An Analysis of the Worldwide Utilization of Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) has an aggressive course and a historically dismal prognosis. For many patients, hematopoietic stem cell transplantation (HSCT) represents the best option for cure, but access, utilization, and health inequities on a global scale remain poorly elucidated. We wanted to describe patterns of global HSCT use in AML for a better understanding of global access, practices, and unmet needs internationally. Estimates of AML incident cases in 2016 were obtained from the Global Burden of Disease 2019 study. HSCT activities were collected from 2009 to 2016 by the Worldwide Network for Blood and Marrow Transplantation through its member organizations. The primary endpoint was global and regional use (number of HSCT) and utilization of HSCT (number of HSCT/number of incident cases) for AML. Secondary outcomes included trends from 2009 to 2016 in donor type, stem cell source, and remission status at time of HSCT. Global AML incidence has steadily increased, from 102,000 (95% uncertainty interval: 90,200-108,000) in 2009 to 118,000 (104,000-126,000) in 2016 (16.2%). Over the same period, a 54.9% increase from 9659 to 14,965 HSCT/yr was observed globally, driven by an increase in allogeneic (64.9%) with a reduction in autologous (-34.9%) HSCT. Although the highest numbers of HSCT continue to be performed in high-resource regions, the largest increases were seen in resource-constrained regions (94.6% in Africa/East Mediterranean Region [AFR/EMR]; 34.7% in America-Nord Region [AMR-N]). HSCT utilization was skewed toward high-resource regions (in 2016: AMR-N 18.4%, Europe [EUR] 17.9%, South-East Asia/Western Pacific Region [SEAR/WPR] 11.7%, America-South Region [AMR-S] 4.5%, and AFR/EMR 2.8%). For patients <70 years of age, this difference in utilization was widened; AMR-N had the highest allogeneic utilization rate, increasing from 2009 to 2016 (30.6% to 39.9%) with continued low utilization observed in AFR/EMR (1.7% to 2.9%) and AMR-S (3.5% to 5.4%). Across all regions, total HSCT for AML in first complete remission (CR1) increased (from 44.1% to 59.0%). Patterns of donor stem cell source from related versus unrelated donors varied widely by geographic region. SEAR/WPR had a 130.2% increase in related donors from 2009 to 2016, and >95% HSCT donors in AFR/EMR were related; in comparison, AMR-N and EUR have a predilection for unrelated HSCT. Globally, the allogeneic HSCT stem cell source was predominantly peripheral blood (69.7% of total HSCT in 2009 increased to 78.6% in 2016). Autologous HSCT decreased in all regions from 2009 to 2016 except in SEAR/WPR (18.9%). HSCT remains a central curative treatment modality in AML. Allogeneic HSCT for AML is rising globally, but there are marked variations in regional utilization and practices, including types of graft source. Resource-constrained regions have the largest growth in HSCT use, but utilization rates remain low, with a predilection for familial-related donor sources and are typically offered in CR1. Further studies are necessary to elucidate the reasons, including economic factors, to understand and address these health inequalities and improve discrepancies in use of HSCT as a potentially curative treatment globally.

New Immuno-oncology Targets and Resistance Mechanisms.

OPINION STATEMENT: Immune checkpoint inhibition (ICI) has revolutionized the field of non-small cell lung cancer (NSCLC); currently, most patients with advanced disease receive upfront ICI either alone or in combination with chemotherapy. These advances have recently extended into early-stage NSCLC, with ICI incorporation into neoadjuvant and adjuvant treatment regimens. However, despite these successes, immunotherapy (IO) resistance remains a fundamental challenge in NSCLC, introducing a central quandary of how to precisely select the appropriate IO therapy or IO combination therapy for each individual patient. To address this vital need in the field, there has been an explosion of research in immuno-oncology to identify mechanisms of resistance, ranging from genomic alterations in the tumor to immunosuppressive conditions in the tumor microenvironment (TME). There remain many questions about how this complex interplay between the tumor and the immune microenvironment translates into clinical phenotypes of primary and acquired resistance. In NSCLC, a number of novel therapeutics are being developed to prevent and overcome resistance to ICI. Particular promise has been shown with therapeutics targeting novel T cell immune checkpoint inhibitors and targeting innate immune cells in the TME, chief among these cells are natural killer cells, neutrophils, and macrophages. Further research into tissue-based and non-invasive biomarkers that can be prospectively integrated into therapeutic trial design will be critical to advance the field's understanding of individual resistance patterns and enable the ultimate goal of precision immuno-oncology.

Germline variants discovered in lymphoma patients undergoing tumor profiling: a case series.

Clinical tumor sequencing protocols often depend on obtaining germline DNA from patients to aid in the identification of de novo variants in the tumor, and therefore come with the possibility for the incidental discovery of germline variants. Ninety-one adult patients with lymphoma were consented and enrolled in MIONCOSEQ, an IRB-approved tumor profiling protocol that utilizes an exome sequencing platform. Charts were retrospectively reviewed for germline variants from sequencing results, personal and/or family history of cancer and genetic counseling referral. After review of the 91 lymphoma cases, seven (8%) cases revealed germline variants. Only one of these, CHEK2 p.I157T, has been previously recovered as a germline variant in lymphoma. Two of the seven patients received genetic counseling, two died before genetic counseling could be arranged and three did not follow-up with a genetics provider. None of the patients had a personal or family history that would have otherwise suggested an indication for cancer genetics referral, especially notable as lymphoma is not traditionally associated with inherited cancer syndromes. Importantly, as only two of seven patients had appropriate genetic counseling for their variant, timely genetic counseling should be a critical part of all tumor profiling platforms that use non-tumor DNA.

Clinical application of next generation sequencing in lymphoma.

Successful treatment of relapsed/refractory and rare subtypes of lymphomas remains a therapeutic challenge. Though the use of tumor profiling is increasing, little is described about how providers ultimately utilize this information in clinical decision-making. We reviewed 92 adult lymphoma patients who underwent an IRB-approved tumor sequencing protocol at the University of Michigan, MI-ONCOSEQ. Of this cohort, 60 had a targeted treatment suggested by their test results, and 11 patients ultimately underwent the MI-ONCOSEQ recommended therapy. One obtained complete response based on precision treatment recommendations. The two main barriers for targeted treatment utilization included inopportune timing (the patient either was sequenced too early or too late in their disease course) and clinical trial availability. While this study demonstrates the success of sequencing lymphomas for the identification of novel therapies, it also underlines the clinical challenges, namely the optimal timing and availability of trials, inherent in the successful application of this technology.