Acute Myeloid Leukemia Ineligible For Intensive Chemotherapy Research Articles

A Comparison of Acute Myeloid Leukemia (AML) Regimens: Hypomethylating Agents Combined with Ivosidenib or Venetoclax in Newly Diagnosed Patients with IDH1 Mutations: A Real-World Evidence Study

Background: Two frontline combination regimens are available for patients with mutant IDH1 (mIDH1) AML: ivosidenib (IVO)+hypomethylating agent (HMA), and venetoclax (VEN)+HMA. Robust comparisons between these regimens have not been performed, and small post hoc analyses have been constrained by low numbers of mIDH1 patients and clustering of IDH1 and IDH2 mutations (Pollyea 2022, Perl 2022). We evaluated a large cohort of patients with newly diagnosed (ND) mIDH1 AML to gain insights into the treatment patterns, efficacy, and safety associated with these combination regimens. Methods: We conducted a US-wide retrospective chart review of patients with ND mIDH1 AML ineligible for intensive chemotherapy (IC), treated with IVO+HMA or VEN+HMA. Treatment was initiated in community and academic settings November 2021 through November 2022, enabling a minimum follow-up of 6 months. Collected data included baseline patient and practice characteristics, treatment patterns and rationale, and efficacy and safety outcomes. Endpoints focused on events likely to occur within 6 months of follow-up, including response rates, tolerability, bridge to transplant, and acute care episodes. Results: Among 283 patients (IVO+HMA, n=182; VEN+HMA, n=101), baseline characteristics were similar between regimens. Median age was 63 years; 65.7% were male. ELN cytogenetic risk status was 59.7% and 15.2% for intermediate and poor, respectively. Prior MDS, myeloproliferative neoplasms, or secondary or secondary-like AML mutations occurred in 37.1%. A higher proportion of VEN+HMA use occurred in the academic setting (68.3% vs 55.5% for IVO+HMA; p=0.035). Median follow-up from treatment initiation was 7.1 vs 8.1 months for IVO+HMA vs VEN+HMA. Complete response (CR) plus CR with incomplete count or incomplete platelet recovery (CRi/p) rates were 63.2% vs 49.5% for IVO+HMA vs VEN+HMA ( p=0.025), with the difference based on the higher CR rate for IVO+HMA (42.9% vs 26.7%; p=0.007) (Figure). Median time to first bone marrow biopsy on treatment across cohorts was 56 days and median time to best response was 3.3 vs 4.1 months for IVO+HMA vs VEN+HMA ( p=0.002). A competing risks regression showed that 6-month event-free survival (EFS; CR within 24 weeks, and no relapse or death) favored IVO+HMA vs VEN+HMA (56.0% vs 39.6%, hazard ratio of 0.773; p=0.044). Bridge to transplant was achieved for 11.5% of patients with IVO+HMA vs 5.0% for VEN+HMA ( p=0.066). Few patients in either cohort had a dose (ie, strength) change following initial ramp-up. Treatment discontinuation was 37% for both regimens. Likewise, toxicity incidence was similar except for higher febrile neutropenia (FN) rates for VEN+HMA vs IVO+HMA within 30 days of initiation (7.9% vs 1.6%; p=0.009). Patients receiving IVO+HMA had 61% lower relative risk of unscheduled acute care use in the first 12 weeks (42.9% vs 70.3% for VEN+HMA; p<0.001). VEN schedule intensity was also captured, with only 22.8% receiving the full FDA-labeled 28 days of VEN during the 28-day cycles; 44.6% did not receive >11 days of VEN per cycle, raising concerns of clinical consequences. Median time from mIDH1 test to receipt of result was 7 days in both cohorts. Median time from diagnosis to start of treatment was 14 vs 20 days for IVO+HMA vs VEN+HMA. The biggest differential driver of regimen choice was favoring selection of VEN+HMA due to hospital protocol (30.7% vs 16.5%). Conclusions: In a large, balanced cohort of nearly 300 patients with ND mIDH1 AML ineligible for IC, patients treated with IVO+HMA had higher rates of CR and CR+CRi/p, achieved CR faster, and had longer EFS compared to those treated with VEN+HMA. Approximately half of patients receiving VEN were unable to receive >11-day schedules, potentially impacting the regimen's efficacy. Despite the reduced intensity of VEN relative to label, patients receiving VEN+HMA had higher early incidence of FN and greater overall need for unscheduled acute care. Wait time for mutational test results was 7 days, well within the 14- to 20-day median times to treatment. Based on the efficacy seen in this real-world assessment, consistent with the efficacy demonstrated in the AGILE clinical trial of IVO+azacitadine, clinicians and hospitals should ensure early mutational testing occurs, to enable consideration of IVO+azacitadine as the frontline treatment of choice for patients with ND mIDH1 AML.

Trial in Progress: An Open Label Phase I/II, Multicenter Study Evaluating Safety, Pharmacokinetics and Efficacy of S65487, a BCL-2 Inhibitor Combined with Azacitidine in Adults with Previously Untreated Acute Myeloid Leukemia Ineligible for Intensive Treatment

