Low-blast Acute Myeloid Leukemia Research Articles

Azacitidine and venetoclax with or without pevonedistat in patients with newly diagnosed acute myeloid leukemia

This phase 2 study investigated pevonedistat + azacitidine + venetoclax (n = 83) versus azacitidine + venetoclax (n = 81) in patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy. The study was stopped early following negative results from PANTHER, which evaluated pevonedistat in higher-risk myelodysplastic syndromes/chronic myelomonocytic leukemia or low-blast AML. Outcomes were analyzed up to the datacut. For pevonedistat + azacitidine + venetoclax versus azacitidine + venetoclax, the median follow-up was 8.44 versus 7.95 months; the complete remission (CR) rate was 45% versus 49%; composite CR (CCR; CR+CR with incomplete blood count recovery) was 77% versus 72%. There were no differences in event-free survival (primary endpoint; hazard ratio [HR]: 0.99; 95% confidence interval [CI]: 0.61–1.60; p = 0.477) or overall survival (HR: 1.42; 95% CI: 0.82–2.49; p = 0.896). In exploratory analyses in IDH-mutated AML, CCR rates were higher with pevonedistat + azacitidine + venetoclax versus azacitidine + venetoclax. Safety was similar between treatment arms. Efficacy/safety with azacitidine + venetoclax was consistent with the phase 3 VIALE-A study. Trial registration NCT04266795

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.

A phase II study of vibecotamab, a CD3-CD123 bispecific T-cell engaging antibody, for MRD-positive AML and MDS after hypomethylating agent failure.

TPS7076 Background: CD123 is a marker of leukemic stem cells that is differentially overexpressed in most patients with acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). In contrast, CD123 is expressed at negligibly low levels on normal hematopoietic progenitors, making it a potentially promising therapeutic target. Vibecotamab (formally XmAb14045) is a CD3-CD123 bispecific engaging antibody that has established clinical activity in relapsed/refractory AML. In a phase I study, the overall response rate was 14.8% in patients who received vibecotamab at a dose of ≥ 0.75 µg/kg (Ravandi F et al. ASH 2020 abstract #460). Response rates were notably higher in those with lower disease burden (bone marrow blasts ≤ 25%) where the overall response rate was 25.9%. In light of the activity of vibecotamab in relapsed/refractory low-blast AML, we designed this phase II study to evaluate vibecotamab in other low-blast states, including CD123-positive, MRD-positive AML and in MDS or CMML after failure of hypomethylating agents. Methods: This is a two-arm, open-label, phase II study of vibecotamab in patients with AML in first or second morphological remission with detectable MRD at a level of ≥0.1% by flow cytometry and in patients with MDS (intermediate or higher-risk by IPSS-R) or CMML (CMML-1 or CMML-2) after failure of hypomethylating agents. CD123 expression ≥20% on aberrant myeloid blasts is required for study eligibility. Vibecotamab is given IV in a ramp-up dose schedule on days 1, 3, 5 and 8 of cycle 1, followed by weekly doses of vibecotamab at a dose of 1.7 µg/kg. Patients may receive up to 4 cycles of vibecotamab in 28-day cycles. The primary objective of the AML MRD cohort is to determine the MRD negativity rate after 4 cycles; the primary objective of the MDS/CMML cohort is to determine the response rate (CR + mCR + PR + HI + clinical benefit) after 4 cycles. The target MRD response in the AML MRD cohort is 50%, and the target response rate in the MDS/CMML cohort is 30%. Secondary endpoints include remission duration, duration of MRD response (AML MRD arm), CR rate (MDS/CMML arm), relapse-free survival, overall survival, and safety. Exploratory endpoints include correlation of clinical outcomes with CD123 expression and the dynamics of CD123 expression at treatment initiation and at the time of relapse. Additional immunological correlatives will be performed, including 1.) determination of molecular immune states that predict response or resistance, 2.) functional interrogation of TCR-antigen interactions, and 3.) nomination of leukemic neo-antigens. The planned enrollment is 40 patients (20 in each of the two cohorts). To date, 13 patients have been enrolled (7 in the AML MRD cohort and 6 in the MDS/CMML cohort). The trial is actively accruing at MD Anderson Cancer Center. Clinical trial information: NCT05285813 .

