8 matched, ABO-blood matched, unrelated female donor and successfully achieved donor cell engraftment. His transplanted heart was viable, and the coronary vessels were not damaged even after allogeneic peripheral blood stem cell transplantation. Although AML relapsed afterward, azacytidine/venetoclax was a tolerable bridging therapy even for early-onset AML after heart transplantation.

Cytogenetic peripheral blood monitoring in azacitidine treated patients with high-risk MDS/sAML: A monocentric real-world experience

In this single center retrospective analysis 76 patients with high-risk (HR) myelodysplastic syndrome (MDS) treated with azacitidine (AZA) were reviewed for response, especially cytogenetic response (cyR) using repeated chromosome banding analyses (CBA) of bone marrow (bm) metaphases and frequent sequential Fluorescence-in-situ Hybridization (FISH) analyses of immunomagnetically enriched CD34 + circulating peripheral blood cells (CD34 +pb-FISH). In total, 526 CD34 +pb-FISH analyses and 236 CBA were examined. Median observation time was 8.45 months, median number of AZA cycles applied was 8, median overall survival (OS) was 14.9 months, 42.1 % of patients responded to therapy according to IWG criteria: 5 complete response (CR), 0 partial response (PR), 12 bmCR, 15 stable disease with hematologic improvement (HI). HI was reached in 36.8 % of patients, 31.5 % became transfusion-independent. By CBA or CD34 +pb-FISH 20.4 % and 31.6 % of patients showed cyR, respectively. HI rate was significantly higher in cytogenetic responders than in non-responders, but there was no impact on OS or leukemia-free-survival. Cytogenetic responders showed significantly better OS than non-responders. Patients with ≥ 6 AZA cycles had significantly better OS than patients with < 6 cycles applied. Karyotype evolution (KE) as a manifestation of cytogenetic progression was diagnosed in 29.5 % and 17.1 % of patients by CBA and CD34 +pb-FISH, respectively. KE was associated with significantly poorer OS and leukemia-free-survival.

High rate of invasive fungal infections during early cycles of azacitidine for patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) is a form of cancer that is characterized by infiltration of the bone marrow, blood, and other tissues by proliferative, clonal, abnormally differentiated, and occasionally poorly differentiated cells of the hematopoietic system. Patients with acute myeloid leukemia (AML) receiving azacitidine (AZA) alone or in combination with venetoclax (VEN-AZA) are at increased risk for invasive fungal infections (IFIs). We compared the incidence and risk of IFI during these treatment regimens in a single Taiwan hospital. A total of 61 patients with AML received at least one course of AZA in the hematology ward of China Medical University Hospital (Taichung, Taiwan) between September 2012 and June 2020. Thirty-eight patients (62.3%) received AZA monotherapy; 23 (37.7%) received VEN-AZA. Incidence rates of probable and proven IFI were 18% and 1.6%, respectively, during AZA treatment. One proven case of Fusarium spp. infection was isolated by skin and soft tissue culture. Most (75%) IFI cases occurred during the first cycle of AZA therapy. Half of all IFI cases occurred in patients with prolonged neutropenia. The risk of IFI was significantly higher for the European LeukemiaNet (ELN) nonfavorable-risk group (intermediate- and adverse-risk group) versus the ELN favorable-risk group and for patients with prolonged neutropenia versus those without (P<0.05 for both comparisons). In this study, median OS did not differ significantly between patients with and without IFIs during AZA-containing regimens (14.6 months vs 13.7 months; P=0.59). The incidence of IFI was high in this AML cohort treated with AZA-containing regiments in Taiwan. The majority of IFI cases occurred during the early cycles of AZA (cycles 1-2). Prospective studies are needed to determine the optimal choice of antifungal prophylaxis agent during VEN-AZA therapy for AML.

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.

