Association between class III obesity and overall survival in previously untreated younger patients with acute myeloid leukemia enrolled on SWOG S1203.

There has been ongoing debate on the association between obesity and outcomes in acute myeloid leukemia (AML). Currently few studies have stratified outcomes by class I obesity, class II obesity, and class III obesity, and a more nuanced understanding is becoming increasingly important with the rising prevalence of obesity. We examined the association between body mass index (BMI) and outcomes in previously untreated AML in younger patients (age ≤60) enrolled in SWOG S1203 (n = 729). Class III obesity was associated with an increased rate of early death (p = 0.004) and worse overall survival (OS) in multivariate analysis (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.62-3.80 versus normal weight). Class III obesity was also associated with worse OS after allogeneic hematopoietic cell transplant (HR 2.37, 95% CI 1.24-4.54 versus normal weight). These findings highlight the unique risk of class III obesity in AML, and the importance of further investigation to better characterize this patient population.

Second Allogeneic Hematopoietic Cell Transplantation for Relapsed Adult Acute Myeloid Leukemia: Outcomes and Prognostic Factors.

Second allogeneic hematopoietic cell transplantation (HCT2) is potentially curative for adults with acute myeloid leukemia (AML) or myelodysplastic neoplasm (MDS)/AML experiencing relapse after a first allograft (HCT1), but prognostic factors for outcomes are poorly characterized. To provide a detailed analysis of HCT2 outcomes and associated prognostic factors in a large single-center cohort, with a focus on identifying predictors of relapse and nonrelapse mortality (NRM). We studied adults ≥18 years who underwent HCT2 at a single institution between April 2006 and June 2022 for relapsed AML (n = 73) or MDS/AML (n = 8). With a median follow-up among survivors of 74.0 (range: 10.4 to 187.3) months, there were 30 relapses and 57 deaths, of which 29 were NRM events, contributing to the estimates for relapse, overall survival (OS), relapse-free survival (RFS), and NRM. Three-year estimates for relapse, RFS, and OS were 37% (95% confidence interval: 27% to 48%), 32% (23% to 44%), and 35% (26% to 47%). The rate of NRM at 100 days and 18 months was 20% (12% to 29%) and 28% (19% to 39%). Outcomes differed markedly across patient subsets and were substantially worse for patients who underwent HCT2 with active disease (ie, morphologic evidence of bone marrow and/or extramedullary disease), for patients who relapsed ≤6 months after HCT1, and for patients with higher HCT-specific Comorbidity Index (HCT-CI) or treatment-related mortality (TRM) score. After multivariable adjustment, active disease was associated with a higher risk of relapse (hazard ratio [HR] = 3.19, P = .006) and shorter RFS (HR = 2.41, P = .008) as well as OS (HR = 2.17, P = .027) compared to transplant in morphologic remission without multiparameter flow cytometric evidence of measurable residual disease. Similarly, a relapse-free interval <6 months after the first allograft was associated with higher risk of relapse (HR = 5.86, P < .001) and shorter RFS (HR = 2.86; P = .001) and OS (HR = 2.45, P = .003). Additionally, a high HCT-CI score was associated with increased NRM (HR = 4.30, P = .035), and shorter RFS (HR = 3.87, P = .003) and OS (HR = 3.74, P = .006). Likewise, higher TRM scores were associated with increased risk of relapse (HR = 2.27; P = .024) and NRM (HR = 2.01, P = .001), and inferior RFS (HR = 1.90 P = .001) and OS (HR = 1.88, P = .001). A significant subset of patients with AML or MDS/AML relapse after HCT1 are alive and leukemia-free 3 years after undergoing HCT2. Our study identifies active leukemia at the time of HCT2 and early relapse after HCT1 as major adverse prognostic factors, highlighting patient subsets in particular need of novel therapeutic approaches, and supports the use of the HCT-CI and TRM scores for outcome prognostication.

Avoiding Delays in Reporting Time-to-Event Randomized Trials: Calendar Backstops and Other Approaches.

New oncology therapies that extend patients' lives beyond initial expectations and improving later-line treatments can lead to complications in clinical trial design and conduct. In particular, for trials with event-based analyses, the time to observe all the protocol-specified events can exceed the finite follow-up of a clinical trial or can lead to much delayed release of outcome data. With the advent of multiple classes of oncology therapies leading to much longer survival than in the past, this issue in clinical trial design and conduct has become increasingly important in recent years. We propose a straightforward prespecified backstop rule for trials with a time-to-event analysis and evaluate the impact of the rule with both simulated and real-world trial data. We then provide recommendations for implementing the rule across a range of oncology clinical trial settings.