Preclinical and clinical data support combining Bcl-2 inhibitors (Bcl-2i) with hypomethylating agents (HMAs) in the treatment of acute myeloid leukemia (AML). S65487, a potent intravenous Bcl-2i, has shown promising synergistic activity when combined with azacitidine against in vitro AML models. Based on those data, we initiated a Phase I/II multicenter study of S65487 combined with azacitidine for newly diagnosed patients aged 18 years or older with de novo or secondary AML ineligible for intensive chemotherapy in 6 countries in Europe and Asia (NCT04742101). Secondary AML was defined as those related to previous leukemogenic therapies or transformed from a myelodysplastic syndrome. Patients with AML originating from myeloproliferative disorders were excluded. Ineligibility to intensive chemotherapy was defined as age of at least 75 years or the presence of significant co-morbidities. Previous use of HMA was allowed in the first six dose levels tested in the Phase I portion of the study, but was excluded afterwards, including during the Phase II part. Other eligibility criteria were standard for this patient population. Each cycle of therapy lasts for 28 days. Subcutaneous or intravenous azacitidine is administered at a dose of 75mg/m 2 in 7 consecutive administrations per cycle starting on day (D) 1 with a 2-day interval during weekends. Three schedules of S65487 are planned to be tested during the Phase I part to increase its concurrent administration with azacitidine and their synergism. Schedule 1 consists of weekly administrations (doses on D1, 8, 15, and 22). Two more intensified schedules consist of S65487 administration on D1, D3, D5, D8 (schedule 2) or D1 through D5, D8, and D9 (schedule 3) on the same days of azacitidine dosing. S65487 is administered over 30 minutes. When administered on the same day, S65487 is given first followed by azacitidine within 30 to 60 minutes. Treatment should be discontinued due to disease progression, or if other standard withdrawal criteria are met. The Phase I portion of the study follows a standard design guided by an adaptive Bayesian Logistic Regression Model with overdose control to estimate the maximum tolerated dose (MTD) based on the occurrence of dose-limiting toxicities during cycle 1. Patient accrual for the Phase I portion of this study is ongoing. The planned testing of schedule 1 is limited due to the expected low synergism with azacitidine. Once the recommended Phase II dose (RP2D) or MTD are established for schedules 2 and 3, the Phase II part will start and will be comprised of a maximum of two cohorts, each containing up to 27 patients. A Bayesian optimal design based on complete remission rate will guide the Phase II. Interim futility analyses are planned after enrollment of 10 and 20 evaluable patients. Randomization will not be used to allocate patients to one of the two cohorts planned during the Phase II portion of the study. The primary objective during the Phase I is to determine the safety, tolerability, and the RP2D or MTD of S65487 in combination with azacitidine. The primary objective of the Phase II is to assess the efficacy of this therapy. Pharmacokinetic analyses are included as secondary objectives in both parts of the study. Measurable residual disease will be assessed as a secondary objective in the Phase II part using a well validated, standard flow-cytometry panel. Pharmacodynamic analyses are conducted as exploratory objectives in both parts of the study. In particular, the disruption of the BCL2/BIM complex is followed in peripheral-blood mononuclear cells to guide the estimation of the RP2D.

Abstract 2530: DELE1 loss and dysfunctional integrated stress signaling in TP53 mutated AML is a novel pathway for venetoclax resistance

Abstract Background: Venetoclax (ven) in combination with hypomethylating agents or low dose cytarabine leads to rapid and durable remission in patients (pts) with acute myeloid leukemia (AML) unfit for intensive chemotherapy (IC), however, pts with TP53 mutations (TP53mut) exhibit adverse prognosis. Here, we identify dysregulation of the integrated stress response (ISR) pathway in pts with TP53mut, specifically through the actions of DAP3 binding cell death enhancer 1 (DELE1) and its activating protease OMA1. Methods: RNA sequencing was performed on pre-treatment bone marrow-derived mononuclear cells (BMMCs) from pts with AML ineligible for IC across four clinical trials (NCT02993523, NCT02203773, NCT03069352, and NCT02287233). CRISPR-Cas9 editing of TP53-intact AML cell lines was used to generate TP53-/-, TP53mut, DELE1-/-, OMA1-/- and TP53/DELE1 double deficient cell lines. Quantification of BCL2 and Myeloid cell leukemia 1 (MCL1) complexes with BCL2 interacting mediator (BIM) was performed using chemiluminescence assays. A drug screen to assess viability and gene expression was performed in cells treated with ven in combination with 63 drugs. Results: In total 401 pts were included in the analyses, of which 17% harbored TP53mut and 83% were TP53wt. Analysis of genes differentially expressed (DE) between pts with TP53mut and TP53wt AML revealed 19 DE genes shared across all trials. DELE1, an ISR adaptor, was associated with genes mapping to the ISR-related eukaryotic initiation factor-α (eIF2α) in TP53mut AML BMMCs. Deletion of DELE1 or OMA1 in AML cell lines blocked eIF2α activation and induction of the transcription factor ATF4, a critical ISR effector, in response to the mitochondrial stressor FCCP, ven, and azacitidine, and resulted in ven resistance similar to that of TP53 deficient cells. All modified AML cell lines exhibited a concomitant decrease in the pro-apoptotic regulator PMAIP1, encoding NOXA, and a 14-18-fold increase in MCL1-BIM complexes following ven treatment, as well as increased MCL1 expression, compared to parental lines. Further screening of these cell lines for ven sensitizing activity revealed the BH3 mimetic S63845, which targets MCL1, as the top hit, suggesting that combined BH3 mimetics may overcome ven resistance during ISR pathway defects. As DELE1 is located on chromosome 5 (CH); the frequent loss of CH 5q among TP53mut AML may contribute to low DELE1 expression. Conclusions: These data suggest that defective ISR signaling may be a factor in TP53mut AML treatment outcome and point to DELE1 dysregulation as a driver of ISR inactivation in pts with TP53mut AML. The ISR induces the expression of NOXA, which displaces MCL1 from BIM and lowers the apoptotic threshold. Our data identify p53, DELE1, and OMA1 as regulators of NOXA expression post ven treatment and indicate that co-targeting MCL1 in pts with TP53mut AML may be beneficial to overcome ven resistance. Citation Format: David Sharon, Paul Jung, Yan Sun, Weiguo Feng, Ziping Yang, Valerie Robinson, Diya Mitra, Wei Liu, Pingping Zheng, Tamar Uziel, Lloyd Lam, Mark D. Minden, Jeremy Ross, Wellington Mendes, Jalaja Potluri, Andrew H. Wei, Marina Konopleva, Monique Dail, Brenda Chyla, PK Epling-Burnette. DELE1 loss and dysfunctional integrated stress signaling in TP53 mutated AML is a novel pathway for venetoclax resistance [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 2530.

Ex vivo venetoclax sensitivity testing predicts treatment response in acute myeloid leukemia.