Favorable Outcomes of DDX41-Mutated MDS and Low Blast Count AML Treated with Azacitidine with or without Lenalidomide (ALLG MDS4 Trial)

Introduction. The Australasian Leukaemia and Lymphoma Group (ALLG) MDS4 phase II trial randomized 160 patients (pts) with higher risk (by IPSS) myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and low blast acute myeloid leukemia (AML) to either azacitidine (AZA) or combination AZA with lenalidomide (LEN, from cycle 3 onwards) (Kenealy, Haematologica 2019; ANZCTR12610000271000). Whilst the combination of LEN and AZA was tolerable, there was no improvement in clinical benefit, response rates or overall survival in patients compared to treatment with AZA alone. We performed a post-hoc genomic analysis of pts on this trial to further understand the molecular changes in this cohort and any correlation with outcomes. Methods. A unique molecular index (UMI) based QIAseq targeted DNA panel (QIAGEN) was performed as previously described (Blombery, Blood 2020). Sensitivity for variant calling was 0.5% variant allele frequency (VAF). HumanCytoSNP-12 BeadChip array (SNP-A) was previously performed and reported (Kenealy, Haematologica 2019). Primary endpoint of the study was ongoing clinical benefit at 12 months, defined as being alive and progression-free. Logistic regression and Cox proportional hazards regression were used respectively to assess the differences in response rates and overall survival between two treatment groups according to the molecular subgroups. Results. A total of 66 pts, representative of the 160 enrolled, had baseline gDNA available for targeted panel testing; 36 and 30 pts on AZA alone and AZA+LEN therapy, respectively. Median age was 71.6 years. IPSS-R risk groups were very low or low (n=20), intermediate (n=18), high or very high (n=25), and not available (n=3 due to missing karyotype). Disease subtypes were MDS (n=52), CMML (n=9), and AML (n=5). 47% of pts had an abnormal SNP-A, including 18% with complex (≥3) copy number changes. The most common gene mutations observed were ASXL1 (48.5%), TET2 (47%) and RUNX1 (30%) (Figure 1). Overall clinical benefit at 12 months was achieved in 39 pts (59%). TET2 was the only gene mutation associated with significantly improved benefit when treated with AZA alone (OR 10 [95% CI, 2 to 81]). Median follow up among survivors was 49 months and the median overall survival was 33.2 months (95% CI, 21.7 - NE). Mutations in TP53, U2AF1, EZH2 and SRSF2 were associated with inferior overall survival. Molecular subgroup analyses did not identify any significant difference between the two treatment arms. Given the recent discovery of DDX41 mutations in MDS/AML and early data supporting a favorable response to AZA/LEN, we focused on 6/66 (9%) patients with detectable DDX41 mutations. All 6 pts had a second mutation detectable in DDX41 as well as no detectable abnormalities on SNP-A. The most commonly co-mutated gene in this group was ASXL1 (in 4/6). One patient with DDX41 mutation died before receiving any therapy. Best responses achieved in DDX41 mutated patients were complete remission (CR, n=1), marrow CR (n=1), hematologic improvement (HI, n=1), and stable disease (SD, n=2). Remarkably, of the 5 patients that received treatment (4 AZA, 1 AZA+LEN), the overall survival at 52 months (range 47-58) follow up was 100% (Figure 2), despite having intermediate (n=3) and high (n=2) R-IPSS. Mutations were also serially assessed on therapy in 45 pts: ≤2 cycles in 38 pts, and ≥4 cycles in 7 pts (2 AZA+LEN). Of 166 mutations observed at baseline, majority (67%) were stable with <10% change in VAF (median +2%). Overall, 27 (60%) pts had clearance or >10% VAF reduction in ≥1 variant, including clearance in 20 (12%) variants (most commonly TET2 [n=4] and RUNX1 [n=3]), and reduction in 33 (20%) variants (ASXL1 [n=6], SF3B1, SRSF2 and TET2 [n=5 each], but no pt had complete molecular clearance. In contrast, new mutations (n=18 variants) or >10% VAF increase (n=2 variants) were observed in 14 (31%) pts, most commonly TET2 (n=6), RUNX1 (n=4), and DNMT3A and BRAF (n=3 each). Conclusions. In summary, our correlative molecular analysis of the ALLG MDS4 trial of AZA vs AZA+LEN in MDS/AML has identified, in addition to established molecular risk factors for inferior outcomes, that pts with DDX41 mutations are associated with highly favorable outcomes with either AZA or AZA+LEN. This observation and subgroup of patients warrants further study in randomized trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MDS-344: Pevonedistat Plus Azacitidine vs Azacitidine Alone in Higher-Risk Myelodysplastic Syndromes (MDS): Efficacy and Safety Results from Study P-2001 (NCT02610777)