Intensive Reinduction Chemotherapy Followed by Early Allogeneic Hematopoietic Cell Transplantation for Relapsed/Refractory High-Grade Myeloid Neoplasms.

Outcomes for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms remain poor, with allogeneic hematopoietic cell transplantation (HCT) the sole therapy likely to result in cure. We conducted the present study to determine the feasibility of early HCT-within 60 days of beginning reinduction chemotherapy-to see whether getting patients to HCT in an expeditious manner would expand the number of patients being offered this curative option. In this proof-of-principle feasibility study, we included adults age 18 to 75 years with R/R myeloid malignancies with ≥10% blood/marrow blasts at diagnosis who were eligible for a reduced-intensity HCT. Subjects received reinduction chemotherapy with cladribine, cytarabine, mitoxantrone, and filgrastim (CLAG-M) and proceeded to HCT with reduced-intensity conditioning (fludarabine/ melphalan). We enrolled 30 subjects, all of whom received CLAG-M reinduction, although only 9 underwent HCT within 60 days (<15, the predetermined threshold for feasibility "success"), with a median time to HCT of 48 days (range, 42 to 60 days). Eleven additional subjects received HCT beyond the target 60 days (off-study), with a median time to transplantation of 83 days (range, 53 to 367 days). Barriers to early HCT included infection, physician preference, lack of an HLA-matched donor, logistical delays, and disease progression, all of which may limit the real-world uptake of such early-to-transplantation protocols.

Association between class III obesity and overall survival in previously untreated younger patients with acute myeloid leukemia enrolled on SWOG S1203.

There has been ongoing debate on the association between obesity and outcomes in acute myeloid leukemia (AML). Currently there are few studies that have stratified outcomes by class I obesity, class II obesity, and class III obesity; and a more nuanced understanding is becoming increasingly important with the rising prevalence of obesity. We examined the association between body mass index (BMI) and outcomes in previously untreated AML in younger patients (age ≤60) enrolled in SWOG S1203 (n=729). Class III obesity was associated with an increased rate of early death (p=0.004) and worse overall survival (OS) in multivariate analysis (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.62-3.80 versus normal weight). Class III obesity was also associated with worse OS after allogeneic hematopoietic cell transplant (HR 2.37, 95% CI 1.24-4.54 versus normal weight). These findings highlight the unique risk of class III obesity in AML, and the importance of further investigation to better characterize this patient population.

Relative prognostic value of flow cytometric measurable residual disease before allogeneic hematopoietic cell transplantation for adults with MDS/AML or AML.

Multiparameter flow cytometry (MFC) measurable residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) independently predicts poor outcomes in acute myeloid leukemia (AML). Conversely, its prognostic value in the newly defined disease entity, myelodysplastic neoplasm (MDS)/AML is unknown. To assess the relationship between disease type, pre-HCT MRD, and post-HCT outcomes, we retrospectively analyzed 1265 adults with MDS/AML (n = 151) or AML (n = 1114) who received a first allograft in first or second morphologic remission at a single institution between April 2006 and March 2023. At 3 years, relapse rates (29% for MDS/AML vs. 29% for AML, p = .98), relapse-free survival (RFS; 50% vs. 55%, p = .22), overall survival (OS; 52% vs. 60%, p = .073), and non-relapse mortality (22% vs. 16%, p = .14) were not statistically significantly different. However, a significant interaction was found between pre-HCT MFC MRD and disease type (MDS/AML vs. AML) for relapse (p = .009), RFS (p = .011), and OS (p = .039). The interaction models indicated that the hazard ratios (HRs) for the association between pre-HCT MRD and post-HCT outcomes were lower in patients with MDS/AML (for relapse: HR = 1.75 [0.97-3.15] in MDS/AML vs. 4.13 [3.31-5.16] in AML; for RFS: HR = 1.58 [1.02-2.45] vs. 2.98 [2.48-3.58]; for OS: HR = 1.50 [0.96-2.35] vs. 2.52 [2.09-3.06]). On the other hand, residual cytogenetic abnormalities at the time of HCT were equally informative in MDS/AML as in AML patients. Our data indicate that MFC-based pre-HCT MRD testing, but not testing for residual cytogenetic abnormalities, is less informative for MDS/AML than AML patients when used for prognostication of post-HCT outcomes.

