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Tumor mutational burden (TMB) is being explored as a predictive biomarker for cancer immunotherapy outcomes in non-small cell lung cancer. BFAST (NCT03178552)—an open-label, global, multicohort trial—evaluated the safety and efficacy of first-line targeted therapies or immunotherapy in patients with unresectable Stage IIIB or IV advanced or metastatic non-small cell lung cancer who were selected for biomarker status using blood-based targeted next-generation sequencing. In the Phase 3 cohort C evaluating blood-based (b)TMB as a biomarker of atezolizumab efficacy, patients with bTMB of ≥10 ( N  = 471) were randomized 1:1 to receive atezolizumab or platinum-based chemotherapy per local standard of care. Cohort C did not meet its primary endpoint of investigator-assessed progression-free survival in the population with bTMB of ≥16 (hazard ratio, 0.77; 95% confidence interval: 0.59, 1.00; P  = 0.053). Adverse events leading to treatment withdrawal occurred in 10% of patients in the atezolizumab arm and 20% in the chemotherapy arm. Adverse events of special interest occurred in 42% of patients in the atezolizumab arm and 26% in the chemotherapy arm. A prespecified exploratory analysis compared the bTMB clinical trial assay with the FoundationOne Liquid Companion Diagnostic assay and showed high concordance between assays. Additional exploration of bTMB to identify optimal cutoffs, confounding factors, assay improvements or cooperative biomarkers is warranted. In a phase 3 trial, selection of non-small cell lung cancer patients based on high blood-based tumor mutation burden did not improve clinical response to the checkpoint blockade inhibitor atezolizumab, as compared with standard of care platinum-based chemotherapy.

Although comprehensive biomarker testing is recommended for all patients with advanced/metastatic non-small cell lung cancer (NSCLC) before initiation of first-line treatment, tissue availability can limit testing. Genomic testing in liquid biopsies can be utilized to overcome the inherent limitations of tissue sampling and identify the most appropriate biomarker-informed treatment option for patients. The Blood First Assay Screening Trial is a global, open-label, multicohort trial that evaluates the efficacy and safety of multiple therapies in patients with advanced/metastatic NSCLC and targetable alterations identified by liquid biopsy. We present data from Cohort D ( ROS1 -positive). Patients ≥18 years of age with stage IIIB/IV, ROS1 -positive NSCLC detected by liquid biopsies received entrectinib 600 mg daily. At data cutoff (November 2021), 55 patients were enrolled and 54 had measurable disease. Cohort D met its primary endpoint: the confirmed objective response rate (ORR) by investigator was 81.5%, which was consistent with the ORR from the integrated analysis of entrectinib (investigator-assessed ORR, 73.4%; data cutoff May 2019, ≥12 months of follow-up). The safety profile of entrectinib was consistent with previous reports. These results demonstrate consistency with those from the integrated analysis of entrectinib in patients with ROS1 -positive NSCLC identified by tissue-based testing, and support the clinical value of liquid biopsies to inform clinical decision-making. The integration of liquid biopsies into clinical practice provides patients with a less invasive diagnostic method than tissue-based testing and has faster turnaround times that may expedite the reaching of clinical decisions in the advanced/metastatic NSCLC setting. ClinicalTrials.gov registration: NCT03178552 . Results from this single-arm cohort of the BFAST trial showed that the clinical efficacy of entrectinib in patients with ROS1 -positive NSCLC, selected using liquid biopsies, is consistent with that seen in previous reports where patients were selected using tissue-based testing methods.

Introduction:This paper presents results from Cohort B (rearranged during transfection [RET], fusion-positive) of the Blood First Assay Screening Trial in patients with advanced non-small cell lung cancer (NSCLC) screened for genetic alterations using blood-based next-generation sequencing.Material and methods:Adults with advanced RET fusion-positive NSCLC received alectinib 900 mg twice daily (BID) in Phase I. Enrolment closed prematurely with Phase II uninitiated.Results:Among eight treated patients, confirmed best overall responses in evaluable patients were stable disease (4/5) and progressive disease (1/5). One dose-limiting toxicity (death, unknown cause) was considered by the investigator to be related to treatment and underlying disease. Serious adverse events (SAEs) occurred in five patients, and SAEs that may be related to treatment occurred in two patients.Conclusions:Alectinib showed limited activity in advanced RET fusion-positive NSCLC, and further investigation was not conducted due to the development of selective RET inhibitors pralsetinib and selpercatinib. No new safety signals were observed, and the safety profile of alectinib was in line with previous reports at the 600 mg BID dose.

