VOLUME 36 • NUMBER 35 • DECEMBER 10, 2018 JOURNAL OF CLINICAL ONCOLOGY REVIEW ARTICLE New Approaches to the Management of Adult Acute Lymphoblastic Leukemia Renato Bassan, Jean-Pierre Bourquin, Daniel J. DeAngelo, and Sabina Chiaretti Author affiliations and support information (if applicable) appear at the end of this ABSTRACT article. Traditional treatment regimens for adult acute lymphoblastic leukemia, including allogeneic Published at jco.org on September 21, fi 2018. hematopoietic cell transplantation, result in an overall survival of approximately 40%, a gure hardly comparable with the extraordinary 80% to 90% cure rate currently reported in children. Corresponding author: Renato Bassan, MD, Hematology Unit, Ospedale When translated to the adult setting, modern pediatric-type regimens improve the survival to dell’Angelo, Via Paccagnella 11, 30174 approximately 60% in young adults. The addition of tyrosine kinase inhibitors for patients with Mestre, Venezia, Italy; e-mail: Renato. Philadelphia chromosome–positive disease and the measurement of minimal residual disease to [email protected]. guide risk stratification and postremission approaches has led to additional improvements in © 2018 by American Society of Clinical outcomes. Relapsed disease and treatment toxicity—sparing no patient but representing a major Oncology concern especially in the elderly—are the most critical current issues awaiting further therapeutic 0732-183X/18/3635w-3504w/$20.00 advancement. Recently, there has been considerable progress in understanding the disease biology, specifically the Philadelphia-like signature, as well as other high-risk subgroups. In ad- dition, there are several new agents that will undoubtedly contribute to additional improvement in the current outcomes. The most promising agents are monoclonal antibodies, immunomodula- tors, and chimeric antigen receptor T cells, and, to a lesser extent, several new drugs targeting key molecular pathways involved in leukemic cell growth and proliferation. This review examines the evidence supporting the increasing role of the new therapeutic tools and treatment options in different disease subgroups, including frontline and relapsed or refractory disease. It is now possible to define the best individual approach on the basis of the emerging concepts of precision medicine. J Clin Oncol 36:3504-3519. © 2018 by American Society of Clinical Oncology INTRODUCTION RECENT ADVANCES USING PEDIATRIC REGIMENS IN ADULTS In Western countries, new cases of adult acute lymphoblastic leukemia (ALL) occur at an an- The results in adult ALL, unfortunately, have nual rate of approximately one per 100,000, with not kept pace with those in pediatric ALL, with 9 a bimodal distribution decreasing at age 45 to 54 OS rates , 45% despite the addition of CNS years and increasing again in people older than prophylaxis, late intensification with prolonged 55 years, totaling approximately 2,300 new cases maintenance chemotherapy, and an extensive use per year for patients older than 15 years (n = of HCT in high-risk (HR) subsets. Currently, 1,750 between ages 15 and 55 years) in the pediatric-inspired regimens are being adminis- United States.1,2 Over the past decade, we have tered in young adult patients, leading to im- witnessed an incredible therapeutic improve- provements in event-free survival (EFS) and OS ment. Currently, pediatric patients have an es- rates as compared with historical controls.10-13 timated 5-year overall survival (OS) approaching This approach, initially reserved for adolescents 90%.3-5 Modern pediatric programs thrive on an and young adults (AYA; , 40 years old)10,14,15 and intensified use of corticosteroids (mainly dexa- later applied to patients up to 50 to 60 years of 11,12,16 ASSOCIATED CONTENT methasone), antimetabolites (especially metho- age, has increased the 5-year OS rate trexate and 6-mercaptopurine) and L-asparaginase/ to $ 50%, and up to 70% to 80% in favorable Appendix DOI: https://doi.org/10.1200/JCO. pegylated-asparaginase, and rely on minimal re- subsets (ie, AYA, standard risk, MRD negative; 17 2017.77.3648 sidual disease (MRD) analysis for additional dose Appendix Table A1, online only), but not in fi DOI: https://doi.org/10.1200/JCO.2017. intensi cation or allogeneic hematopoietic cell older patients, whose survival decreases pro- 6-8 2-4 77.3648 transplantation (HCT). gressively to , 20%. Finally, allogeneic HCT is 3504 © 2018 by American Society of Clinical Oncology Downloaded from ascopubs.org by Journals Press Access on December 10, 2018 from 162.234.150.177 Copyright © 2018 American Society of Clinical Oncology. All rights reserved. jco.org Table 1. Summary of Clinical Evidence of Antibody Therapy in Acute Lymphoblastic Leukemia in Selected Clinical Trials Clinical Trials Target Antigen Agents Class Patients No. Regimen Study Results 2 CD19 Blinatumomab BiTE (CD19 3 CD3) MRD positive (. 10 4) 21 Blinatumomab IVCI 3 Phase II: 61% RFS rate at antibody 4 weeks median follow-up of 33 months35 2 MRD positive (. 