The return of gemtuzumab ozogamicin: a humanized anti-CD33 monoclonal antibody–drug conjugate for the treatment of newly diagnosed acute myeloid leukemia

OncoTargets and Therapy Dovepress open access to scientific and medical research Review OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 213.32.98.221 on 21-Dec-2018 For personal use only. Open Access Full Text Article The return of gemtuzumab ozogamicin: a humanized anti-CD33 monoclonal antibody–drug conjugate for the treatment of newly diagnosed acute myeloid leukemia This article was published in the following Dove Press journal: OncoTargets and Therapy Pamela C Egan John L Reagan Division of Hematology and Oncology, Rhode Island Hospital, The Alpert Medical School of Brown University, Providence, RI, USA Introduction Correspondence: John L Reagan Rhode Island Hospital, George 3, Providence, RI 02903, USA Tel +1 401 444 5391 Fax +1 401 444 4184 Email From the 1970s to 2000, the treatment of acute myeloid leukemia (AML) remained essentially stagnant.1 Most patients with a good performance status received a combination of an anthracycline and cytarabine. Meanwhile, patients with a poor performance status received best supportive care and, predictably, outcomes remained dismal.1,2 While the treatment of patients not eligible for intensive therapy changed significantly with the advent of hypomethylating agents, progress in the treatment of patients suitable for intensive therapy was limited to the refinement of dosing and schedules.2 The efforts to elucidate different subtypes of AML based on molecular and cytogenetic changes raised great hopes of improvements in therapies with targeted agents, and in the last 2 years those improvements have begun to take shape.3,4 Played out in parallel to this overarching story of promise, disappointment, and newfound promise is the saga of gemtuzumab ozogamicin (GO), the first antibody–drug conjugate to be approved for cancer treatment.5,6 With its approval in 2000 for the single-agent treatment of relapsed/refractory AML, GO was among the first wave of the new age of cancer drugs that seemed poised to change the course of cancer treatment with the promise of precision treatment based 8265 submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 8265–8272 Dovepress © 2018 Egan and Reagan. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://dx.doi.org/10.2147/OTT.S150807 Powered by TCPDF (www.tcpdf.org) Abstract: Through the years gemtuzumab ozogamicin (GO) has moved from a panacea in the treatment of acute myeloid leukemia (AML) to a pariah and back again. Early promise of targeted therapy with accelerated approval in the United States in 2000 gave way to fear over increased toxicity in the absence of efficacy, which subsequently resulted in the drug manufacturer voluntarily withdrawing GO from the market in 2010. We outline the history of GO in terms of initial drug development and early clinical trials that ultimately led the way to GO frontline use in AML based on a series of Phase III studies. Among these studies, we discuss the similarities and differences in terms of dosing, frequency, response rates, and toxicities that ultimately led to the re-approval of GO in 2017 based on efficacy, particularly in patients with core-binding factor (CBF) leukemia. Herein, we also review the clinical efficacy of GO in the frontline treatment of acute promyelocytic leukemia, which is based on either initial patient high-risk disease or potential co-morbidities that preclude the use of arsenic trioxide (ATO). Finally, we assess the current evidence for biomarkers aside from initial cytogenetics that may predict a favorable response to GO. Keywords: leukemia, AML, treatment, core binding factor Dovepress OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 213.32.98.221 on 21-Dec-2018 For personal use only. Egan and Reagan on direct chemotherapeutic targeting of cluster of differentiation 33 (CD33). When an interim analysis showed no benefit and increased induction fatalities, GO was removed from the market in 2010.7 The results of a subsequent trial, ALFA0701, and an individual patient level data meta-analysis of GO used in the frontline setting showing a survival benefit led to its re-approval in 2017.7 In light of this approval, for both newly diagnosed adults with CD33-positive AML and patients 2 years of age and older with relapsed/refractory CD33-positive AML, we endeavor to review the drug’s history from pre-clinical promise and initial early data supporting it’s conditional approval to the events that led to its removal from the market and the subsequent clinical data that allowed re-approval. Pre-clinical data CD33, or myeloid differentiation antigen, is expressed only on hematopoietic cells committed to the myeloid lineage and is expressed on the surface of the majority of AML blasts.8 Development of GO grew out of the thought that specifically targeting the CD33 antigen would spare the presumably normal precursors and allow for restoration of normal hematopoiesis.5,8,9 This idea was supported in work by Bernstein et al that demonstrated that CD33-CD34+ cells from patients with CD33+ AMLs in vitro grew normal colony-forming cells.10 It was first demonstrated that an anti-CD33 radioimmunoconjugate was efficiently internalized by CD33positive cells, first in a xenograft murine model and then in humans.11,12 Collaborators in academia then worked with industry to develop a humanized anti-CD33 antibody conjugated with a derivative of calicheamicin, a chemotherapeutic agent that causes tumor cell death through DNA binding and resultant double strand cuts.5,9,13 The bond between antibody and drug is stable in circulation and then dissolves, once intracellular, to allow the calicheamicin to bind with the DNA.6 This drug antibody conjugate, CMA-676, became known as GO. Early trials and initial approval The first trial to use GO was a Phase I dose escalation study in 40 adult patients (age 16–70) with relapsed or refractory AML, more than 50% of whom had poor risk disease.14 Three patients had a complete remission (CR) and five had a CR with incomplete platelet recovery (CRp); the idea of CRp as a response to be included in overall response (OR) was a designation novel to this trial.6,14 Infusion reactions, prolonged myelosuppression, and reversible hepatotoxicity 8266 Powered by TCPDF (www.tcpdf.org) submit your manuscript | www.dovepress.com Dovepress were the most frequent adverse effec (...truncated)