SWOG 1609 cohort 48: anti-CTLA-4 and anti-PD-1 for advanced gallbladder cancer.

INTRODUCTION: Most patients with advanced gallbladder cancer are treated with multiagent chemotherapy. Immune checkpoint inhibitors offer the possibility of a durable response with less toxicity. This prospective, multicenter, open-label study was designed to evaluate the anticancer activity of nivolumab plus ipilimumab in patients with advanced gallbladder cancer. METHODS: Nineteen patients with advanced gallbladder cancer refractory to ≥1 previous therapy received nivolumab 240 mg intravenously every 2 weeks and ipilimumab 1 mg/kg intravenously every 6 weeks until disease progression or unacceptable toxicity. The primary end point was confirmed radiographic overall response rate (ORR) (complete response [CR] + partial response [PR] confirmed on subsequent scan); secondary end points included unconfirmed overall response, clinical benefit rate (confirmed and unconfirmed responses + stable disease >6 months), progression-free survival, overall survival, and toxicity. RESULTS: The confirmed ORR was 16% (CR, n = 1 [5%]; PR, n = 2 [11%]); all were microsatellite stable, and the confirmed CR had undetectable programmed death-ligand 1 by immunohistochemistry. The unconfirmed ORR and clinical benefit rates were both 32%. The median duration of response was 14.8 months (range, 4-35.1+ months). The 6-month progression-free survival was 26% (95% CI, 12-55). The median overall survival was 7.0 months (95% CI, 3.9-19.1). The most common toxicities were fatigue (32%), anemia (26%), and anorexia (26%). Aspartate aminotransferase elevation was the most common grade 3/4 toxicity (11%). There was 1 possibly related death (sepsis with attendant hepatic failure). CONCLUSIONS: Ipilimumab plus nivolumab was well tolerated and showed modest efficacy with durable responses in previously treated patients with advanced gallbladder cancer. CLINICAL TRIAL REGISTRATION: NCT02834013 (ClincialTrials.gov). PLAIN LANGUAGE SUMMARY: This prospective study assessed the efficacy and safety of nivolumab plus ipilimumab in 19 patients with advanced gallbladder cancer refractory to previous therapy. The combination demonstrated modest efficacy with a 16% confirmed overall response rate, durable responses, and manageable toxicities, suggesting potential benefits for this challenging patient population.

Impact of socioeconomic disparities on outcomes in adults undergoing allogeneic hematopoietic cell transplantation for acute myeloid leukemia.

Racial and socioeconomic disparities impact outcomes after chemotherapy and limit access to allogeneic hematopoietic cell transplantation (HCT) in acute myeloid leukemia (AML), yet studies have yielded mixed results on the influence of disparities on post-HCT outcomes. Therefore, we studied 1024 adults with AML who underwent allogeneic HCT between 5/2006 and 10/2021 at a single large university-affiliated cancer center. Collected data included non-biologic and demographic characteristics (including race/ethnicity, marital status, distance traveled, and household size), transplant- and disease-related characteristics, and area-level and individual-level socioeconomic factors (i.e., area deprivation index and occupational status). After multivariable adjustment, no socioeconomic- or non-biologic factors were associated with non-relapse mortality (NRM), overall survival (OS), relapse-free survival (RFS), or relapse except being married (associated with improved NRM: hazard ratio [HR] = 0.7 [0.50-0.97]) and having no insurance (associated with worse OS: HR = 1.49 [1.05-2.12] and RFS: HR = 1.41 [1.00-1.98]). Despite a relatively racially homogenous cohort, Asian race was associated with improved NRM (HR = 0.47 [0.23-0.93]) and American Indian/Alaskan Native race was associated with higher relapse risk (HR = 2.45 [1.08-5.53]). In conclusion, in our retrospective analysis, socioeconomic-, demographic-, and non-biologic factors had limited impact on post-HCT outcomes in AML patients allografted in morphologic remission. Further research is needed to investigate disparities among HCT-eligible patients.

A phase 1 study of triple-targeted therapy with BRAF, MEK, and AKT inhibitors for patients with BRAF-mutated cancers.