The BCL-2 inhibitor venetoclax has revolutionized the treatment of acute myeloid leukemia (AML) in patients not benefiting from intensive chemotherapy. Nevertheless, treatment failure remains a challenge, and predictive markers are needed, particularly for relapsed or refractory AML. Ex vivo drug sensitivity testing may correlate with outcomes, but its prospective predictive value remains unexplored. Here we report the results of the first stage of the prospective phase II VenEx trial evaluating the utility and predictiveness of venetoclax sensitivity testing using different cell culture conditions and cell viability assays in patients receiving venetoclax-azacitidine. Participants with de novo AML ineligible for intensive chemotherapy, relapsed or refractory AML, or secondary AML were included. The primary endpoint was the treatment response in participants showing ex vivo sensitivity and the key secondary endpoints were the correlation of sensitivity with responses and survival. Venetoclax sensitivity testing was successful in 38/39 participants. Experimental conditions significantly influenced the predictive accuracy. Blast-specific venetoclax sensitivity measured in conditioned medium most accurately correlated with treatment outcomes; 88% of sensitive participants achieved a treatment response. The median survival was significantly longer for participants who were ex vivo-sensitive to venetoclax (14.6 months for venetoclax-sensitive patients vs. 3.5 for venetoclax-insensitive patients, P<0.001). This analysis illustrates the feasibility of integrating drug-response profiling into clinical practice and demonstrates excellent predictivity. This trial is registered with ClinicalTrials.gov identifier: NCT04267081.

Preliminary Safety and Efficacy of Bgb-11417, a Novel Bcl-2 Inhibitor, in Combination with Azacitidine in Patients with Acute Myeloid Leukemia (AML)

Background/Introduction: The efficacy of Bcl-2 inhibitors for treating AML was recognized by the approval of venetoclax and azacitidine (aza) in patients (pts) with newly diagnosed AML ineligible for intensive chemotherapy. However, survival rates beyond 2 years are low. Compared to venetoclax, BGB-11417 is a much more potent Bcl-2 inhibitor (>10-fold in biochemical assays) with improved selectivity and the potential to achieve deeper target inhibition and responses in the clinical setting. Here, we present updated preliminary results of pts with AML enrolled in BGB-11417-103 (NCT04771130). Methods: BGB-11417-103 is an ongoing dose finding/expansion study evaluating BGB-11417 and aza in pts with AML (treatment-naïve [TN] unfit for intensive chemotherapy or relapsed/refractory [R/R]), myelodysplastic syndrome (MDS), or MDS/myeloproliferative neoplasm. For all indications, pts who received prior aza or Bcl-2 inhibitors were excluded. For pts with AML, the 10-day regimen comprised BGB-11417 at 40 mg (cohort 1), 80 mg (cohort 2), or 160 mg (cohort 3); 160 mg was also used in a 28-day regimen (cohort 4). All dose levels were given in combination with aza (75 mg/m2 x 7 days). In cycle 1, a 4-day ramp-up of BGB-11417 starting at 1/8 target dose was used. Patients with dose-limiting toxicities (DLTs) in cycle 1 were assessed against the number of patients dosed. The safety stopping criteria were based on the number of patients with events where posterior probability of event rate exceeding 0.25 was at least 80%. Responses were determined using 2017 European LeukemiaNet (ELN) criteria with assessment of hematologic improvement. Treatment-emergent adverse events (TEAEs), minimal residual disease (MRD) by flow cytometry, and pharmacokinetics (PK) were also assessed. Results: As of June 1, 2022, 51 pts with AML were treated (16 in cohort 1; 17 in cohort 2; 14 in cohort 3; 4 in cohort 4). Median age was 77 yrs (TN, n=28) and 64 yrs (R/R, n=23) (Table 1). At baseline, 23 pts (45.1%) had adverse-risk cytogenetics, 37 (72.5%) had grade ≥3 neutropenia, and 27 (52.9%) had grade ≥3 thrombocytopenia. At a median follow-up of 2.8 mo (range 0.1-12.3) and median duration of treatment of 1.9 mo (range 0.0-12.3), 2 of 41 evaluable pts experienced DLTs (grade 4 neutropenia and grade 4 thrombocytopenia at 80 mg) (Table 2), which did not meet the safety stopping protocol criteria. Laboratory tumor lysis syndrome (TLS; Howard criteria) was observed in 1 pt (160 mg x 10 days) with a known history of chronic kidney disease; TLS resolved within 4 days. Twenty-one (41%) pts discontinued study drugs: 7 (13.7%) due to AEs, 5 (9.8%) due to disease progression, 4 (7.8%) proceeded to transplant, 3 (5.9%) withdrew consent, 1 (2.0%) per investigator decision, and 1 (2.0%) started new anti-cancer treatment. The most common TEAEs were neutropenia (58.8%), thrombocytopenia (45.1%), anemia (43.1%), febrile neutropenia (33.3%), nausea (39.2%), and constipation (37.3%). Neutropenia was the most common grade ≥3 TEAE observed in 30 (58.8%) pts; most cases did not require dose modification. Grade ≥3 infections occurred in 23 (45.1%) pts, mostly in cycle 1. The general incidence of febrile neutropenia and infections decreased with subsequent cycles. Four (7.8%) pts died due to unrelated TEAEs: bronchopulmonary aspergillosis, pneumonia, pulmonary sepsis, and possible intracranial hemorrhage after a fall. TEAEs leading to dose reduction (5.9%) or dose interruption (11.8%) were infrequent. In TN AML, complete remission (CR)/CR with partial hematologic recovery (CRh) was achieved in 16 (59.3%) and CR in 13 (48.1%) evaluable pts (Table 1). Of the 13 pts in CR, 7 (53.8 %) reached CR by end of cycle 1. In cohort 2 with the longest follow-up, CR was achieved in 8 (72.7%) pts with TN AML. Notably, 7 of these pts are continuing study treatment (median of 5 cycles, range 1-12) without progression. In R/R AML, CR/CRh was seen in 50% of evaluable pts, with a CR rate of 25%. Nine (50.0%; 6 TN, 3 R/R) of 18 evaluable pts with CR/CRh achieved MRD negativity (<0.1% per ELN 2018). In pts with AML treated with 40, 80, and 160 mg, PK increased in a dose-dependent manner at steady state with no drug-drug interaction observed with aza. Conclusion: These results demonstrate that BGB-11417 in combination with aza was effective and generally well tolerated at the 4 dose levels tested in pts with AML, with no dose-dependent toxicities observed. Further evaluation of the 28-day regimen is underway. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparison of Patients with Newly Diagnosed (ND) Acute Myeloid Leukemia (AML) Treated with Venetoclax and Hypomethylating Agents Vs Other Therapies By TP53 and IDH1/2 Mutation: Results from the AML Real World Evidence (ARC) Initiative