Introduction: Pevonedistat, an investigational, first-in-class NEDD8-activating enzyme inhibitor, disrupts protein homeostasis, leading to cancer cell death. For patients with higher-risk MDS ineligible for transplant, real-world data reveal median overall survival (OS) is 11–15 months with treatment, yet no novel treatments have been approved in a decade. Methods: Patients with higher-risk MDS/chronic myelomonocytic leukemia or low-blast acute myeloid leukemia (AML) naive to hypomethylating agents were randomized 1:1, receiving pevonedistat (20 mg/m2 intravenously [IV], days 1, 3, 5) + azacitidine (75 mg/m2 IV/subcutaneously, days 1–5, 8, 9) (n=58) or azacitidine alone (n=62) in 28-day cycles until unacceptable toxicity, relapse, AML transformation, or progression. The study was powered for event-free survival (EFS: time from randomization to death/AML transformation, whichever occurred first). This report focuses on higher-risk MDS, including their cytogenetic and genetic characterization. Results: In patients with higher-risk MDS (n=67/120), baseline characteristics were balanced between arms. EFS was longer with pevonedistat+azacitidine vs azacitidine (median 20.2 vs 14.8 months; HR 0.54; 95% CI 0.29–1.00; p=.045). For patients with high-risk MDS assessed using the Cleveland Clinic model formula (n=16/arm), median EFS was 20.2 vs 11.7 months (HR 0.39; 95% CI 0.17–0.90; p=.023); median OS was 24.2 vs 14.2 months (HR 0.45; 95% CI 0.19–1.05; p=.056) with pevonedistat+azacitidine vs azacitidine. Overall response rate (complete remission [CR]+partial remission [PR]+hematological improvement, n=59 response-evaluable patients) was 79% with pevonedistat+azacitidine vs 57% with azacitidine, with a CR rate of 52% vs 27% (p=.050); median duration of response (DOR, CR+PR) was 34.6 vs 13.1 months (p=.106). Median (range) time to transformation (pevonedistat+azacitidine [n=5] vs azacitidine [n=9]) was 12.2 (4.6–12.6) vs 5.9 (1.7–14.8) months. Median dose intensity of azacitidine was 98% in both arms. Exposure-adjusted adverse event (AE) rates, normalized by mean cycles dosed, were lower with pevonedistat+azacitidine vs azacitidine. Pevonedistat+azacitidine clinical activity was observed in patients with adverse-risk mutations. Conclusions: In patients with higher-risk MDS, pevonedistat+azacitidine prolonged EFS, delayed AML transformation, nearly doubled CR rate, and tripled DOR vsazacitidine alone. EFS and OS favored pevonedistat+azacitidine vs azacitidine in patients with high-risk MDS. Exposure-adjusted AE rates were lower with pevonedistat+azacitidine vs azacitidine without added myelosuppression.

Patient Perspectives on Symptom Experience and Impact on Health-Related Quality of Life in Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia and Low-Blast Acute Myeloid Leukemia

INTRODUCTIONMyelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML) are rare hematological stem cell disorders resulting in cytopenias, disease-related complications, and death. Given the lack of curative treatment options available to patients with these conditions, patient quality of life is a significant factor when making treatment decisions. The Food and Drug Administration defines health-related quality of life (HRQL) as a multidimensional concept encompassing a patient's overall disease- and treatment-related impact experience associated with physical, psychological (including emotional and cognitive), and social functioning domains. Importantly, regulatory agencies are emphasizing patient-centeredness in clinical trial design to capture benefits of new treatments, and qualitative research is essential to ensure that important aspects of the patients' experiences are captured in pivotal trials. Unfortunately, research on patients' perspectives on their symptoms, treatment and impact on HRQL is limited.This study aimed to better understand the overall symptom experience and impact on HRQL from the perspective of patients living with higher risk (HR) MDS, CMML, and low blast (LB) AML. Findings informed the development of a conceptual framework (CF) for disease- and treatment-related symptoms and impacts on HRQL.METHODSA literature review was conducted in Medline (January 2000-July 2016) for studies reporting on patient symptoms and impacts related to HR MDS, CMML, and LB AML, and supplemented with further medical and advocacy website reviews. Relevant information regarding patients' symptom experience and impact on HRQL was compiled. Semi-structured qualitative interviews with clinicians (n=3) and patients (n=14) elicited further information about core symptoms and related impacts of disease and treatment. Following approval from an independent review board, HR MDS, CMML, and LB AML patients were recruited through the MDS Foundation or physician referral. Patients were screened and compensated. Symptom and impact concepts from all sources were organized into a CF describing the patients' disease and treatment experience and impact on HRQL.RESULTSForty-four disease- and treatment-related symptoms and 49 impacts on HRQL were identified through the literature and website reviews. Clinical experts provided additional background on symptoms of the conditions and common treatment regimens, associated side effects, and potential impact on HRQL. The mean age of patients interviewed was 69 years (±8.5); 64% female; n=11 HR MDS, n=2 CMML, n=1 LB AML. Most patients were treated with azacitidine (n=9; 64%) and date of diagnosis ranged from 4-55 months, with 76% of patients diagnosed within the last 2 years. Eastern Cooperative Oncology Group (ECOG) status was reported by clinicians (n=8; 87% ECOG: 1) or patients (n=6; 83% ECOG: 2). Symptom and impact concepts elicited from patients reflected those identified in the literature review and expert interviews; however, patients provided additional detail that was not reported in other sources. All patients reported fatigue (n=14, 100%); most reported shortness of breath (n=12, 86%), weakness (n=11, 79%), pain (n=10, 64%), nausea (n=9, 64%), bruising (n=9, 64%), constipation (n=9, 64%) and dizziness (n=9, 64%). Symptoms of the disease and treatment had substantial impact on HRQL. Most patients reported difficulty walking (n=11, 79%); performing daily activities such as working (n=9, 64%), household chores (n=8, 57%), shopping (n=7, 50%); and participating in activities that could expose them to infection such as caring for grandchildren (n=7, 50%), traveling (n=6, 43%), and eating out (n=4, 29%). Concepts derived from the literature reviews and clinician and patient interviews were consolidated into two draft CFs (see figures) for disease- and treatment-related symptoms (n=49 concepts) and impacts on HRQL (n=54 concepts).CONCLUSIONSIncorporation of the patient voice allowed for direct patient engagement, which provided valuable in-depth insight about the patient experience with HR MDS, CMML and LB AML. The CF for disease- and treatment-related symptoms and impacts on HRQL can guide the evaluation of treatment benefit from the patient perspective in these diseases, which will fill an important gap and help to inform treatment decision making. [Display omitted] DisclosuresBell:Takeda Pharmaceuticals: Employment, Equity Ownership. Galaznik:Takeda Pharmaceuticals: Employment, Equity Ownership. Pompilus:Modus Outcomes: Employment; Takeda Pharmaceuticals: Research Funding. Strzok:Takeda Pharmaceuticals: Research Funding; Modus Outcomes: Employment. Fram:BeyondSpring Pharmaceuticals, Inc.: Consultancy; Takeda Pharmaceuticals: Consultancy. Faller:Takeda Pharmaceuticals: Employment, Equity Ownership. Marquis:Takeda Pharmaceuticals: Research Funding; Modus Outcomes: Employment.

