tbuckley/cabot-search huggingface dataset:
7+3 versus decitabine + venetoclax: A global, propensity-matched study comparing outcomes for both regimens in AML.
Authors: Varada Salimath, James David Mackey, Brittany Miles, Ankit Mehta
Journal: Journal of Clinical Oncology (2024)

6537 Background: In the treatment of AML, 7+3 (seven days of standard-dose cytarabine and three days of anthracycline therapy) has long been the standard for attempted remission induction. Recently published studies have explored the efficacy and tolerability of decitabine and venetoclax as a favorable alternative regimen in older adults with AML. However, there has not yet been a head-to-head study in the literature comparing real world outcomes for both regimens. Here we present a retrospective database analysis comparing remission status and mortality among elderly patients treated with 7+3 versus decitabine and venetoclax. Methods: The TriNetX research network was used for this study. Two patient cohorts were created by utilizing International Classification of Disease 10 (ICD-10) codes and medication codes in the TriNetX platform. Both cohorts had patients age 65 and up with a diagnosis of AML (C92.0) and who started treatment within six weeks of diagnosis. The 7+3 cohort received cytarabine and either idarubicin or daunorubicin, while the other cohort received decitabine and venetoclax. Each cohort was excluded from the other treatment to remove crossover as a confounding factor. The cohorts were balanced for age, race, gender, and ethnicity by propensity score matching and the greedy nearest neighbor algorithm. This resulted in 519 patients in each arm. They were then evaluated for the outcome of AML in remission (C92.01) and for death within 12 months. Results: Patients treated with 7+3 were more likely to obtain remission status (54.5% vs 34.7%, RR 1.57, 95% CI (1.36,1.81), P value &lt; 0.0001). The 7+3 cohort also had a lower rate of mortality at 12 months (37% vs 54%, RR 0.69, 95% CI (0.60,0.79), P value &lt; 0.0001). Conclusions: These results show that among elderly patients with AML, treatment with 7+3 is associated with statistically higher remission rates and lower mortality when compared with decitabine and venetoclax therapy. One limitation of our study was that we were not able to determine the cytogenetics in either arm. These results should be taken into consideration when choosing an induction regimen in this population.
Improved overall survival in acute myeloid leukemia over the last 15 years.
Authors: Prajwal Dhakal, Bradley T. Loeffler, Aditya Ravindra, Luna Acharya, Avantika Pyakuryal, Vijaya Raj Bhatt
Journal: Journal of Clinical Oncology (2024)

6543 Background: Overall survival (OS) for acute myeloid leukemia (AML) has remained dismal over the past decades. In the last five years, 11 drugs have been approved for newly diagnosed and relapsed/refractory AML. We, therefore, hypothesized that OS has increased significantly in recent years. Methods: We identified 78,092 pts diagnosed with AML between 2004 and 2019 from the National Cancer Database and divided them into 2 cohorts based on year of diagnosis, 2004-2010 and 2011-2019. The Kaplan-Meier method was used to estimate OS probabilities. Cox regression was used to evaluate the association of patient and disease characteristics with OS and differences in these associations between the two cohorts. Results: Sixty-one percent of patients were ≥60 years old, 46% were female, 85% were white, and 90% had Charlson comorbidity index of 0-1. Forty-five percent were diagnosed in 2004-2010, and the rest were diagnosed in 2011-2019. Chemotherapy use increased over the years, with 81% of patients receiving chemotherapy in 2019 compared to 73% in 2004. Similarly, 12.2% of patients in 2012 received hematopoietic cell transplant (HCT) compared to 6.5% in 2004. One-year, 3-year, and 5-year OS for patients diagnosed in 2011-2019 were 48%, 31%, and 28% compared to 42%, 25%, and 22%, respectively, for patients diagnosed in 2004-2010. On multivariable analysis, OS differed significantly over the years based on race, AML subtype, receipt of chemotherapy, and HCT use. OS for white people was better compared to black in 2004-2010 but similar in 2011-2019. Both white and black people had worse OS compared to other race types in 2004-2010 and 2011-2019. Acute promyelocytic leukemia had the best OS compared to core-binding factor, therapy-related, and other AML types; OS improved the most in acute promyelocytic leukemia and core-binding factor AML over the years. Compared to 2004-2010, OS increased significantly in 2011- 2019 with the receipt of chemotherapy and HCT. Older age, male sex, lower income, no insurance, higher Charlson comorbidity index, and lower educational attainment were associated with worse OS with no significant change in recent years. Conclusions: In one of the largest studies, we identified improved OS in patients with AML in recent years. Improvement in OS is likely multifactorial, including recent drug approvals, increased use of chemotherapy and HCT, and better supportive care. Despite a meaningful improvement in OS, only one out of four patients with AML were alive after five years, highlighting a continued need for further drug development and the importance of HCT.