BACKGROUND: Aberrant PI3K/AKT signaling in BRAF-mutant cancers contributes to resistance to BRAF inhibitors. The authors examined dual MAPK and PI3K pathway inhibition in patients who had BRAF-mutated solid tumors (ClinicalTrials.gov identifier NCT01902173). METHODS: Patients with BRAF V600E/V600K-mutant solid tumors received oral dabrafenib at 150 mg twice daily with dose escalation of oral uprosertib starting at 50 mg daily, or, in the triplet cohorts, with dose escalation of both oral trametinib starting at 1.5 mg daily and oral uprosertib starting at 25 mg daily. Dose-limiting toxicities (DLTs) were assessed within the first 56 days of treatment. Radiographic responses were assessed at 8-week intervals. RESULTS: Twenty-seven patients (22 evaluable) were enrolled in parallel doublet and triplet cohorts. No DLTs were observed in the doublet cohorts (N = 7). One patient had a DLT at the maximum administered dose of triplet therapy (dabrafenib 150 mg twice daily and trametinib 2 mg daily plus uprosertib 75 mg daily). Three patients in the doublet cohorts had partial responses (including one who had BRAF inhibitor-resistant melanoma). Two patients in the triplet cohorts had a partial response, and one patient had an unconfirmed partial response. Pharmacokinetic data suggested reduced dabrafenib and dabrafenib metabolite exposure in patients who were also exposed to both trametinib and uprosertib, but not in whose who were exposed to uprosertib without trametinib. CONCLUSIONS: Concomitant inhibition of both the MAPK and PI3K-AKT pathways for the treatment of BRAF-mutated cancers was well tolerated, leading to objective responses, but higher level drug-drug interactions affected exposure to dabrafenib and its metabolites.

Correlation between tumor size change and outcome in a rare cancer immunotherapy basket trial.

BACKGROUND: RECIST criteria for progressive disease, partial response, and complete response, reflecting +20%, -30%, and -100% tumor size changes, respectively, are critical outcome variables in oncology clinical trials. Herein, we evaluated post-immunotherapy tumor size change correlation with outcomes. METHODS: We used a unique clinical trial data resource, a multicenter basket trial in patients with rare solid tumors treated with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) between 2017 and 2023 (National Cancer Institute/Southwest Oncology Group-sponsored DART trial [NCT02834013]) (open at 1083 sites at its peak). Outcome associations were evaluated by survival analysis techniques including Martingale residuals. RESULTS: In 638 evaluable patients, we found strong linear relationships between percent change in tumor measurement up to a 40%-50% increase and progression-free (PFS) and overall survival (OS) (both Cox regression P < .001; landmark analyses based on day 65). Pearson R correlation between survival estimates and tumor change category were -0.94, -0.89, and -0.89 (PFS) and -0.84, -0.90, and -0.90 (OS) for median, 6-month (PFS), and 1-year (OS) and for 1-year (PFS) and 2-year (OS) estimates. CONCLUSIONS: Percent change in tumor measurement per RECISTv1.1 (the sum of longest dimensions of target lesions) has a linear association with PFS and OS up to a 40% to 50% increase in tumor measurement in this cohort of patients with rare cancers who received combination immune checkpoint blockade. Quantitative first scan tumor measurement changes include important information to evaluate the potential efficacy of a therapy beyond the proportion of patients who achieve an objective response.

Prognosis and conditional survival among women with newly diagnosed ovarian cancer.

OBJECTIVE: An important question in determining long-term prognosis for women with ovarian cancer is whether risk of death changes the longer a woman lives. Large real-world datasets permit assessment of conditional survival (CS) given both prior overall survival (OS) and real-world progression-free survival (rwPFS). METHODS: Using a longitudinal dataset from US oncology centers, this study included 6778 women with ovarian cancer. We calculated CS rates as the Kaplan-Meier probability of surviving an additional 1 or 5 years, given no mortality (OS) or disease progression (rwPFS) event in the previous 0.5-5 years since first-line chemotherapy initiation, adjusted for factors associated with OS based on multivariable Cox regression. RESULTS: Median study follow-up was 9 years (range, 1-44) from first-line initiation to data cutoff (17-Feb-2021). Median OS was 58.0 months (95% CI, 54.9-60.8); median rwPFS was 18.4 months (17.4-19.4). The adjusted 1-year CS rate (ie, rate of 1 year additional survival) did not vary based on time alive, whereas the adjusted 5-year CS rate increased from 48.5% (47.0%-50.1%) for women who had already survived 6 months to 66.4% (63.3%-69.6%) for those already surviving 5 years (thus surviving 10 years total). The adjusted 1-year CS rate increased from 90.4% (89.5%-91.4%) with no rwPFS event at 6 months to 97.6% (96.4%-98.8%) with no rwPFS event at 5 years; adjusted 5-year CS rate increased from 53.7% (52.0%-55.5%) to 85.0% (81.2%-88.9%), respectively. CONCLUSIONS: This analysis extends the concept of CS by also conditioning on time progression-free. Patients with longer rwPFS experience longer survival than patients with shorter rwPFS.