Introduction: Venetoclax (VEN; a BCL-2 inhibitor) is approved in combination with hypomethylating agents (HMA) or low dose cytarabine for ND adults with AML ineligible for intensive chemotherapy (IC) (i.e., ≥75 years old or comorbidities that preclude use of IC). This study describes the real-world characteristics and clinical outcomes of patients (pts) treated with VEN-HMA vs. non-VEN-based regimens in the ARC Initiative, overall and specifically among pts ≥75 years old or with comorbidities. Methods: A multicenter chart review study including randomly selected adult pts with ND AML treated with VEN (VEN cohort) after April 2016 from 14 academic sites (US: 10; Israel: 4) matched 1:1 to control pts who received non-VEN-based regimens after May 2015 (CON cohort) based on age (<60, 60-74, ≥75) and ELN risk. Interim descriptive results from May 2022 are presented; data collection is ongoing. Clinical outcomes, including composite complete remission (CRc; i.e., CR, CRh, or CRi), minimal residual disease (MRD; assessed by flow cytometry or molecular monitoring), overall survival (OS), hematopoietic cell transplantation (HCT), and transfusion independence (TI), were compared between the VEN cohort and matched CON cohort. A subset of VEN pts ≥75 years old or with ≥1 comorbidity of interest (based on the Ferrara criteria) and their matched CON pts were analyzed separately (unfit subgroup) and results among pts with TP53 and IDH1/2 mutation were also reported. Results: Results are described in Table 1. A total of 176 VEN pts and 176 CON pts were included, including 116 unfit VEN with their matched CON pts. Overall, VEN pts received VEN-azacitidine (AZA; 76.1%) or VEN-decitabine (DEC; 23.9%) and 65.3% of CON pts received high intensity regimens. In the unfit subgroup, VEN pts received VEN-AZA (77.6%) or VEN-DEC (22.4%) and 55.2% of CON pts received high intensity regimens. The proportion of pts who were ≥75 years old was 34.1% and 50.9% in the unfit subgroup. A total of 64.8% of all pts were classified as ELN adverse risk, which was 67.2% in the unfit subgroup. Among pts with genetic mutations tested, 22.2% of VEN pts and 13.5% of CON pts had TP53 mutations and 19.9% and 14.6% had IDH1/2 mutations, respectively, which was similar in the unfit subgroup of each cohort. Among pts with a response assessment, 65.7% of VEN pts and 53.5% of CON pts achieved CRc (p<0.05) and 39.6% of VEN pts and 43.4% of CON pts achieved CR (p=0.53). In the unfit subgroup with a response assessment, 66.1% of pts in the VEN cohort and 44.6% of pts in the CON cohort achieved CRc (p<0.01) and 37.5% of VEN pts and 36.0% of CON pts achieved CR (p=0.91). Among pts with TP53 mutations, response was not statistically different for the overall and unfit subgroup. Among pts with IDH1/2 mutations, CRc was significantly higher in overall VEN versus CON (87.9% vs. 54.2%; p<0.01) and in the unfit subgroup (85.7% vs. 52.9%; p<0.05). The duration of CRc was not statistically different between the VEN and CON cohorts, overall or in the unfit subgroup. For pts who achieved CRc and had MRD assessed, 74.0% of VEN pts and 66.7% of CON pts had negative MRD. Similar proportions were observed overall and for IDH1/2 in the unfit subgroup although statistical significance was not met. HCT rate was 6.8% and 14.2% in the VEN and CON cohorts (p<0.05) and 6.9% and 12.1% in the unfit subgroup, respectively (p=0.26). The median OS was 15.8 and 13.9 months in the VEN and CON cohorts, respectively (p=0.20) and 17.1 and 12.4 months in the unfit subgroup (p=0.30). The 6-month OS rate was 74.3% and 70.1% in the VEN and CON cohorts (p=0.30) and 75.6% and 66.2% in the unfit subgroup (p=0.10). Among the pts with ≥56 days of follow-up, 61.9% and 54.8% in the VEN and CON cohorts (p=0.29) and 67.0% and 51.1% in the unfit subgroup (p=0.05), respectively, achieved TI. Conclusions: Pts with ND AML receiving VEN-HMA had significantly higher rates of CRc than matched pts on non-VEN-based regimens in the overall population, those unfit for IC, and with IDH1/2 mutations. OS and durability of response were similar in VEN and CON pts, despite 65% of pts in the overall CON cohort receiving IC and 55% in the unfit subgroup. VEN pts who were considered as unfit had similar clinical outcomes to the overall VEN pts. Although VEN pts with TP53 mutation had non-significantly higher CRc rates compared with CON pts, median OS was poor in both groups highlighting the need for novel approaches in this high-risk molecular subset. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Costs per patient achieving remission with venetoclax-based combinations in newly diagnosed patients with acute myeloid leukemia ineligible for intensive induction chemotherapy.

