Lin, Tara L.

Abstract Although the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults ≥60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML aged ≥60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% had favorable-, 11% intermediate-, and 78% had adverse-risk AML. ELN risk was prognostic for overall survival (OS) (P < .001) but did not stratify favorable- from intermediate-risk (P = .71). Within adverse-risk AML, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (n = 316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P < .05). A “mutation score” was calculated for each combination of these mutations, assigning adverse-risk patients to 2 risk groups: −1 to 0 points (“Beat-AML intermediate”) vs 1+ points (“Beat-AML adverse”). In the final refined risk classification, ELN favorable- and intermediate-risk were combined into a newly defined “Beat-AML favorable-risk” group, in addition to mutation scoring within the ELN adverse-risk group. This approach redefines risk for older patients with ND AML and proposes refined Beat-AML risk groups with improved discrimination for OS (2-year OS, 48% vs 33% vs 11%, respectively; P < .001), providing patients and providers additional information for treatment decision-making.

PURPOSE Cancer center clinical trial offices (CCTOs) support trial development, activation, conduct, regulatory adherence, data integrity, and compliance. In 2018, the Association of American Cancer Institutes (AACI) Clinical Research Innovation (CRI) Steering Committee conducted and published survey results to benchmark North American CCTOs, including trial volume, accrual, full time equivalents (FTEs), and budget. The survey was readministered in 2023 to assess contemporary CCTO performance and capacity with results presented here. METHODS The 28 question 2023 survey was sent to directors of AACI's clinical member cancer centers. Survey participation was voluntary, no compensation was provided, and data requested covered operations during 2022. Definitions were consistent with National Cancer Institute (NCI) CCTO reporting requirements and AACI staff anonymously compiled results for descriptive statistical reporting. RESULTS The survey response rate was 61% (60/99). The median annual CCTO budget was $11.5 million (M) US dollars (USD) versus $8.2M USD in 2018. These budgets support a median of 150 FTEs versus 104 previously, and a median total of 384 versus 280 interventional treatment trials and a median of 479 versus 531 interventional treatment accruals. Sources of support for CCTO annual budgets were primarily from industry revenue (45.3%) or institutional support (31.7%). Nearly 60% of centers reported activating NCI-sponsored studies within 90 days but only 9% reported meeting a 90-day activation timeline for industry sponsored studies. CONCLUSION Contemporary benchmarks for CCTO operations through this survey demonstrate larger staff sizes, larger budgets, more trials supported, but fewer patients enrolled to interventional treatment trials in comparison with 2018. These data shine a critical light on the increasing complexity of cancer clinical trials, the importance of external funding sources, and necessary operational efficiency upgrades to provide cutting-edge cancer research and care.

Background: Acute myeloid leukemia (AML) therapy in older patients (age ≥ 60) has undergone a transformation with the introduction of multiple targeted therapies, which has allowed more patients to receive therapy than before. The most successful has been the combination of venetoclax + azacitidine (VA) which generated higher overall complete response rates in phase 2 studies than would be expected with azacitidine alone, leading to accelerated FDA approval on 21Nov2018. The VIALE-A phase 3 study confirmed the improved overall survival (OS, median 14.7 versus 9.6 months) of VA, leading to full FDA approval for marketing. This retrospective analysis provides real world data on the impact of baseline clinical and genomic markers of individuals receiving intensive chemotherapy versus VA. Methods: The precision medicine Beat AML Master Trial (NCT03013998) assigns patients to biomarker specific sub-study treatments based on targeted DNA sequencing and cytogenetics. However, a large subset of patients did not enroll on a sub-study, but were followed for off-study treatment and OS. From this subset, patients enrolled onward from 21Nov2018, when VA received accelerated approval, were examined for differences in clinical/genetic characteristics and OS in those receiving venetoclax + hypomethylating agent (V/HMA), any form of intensive chemotherapy (IC), alternative non-intensive therapy (NIT), or no therapy. The genetic mutations identified in this study are characterized by a variant allele frequency of 20%+, as defined in the trial for determining the dominant clone. The method of Kaplan-Meier was used to estimate OS, and the Cox model was fit to associate patient characteristics with OS. Results: From 21Nov2018, a total of 468 AML patients consented to the Beat AML trial and did not enroll to a sub-study. Treatment was chosen by the investigator based upon available clinical and genomic data. Of these 468 patients, 62 did not receive treatment, 2 had treatment data missing, 226 were treated with V/HMA, 112 with IC, and 66 with NIT. Demographics for all patients include median age 71 (60-90), 40% female, performance status (PS) (0-20%; 1-55%; 2-22%; 3-3%), median white blood cell (WBC) 4.1 (range 0.3-298.6), complex karyotype (CK) 20.6%, core binding factor (CBF) 7.8%, KMT2A-rearranged 3.6%, NPM1-mutated (m) 15.6%, IDH2m 14.6%, TP53m 13.2%, FLT3-ITD/TKD 12.9%, and NRASm/ PTPN11m/ KRASm/ NF1m/ CBLm 23.6%. Demographics that were significantly different (p<0.01) among the three groups (V/HMA, IC, and NIT) include age (younger in IC), PS (worse in NIT), AST/ALT (worse in NIT), CBF (more in IC), CK and TP53m (less in IC). Of the 404 patients who underwent treatment with V/HMA, IC, or NIT, 208 have died with those surviving having a median follow-up of 22.3 months. Figure 1 summarizes the OS of each treatment group. The median OS (95% CI) from time of initiating therapy is 13.6 (10.9-16.8) for V/HMA, 33.8 (20.7-not reached) for IC, and 11.6 (5.2-21.3) months for NIT. Univariable analysis for OS was significant at p<0.05 for increased age, WBC, PS, hemoglobin, CBF, CK, NPM1m, TP53m, TET2m and IC versus V/HMA. Multivariable analysis was significant at p<0.05 (hazard ratio) for increased age (1.14), PS (1.83), WBC (1.08), hemoglobin (0.91), and select genomic aberrations including CBF (0.37), NPM1m (0.35), and TP53m (2.1). Conclusions: These results from a large cohort of older AML patients treated with V/HMA, IC, or NIT show that their outcome is best defined by pre-treatment clinical features previously identified including age, performance status, WBC and hemoglobin along with limited genomic characteristics including CBF, NPM1m, and TP53m. While univariate analysis of OS favored IC over V/HMA and NIT, multivariable analysis supports that this advantage was most likely due to the favorable clinical and genomic features. The OS of V/HMA patients in this cohort is similar to that in the VIALE-A registration study of VA, providing further justification for this treatment for older AML patients deemed ineligible for intensive chemotherapy. Additionally, this data supports use of the patient cohort in this study for ongoing work in understanding and/or validating biomarkers associated with survival with V/HMA.