Acute lymphoblastic leukemia (ALL) in adults is a very challenging disease. Adults tend to present with higher-risk features and are unable to tolerate chemotherapy regimens as intense as those administered to children. The overall treatment plan for adult ALL is modeled after the pediatric paradigm and includes multi-agent chemotherapy in the forms of induction, consolidation, maintenance, and central nervous system prophylaxis. Most patients will go into complete remission but often relapse; relapse is typically indicative of chemotherapy-refractory disease. Salvage therapy generally consists of cytotoxic agents from drug classes the patient has had limited or no exposure to. The results of conventional chemotherapy for relapsed ALL are unacceptable. The goal of therapy in these patients is to achieve a second remission followed by allogeneic stem-cell transplantation. Monoclonal antibodies directed at cell-surface antigens offer a targeted approach to treating leukemia and other cancers. Anti-CD20 monoclonal antibodies have been shown to improve survival when used in the frontline setting. Novel, highly active antibodies directed at CD19 and CD22 are being investigated in the relapsed and refractory settings. These agents will likely be explored as components of first-line therapy as clinical development continues.

Acute myeloid leukemia is most often diagnosed in patients older than 60 years of age. Overall, these patients have a poor prognosis, partly because they are typically unable to tolerate intensive chemotherapy regimens traditionally offered to younger individuals. Furthermore, responses attained in these older patients are not durable, with most experiencing relapse within 1-2 years. Therefore, new strategies are needed to improve the outcome of older patients with acute myeloid leukemia. Tosedostat is an orally available aminopeptidase inhibitor shown to have activity in leukemia. This commentary discusses the background and results of an ongoing Phase II evaluation of tosedostat in elderly patients with relapsed or refractory acute myeloid leukemia. The data available to date is analyzed and future perspectives regarding the development of this agent is discussed.

To the Editor: We recently admitted a patient to our intensive care unit with methemoglobinemia and severe hemolytic anemia after he received a single dose of rasburicase. The patient was a 55-year-old black man with chronic lymphocytic leukemia in whom the tumor lysis syndrome developed after rituximab and bendamustine treatment despite saline and allopurinol prophylaxis. Within 6 hours after receiving rasburicase at a dose of 0.2 mg per kilogram of body weight, he became hypoxic, with a methemoglobin concentration of 12.2% (Table 1). He subsequently had acute intravascular hemolysis, with the hemoglobin level decreasing from 13.1 to 4.5 mg per . . .

To the Editor: Löwenberg et al. (March 17 issue) 1 report that induction therapy with high-dose cytarabine results in excessive toxic effects without therapeutic benefit. These results should be interpreted with caution. Most physicians believe that four courses of consolidation therapy with high-dose cytarabine is optimal for acute myeloid leukemia (AML). 2 However, only one consolidation course of chemotherapy was included in this study. Outcomes of induction therapy should be evaluated in the context of consolidation therapy. The efficacy of induction therapy with high-dose cytarabine might be overestimated if patients were treated with insufficient consolidation therapy. We would be grateful if the . . .

To the Editor: In their randomized trial comparing rabbit antithymocyte globulin (ATG) with horse ATG, Scheinberg et al. (Aug. 4 issue) 1 report the superiority of horse ATG in terms of response and survival. We previously conducted a phase 2 study of rabbit ATG plus cyclosporine as first-line therapy in patients with severe aplastic anemia. 2 The perception of our transplantation team was that rabbit ATG led to a decreased risk of infusion reactions, an impression that was largely confirmed in our study. However, Scheinberg et al. report very little infusion-related toxicity with horse ATG, which has not been our experience. Several . . .