The Clinical Significance of Chromosome 17 Abnormalities in Myelodysplastic Syndrome Treated with 5-Azacytidine. Results from the Hellenic 5-Azacytidine Registry

IntroductionAberrations of chromosome 17 have been correlated to poor prognosis and resistance to treatment in several hematologic malignancies. Their role in myelodysplastic syndrome (MDS) has not yet been fully elucidated. Inversion of chromosome 17 (inv17) has been characterized as an intermediate risk cytogenetic abnormality in the revised International prognostic scoring system (IPSS-R), but chromosome 17 monosomy and other chromosome 17 abnormalities have not yet been fully characterized. Moreover, mutations of TP53 located on chromosome 17p, have been correlated to poor prognosis and resistance to treatment.AimTo determine the incidence and clinical significance of acquired abnormalities of chromosome 17 in adult patients with MDS treated with 5-azacytidine, in the context of the Hellenic 5-azacytidine registry.Patients and methodsPatients diagnosed with myelodysplastic syndrome per the 2008 WHO classification were included in the study. Conventional cytogenetic testing was performed at diagnosis. All patients were treated with 5-azacytidine during the course of their disease according to common clinical practice. Demographic, clinical and laboratory data were recorded retrospectively (Hellenic 5-azacytidine registry). Statistical analysis was performed using IBM SPSS statistics, version 23.0 (IBM Corporation, North Castle, NY, USA).ResultsWe analyzed the results of the cytogenetic analysis of 465 patients with MDS at diagnosis. Patients with chronic myelomonocytic leukemia, MDS/myeloproliferative neoplasm (MDS/MPN), and low-blast acute myeloid leukemia were excluded from the analysis. The main characteristics of the patients are shown in Figure 1A. We found 23/465 (4.9%) patients with chromosome 17 aberrations (6 with chromosome 17 inversion, 13 with a complex karyotype including chromosome 17 monosomy, 3 with a complex karyotype with add(17) and 1 with t(17;19)). All cases of inv(17) were found as an isolated cytogenetic abnormality, while all cases of chromosome 17 monosomy were found in the context of a complex karyotype. Abnormalities of chromosome 17 were the 7th more common cytogenetic abnormalities after complex karyotype and abnormalities of chromosomes 7, 8, 3, 5 and 12.Patients with chromosome 17 abnormalities from our registry tended to be higher risk per both the IPSS and the IPSS-R. The median follow-up of the patients was 23.1 (0.7-203.8) months. Patients with chromosome 17 aberrations had a median overall survival (OS) of 20.7 months versus 35.3 months for patients without chromosome 17 aberrations (log Rank 2-sided p<0.0001, Figure 1B). Patients with any type of chromosome 17 abnormalities carried a worse prognosis than patients without abnormalities of chromosome 17 (OS was as follows: inv(17), 28.9 months; chromosome 17 monosomy, 20.7 months; add(17), 14.8 months; t(17;19), 5.7 months). Patients with a complex karyotype carried a poor prognosis irrespective of chromosome 17 aberrations. The presence of chromosome 17 abnormalities did not affect response to 5-azacytidine, and the rate of transformation to AML was comparable to that of the rest of the studied population. Moreover, t(17;19) has been correlated with poor prognosis in patients with acute lymphoblastic leukemia. Here we report for the first time the same chromosome abnormality in a patient with RAEB1 with poor prognosis.DiscussionThe present study evaluates the cytogenetic analysis of the largest, to our knowledge, cohort of patients with MDS treated with 5-azacytidine. Chromosome 17 abnormalities in patients with MDS comprise a group of cytogenetic disorders with poor prognosis since most of them are found in the context of a complex karyotype with the exception of inv(17) that occurs typically as a single cytogenetic abnormality. 5-azacytidine seems to be equally effective in patients with a complex karyotype with and without chromosome 17 abnormalities. Nevertheless, overall survival and survival after 5-azacytidine treatment remain short, although patients with inv(17) have a better prognosis from patients carrying other chromosome 17 abnormalities, with survival rates exceeding the historical control of 12 months for patients with high-risk MDS treated with best supportive care. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Enhancing the Content of the EORTC QLQ-C30 to Maximize the Detection of Treatment Benefit in Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Low-Blast Acute Myeloid Leukemia Using the EORTC Item Bank

INTRODUCTIONMyelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myelogenous leukemia (AML) are rare hematological stem cell disorders resulting in cytopenias, disease-related complications, and substantial impact on health-related quality of life (HRQOL). A literature review, clinician interviews, and qualitative interviews with high risk (HR) MDS, CMML, and low blast (LB) AML patients confirmed the relevance of concepts assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) for measuring HRQL, but also suggested that concepts important to evaluate the complete experience of patients with these conditions were missing, or only addressed in a limited fashion.The present study involved testing supplemental items from the EORTC item bank with patients to confirm item relevance and aimed to enhance the content of the EORTC QLQ-C30 to detect treatment benefit in patients with HR MDS, CMML and LB AML.METHODSSupplemental items were selected from the EORTC item bank to address the conceptual gaps of the core EORTC QLQ-C30 instrument in this patient population. Items were selected based on concepts drawn from the literature review and prior qualitative work with patients. After ethical approval from an independent review board, HR MDS, CMML, and LB AML patients were identified through clinical sites and the MDS Foundation and screened for eligibility. Using a semi-structured interview guide, 45-minute cognitive debriefing interviews (CDIs) were conducted with each patient to evaluate item understanding, response option clarity, and item relevance. Audio-recorded interviews were transcribed, coded, and analyzed. Patient responses to the EORTC QLQ-C30 and supplemental items were collected for quantitative analysis (i.e., item level endorsement frequencies). An interview with a hematologist provided additional clinical perspective on the results.RESULTSCDIs were performed with 18 patients (mean age 68 (±10.1); 56% female; n=14 HR MDS, n=3 CMML, and n=1 LB AML). Most patients were treated with azacitidine (n=12; 67%), had an ECOG status of 1 (n=6, 33%) or a patient-rated ECOG of 2 (n=6, 33%), and were diagnosed within the last 12 months (n=10, 56%).To address conceptual gaps identified in our initial qualitative work, 9 supplemental symptom items (bone pain, weakness, feeling slowed down, easily tired, lacking energy, bruising/petechiae, dizziness, and shortness of breath [2 items]) and 4 supplemental impact items (limitations with climbing stairs or getting up out of a chair, travel limitations, doing housework, and shopping or running errands) were selected from the EORTC item bank. These items were presented to patients for additional testing. Supplemental items were generally well understood and considered relevant, with two exceptions. Bone pain was often attributed to injury or arthritis rather than MDS, CMML, or AML or its treatments; travel limitations lacked clarity as patients were unsure what type of travel to consider (i.e., car travel vs. air travel). Item level endorsement frequencies showed good distribution across most response options without skewness, indicating that most supplemental items assessed concepts relevant to this sample (Table 1). Clinician feedback confirmed the relevance of most supplemental items and reinforced that the bone pain and travel limitation items were problematic. Based on the qualitative and quantitative analysis of the CDIs, the bone pain and travel limitation supplemental items were removed (Table 2). A total of 11 supplemental items were retained to enhance the content of EORTC QLQ-C30 instrument to better capture treatment benefit from the patient perspective.CONCLUSIONSOur study suggests that engagement with patients to address conceptual gaps in EORTC QLQ-C30 coverage provided valuable information regarding supplemental items from the EORTC item bank that could potentially provide more clinically relevant and better targeted measurement of HRQOL in HR MDS, CMML, and LB AML patients, thus improving the detection of treatment benefit. To confirm this, the EORTC QLQ-C30 and the proposed supplemental items should be tested in a larger clinically-defined sample to evaluate their combined measurement properties in these patient populations. [Display omitted] DisclosuresBell:Takeda Pharmaceuticals: Employment, Equity Ownership. Galaznik:Takeda Pharmaceuticals: Employment, Equity Ownership. Pompilus:Takeda Pharmaceuticals: Research Funding; Modus Outcomes: Employment. Strzok:Takeda Pharmaceuticals: Research Funding; Modus Outcomes: Employment. Bejar:AbbVie/Genetech: Honoraria, Other: Ad-hoc advisory board; Genoptix: Consultancy, Honoraria, Patents & Royalties; Modus Outcomes: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: DSMB, Steering Committee, Research Funding; Otsuka/Astex: Honoraria, Other: Ad-hoc advisory board; Foundation Medicine: Honoraria, Other: Ad-hoc advisory board. Fram:Takeda Pharmaceuticals: Consultancy; BeyondSpring Pharmaceuticals, Inc.: Consultancy. Faller:Takeda Pharmaceuticals: Employment, Equity Ownership. Marquis:Takeda Pharmaceuticals: Research Funding; Modus Outcomes: Employment.