Real-World Treatment Patterns, Outcomes and Disease Burden of Japanese Patients with High-Risk Myelodysplastic Syndrome: A Claims Database Study

Introduction Inherent complex pathophysiology of myelodysplastic syndrome (MDS) along with its higher occurrences in elderly population often limits available treatment options. In Japan, azacitidine (AZA) is the only first-line (1L) treatment, which is not cytarabine-based, available for patients (pts) with high-risk MDS (HR-MDS) ineligible for hematopoietic stem cell transplantation (HSCT). Prior autoimmune diseases have been associated with susceptibility of MDS. However, durability of AZA treatment and data on MDS-specific comorbidities, especially immune-driven events are currently lacking in Japanese pts. This study aimed to answer clinical questions on AZA real-world treatment outcomes in Japan, the epidemiology of autoimmune diseases in this specific pt cohort, as well as treatment cost. Methods This was a retrospective, longitudinal study utilizing hospital-based administrative claims for MDS patients in the Medical Data Vision (MDV) database in Japan. Data on pt demographics, clinical characteristics, treatments, procedures and hospitalization records were collected. Adult pts with first a confirmed MDS diagnosis either as an inpatient or twice in outpatient setting during the identification period (1October 2008 - 30 September 2017), who had a bone marrow biopsy in ±3 months from index date and at least 1 MDS-related treatment post-index date, were included in this real-world study. Pts with confirmed acute myeloid leukemia (AML) diagnosis or who had any history of HSCT, graft-versus-host-disease or transplant-related disorder/complications were excluded. As IPSS/R scoring is unavailable in MDV, pts were classified as HR-MDS if they had either AZA treatment or HSCT within 6 months post-index date, or pancytopenia diagnosis within 6 months post-index date and initiated AZA within 12 months. Results Of 6204 pts who met the eligibility criteria (main cohort), 2138 pts were assigned as HR-MDS. The median age of pts in the main cohort was 74.0 years (range: 18.0 - 100.0 years, ≥60 years old: 87.8%) vs 73.0 years (range: 20.0 - 95.0 years; ≥60 years old: 88.6%) in the HR-MDS cohort. Mean Charlson Comorbidity Index was 1.7 (± 1.66) and 1.6 (± 1.47) for the main cohort and HR-MDS cohort respectively. The proportion of transfusion-dependent pts in the main cohort was 9.4% vs 7.1% of patients in the HR-MDS cohort. Among 2138 pts with HR-MDS, 251 pts reported having concomitant autoimmune disease with rheumatoid arthritis (32.3%), glomerulonephritis (26.7%) and seronegative arthritis (23.1%) being the most common. More pts in the main cohort (53.2%) compared to pts with HR-MDS (38.9%) received anti-anemic drugs, G-CSF and iron chelators as supportive therapy at 1L. Compared to 39.5% pts in main cohort, 88.3% pts with HR-MDS received antineoplastic agents at 1L therapy. In HR-MDS cohort, 2078 pts received AZA in different cycles (1-3 cycles: 40.5%, 4-6 cycles: 21.1%, 7-9 cycles: 11.5%, >9 cycles: 26.9%) but only 121 pts received intensive chemotherapy (1 cycle: 90.1%, 2 cycles: 9.1%, >2 cycles: 0.8%). Median duration of MDS-specific treatment for patients with HR-MDS was 9.8 months. Significantly higher median OS (P<0.001) was achieved in pts with HR-MDS who received more cycles of AZA (Fig. 1: 1-3 cycles: 14.6 months, 4-6 cycles: 21.4 months, 7-9 cycles: 22.8 months, >9 cycles 40.8 months). After controlling for death as a competing risk, the cumulative incidence function (CIF) of HSCT and AML transformation was not affected by the number of cycles of AZA received. Although more cycles of AZA treatment increased the total treatment cost, median cost per pt per month was inversely affected with the lowest cost for pts receiving >9 cycles (Fig. 2). Conclusion Our findings based on the real-world data analysis in Japanese pts follow the similar trend of elderly pts with HR-MDS mostly receiving AZA as 1L treatment. Despite higher median OS being associated with higher number of AZA cycles, only ~27% pts with HR-MDS received >9 cycles of AZA. Autoimmune disease was reported by 11.7% of pts with HR-MDS. Although treatment cost increased with number of cycles of AZA received, median cost per pt per month was lowest in patients receiving >9 cycles. The cost per pt per month for other MDS-related treatment as well as costs for blood transfusions and infection related treatments were lower as increasing cycles of AZA were given which contributed to lower cost per pt per month. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal