Facts and Hopes in Neoadjuvant Immunotherapy: Current Approvals and Emerging Evidence.

In 2021 and 2022, two immune checkpoint inhibitors received FDA approval in the neoadjuvant setting for the treatment of early-stage triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). Several more studies have since indicated the benefits, and challenges, of administering neoadjuvant immunotherapy prior to definitive surgery in the gastrointestinal, head and neck, and cutaneous realms. In addition, numerous ongoing phase II and phase III trials are investigating outcomes of neoadjuvant immune treatment in early-stage disease. As such, it is anticipated that more immune checkpoint inhibitors will receive approval for various neoadjuvant indications in the next several years. Medical oncologists, surgeons, and other providers in a multidisciplinary cancer care team will be presented with alternate treatment paradigms and clinical decisions regarding upfront surgery versus neoadjuvant treatment. Here, we describe the current evidence supporting use of immune checkpoint inhibitors for neoadjuvant treatment, ongoing studies, and clinical considerations of this treatment approach.

IDH2-mutated near ETP-ALL with aggressive leukemia cutis and brisk response to venetoclax and decitabine.

Near early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a rare hematologic malignancy, for which second line therapeutic options are limited. T-cell leukemias are also rarely associated with leukemia cutis, which is more often seen in leukemias of myeloid origin. We present the case of an adult male diagnosed with near ETP-ALL, with IDH2 and DNMT3A mutations, suggestive of a myeloid origin, and leukemia cutis. After the patient progressed on hyper-CVAD and nelarabine, we treated him with the BCL-2 inhibitor venetoclax and the hypomethylating agent decitabine. The regimen induced a rapid bone marrow response and resolution of the leukemia cutis.

PD-1 inhibition therapy for advanced cutaneous squamous cell carcinoma: a retrospective analysis from the University of Southern California.

PURPOSE: Approximately 5% of patients with cutaneous squamous cell carcinoma (CSCC) may develop recurrent or metastatic disease. The management of such cases is challenging and requires multi-disciplinary care. Immunotherapy using PD-1 inhibition was approved to treat unresectable or metastatic CSCC in 2018. Given limited data regarding clinical outcomes outside of published trials, we describe our experience using this therapy. METHODS: We retrospectively reviewed all patients treated with PD-1 inhibition as therapy for locally advanced, regionally metastatic or distant metastatic CSCC at the University of Southern California. Clinicopathological characteristics, treatment data using PD-1 inhibitors, and outcomes were assessed. RESULTS: Among 26 patients treated with PD-1 inhibition, the objective response rate was 42.3%, with 19.2% of patients having partial response and 23.1% having complete response to therapy. The median progression-free survival was 5.4 months. Median tumor mutational burden (TMB) was higher among responders compared to non-responders (60 vs. 9 Mut/Mb, p = 0.04). Primary CSCC tumor location on the head/neck was also associated with response to PD-1 inhibition (p = 0.04). Two patients with mutations affecting mismatch repair deficiency were noted to have complete response to treatment. No other variables were associated with treatment outcomes. CONCLUSION: PD-1 inhibition produces durable responses among patients with advanced or metastatic CSCC. PD-1 inhibition therapy is well tolerated, but patients should be monitored closely for immune-related adverse events, particularly frail or immune-suppressed patients. Further investigation of potential biomarkers to help identify patients who will derive the most benefit from this therapeutic option is needed.

Quantified Kinematics to Evaluate Patient Chemotherapy Risks in Clinic.

PURPOSE: Performance status (PS) is a key factor in oncologic decision making, but conventional scales used to measure PS vary among observers. Consumer-grade biometric sensors have previously been identified as objective alternatives to the assessment of PS. Here, we investigate how one such biometric sensor can be used during a clinic visit to identify patients who are at risk for complications, particularly unexpected hospitalizations that may delay treatment or result in low physical activity. We aim to provide a novel and objective means of predicting tolerability to chemotherapy. METHODS: Thirty-eight patients across three centers in the United States who were diagnosed with a solid tumor with plans for treatment with two cycles of highly emetogenic chemotherapy were included in this single-arm, observational prospective study. A noninvasive motion-capture system quantified patient movement from chair to table and during the get-up-and-walk test. Activity levels were recorded using a wearable sensor over a 2-month period. Changes in kinematics from two motion-capture data points pre- and post-treatment were tested for correlation with unexpected hospitalizations and physical activity levels as measured by a wearable activity sensor. RESULTS: Among 38 patients (mean age, 48.3 years; 53% female), kinematic features from chair to table were the best predictors for unexpected health care encounters (area under the curve, 0.775 ± 0.029) and physical activity (area under the curve, 0.830 ± 0.080). Chair-to-table acceleration of the nonpivoting knee (t = 3.39; P = .002) was most correlated with unexpected health care encounters. Get-up-and-walk kinematics were most correlated with physical activity, particularly the right knee acceleration (t = -2.95; P = .006) and left arm angular velocity (t = -2.4; P = .025). CONCLUSION: Chair-to-table kinematics are good predictors of unexpected hospitalizations, whereas the get-up-and-walk kinematics are good predictors of low physical activity.

Bone Marrow Features in Patients With Acute Myeloid Leukemia Treated With Novel Targeted Isocitrate Dehydrogenase 1/2 Inhibitors.

This case report aimed to review the bone marrow features of patients with acute myeloid leukemia (AML) treated with isocitrate dehydrogenase 1/2 (IDH1/2) inhibitors. Five patients with AML treated with an IDH1/2 inhibitor were identified and retrospectively reviewed. We described the morphologic and immunophenotypic findings in the bone marrow, as well as ancillary study results. Two patients showed a hypercellular bone marrow with morphologic and immunophenotypic differentiation of blasts. The bone marrow of one patient displayed a hypoplastic phase. Four of the five patients demonstrated unusual morphologic and/or immunophenotypic populations, including basophilia with mild alterations on the myeloid blasts, a small subset of blasts with expression of T-cell markers not seen in the original immunophenotype, a cluster of differentiation 117 (CD117)-positive progenitor population with erythroid differentiation, and another population reminiscent of erythroid differentiation. Unusual morphologic and immunophenotypic populations can be seen in the bone marrows of patients treated with IDH1/2 inhibitors in the presence or absence of definite residual disease. The significance of these populations is uncertain, but further studies could be helpful to understand the meaning of these findings.

IL-32 is a molecular marker of a host defense network in human tuberculosis.

Tuberculosis is a leading cause of infectious disease-related death worldwide; however, only 10% of people infected with Mycobacterium tuberculosis develop disease. Factors that contribute to protection could prove to be promising targets for M. tuberculosis therapies. Analysis of peripheral blood gene expression profiles of active tuberculosis patients has identified correlates of risk for disease or pathogenesis. We sought to identify potential human candidate markers of host defense by studying gene expression profiles of macrophages, cells that, upon infection by M. tuberculosis, can mount an antimicrobial response. Weighted gene coexpression network analysis revealed an association between the cytokine interleukin-32 (IL-32) and the vitamin D antimicrobial pathway in a network of interferon-γ- and IL-15-induced "defense response" genes. IL-32 induced the vitamin D-dependent antimicrobial peptides cathelicidin and DEFB4 and to generate antimicrobial activity in vitro, dependent on the presence of adequate 25-hydroxyvitamin D. In addition, the IL-15-induced defense response macrophage gene network was integrated with ranked pairwise comparisons of gene expression from five different clinical data sets of latent compared with active tuberculosis or healthy controls and a coexpression network derived from gene expression in patients with tuberculosis undergoing chemotherapy. Together, these analyses identified eight common genes, including IL-32, as molecular markers of latent tuberculosis and the IL-15-induced gene network. As maintaining M. tuberculosis in a latent state and preventing transition to active disease may represent a form of host resistance, these results identify IL-32 as one functional marker and potential correlate of protection against active tuberculosis.