Elsevier

Leukemia Research

Volume 60, September 2017, Pages 63-73
Leukemia Research

Invited review
Immunotherapy in adult acute leukemia

https://doi.org/10.1016/j.leukres.2017.06.011Get rights and content

Highlights

Abstract

The treatment of acute myeloid leukemia (AML) did not evolve profoundly in the last decades. Some improvement has been made for acute lymphoblastic leukemia (ALL). Emerging new treatment modalities, such as immunotherapy, are now beginning to be available for acute leukemia, mostly for patients suffering from ALL. This review aims to give an overview of these new therapeutic approaches, especially those already available. The focus is on cell-based immunotherapy, or molecules using preexisting host cells. Underlying mechanisms are explained and an overview of clinical experience with phase 1–3 studies is given. Immunotherapies discussed are antibody-drug conjugates, bispecific T-cell engagers (BiTEs), chimeric antigen receptor T cells (CARTs) and immune checkpoint inhibitors (ICPIs). Most of the clinical studies reviewed are in ALL patients, usually in the relapse setting, but where available, studies on AML patients were also considered. This new general treatment approach offers hope to patients with until now dismal clinical outcome. Hopes are high that future developments, and moving these therapies to an earlier treatment phase, will improve the prognosis of patients suffering from acute leukemia.

Introduction

In this review, we focus on immunotherapy for acute lymphoblastic leukemia (ALL), and as far as available, acute myeloid leukemia (AML). Acute promyelocytic leukemia will not be discussed, as the treatment approach differs largely from both other entities and is discussed elsewhere. ALL and AML remain two major challenges for hematologists when it comes to cure. Roughly around half of these patients will ultimately relapse and die of their disease [1], [2]. In ALL, complete remission (CR) rate after salvage chemotherapy are low and ranges between 25 and 45% [2], [3], with most of these patients ultimately dying, resulting in a lot of room for improvement. A positive minimal residual disease (MRD) status is considered a negative predictive factor and also as an established marker for relapse in ALL [4]. The same trend seems to emerge for AML [5], [6]. Immunotherapy can be used to modify otherwise inevitable relapse in these scenarios.

The definition of immunotherapy varies slightly from one publication to another. In the treatment of leukemias, allogeneic hematopoietic stem cell transplantation (HSCT) is certainly its most classical example, based on cellular graft versus leukemia effect that can lead to cure, with graft versus host disease (GvHD) as its most feared complication. The definition can include the use of monoclonal antibodies such as anti-CD20 (rituximab), or can be defined as using the host’s own cellular immunity to fight the underlying disease. This is done either by enhancing the host’s immune system or suppressing negative regulators, depending on the targeted function, as T cells are known to play a major role in tumor surveillance [7]. In this review, we aim to focus on the more recent immunotherapy approaches; especially cell-based or modalities using preexisting host T-cells. We will concentrate on treatments already available, but we will also give an outlook on upcoming ones. With these new agents and cell-based therapies, a whole new spectrum of complications is emerging, a challenge for patients and their hematologists to deal with. Main challenges are cytokine release syndrome (CRS) and neurological complications. At the moment, mechanisms underlying these syndromes are not completely understood. Consequently, their ideal management is yet to be defined. For now, immunotherapy in acute leukemia is used in the relapse or MRD positive setting, aiming at a population with a very bad-risk profile.

Section snippets

Gemtuzumab ozogamicin

GO is an anti-CD33 antibody linked to calicheamicin, a toxin inducing DNA double-strand breaks. The drug was FDA approved in 2000 for elderly patients with relapsing AML [8], but was thereafter withdrawn from the market in 2010 when it failed to prove its efficacy in younger patients [9]. However, it seems that at least for a subset of patients, GO added to chemotherapy is able to improve outcome [10]. Because of heterogeneous anthracycline schedules and cumulative doses, this question cannot

Discussion

The current use of immunotherapy in acute leukemia is reserved for patients with either relapse of their disease, a refractory status or MRD positivity. Of note, despite this high risk profile, current available immunotherapy treatments showed efficacy. In future use, there is an interest to move at least part of the less dangerous immunotherapeutic approaches to frontline treatment, in order to improve outcome of patients with acute leukemia. These approaches are more developed for ALL than

Acknowledgements

The authors thank Roger Guindon for the realization of the figures. ML is supported by DKTK (L660) and DFG (CRC992, C04).

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