Randomized Phase 2 Trial of Pevonedistat Plus Azacitidine Versus Azacitidine in Higher-Risk Myelodysplastic Syndromes/Chronic Myelomonocytic Leukemia or Low-Blast Acute Myeloid Leukemia: Exploratory Analysis of Patient-Reported Outcomes

Randomized Phase 2 Trial of Pevonedistat Plus Azacitidine Versus Azacitidine in Higher-Risk Myelodysplastic Syndromes/Chronic Myelomonocytic Leukemia or Low-Blast Acute Myeloid Leukemia: Exploratory Analysis of Patient-Reported Outcomes

A Randomized Phase 2 Study of Pevonedistat, Venetoclax, and Azacitidine Versus Venetoclax Plus Azacitidine in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) Who Are Unfit for Intensive Chemotherapy

A Randomized Phase 2 Study of Pevonedistat, Venetoclax, and Azacitidine Versus Venetoclax Plus Azacitidine in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) Who Are Unfit for Intensive Chemotherapy

Preliminary Results from a Phase II Study of the Combination of Pevonedistat and Azacitidine in the Treatment of MDS and MDS/MPN after Failure of DNA Methyltransferase Inhibition

Preliminary Results from a Phase II Study of the Combination of Pevonedistat and Azacitidine in the Treatment of MDS and MDS/MPN after Failure of DNA Methyltransferase Inhibition

Assessing Patient-Reported Outcomes in People with Myelodysplastic Syndromes: Can a Customized Selection of Items from the EORTC Library Enhance the EORTC QLQ-C30?

INTRODUCTIONAssessing patient-reported outcomes (PROs) is an essential part of understanding the ways in which a new drug might affect how a patient with cancer feels and functions within a clinical trial. Certain widely used PRO measures are now being supplemented with a selection of items from available item banks to ensure the measure is targeted to the specific context of use. Previous mixed methods research in higher risk myelodysplastic syndromes (HR MDS), chronic myelomonocytic leukemia (CMML), and low blast acute myeloid leukemia (LB AML) led to the development of a conceptual model of the symptoms and impacts for this population. It informed a PRO measurement strategy based on the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30) along with an additional, customized selection of 10 supplemental items from the EORTC library to cover unaddressed concepts. Clinical features such as anemia cause fatigue and dyspnea, which may negatively impact patient functioning, thus further emphasizing the importance of the patient voice when evaluating the value of a new therapy to patients. The purpose of this research was to incorporate the patient voice and generate information on this measurement strategy in a sample of people with HR MDS/ CMML and LB AML.METHODSThis study was a one-time, cross-sectional patient-reported survey administered online. People living with HR MDS, non-proliferative CMML, and LB AML were recruited through the MDS Foundation, social media, and recruitment agencies. Patients completed the EORTC QLQ-C30 plus 10 supplemental items from the EORTC item library. In addition to PRO data, they were also asked to record demographics and disease-related information. Responses to the 40 PRO items were described and psychometric analyses based on Rasch measurement theory (RMT) were conducted on the original multi-item domains of the EORTC QLQ-C30. RMT analysis defines how a set of items should perform to generate reliable and valid measurements, which is important for the generalizability of the PRO instrument's psychometric evaluations to other contexts of use. RMT analyses were also performed on the following, enhanced domain measures which included original items and supplemental items: fatigue, dyspnea, physical functioning, and role functioning.RESULTSA total of 51 patients were recruited and participated in the online survey (HR MDS: 51%; CMML: 27%; LB AML: 10%). The mean age was 67.2 (SD: 11.8) and 49% of patients were female. The description of responses showed a possible floor effect for several EORTC QLQ-C30 items (i.e. a substantial percentage of responder reported the lowest value of the scale), whereas the responses to the supplemental items were well distributed across the response categories (Figure). This confirmed that the customized supplemental item selection was well targeted to the patient sample. Overall, the RMT psychometric examination of the original EORTC QLQ-C30 domain scores showed satisfactory ability to assess key outcomes for people with HR MDS/CMML and LB AML including fatigue and physical functioning. However, it highlighted some areas for possible improvement, due to gaps in the conceptual coverage of symptoms and impacts of HR MDS/CMML and LB AML. The enhanced fatigue, physical functioning and dyspnea measures that combined the original QLQ-C30 items with the supplemental items from the EORTC library showed improved measurement performances for these key domains for people with HR MDS/CMML and LB AML, typically in terms of conceptual coverage.CONCLUSIONSOur data shows how incorporating the patient voice early on in PRO measurement selection and a conceptually-driven approach to the development of customized item sets can lead to more fit-for-purpose PRO measures to be used in the context of clinical trials of patients with cancer. Specifically, while the QLQ-C30 may be a satisfactory PRO instrument for use in people with hematological stem cell disorders, it can be made more targeted and disease-specific by carefully utilizing mixed methods and selecting supplemental items from the EORTC item library. This patient-reported online survey provides early evidence, in a small sample of patients, on the appropriateness of both the original QLQ-C30 and enhanced item sets to assess PROs in HR MDS/CMML, and AML and should be further analyzed in future research. DisclosuresBell:Takeda Pharmaceuticals: Employment, Equity Ownership. Pompilus:Modus Outcomes: Employment; Takeda Pharmaceuticals: Research Funding. Christian:Modus Outcomes: Employment; Takeda Pharmaceuticals: Research Funding. Mazerolle:Modus Outcomes: Employment; Takeda Pharmaceuticals: Research Funding. Scipione:Takeda Pharmaceuticals: Employment. Bejar:Takeda: Research Funding; Celgene: Consultancy, Honoraria; Foundation Medicine: Consultancy; Modus Outcomes: Consultancy; Genoptix: Consultancy; AbbVie/Genentech: Consultancy, Honoraria; Astex/Otsuka: Consultancy, Honoraria. Galaznik:Takeda Pharmaceuticals International Co.: Employment. Fram:Takeda Pharmaceuticals: Consultancy; BeyondSpring Pharmaceuticals, Inc.: Consultancy. Faller:Takeda Pharmaceuticals: Employment, Equity Ownership. Cano:Modus Outcomes: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Research Funding. Regnault:Modus Outcomes: Employment, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Research Funding.