A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609 Cohort 47) in Patients with Gestational Trophoblastic Neoplasia.

PURPOSE: The efficacy of immune checkpoint blockade in gestational trophoblastic neoplasia (GTN) remains uncertain. We report the results of the GTN cohort of SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART). PATIENTS AND METHODS: This prospective, open-label phase II trial evaluated ipilimumab plus nivolumab across multiple rare tumor cohorts, including GTN. Eligible patients received nivolumab 240 mg, i.v. every 2 weeks and ipilimumab 1 mg/kg i.v. every 6 weeks. The primary endpoint was overall response rate [ORR; complete response (CR) + partial response (PR)] by quantitative serum beta human chorionic gonadotropin (ß-hCG); secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: Four patients with refractory GTN enrolled and received therapy. At 11 months of ongoing follow-up, 3 of 4 patients responded [ORR = 75% (CR, 25%, n = 1, tumor mutation burden = 1 mutation/megabase; PD-L1 tumor proportion score = 50%); PR, 50%, n = 2)]. Responders included malignant gestational trophoblastic neoplasm (n = 1, CR, PFS 11+ months) and choriocarcinoma (n = 2, both PRs, PFS 10+ and 6+ months). One patient with epithelioid trophoblastic tumor experienced disease progression. The 6-month PFS was 75% [95% confidence interval (CI), 43%-100%], and the median PFS was not reached (range, 35-339+ days); all 4 patients were alive at last follow-up. Two patients experienced grade 3 immune-related toxicity (arthralgia and colitis); there were no grade ≥4 events. CONCLUSIONS: Ipilimumab plus nivolumab demonstrated efficacy in chemotherapy-refractory GTN, an ultra-rare cancer affecting young women. Three of 4 patients achieved ongoing objective responses with a reasonable safety profile at 6-11+ months.

A randomized phase III study of standard versus high-dose cytarabine with or without vorinostat for AML.

Prior experience indicated that use of higher doses of cytarabine during induction for acute myeloid leukemia (AML) with a histone deacetylase inhibitor resulted in high response rates. S1203 was a randomized multicenter trial for previously untreated patients aged 18-60 with AML which compared daunorubicin and cytarabine (DA), idarubicin with higher dose cytarabine (IA) and IA with vorinostat (IA + V). The primary endpoint was event free survival (EFS). 738 patients were randomized: 261 to each DA and IA arms and 216 to the IA + V arm. 96, 456, and 150 patients had favorable-, intermediate-, and unfavorable-risk cytogenetics, respectively. 152 were NPM1 and 158 FLT3 mutated. The overall remission rate was 77.5% including 62.5% CR and 15.0% CRi. No differences in remission, EFS, or overall survival were observed among the 3 arms except for the favorable cytogenetics subset who had improved outcomes with DA and postremission high dose cytarabine. A trend towards increased toxicity was observed with the IA and IA + V arms. The use of higher dose cytarabine during induction therapy in younger patients with AML, with or without vorinostat, does not result in improved outcomes. (Funded by the US National Institutes of Health and others, ClinicalTrials.gov number, NCT01802333.).

Alcohol, Smoking, and Risks of Breast Cancer Recurrence and Mortality among Women with Luminal, Triple-Negative, and HER2-Overexpressing Breast Cancer.

BACKGROUND: This study evaluates the relationship between smoking, alcohol, and breast cancer outcomes according to molecular subtype. METHODS: This population-based prospective cohort consisted of 3,876 women ages 20 to 69 diagnosed with a first primary invasive breast cancer from 2004 to 2015 in the Seattle-Puget Sound region. Breast cancer was categorized into three subtypes based on estrogen receptor (ER), progesterone receptor (PR), and HER2 expressions: luminal (ER+), triple-negative (TN; ER-/PR-/HER2-), and HER2-overexpressing (H2E; ER-/HER2+). We fit Cox proportional hazards models to assess the association between alcohol consumption and smoking status at diagnosis and risks of recurrence, breast cancer-specific mortality, and all-cause mortality. RESULTS: Histories of ever smoking [HR, 1.33; 95% confidence interval (CI), 1.01-1.74] and current smoking (HR, 1.59; 95% CI, 1.07-2.35) were associated with greater risk of breast cancer recurrence among TN cases. Smoking was also associated with greater risk of recurrence to bone among all cases and among luminal cases. Elevated risks of breast cancer-specific and all-cause mortality were observed among current smokers across all subtypes. Alcohol use was not positively associated with risk of recurrence or mortality overall; however, TN patients who drank four or more drinks per week had a decreased risk of recurrence (HR, 0.71; 95% CI, 0.51-0.98) and breast cancer-specific mortality (HR, 0.73; 95% CI, 0.55-0.97) compared with non-current drinkers. CONCLUSIONS: Patients with breast cancer with a history of smoking at diagnosis have elevated risks of recurrence and mortality. IMPACT: These findings underscore the need to prioritize smoking cessation among women diagnosed with breast cancer.

Quantification of measurable residual disease using duplex sequencing in adults with acute myeloid leukemia.

The presence of measurable residual disease (MRD) is strongly associated with treatment outcomes in acute myeloid leukemia (AML). Despite the correlation with clinical outcomes, MRD assessment has yet to be standardized or routinely incorporated into clinical trials and discrepancies have been observed between different techniques for MRD assessment. In 62 patients with AML, aged 18-60 years, in first complete remission after intensive induction therapy on the randomized phase III SWOG-S0106 clinical trial (clinicaltrials gov. Identifier: NCT00085709), MRD detection by centralized, high-quality multiparametric flow cytometry was compared with a 29-gene panel utilizing duplex sequencing (DS), an ultrasensitive next-generation sequencing method that generates double-stranded consensus sequences to reduce false positive errors. MRD as defined by DS was observed in 22 (35%) patients and was strongly associated with higher rates of relapse (68% vs. 13%; hazard ratio [HR] =8.8; 95% confidence interval [CI]: 3.2-24.5; P<0.001) and decreased survival (32% vs. 82%; HR=5.6; 95% CI: 2.3-13.8; P<0.001) at 5 years. DS MRD strongly outperformed multiparametric flow cytometry MRD, which was observed in ten (16%) patients and marginally associated with higher rates of relapse (50% vs. 30%; HR=2.4; 95% CI: 0.9-6.7; P=0.087) and decreased survival (40% vs. 68%; HR=2.5; 95% CI: 1.0-6.3; P=0.059) at 5 years. Furthermore, the prognostic significance of DS MRD status at the time of remission for subsequent relapse was similar on both randomized arms of the trial. These findings suggest that next-generation sequencing-based AML MRD testing is a powerful tool that could be developed for use in patient management and for early anti-leukemic treatment assessment in clinical trials.

The New NCI Precision Medicine Trials.

Basket, umbrella, and platform trial designs (master protocols) have emerged over the last decade to study precision medicine approaches in oncology. First-generation trials like NCI-MATCH (Molecular Analysis for Therapy Choice) have proven the principle that studying targeted therapies on a large scale is feasible both from the laboratory and clinical perspectives. However, single-agent targeted therapies have shown limited ability to control metastatic disease, despite careful matching of drug to target. As such, newer approaches employing combinations of targeted therapy, or targeted therapy with standard therapies, need to be considered. The NCI has recently embarked on three second-generation precision medicine trials to address this need: ComboMATCH, iMATCH, and myeloMATCH. The design of these trials and necessary infrastructure are discussed in the following perspective.

Prognostic impact of secondary versus de novo ontogeny in acute myeloid leukemia is accounted for by the European LeukemiaNet 2022 risk classification.

Secondary AML (sAML), defined by either history of antecedent hematologic disease (AHD) or prior genotoxic therapy (tAML), is classically regarded as having worse prognosis than de novo disease (dnAML). Clinicians may infer a new AML diagnosis is secondary based on a history of antecedent blood count (ABC) abnormalities in the absence of known prior AHD, but whether abnormal ABCs are associated with worse outcomes is unclear. Secondary-type mutations have recently been incorporated into the European LeukemiaNet (ELN) 2022 guidelines as adverse-risk features, raising the question of whether clinical descriptors of ontogeny (i.e., de novo or secondary) are prognostically significant when accounting for genetic risk by ELN 2022. In a large multicenter cohort of patients (n = 734), we found that abnormal ABCs are not independently prognostic after adjusting for genetic characteristics in dnAML patients. Furthermore, history of AHD and tAML do not confer increased risk of death compared to dnAML on multivariate analysis, suggesting the prognostic impact of ontogeny is accounted for by disease genetics as stratified by ELN 2022 risk and TP53 mutation status. These findings emphasize the importance that disease genetics should play in risk stratification and clinical trial eligibility in AML.