BACKGROUND: Venetoclax, in combination with azacitidine, decitabine, or low-dose cytarabine (LDAC), received confirmatory approval in 2020 by the US Food and Drug Administration for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients aged 75 years or older or who are ineligible for intensive induction chemotherapy. The economic value associated with response to venetoclax combinations compared with other treatments for this patient population has not been comprehensively evaluated. OBJECTIVE: To assess the cost per patient achieving remission with venetoclax combination therapies, compared with other therapies for newly diagnosed patients with AML who are ineligible for intensive induction chemotherapy, from a US third-party payer perspective. METHODS: The analysis used treatment effect estimates (ie, complete remission [CR] + CR with incomplete blood count recovery [CRi]) from a network meta-analysis and annual cost estimates from a prior budget impact model. The model considered the total cost of care including the costs of drug and administration, adverse events, hospitalization, disease monitoring, blood transfusions, and subsequent AML management when patients discontinued active treatment. Costs per patient achieving CR + CRi associated with venetoclax + azacitidine, venetoclax + LDAC, azacitidine, decitabine, LDAC, and best supportive care (ie, treatment given with the intent to maximize quality of life without specific antileukemic intent, such as blood transfusion products and antibiotics) were calculated as the annual total cost of care per patient divided by the CR + CRi rate. All costs were adjusted to 2020 US dollars. RESULTS: Venetoclax combination therapies were estimated to have substantially lower costs per patient achieving CR + CRi (venetoclax + azacitidine: $473,960; venetoclax + LDAC: $428,071) than alternative treatments. Azacitidine was estimated to have the the highest cost per patient achieving CR + CRi ($1,197,438), followed by best supportive care ($869,849), LDAC ($689,101), and decitabine ($594,074). A pair-wise matrix of the difference between therapies estimated that both venetoclax + azacitidine and venetoclax + LDAC were associated with significantly lower costs per patient achieving CR + CRi than azacitidine (by $723,477 and $769,367, respectively) and LDAC (by $215,141 and $261,030; all P < 0.05). CONCLUSIONS: From a US third-party payer perspective, venetoclax in combination with azacitidine or LDAC was estimated to be associated with a significantly lower cost per patient achieving CR + CRi than azacitidine or LDAC among newly diagnosed patients with AML ineligible for intensive chemotherapy. DISCLOSURES: This research was supported by AbbVie Inc. and Genentech. The sponsors helped design the study, interpret the data, and draft the manuscript. Drs Bui and Kapustyan are employees of and have equity ownership in AbbVie; Dr Choi was an employee of AbbVie during the study's conduct and has equity ownership. Ms Ma and Dr Montez are employees of and have equity ownership in Genentech. Drs Song and Chai, Ms Yin, and Dr Betts are employees of Analysis Group, Inc., which has received funding from AbbVie and Genentech for the conduct of this research. Dr LeBlanc reports personal fees for consulting or advisory boards from AbbVie, Agios/Servier, AstraZeneca, Amgen, Astellas, BlueNote, CareVive, BMS/Celgene, Daiichi-Sankyo, Flatiron, Genentech, GSK, Pfizer, and Seattle Genetics; royalties from UpToDate; speakers bureau fees from Agios/Servier, AbbVie, and BMS/Celgene; and grants and/or research contracts from the American Cancer Society, AstraZeneca, BMS, Jazz Pharmaceuticals, and Seattle Genetics.

Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy

AbstractTreatment results for patients with newly diagnosed FMS-like tyrosine kinase 3 (FLT3)-mutated (FLT3mut+) acute myeloid leukemia (AML) ineligible for intensive chemotherapy are disappointing. This multicenter, open-label, phase 3 trial randomized (2:1) untreated adults with FLT3mut+ AML ineligible for intensive induction chemotherapy to receive gilteritinib (120 mg/d orally) and azacitidine (GIL + AZA) or azacitidine (AZA) alone. The primary end point was overall survival (OS). At the interim analysis (August 26, 2020), a total of 123 patients were randomized to treatment (GIL + AZA, n = 74; AZA, n = 49). Subsequent AML therapy, including FLT3 inhibitors, was received by 20.3% (GIL + AZA) and 44.9% (AZA) of patients. Median OS was 9.82 (GIL + AZA) and 8.87 (AZA) months (hazard ratio, 0.916; 95% CI, 0.529-1.585; P = .753). The study was closed based on the protocol-specified boundary for futility. Median event-free survival was 0.03 month in both arms. Event-free survival defined by using composite complete remission (CRc) was 4.53 months for GIL + AZA and 0.03 month for AZA (hazard ratio, 0.686; 95% CI, 0.433-1.087; P = .156). CRc rates were 58.1% (GIL + AZA) and 26.5% (AZA) (difference, 31.4%; 95% CI, 13.1-49.7; P < .001). Adverse event (AE) rates were similar for GIL + AZA (100%) and AZA (95.7%); grade ≥3 AEs were 95.9% and 89.4%, respectively. Common AEs with GIL + AZA included pyrexia (47.9%) and diarrhea (38.4%). Gilteritinib steady-state trough concentrations did not differ between GIL + AZA and gilteritinib. GIL + AZA resulted in significantly higher CRc rates, although similar OS compared with AZA. Results support the safety/tolerability and clinical activity of upfront therapy with GIL + AZA in older/unfit patients with FLT3mut+ AML. This trial was registered at www.clinicaltrials.gov as #NCT02752035.

Long-Term Subgroup Analyses from Azacitidine Vs. Decitabine in Unfit Newly Diagnosed Acute Myeloid Leukemia Patients: Results from the Pethema Registry

Long-Term Subgroup Analyses from Azacitidine Vs. Decitabine in Unfit Newly Diagnosed Acute Myeloid Leukemia Patients: Results from the Pethema Registry

A Real World Study of Venetoclax Combined with Azacitidine in 64 Chinese Patients Newly Diagnosed Acute Myeloid Leukemia