Azacitidine With or Without Lenalidomide in Higher Risk Myelodysplastic Syndrome &amp; Low Blast Acute Myeloid Leukemia

Standard treatment for higher risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and low blast acute myeloid leukemia (AML) is azacitidine. In single arm studies, the addition of lenalidomide had been suggested to improve outcomes. The ALLG MDS4 phase II clinical trial randomized such patients to standard azacitidine or combination azacitidine (75mg/m2/d days 1 to 5) with lenalidomide (10mg days 1 to 21 of 28-day cycle from cycle 3) to assess clinical benefit (alive without progressive disease) at 12 months. A total of 160 patients were enrolled; median age 70.7 years (range 42.5-87.2), 31.3% female with 14% CMML, 12% AML and 74% MDS. Adverse events were similar in both arms. There was excellent delivery of protocol therapy (median aza cycles 11 both arms) with few dose reductions, delays or early cessations. At median follow up 33.1 months (range 0.7-59.5), the rate of clinical benefit at 12 months was 65% AZA arm and 54% LEN AZA arm (p=0.2). There was no difference in clinical benefit between each arm according to WHO diagnostic subgroup (MDS, AML or CMML) or IPSS-R. ORR was 57% in AZA arm and 69% in LEN AZA (p=0.14). There was no difference in progression free or overall survival between the arms (each p > 0.12). Although the combination of lenalidomide and azacitidine was tolerable, there was no improvement in clinical benefit, response rates or overall survival in higher risk MDS, CMML or low blast AML patients compared to treatment with azacitidine alone. This trial was registered at www.anzctr.org.au as ACTRN12610000271000. Funding: This study was supported by Celgene with grant funding for study conduct, Snowdome Foundation and the Victorian Epigenetic Group for funding support for molecular studies. Conflict of Interest Disclosure: MK, DH, JFS received research funding from Celgene MK and JFS are advisory board members for Celgene JFS is a member of speakers bureau for Celgene MH is an advisory board member for Takeda, Roche, MSD, Gilead, Janssen WS receives honoraria from Amgen and Novartis The remaining authors declare no conflict of interest; IC, KT, DZant, MW, MD, RE, SJ, TG, DZann, PB, WB. Ethics Approval Statement: Study design and treatment ALLG MDS4 was an open-label, multi-centre study conducted across 30 Australian sites. The study was reviewed and approved by the Human Research Ethics Committees of each centre and conducted according to the Declaration of Helsinki. All patients provided written informed consent prior to participation.