Background. Acute myeloid leukemia (AML) is a heterogenous disease that occurs primarily in older adults with a median age of 69 years at diagnosis. Most studies that characterize the genomic landscape of AML include younger adults with the majority of patients being younger than 60 years of age. We aimed to study the mutational landscape of newly diagnosed AML patients aged 60 years or older. Methods.Samples were collected from the multi-center Beat AML Master Trial (Burd, Nat Med 2020). Patients were enrolled between 2016 and 2023. Informed consent was obtained according to the Declaration of Helsinki. Patients diagnosed with non-APL AML and who were aged ≥ 60 years old were included. Patients underwent bone marrow aspiration and biopsy, cytogenetic analysis, FLT3-ITD ratio assessment (LeukoStrat CDx FLT3 Mutation Assay, Invivoscribe) and next generation sequencing (NGS) using FoundationOne®Heme(Foundation Medicine) to interrogate the entire coding region of 406 genes and select introns of 31 genes involved in rearrangements, as well as RNA sequencing to interrogate 265 genes known to be somatically altered in human hematological malignancies. The presence of multiple hotspot mutations within one gene in an individual patient was counted as one gene mutation. Patterns of co-occurrence between gene mutations were calculated using the Phi correlation coefficient. Statistical analyses were performed using R statistical software. P<0.01 was considered statistically significant. Results. A total of 1088 newly diagnosed AML patients were identified, of whom 1032 were 60 years or older. Patients had a median age of 72 years at time of diagnosis (range 60-92 years). Forty-two percent of the patients were female, most patients were non-Hispanic and 79% were Caucasian. NGS data were available for 1024 patients and mutations were identified in 461 different genes. Patients had a median number of 11.0 mutations (range 3.0 to 28.0). The most frequently mutated genes were DNMT3A (n=257; 25.1%), TP53(n=255; 24.9%), TET2 (n=243; 23.7%), RUNX1 (n=225; 22.0%), SRSF2 (n=221; 21.6%), ASXL1 (n=216; 21.1%), NPM1 (n=206; 20.1%), FLT3 (n=205; 20.0%), IDH2 (n=190; 18.6%), NRAS (n=208; 16.9%), PTPN11(n=104; 10.2%), STAG2 (n=101, 9.9% and IDH1 (n=99; 9.7%) (Figure 1A). FLT3-ITD was present in 98 (12.1%) of the 810 patients who were tested. Strongest significant co-occurrence was found between FLT3and NPM1 (n=103), STAG2 and ASXL1 (n=63), ASXL1 and RUNX1 (n=92), ASXL1 and SRSF2 (n=88), RUNX1 and SRSF2 (n=94), STAG2 and SRSF2 (n=51) and DNMT3A and NPM1 (n=92) (p<0.01). Pairwise negative correlations were observed between TP53 and NPM1 (n=6), TP53 and SRSF2 (n=17), and between NPM1 and RUNX1 (n=6) (p<0.01) (Figure 1B). The cytogenetic profiles and the full genomic landscape will be presented during the ASH meeting. Discussion. This is the largest study investigating the mutational profile in older adults with AML aged 60 years and older. Due to the 7-day screening period of the Beat AML study, patient selection was biased towards less-rapidly proliferative AML. We showed that the pattern of gene mutations was markedly different from other studies in AML that mainly included younger AML patients (Papaemmanuil, NEJM 2016; TCGA, NEJM 2013 ). The frequency of mutated TP53 was substantially higher in older AML patients, as was the occurrence of myelodysplasia-related gene mutations (e.g., SRSF2, RUNX1, ASXL1, STAG2, U2AF1, and SF3B1) and gene mutations in IDH1, IDH2 and TET2. In contrast, NPM1 mutation was less frequently mutated in older AML patients. Furthermore, we demonstrated that a large proportion (46%) of the AML patients older than 60 years of age do have a mutation that is potentially targetable for treatment ( FLT3 IDH1 IDH2 and NPM1). The high incidence of mutated TP53 and MDS-related gene mutations underscores the increased incidence of high-risk AML and the need for innovative personalized therapies in this older age group. Figure 1. A. Co-occurrence of the 15 most frequently mutated genes, and B. co-correlation between the 15 most frequently mutated genes. Blue indicates positive correlation, red indicated negative correlation. Only significant correlations (p<0.01) are shown.