Olutasidenib for mutated IDH1 acute myeloid leukemia: Final five-year results from the phase 2 pivotal cohort.
Authors: Jorge E. Cortes, Brian Andrew Jonas, Justin M. Watts, Mwe Mwe Chao, Stéphane De Botton
Journal: Journal of Clinical Oncology (2024)

6528 Background: Olutasidenib is a potent, selective, oral inhibitor of mIDH1 and is FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML) based on a registrational, Phase 2, open-label, multicenter trial (NCT02719574). We report final five-year results from the pivotal cohort. Methods: In the pivotal cohort of the Phase 2 trial, patients with mIDH1 AML received olutasidenib 150mg BID. Primary endpoint was complete remission (CR) + CR with partial hematologic recovery (CRh) by modified IWG Criteria 2003. Data cutoff: May 15, 2023. Results: Baseline characteristics of 153 enrolled patients are shown in Table. Of 147 efficacy evaluable patients, CR was achieved in 32% (95% CI: 24.5, 40.2) and CR/CRh in 35% (95% CI: 27, 43; P&lt;0.0001). Median time to CR/CRh was 1.9 mo (range: 0.9, 5.6). The median duration of CR/CRh was 25.3 mo (95% CI: 13.5, not reached), with maximum duration 54.6 mo. Overall response rate was 48% (95% CI: 40, 56.7), with median duration 15.5 mo (95% CI: 7.4, 26.2) and maximum duration 54.6 mo. Median overall survival was 11.6 mo (95%CI: 8.9, 15.5). In the 12 patients R/R to prior venetoclax, 33% achieved a CR/CRh; median duration of CR/CRh is not reached (ongoing at 54.3 months), and median overall survival is 16.2 months (95%CI: 2.6, not reached). Transfusion independence from red blood cells and platelets was achieved in 34 of 87 (39%) patients and 28 of 69 (41%) patients, respectively, who were dependent at baseline. 16 (11%) patients proceeded to stem cell transplant. The 5-year safety profile was consistent with what was previously reported. The most common AEs (% reported over 3 years and over the full 5 years) were: febrile neutropenia (22% and 22%), constipation (26% and 27%), diarrhea (20% and 21%), nausea (38% and 39%), fatigue (23% and 23%), pyrexia (24% and 24%), hypokalaemia (20% and 22%), red blood cell count decreased (26% and 26%), white blood cell count increased (25% and 25%). Differentiation syndrome was reported in 14% by Year 3, with no new events by Year 5. The safety profile was stable with long-term follow up. Conclusions: This analysis provides an additional 2 years of data beyond the results that led to FDA approval of olutasidenib. This first report of the five-year data further demonstrates the rapid and durable responses observed with olutasidenib in heavily pretreated patients with mIDH1 AML, including those R/R to prior venetoclax. Clinical trial information: NCT02719574 . [Table: see text]
Safety and efficacy of lisaftoclax, a novel BCL-2 inhibitor, in combination with azacitidine in patients with treatment-naïve or relapsed or refractory acute myeloid leukemia.
Authors: Huafeng Wang, Xudong Wei, Yang Liang, Qian Jiang, Wenjuan He, Qiubai Li, Jianyu Weng, Suning Chen, Chunkang Chang, Hongbing Ma, Yajing Xu, Qun He, Zi Chen, Lihui Liu, Lichuang Men, Danhua Cong, Zhang Zhang, Dajun Yang, Yifan Zhai, Jie Jin
Journal: Journal of Clinical Oncology (2024)

6541 Background: Investigational agent lisaftoclax (Lisa) was shown in preclinical findings to synergistically induce apoptosis in acute myeloid leukemia (AML). Here, we present follow up safety and efficacy data from a phase 1b/2 study evaluating Lisa + azacitidine (AZA) in adults with AML. Methods: Elderly (≥ 75 years)/unfit treatment-naïve (TN) and relapsed or refractory (R/R) AML (≥ 18 years) patients (pts) were enrolled. Lisa (400/600/800 mg) was administered orally once daily in 28-day cycles (a daily ramp up schedule was used for Lisa to prevent tumor lysis syndrome, TLS) combined with AZA (75 mg/m 2 /day on D1-7). Results: As of January 25, 2024, 76 AML pts were enrolled (R/R [n = 37]; elderly/unfit TN [n = 39]). The median (range) age was 66 (20-81) years and 61.8% of pts were male. All pts treated with Lisa + AZA reported TEAEs, with 89.5% Grade 3/4 AEs; and 43.4% SAEs. Common TEAEs (≥ 30%) included neutropenia (60.5%), thrombocytopenia (60.5%), diarrhea (42.1%), hypokalemia (40.8%), pyrexia (35.5%), and vomiting (30.3%). Grade ≥ 3 TEAEs reported in ≥ 10% of pts were neutropenia (57.9%), thrombocytopenia (50.0%), anemia (27.6%), pneumonia (17.1%), and febrile neutropenia (10.5%). No TLS was reported, and the 30-/60-day mortality rates were 1.3% and 3.9%, respectively. In pts with R/R AML treated with Lisa + AZA, the overall response ([ORR] = CR + CRi + morphologic leukemia-free state [MLFS] + PR) and composite complete remission (CRc = CR + CRi) rates were 72.7% and 45.5%, respectively. In the 600 mg cohort (n = 30), ORR and CRc were 76.7% and 50.0%; the median (range) duration of treatment (mDoT), 3.8 (0.8‒15.4) month (mo); median time to CRc (mTTCRc), 2.5 (95% CI, 1.5-6.1) mo; median PFS was 10.2 (95% CI, 6.5-NR) mo; and median OS was 14.7 (95% CI, 7.8-NR) mo. Among 39 pts with TN AML treated with Lisa + AZA, ORR and CRc were 64.1% and 51.3%, respectively (Table). In the 600 mg cohort (n = 29), mDoT was 3.3 (1.0- 9.9) mo; mTTCRc was 1.9 (95% CI, 1.2-3.3) mo; median PFS was not reached (3.5, NR). 600 mg of Lisa + AZA was established as the recommended phase 2 dose. Conclusions: Our data support an emerging role for this new BCL-2 inhibitor Lisa combined with AZA for the treatment of elderly/unfit TN and R/R AML pts, especially with low early mortality and promising mPFS. A phase 3, randomized, double-blind clinical study is in progress to determine whether Lisa + AZA improves OS in elderly/unfit pts with AML. *HW, XW, and YL are co-first authors. Clinical trial information: NCT04501120 . [Table: see text]
Evaluation of treatment outcomes with CPX-351 in adults with AML: A meta-analysis.
Authors: Michael Sandhu, Prashanth Ashok Kumar, Charles W Shi, Jasleen Sidhu, Mulham Ombada, Deevyashali Parekh, Krishna Bilas Ghimire, Teresa Gentile
Journal: Journal of Clinical Oncology (2024)

6540 Background: CPX-351 is a liposomal formulation of cytarabine and daunorubicin which has shown survival benefit when compared to 7+3 in older adults with myelodysplasia-related (AML-MRC) and therapy-related AML (t-AML). Aiming to investigate the clinical efficacy of CPX-351 against 7+3 in adults with AML, we performed a meta-analysis. Methods: A systematic search with controlled vocabulary encompassing AML, CPX-351 and 7+3 was conducted in PubMed, Embase, Scopus, and Cochrane on November 1, 2023 with no search restrictions. 3461 were found; 2581 were left after duplicates were removed using Mendeley 1.19.8. Remaining records were imported into Rayyan and independently screened by 2 reviewers. 8 studies were included in the analysis as they provided data for both CPX-351 and 7+3. 17 studies only including CPX-351 were identified. RevMan was used to analyze the Odds Ratio (OR) with 95% Confidence Interval (CI), derived from random effects (RE) model with Mantel-Haenszel (MH) method. Results: We identified 8 studies comparing CPX-351 to 7+3, encompassing a total of 1368 total patients: 44% (604/1368) received CPX-351, 56% (764/1368) received 7+3. Most patients had AML-MRC or t-AML. The median age in the CPX-351 group was 66 (range 58-67) and in the 7+3 group was 67 (range 58-67). The median overall survival grossly favored CPX-351 with 10.3 months (range 8.8-22 months) compared to 6.2 months (range 4.6-12 months) in 7+3. The OR of complete remission (CR) for CPX-351 versus 7+3 using the RE model was 1.66 (CI=1.15-2.39, p=0.006, I 2 =55%). Similarly, the OR of patients undergoing hematopoietic stem cell transplantation (HSCT) for CPX-351 versus 7+3 was 1.52 (CI=1.01-2.30, p=0.05, I 2 =47%). Including the additional 17 studies with CPX-351, the overall CR rate for all patients was 49%. Average 30-day mortality with CPX-351 was 4.9%. Conclusions: From our analysis, the OR of attaining CR and HSCT were shown to be significantly improved with CPX-351 when compared to conventional 7+3 chemotherapy in adult patients with AML. Both groups had similar median age, and patients in the CPX-351 arm had longer median overall survival. Our meta-analysis highlights that while CPX-351 achieves CR/HSCT at a higher rate than 7+3, data in younger populations (&lt;60 years old) and patients with de novo AML are sparse. Heterogeneity between studies and lack of mutational analysis are limitations of our study. [Table: see text]
<i>TP53</i> mutation screening for patients at risk of myeloid malignancy.
Authors: Devdeep Mukherjee, Rialnat A. Lawal, Courtney Fitzhugh, Laura Williams Dillon, Christopher S. Hourigan
Journal: Journal of Clinical Oncology (2024)

6546 Background: Cellular therapy is a promising approach for many diseases but is associated with a risk of subsequent myelodysplastic syndrome and/or acute myeloid leukemia, also known as therapy-related myeloid neoplasms (tMN). This phenomenon has recently been described with allogeneic hematopoietic cell transplantation (HCT) and gene therapy for sickle cell disease (SCD). Mutation(s) in functional domains of TP53 are often associated with the development of tMN but currently no prospective screening or monitoring technology is available. Methods: A next-generation sequencing (NGS) assay with unique molecular identifiers (UMI) and bioinformatic noise-suppression was designed to discover somatic mutations at a variant allele frequency (VAF) 1% throughout the TP53gene. The background error profile at each base position was calculated using blood genomic DNA from healthy donors. The minimal detectable allele fraction with 95% confidence (MDAF) was calculated for all reported known AML/tMN TP53 hotspots. Orthogonal validation was performed using droplet digital PCR (ddPCR). Results: The median error corrected sequencing depth at 62 known TP53 hotspot regions was 14,512 (95% CI: 14,769 – 15,430) with a theoretical median de novo NGS variant discovery limit of 0.058% (range: 0.037% - 0.13%). Experimental evidence of assay performance characteristics was produced using serial dilutions of 4 missense, 2 splicing, and 1 frameshift TP53 variants with 100% discovery specificity observed (lowest detected VAF range: 0.05 – 0.12%). High correlation was observed in quantification using NGS discovery and ddPCR validation ( r = 0.958, p&lt;0.0001). Pre- and post-HCT clinical samples from 19 patients with SCD, 11 of which had graft failure including 4 who developed tMN, were screened for TP53 mutations. In all tMN cases, the AML-associated TP53 variant was detectable at least 6 months and up to 2.5 years prior to clinical diagnosis of myeloid malignancy. In contrast, no pathogenic TP53 variants were detected in 15 SCD patients who underwent HCT but did not develop tMN. Conclusions: This study provides generalizable evidence that ultra-sensitive discovery of TP53 mutations prior to cellular therapy is possible and could be a potentially valuable clinical tool to screen for tMN risk.
Efficacy of GCN2 inhibition by a novel small molecule AP030 in acute leukemia.
Authors: Nadine Clemo, Monica Roman-Trufero, Holger Auner, Richard Butt, Armin Zebisch, Panagiota Chaida, Sereina Herzog, Matthew Fuchter
Journal: Journal of Clinical Oncology (2024)

6532 Background: GCN2 is an evolutionarily conserved kinase and a pivotal regulator of the Integrated Stress Response (ISR) that is activated in response to amino acid scarcity. Active GCN2 phosphorylates translation initiation factor eIF2α resulting in the attenuation of global protein synthesis. ISR signaling primarily promotes cell survival but may trigger cell death, dependent on the cellular context. In hematological tumors GCN2 promotes tumor cell survival under conditions of nutrient scarcity. Several GCN2 inhibitors are in clinical development for treatment of both solid and hematological tumors. Here, we describe the preclinical results of a novel, selective ATP-competitive inhibitor of GCN2. Methods: GCN2 inhibition by AP030 was determined using a biochemical Lanthascreen assay and a cell based HTRF assay measuring eIF2a phosphorylation following stimulation with Borrelidin. Kinase selectivity was determined using KinomeScan, and bespoke biochemical and cell-based assays. Interaction of AP030 with GCN2 was determined using X-ray crystallography. AP030 activity in disease-relevant tumor cell lines was determined using cell viability, caspase activation, protein expression and qPCR gene expression endpoints. Inhibition of hematological tumor growth and induction of cell death was investigated in patient samples, and ALL and AML in vivo animal models. Results: Potent inhibition of GCN2 in the Lanthascreen assay was demonstrated with AP030 (Ki of 4.4nM). Following stimulation with Borrelidin, AP030 inhibited eIF2a phosphorylation with an IC 50 of 50.8nM and inhibited downstream targets CHAC1 and DDIT3 measured by qPCR. X-ray crystallography confirmed that AP030 binds to the ATP-binding site of GCN2. The KinomeScan confirmed that AP030 was highly selective against the human kinome. AP030 led to partial or complete reduction of AML cell line viability as a single agent and acted synergistically with asparaginase in ALL cell lines. Caspase 3/7 induction was observed in the AML and ALL cell lines evaluated and AP030 increased the proportion of cells undergoing apoptosis in AML patient primary samples. In the CCRF-CEM ALL systemic in vivo tumor model AP030 inhibited tumor growth in combination with asparaginase (TGI 79.33%). Treatment with 0.5-5mg/kg (q.d.) of AP030 resulted in dose-dependent tumor growth inhibition and regression of the MOLM-16 AML in vivo model (TGI 97.37% 5mg/kg). RNA sequencing of residual tumor cells revealed disruption of amino acid and protein metabolism, consistent with GCN2 inhibition. Conclusions: Targeting hematological tumor reliance on the GCN2 arm of the ISR during nutrient scarcity is a novel approach to preventing tumor cell survival. AP030 a novel, potent, selective, ATP-competitive kinase inhibitor has been shown to lead to impressive efficacy in acute leukemia. Based on these preclinical results, a phase 1/2 study has been initiated in AML.
Safety outcomes in patients with acute myeloid leukemia receiving gemtuzumab ozogamicin and proceeding to allogeneic hematopoietic stem cell transplantation.
Authors: Partow Kebriaei, Vincent Ho, Miguel-Angel Perales, Nelli Bejanyan, Manmeet Kaur, Mei-Jie Zhang, Paul G. D'Amico, Simon Purcell, Stephanie Dorman, Erik Vandendries, Kofi Asomaning, Wael Saber
Journal: Journal of Clinical Oncology (2024)

6516 Background: Gemtuzumab ozogamicin (GO) is a CD33-directed antibody-drug conjugate approved by the FDA in 2017 for the treatment of newly diagnosed and relapsed/refractory (R/R) CD33-positive acute myeloid leukemia (AML) in adults and pediatric patients of 1 month and older and 2 years and older, respectively. Previous data have associated GO with adverse events (AEs) including hepatotoxicity and hepatic veno-occlusive disease (VOD). Patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) may be at greater risk of VOD with GO. This study aimed to characterize AEs after HSCT in adult patients with AML who were treated with GO. Methods: This non-interventional post-authorization safety study used de-identified healthcare data from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Data were collected from 01 September 2017. Safety outcomes post-HSCT were evaluated in adult patients with newly diagnosed or R/R AML who received GO prior to first HSCT. Data cutoff was 04 July 2023. Results: We present the interim data of 157 patients from 24 centers with a median follow-up of 12.9 months (range, 3.0-49.7). At the time of HSCT, 84 patients were in first complete remission (CR1), 48 patients were in second CR (CR2) and 25 patients were in third or greater CR, relapse or primary induction failure (CR3, n=5; Rel, n=12; PIF, n=8). Most patients (n=105; 67%) received GO as first line therapy. Median lines of therapy prior to HSCT were 2, 3.5 and 5 in CR1, CR2 and CR3/Rel/PIF groups, respectively. Median age was 52.5 y (range, 18.7-74.9); 53% male. Time from diagnosis to first GO dose was &lt;3 months for most patients (n=120; 76%). Total cumulative GO dose was 1-3 mg/m2 in 25 (16%), 4-6 mg/m2 in 28 (18%), 7-9 mg/m2 in 45 (29%) and ≥10 mg/m2 in 14 (9%) patients. The most common HSCT donor type was unrelated (n=93; 59%), and 55% of patients received myeloablative conditioning regimens. Non-fatal VOD was reported in 7 (4%) patients. Median time from HSCT to VOD was 0.9 months (range, 0.4-2.2). No VOD-related deaths occurred. Outcome probabilities for 6-month transplant-related mortality (TRM) were 8% (95% CI, 4-13) and 5% (95% CI, 2-8) for 100-day VOD. Conclusions: The use of GO appears to be safe prior to HSCT in adults with AML. Rates for 100-day VOD and TRM were comparable to those previously reported for patients with AML who received HSCT with or without prior GO. Clinical trial information: B1767034.