10 3) 116 Blinatumomab IVCI 3 Phase II: complete MRD 4 weeks (HCT after response, 80% (78% at response) cycle 1); median OS, 38.9 months; and RFS, 23.6 months in MRD responders (P 5 .002 v nonresponders)36 Relapsed/refractory 36 Blinatumomab IVCI 3 Phase I/II: 69% CR/CRi with 4 weeks 88% MRD negative37 189 Blinatumomab IVCI 3 Phase II: 43% CR/CRi with 4 weeks 82% MRD negative; median OS of responders, 6.1 months v nonresponders, 3.5 months38 Relapsed/ refractory (Ph2) 376 Blinatumomab IVCI 3 Phase III v SOC: Improved CR/ New Treatments for Adult ALL 4 weeks CRi 44 v 25%; MRD negative rate 76% v 48%; OS 7.7 v 4.0 months39 (P =.01) Relapsed/ refractory (Ph+) 45 Blinatumomab IVCI 3 36% CR/CRi (40% with 4 weeks T315I), with 88% MRD negative; median RFS, 6.7 months40 SGN19a (denintuzumab mafodotin) Immunoconjugate Relapsed/ refractory 59 Weekly (days 1 and 8) Phase I: 19% CR/CRi weekly (monomethyl or day 1 every arm and 35% in the every- auristatin F) 3 weeks 3-week arm41 SAR3419 (coltuximab ravtansine) Immunconjugate 36 Monotherapy Study discontinued because (maytansine weekly of toxicity; overall response DM4) (escalating dose rate, 25.5%42 and selected dose in expansion cohort) CD19/22 Combotox Immunotoxin (ricin Relapsed/refractory 17 Maximum tolerated Phase I: one patient achieved A chain) dose, 7 mg/m2 partial remission43 © 2018 by American Society of Clinical Oncology CD20 Rituximab Naked antibody Newly diagnosed 282 Rituximab + hyper- Phase II: Improved CMR, CVAD RFS, and OS in patients , 60 years old44 263 Rituximab + Phase II: improved rate of chemotherapy negative MRD, CRD, and 3-year OS45 209 Rituximab + Phase III: improved rate of chemotherapy 2-year EFS (65% v 52%, P 5 .04)13 Ofatumumab Naked antibody Newly diagnosed 55 Ofatumumab + Phase II: CR 98% and MRD hyper-CVAD negativity 93%; 3-year CRD rate, 78%; and OS, 68%46 (continued on following page) 3505 Downloaded from ascopubs.org by Journals Press Access on December 10, 2018 from 162.234.150.177 Copyright © 2018 American Society of Clinical Oncology. All rights reserved. 3506 Table 1. Summary of Clinical Evidence of Antibody Therapy in Acute Lymphoblastic Leukemia in Selected Clinical Trials (continued) © 2018 by American Society of Clinical Oncology Clinical Trials Target Antigen Agents Class Patients No. Regimen Study Results CD22 Epratuzumab Naked antibody Relapsed/refractory 15 Epratuzumab + Phase I: 60% CR, 40% MRD chemotherapy negative47 Relapsed (first) 114 Epratuzumab + Phase II: 65% and 66% CR chemotherapy (two rates, 42% MRD negative schedules of rate (higher than historical epratuzumab) controls)48 Relapsed/refractory 32 Epratuzumab + Phase II: 52% CR/CRi rate; clofarabine + median OS, 5 months49 cytarabine 20 Epratuzumab + hyper- Phase II:CR/CRi, 33%; CVAD median OS, 3 months50 Radioconjugate Relapsed/refractory 17 90Y-Epratuzumab Phase I: well tolerated, with (90Y-labeled) days 1 and 8, dose three CRs; recommended level 1-4 dose for phase II study (2 3 10.0 mCi/m2)51 Inotuzumab Immunconjugate Relapsed/refractory 90 Inotuzumab every 3 Phase I/II: CR/CRi rate 58%, (calicheamicin) to 4 weeks (n = 49 and 72% MRD negative patients) or weekly rate52 (n = 41 patients) 72 Inotuzumab weekly Phase I/II; multicenter trial with CR/CRi rate of 68% and 84% MRD negative; median OS, 7.4 months53 Bassan et al 326 Inotuzumab weekly Phase III v SOC: Improved CR rate 81% v 33%; MRD negative rate 78% v 28%; OS 7.7 v 6.7 months (P 5 .04)54,99 59 Inotuzumab weekly + Phase II: CR/CRi rate of 78%, mini–hyper-CVD with 82% MRD negative; median RFS and OS, 8 and 11 months, respectively; 1-year RFS in first salvage, 77%55 Newly diagnosed, older age (. 48 Inotuzumab weekly + Phase II: 98% CR/CRi rate 60 years) mini–hyper-CVD with 76% MRD negative; 2-year PFS, 52%; OS, 66% (v historical OS 36% (P,.05)56,108 BL22 and moxetumomab Immunotoxin Relapsed/refractory (children) 47 BL22 and Phase I: 32% objective response pasudotox (Pseudomonas moxetumomab with 23% CR (n = 11, with 5 exotoxin) pasudotox every MRD negative)57 other day 3 6 Relapsed/refractory 16 BL22 and Phase I: overall response rate moxetumomab 13%, 2 CR/CRi; safe at pasudotox every higher dose level58 other day 3 6 CD52 Alemtuzumab Naked antibody Newly diagnosed 24 Postremission in Phase I: median OS, fourth treatment 55 months; 1-log MRD J module reduction; immune OURNAL OF suppression/toxicity led to study discontinuation59 fi C Abbreviations: BiTE, bispeci c T-cell engaging; CMR, complete molecular remission; CR, complete remission; CRD, complete remission duration; CRi, complete remission with incomplete neutrophil and/or platelet LINICAL count recovery/; HCT, hematopoietic cell transplantation; hyper-CVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; hyper-CVD, cyclophosphamide, vincristine, dexamethasone; ICVI, intravenous continuous infusion; MRD, minimal residual disease; OS, overall survival; PFS, progression free-survival; Ph, Philadelphia chromosome; RFS, relapse-free survival; SOC, standard of care.