Background: Venetoclax combined with azacitidine has been demonstrated to have a favorable overall response rate and tolerable safety in acute myeloid leukemia (AML) patients who are unfit for intensive chemotherapy.Methods: This study retrospectively recruited 64 Adults (≥18 years) with newly diagnosed AML ineligible for intensive chemotherapy who had received at least one cycle of treatment with venetoclax plus azacitidine. The primary endpoint was overall survival (OS). Secondary endpoints were remission rates. Safety was evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.Results: The median age of the enrolled patients was 69 years. The median OS for the cohort was 15.5 months, with 21.2 months for complete responders as opposed to 13.3 months for those who did not achieve a complete response. 39 (60.9%) patients achieved composite complete remission (completeremission (CR) + CR with incomplete count recovery (CRi)) and 7/64 (10.9%) achieved morphologic leukemia-free state (MLFS) with a median follow-up time of 14.7 months. The median CR+CRi duration was 10.9 months. It is noteworthy that 43/64 (67.2%) patients achieved the best response after one cycle with a median time of 1.2 months. Normal karyotype (P=0.015) was significantly associated with extended OS in multivariate analysis, while higher white blood cell count (P=0.032), lower platelet count (p=0.018) and antifungal drug combination (P=0.013) were predictors of shortened OS in univariate analysis. Common grade 3/4 Adverse Events (AEs) included infection (68%) and hematological AEs consisting of neutropenia (93%), anemia (90%), leukopenia (86%), thrombocytopenia (77%) and febrile neutropenia (52%). The median neutropenia duration was 16 days.Conclusions: The novel venetoclax-azacitidine combination regimen showed prolonged survival period, promising efficacy, sound and rapid response, and superior tolerance in Chinese patients newly diagnosed AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Quizartinib (Quiz) with Decitabine (DAC) and Venetoclax (VEN) Is Highly Active in Patients (pts) with FLT3-ITD Mutated Acute Myeloid Leukemia (AML) - RAS/MAPK Mutations Continue to Drive Primary and Secondary Resistance

Quizartinib (Quiz) with Decitabine (DAC) and Venetoclax (VEN) Is Highly Active in Patients (pts) with FLT3-ITD Mutated Acute Myeloid Leukemia (AML) - RAS/MAPK Mutations Continue to Drive Primary and Secondary Resistance

First Description of Upfront Target Therapy Treating AML and Bcll Presented Simultaneously As First Line

INTRODUCTION: The occurrence of acute myeloid leukemia (AML) and chronic lymphoid leukemia (B-CLL) simultaneously is rarely described. We describe a case report of AML and B-CLL, diagnosed simultaneously, without any previous treatment for any of the hematological neoplasms [1]. The patient received low-dose cytarabine (ARA-C) and Venetoclax, which is medically indicated on label for both hematological neoplasms. CASE REPORT: A 75-year-old male, presented with edema and joint pain one month before hospital admission, showing pancytopenia on a complete blood count and presence of blasts in peripheral blood. The patient was then referred to the hematology service. The morphological analysis of the bone marrow aspirate showed 67.7% of myeloblasts, compatible with AML. Bone marrow immunophenotyping was performed, which identified 34.10% of myeloblasts, compatible with AML and 50.48% of monoclonal B lymphocytes (chronic B-cell lymphoproliferative disease). In flow cytometry there were two distinct populations of myeloblasts. Type 1 myeloblasts labeling CD7 +, CD13 +, CD34 ++, CD38 ++, CD45 ++, CD56 ++, CD117 ++, CD123 +, HLA-DR +++ and MPO + / ++. The second population marked CD13 + / ++, CD34 + / ++, CD38 ++, CD45 +, CD117 ++, CD123 +, HLA-DR ++ / +++ and MPO + (30%). Monoclonal lymphocytes showed CD11c + / ++ (70%), CD19 ++, CD20 + / ++ (84%), CD22 + (39%), CD23 + / ++, CD25 +, CD31 +/-, CD43 ++, CD45 ++ / +++, CD81 + (38%), CD200 + (85%) and Lambda +. The molecular study was negative for genetic abnormalities: FLT3, KIT and NPM, configuring the patient as an intermediate risk for AML. In the cytogenetic analysis there was no growth of metaphases. Patient received simultaneous diagnosis of AML and B-CLL. As he was ineligle to intensive chemotherapy (IC), we started original protocol Subcutaneous Cytarabin+venetoclax(VIALE C). The patient had grade 2-3 AE(neutropenia managed with GCSF) ending the fourth cycle in July 2020. The evolution of hematimetric parameters and diseases are described in graphics. DISCUSSION: This is the first described case in our knowledge treated upfront with bcl2-inh target therapy for two absolutely different hematological neoplasms: AML and BCLL. Nowadays we are experiencing a new therapeutic model in oncohematology, in which the targeted therapy is gaining ground in relation to IC with excellent results. In this way, the importance of comprehension of the pathophysiological mechanism of the neoplasms and the way we can stop the disease proliferation is progressively guiding the new protocols. Elderly patients are more likely to have early treatment-related death and exhibit therapeutic resistance, limiting alternatives. We decided to start first-line treatment with ARA-C and Venetoclax [2]. Venetoclax associated with ARA-C has a manageable safety profile, producing quick and durable remissions in elderly people with AML ineligible for IC, as well as in B CLL, being the best therapeutic alternative for the case, in our opinion. Venetoclax belongs to a group of drugs called Bcl-2 inhibitors, an anti-apoptotic protein, which works by blocking this protein in the body, causing apoptosis of both neoplastic cells. The high rate of remission and low early mortality, combined with fast and durable remission, make Venetoclax and ARA-C a new and attractive treatment for the elderly [2]. In our case, the intention of the product in the first line was not B-CLL, but it would certainly be a good option for this profile of elderly patients. CONCLUSION: We report the first description of simultaneous diagnosis of AML and B CLL treated with a Bcl-2 inhibitor, demonstrating that antitumor mechanisms can be extremely effective in completely different diseases. We have a long way to go in the search for full knowledge of oncohematological diseases and targeted therapies. However, this case report shows that we are on the right track.