Introduction: ECOG ACRIN E1910 is a randomized phase III trial that showed that adults with newly diagnosed BCR::ABL1 negative acute lymphoblastic leukemia (ALL) who become MRD negative (<0.01%) after induction chemo who receive blinatumomab with conventional chemotherapy (chemo) have improved survival compared with those who received chemo only (Litzow et al, Blood (2022) 140: Supplement 2, LBA-1). However, not all pts were able to receive all four planned cycles of blinatumomab in consolidation. In this report we assessed outcomes of pts in the blinatumomab arm of the trial who received all 4 cycles of blinatumomab compared to those who received 1-2 cycles. Methods: Patient between the ages of 30 and 70 with newly diagnosed BCR::ABL1 negative B-lineage ALL were enrolled and initially received 2.5 months of combination induction chemo utilizing a BFM-like regimen adapted from the E2993/UKALLXII clinical trial, with pegaspargase (after induction only for patients >=55 years of age) and addition of rituximab for CD20 positive patients. After remission induction (step 1) pts in morphologic complete remission (CR/CRi) received an intensification course of high dose methotrexate with pegaspargase for CNS prophylaxis (step 2). At the conclusion of step 2, remission and MRD status were determined centrally by 6-color flow cytometry with MRD negativity defined as <0.01%. In the primary analysis subset, MRD negative patients were randomized to receive an additional 4cycles of consolidation chemo or 2 cycles of blinatumomab at 28 mcg/day (flat dose) for 28 days each cycle followed by 3 cycles of consolidation chemo, another 4-week cycle of blinatumomab (3rd cycle of blinatumomab) followed by an additional cycle of chemo and then a 4th cycle of blinatumomab (step 3). Following completion of consolidation chemo +/- blinatumomab, pts were given 2.5 years of POMP maintenance therapy timed from the start of the intensification cycle (step 4). Estimates of OS were calculated using the Kaplan-Meier method. Comparison of OS between treatment arms were conducted using the stratified log-rank test and Cox proportional-hazards model with age, CD20 status, rituximab use, and whether pts intend to receive HSCT or not as stratification factors. As the number of cycles needed to optimize outcome has not been studied, an unplanned landmark analysis was used to compare OS of pts in the blinatumomab arm who received all 4 cycles o those who received 1-2 cycles. Time 0 was chosen as 9 months post step 3 randomization (the time that patients were supposed to complete 4 cycles of blina). Four pts who received blinatumomab but died within 9 months post step 3 randomization were therefore excluded from this analysis. Results: The study was activated on December 17, 2013 and closed to enrollment on October 15, 2019. 772 pts were screened for the trial and 488 were enrolled on step 1 induction therapy. The median age of the pts was 51 years (range 30-70). 224 MRD negative pts were randomized, 112 pts to each arm. In the blinatumomab arm 12 pts received 1 cycle (11%), 32 pts received 2 cycles (29%), 4 pts received 3 cycles (4%) and 63 pts received 4 cycles (57%). The OS of pts who received 1-2 cycles of blinatumomab was compared to control (Figure 1) The difference was not significant (hazard ratio 0.62, 95% CI 0.28 to 1.34, p=0.22). Fig 2 compares the survival of those who received 1-2 cycles to those who received 4 cycles ( (HR: 0.39, 95% CI 0.12 to 1.16, p=0.076). Conclusion: The addition of blinatumomab to consolidation chemotherapy resulted in a significantly better overall survival compared to chemotherapy alone in pts with newly diagnosed B-lineage ALL who were MRD negative after intensification. This represents a new standard of care for pts aged 30-70 years with BCR::ABL1 negative ALL. The optimal dose and number of cycles is however unknown. In this unplanned subgroup analysis we demonstrate that a survival benefit can only be confirmed in patients who receive the intended 4 cycles of blinatumomab during consolidation. Further studies will be needed to determine if fewer cycles can provide a similar benefit.

Abstract Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998.

AbstractBackgroundPatients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population.MethodsThis was a multicenter, open‐label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two‐stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1–10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1–5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy.ResultsThe composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%–26.8%) and 30.8% (95% confidence interval, 9.1%–61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts.ConclusionsThe combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need.