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Review Hematologic Malignancies Updates in Adult Acute Lymphoblastic Leukemia—Current Status of Antigen- targeted Treatments and Immunotherapy Xavier Thomas Hospices Civils de Lyon, Hematology Department, Lyon-Sud Hospital, Pierre Bénite, France T he outcomes of adult acute lymphoblastic leukemia (ALL) remain inferior to those observed in pediatric populations. Targeted therapy with monoclonal antibodies and immunotherapy represents the most promising new way to fight ALL without significant additive toxicity. Since the use of rituximab in combination chemoimmunotherapy for treatment of B cell lineage ALL, a number of other monoclonal antibodies are under investigation for the treatment of this disease. Deep molecular remissions with anti-CD19- and anti-CD22-directed therapy have been shown in relapsed/refractory (R/R) disease, allowing for the opportunity to transplant. Blinatumomab is the first antigen-directed treatment approved for use in R/R ALL. Adoptive cellular therapy with human T cells genetically engineered to express CD19 redirected chimeric antigen receptors (CARs) has also recently demonstrated efficacy in patients with B cell lineage ALL. In this article, we review the therapeutic implications, primary results, and current status of antigen-targeted treatments and immunotherapy in adult B cell lineage ALL. Keywords Acute lymphoblastic leukemia, monoclonal antibodies, prognosis, blinatumomab, chimeric antigen receptor (CAR) T cells, inotuzumab ozogamicin, rituximab, epratuzumab Disclosure: Xavier Thomas has nothing to declare in relation to this article. No funding was received in the publication of this article. Compliance with Ethics: This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: July 3, 2017 Accepted: September 7, 2017 Citation: Oncology & Hematology Review, 2017;13(2):92–9 Corresponding Author: Xavier Thomas, Hospices Civils de Lyon, Hematology Department, Lyon-Sud Hospital, Bât. 1G, 165 chemin du Grand Revoyet, 69495 Pierre Bénite, France. E: Acute lymphoblastic leukemia (ALL) is of B cell precursor lineage (BCP-ALL) or, less commonly, T cell precursor lineage (T-ALL), which comprise multiple subtypes defined by structural chromosomal alterations that are initiating lesions, with secondary somatic DNA copy number alterations and sequence mutations that contribute to leukemogenesis. Survival rates for ALL have steadily improved in children, such that more than 85% of children can expect to be cured with current cytotoxic therapies. Unfortunately, the same increases have not been demonstrated in adult patients. Despite high rates of complete remission (CR) (80–90%), the cure rates are only 40–50%, because of relapses. 1 One approach to improving outcomes in adult ALL involves intensification of existing chemotherapy combinations or the addition of chemotherapeutic agents. 2 The results of allogeneic hematopoietic stem cell transplantation (HSCT) for adults with ALL in first-line therapy have also improved significantly over time, 3 but it is unlikely that the sole intensification of regimens can continue to improve prognosis substantially. Intensifying chemotherapy may reduce the incidence of resistance, but at the cost of increased toxicities. Outcomes remain particularly poor in relapsed/refractory (R/R) patients. Response rates after salvage treatment range from 18–45% and median survival times from 2–8 months, with less than 10% survival after 5 years. 4–9 In this setting, allogeneic HSCT is the only curative option, but this can only be achieved in a subgroup of patients. 4,5,8 A retrospective analysis of 1,706 adult patients with Philadelphia chromosome-negative R/R BCP-ALL from 11 study groups and large centers was recently conducted in order to provide detailed reference outcomes for this patient population. 10 The overall CR rate after first salvage was 40%, ranging from 35–41% across disease status categories (primary refractory, relapsed with or without prior transplant), and was lower after second (21%) or further (11%) salvage. The 3-year survival rates range from 2–5%. Thus, new treatment options are needed for this patient population. This, combined with a better understanding of disease pathogenesis has led to major advances in drug development and reassessment of risk stratification. 11 The landscape of treatment is currently rapidly changing, ranging from the application of precision genomic medicine in subsets of ALL to the delivery of novel immunotherapeutic approaches. Emerging therapies in the frontline and salvage settings offer the promise of improved response rates and opportunities for long-term survival, with the potential for less toxicity than chemotherapy. 12–14 In this review, we will discuss the use of monoclonal antibodies and novel immunotherapeutic approaches in ALL, including bispecific T cell-engaging molecules and chimeric antigen receptor (CAR) T cells. 92 TOUCH ME D ICA L ME D IA