First Results from a Nationwide Prospective Non-Interventional Study of Venetoclax-Based 1st Line Therapies in Patients with Acute Myeloid Leukemia (AML) - Revive Study

First Results from a Nationwide Prospective Non-Interventional Study of Venetoclax-Based 1st Line Therapies in Patients with Acute Myeloid Leukemia (AML) - Revive Study

Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial

AbstractEffective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. Adults age ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this international phase 3 randomized double-blind placebo-controlled trial. Patients (N = 211) were randomized 2:1 to venetoclax (n = 143) or placebo (n = 68) in 28-day cycles, plus low-dose cytarabine (LDAC) on days 1 to 10. Primary end point was overall survival (OS); secondary end points included response rate, transfusion independence, and event-free survival. Median age was 76 years (range, 36-93 years), 38% had secondary AML, and 20% had received prior hypomethylating agent treatment. Planned primary analysis showed a 25% reduction in risk of death with venetoclax plus LDAC vs LDAC alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.52-1.07; P = .11), although not statistically significant; median OS was 7.2 vs 4.1 months, respectively. Unplanned analysis with additional 6-month follow-up demonstrated median OS of 8.4 months for the venetoclax arm (HR, 0.70; 95% CI, 0.50-0.98; P = .04). Complete remission (CR) plus CR with incomplete blood count recovery rates were 48% and 13% for venetoclax plus LDAC and LDAC alone, respectively. Key grade ≥3 adverse events (venetoclax vs LDAC alone) were febrile neutropenia (32% vs 29%), neutropenia (47% vs 16%), and thrombocytopenia (45% vs 37%). Venetoclax plus LDAC demonstrates clinically meaningful improvement in remission rate and OS vs LDAC alone, with a manageable safety profile. Results confirm venetoclax plus LDAC as an important frontline treatment for AML patients unfit for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03069352.

High Rate of IDH1 Mutation Clearance and Measurable Residual Disease Negativity in Patients with IDH1-Mutant Newly Diagnosed Acute Myeloid Leukemia Treated with Ivosidenib (AG-120) and Azacitidine

High Rate of IDH1 Mutation Clearance and Measurable Residual Disease Negativity in Patients with IDH1-Mutant Newly Diagnosed Acute Myeloid Leukemia Treated with Ivosidenib (AG-120) and Azacitidine

PF292 LOW‐DOSE CYTARABINE WITH OR WITHOUT GLASDEGIB IN NEWLY DIAGNOSED PATIENTS WITH ACUTE MYELOID LEUKEMIA: LONG‐TERM ANALYSIS OF A PHASE 2 RANDOMIZED TRIAL

Background:Glasdegib is a potent, selective, oral inhibitor of the Hedgehog signaling pathway, approved in the US – in combination with low‐dose cytarabine (LDAC) – for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients unable to receive intensive chemotherapy due to comorbidities or age (75 years or older).Aims:To evaluate long‐term efficacy and safety of LDAC with or without glasdegib in patients newly diagnosed with AML unable to receive intensive chemotherapy due to comorbidities or age.Methods:In this follow‐up analysis from the phase 2 BRIGHT AML trial (NCT01546038), newly diagnosed patients with AML ineligible for intensive chemotherapy were randomized 2:1 to glasdegib + LDAC or LDAC alone (study design was reported previously: Cortes et al., Leukemia 2018). This long‐term analysis evaluated efficacy and safety after approximately 20 months of additional follow‐up.Results:As of October 11, 2018, 116 patients were assigned to treatment with glasdegib + LDAC (n = 78) or LDAC alone (n = 38). The median follow‐up time for glasdegib + LDAC and LDAC alone was 43.4 and 42.0 months, respectively. The median overall survival was higher with glasdegib + LDAC vs LDAC alone (Table). Improvement in overall survival was consistent across the prespecified subgroups. The main cause of death in both arms was disease progression (both during study and follow‐up). The incidence of adverse events (AEs) and serious AEs on glasdegib was generally lower long term (after 90 days) than short term (during the first 90 days) (83.7% and 51.2% vs 98.7% and 65.3%, respectively).Summary/Conclusion:Addition of glasdegib to LDAC vs LDAC alone continued to demonstrate improved overall survival in patients with AML in this analysis; improvement was consistent across groups stratified by cytogenetic risk. Long‐term follow‐up confirmed that treatment with glasdegib was associated with an acceptable safety profile.image

Low-dose cytarabine with or without glasdegib in newly diagnosed patients with acute myeloid leukemia: Long-term analysis of a phase 2 randomized trial.

7010 Background: Glasdegib is a potent, selective, oral inhibitor of the Hedgehog signaling pathway, approved in the US – in combination with low-dose cytarabine (LDAC) – for treatment of newly diagnosed acute myeloid leukemia (AML) in patients (pts) unable to receive intensive chemotherapy due to comorbidities or age (≥75 y). Methods: In this follow-up analysis from the phase 2 BRIGHT AML trial (NCT01546038), newly diagnosed pts with AML ineligible for intensive chemotherapy were randomized 2:1 to glasdegib + LDAC or LDAC alone (study design: Cortes et al., Leukemia 2018). This long-term analysis evaluated efficacy and safety after ~20 mo of additional follow-up. Results: As of Oct 11, 2018, 116 pts were assigned to treatment with glasdegib + LDAC (n = 78) or LDAC alone (n = 38) (median follow-up: 43.4 and 42.0 mo, respectively). Median overall survival (OS) was higher with glasdegib + LDAC vs LDAC alone (Table). Improvement in OS was consistent across the prespecified subgroups. The main cause of death in both arms was disease progression (both during study and follow-up). The incidence of adverse events (AEs) and serious AEs on glasdegib was generally lower long term (after 90 days) than short term (during the first 90 days) (83.7% and 51.2% vs 98.7% and 65.3%, respectively). Clinical trial information: NCT01546038. Conclusions: Addition of glasdegib to LDAC vs LDAC alone continued to demonstrate improved OS in pts with AML in this analysis; improvement was consistent across groups stratified by cytogenic risk. Long-term follow-up confirmed treatment with glasdegib was associated with an acceptable safety profile.[Table: see text]

Patient-Reported Outcomes Validation of the FACT-Leu in Acute Myeloid Leukemia: A Review of Baseline Characteristics in AML2002

Introduction: Acute Myeloid Leukemia (AML) is an aggressive disease associated with poor health related quality of life (HRQoL) and short overall survival (OS), particularly for patients' ineligible for intensive chemotherapy. The HRQoL was evaluated in a cohort of patients with AML who were not considered eligible for standard chemotherapy based on the Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) collected at baseline of AML2002 study (NCT02472145).Methods: This analysis was based on a randomized, phase 2/3, parallel design study conducted in patients with AML. Patients' perceptions to HRQoL were evaluated using a 44-item, self-reported leukemia-specific measure, FACT-Leu. It was assessed based on 5 subscales: physical well-being (PWB), social well-being (SWB), emotional well-being (EWB), functional well-being (FWB) and leukemia-specific concerns. Additionally, FACT-Leu was also evaluated based on the trial outcome index (TOI). European Quality of Life- 5 Dimension 5-Level (EQ-5D-5L) was reported based on index values and visual analogue scale (VAS). The summary statistics from the FACT-Leu was compared to the validation paper [1]. FACT-Leu by eastern cooperative oncology group (ECOG) performance status score was also assessed based on generalized linear model and the correlation among FACT-leu subscales was assessed using the Pearsons correlation coefficientResults: Of the 309 patients (mean age 74.9 years) enrolled, 46.3% were women, 87.3% were white (Caucasian) and 70.9% had de novo AML. For these patients, ECOG performance status distribution was 0 (18%), 1 (41.9%) and 2 (40.2%). At baseline, the mean index values for VAS of EQ-5D-5L were 0.68 and 62.5, respectively, and the mean FACT-Leu was 119.6. Except SWB, other FACT-Leu subscale and aggregated scores highly correlated with FACT-Leu (0.74-0.96; p<0.0001). Both index values (0.65) and VAS of EQ-5D-5L (0.57) showed moderate correlation with FACT-Leu. The EQ-5D-5L (0.71) and VAS (0.60) showed moderate correlation with FACT-TOI (p<0.0001). Except SWB and EWB, other FACT-Leu subscales and aggregated scores showed predicted differences in means based on the ECOG score, with higher scores associated with better ECOG status. However, compared to the results of the validation paper [1], the mean subscale scores of AML ineligible for intensive chemo therapy were lower. In addition to ECOG status, sex was also a significant predictor of FACT-Leu subscales as aggregated scores except SWB and EWB with men reporting better scores.Conclusions: FACT-Leu scores were significantly associated with PS and sex. The lower mean subscale scores in Patients with AML ineligible for intensive chemotherapy highlight the need for new therapies to improve patient HRQoL in this group of patients and suggested that there is a need for optimized instruments for women. The FACT-Leu tool could facilitate targeted population interventions, potentially improving quality of life.[1] Cella, Value in Health 15 (2012) 1051-1058 DisclosuresHe:Janssen Global services: Employment. Pierson:Janssen Global Services LLC: Employment. Loefgren:Janssen Global Services LLC: Employment. Cella:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen Global services: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.

Venetoclax with Low-Dose Cytarabine Induces Rapid, Deep, and Durable Responses in Previously Untreated Older Adults with AML Ineligible for Intensive Chemotherapy

Venetoclax with Low-Dose Cytarabine Induces Rapid, Deep, and Durable Responses in Previously Untreated Older Adults with AML Ineligible for Intensive Chemotherapy

Azacitidine in Patients with Acute Myeloid Leukemia: Assessing the Potential Negative Impact of Elevated Baseline White Blood Cell Count on Outcome

Background Recent phase III data indicate that azacitidine (AZA) is active, and well tolerated, in patients with acute myeloid leukemia (AML) and baseline white blood cell (WBC) counts of Methods In this retrospective study of the Austrian AZA Registry (N=346), we assessed outcomes in patients with WHO-AML who received ≥1 dose of AZA, according to baseline WBC count. Patients were divided according to WBC Results A comparison of baseline characteristics between the two groups revealed significantly higher levels of serum lactate dehydrogenase (LDH), peripheral blood (PB) and bone marrow (BM) blasts in patients with WBC ≥15G/L vs those with WBC In the 1st line setting, overall response rate (ORR) was similar in the WBC In contrast, in the ≥2nd line setting, ORR was significantly higher in the WBC Different baseline factors appeared to significantly impact OS in the 0% and LDH >225IU/L negatively affected OS, irrespective of treatment line. Adverse cytogenetics reached statistical significance for the whole 3, primarily in the AZA 1st line setting. Conclusions Previous retrospective studies have suggested that WBC ≥15G/L has a negative impact on OS in AML patients treated with AZA.2,3 This report is the first to describe the impact of WBC ( 1. Dombret H, et al. Oral presentation at EHA 2014. Abstract LB-2433 2. Thepot S, et al. Am J Hematol 2014;89:410–6 3. van der Helm LH, et al. Leuk Res 2013;37:877–82 4. Cheson BD, et al. J Clin Oncol 2003;21:4642–9 5. Cheson BD, et al. Blood 2006;108:419–25 Disclosures Pleyer:Celgene: Consultancy, Honoraria; AOP Orphan Pharmaceuticals: Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Off Label Use: Vidaza (azacitidine) is indicated for the treatment of adult AML patients who are not eligible for haematopoietic stem cell transplantation with 20–30 % blasts and multi-lineage dysplasia, according to WHO classification. This cohort also includes AML-patients with >30% bone marrow blasts.. Burgstaller:AOP Orphan Pharmaceuticals: Honoraria; Novartis: Honoraria; Mundipharma: Honoraria; Celgene: Consultancy. Stauder:Ratiopharm: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Girschikofsky:Pfizer: Honoraria, Research Funding; Mundipharm: Consultancy, Honoraria. Pfeilstocker:Janssen-Cilag: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Lang:Celgene: Consultancy. Sperr:Phadia: Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees. Valent:Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; BMS: Membership on an entity9s Board of Directors or advisory committees; Novartis: Membership on an entity9s Board of Directors or advisory committees. Greil:Amgen: Honoraria, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Honoraria; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Honoraria; Astra-Zeneca: Honoraria; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Roche: Honoraria; Sanofi Aventis: Honoraria; GSK: Research Funding; Ratiopharm: Research Funding; Celgene: Consultancy, Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria.