B-cell depleting immunotherapies: therapeutic opportunities and toxicities

ABSTRACT

Introduction: The last few years have witnessed what can certainly be defined as a ‘period of renaissance’ for immunotherapy in the field of hematological malignancies. In particular, antibody-mediated and cell-mediated immunotherapy have significantly changed the treatment approach of patients with B-cell lymphoproliferative disorders. These therapies, initially employed in patients with refractory/relapsed disease, are now integrated in the treatment of newly diagnosed patients. Together with the therapeutic success, we have also learnt that these innovative therapies can induce relevant, sometimes life-threatening or even fatal, side effects.

Areas covered: In this review article, we analyzed the applicative therapeutic scenario and the peculiar toxicities associated with approaches of immunotherapy, paying particular attention to the new emerging side effects, substantially unknown before the introduction of these therapies.

Expert commentary: Both monoclonal antibodies and cell therapy with lymphocytes genetically modified to be redirected against leukemia targets through the transduction with chimeric antigen receptors (CARs) have obtained unprecedented success in rescuing patients with resistant B-cell malignancies. Complications, such as neurotoxicity, cytokine release syndrome or persistent B-cell lymphopenia, must always be taken into consideration and diagnosed in a timely manner in patients with B-cell neoplasms to guarantee optimal management, thus avoiding they blunting the efficacy of immunotherapy.

KEYWORDS:

• Bispecific T-cell engagers
• CAR T cells
• immunotherapy
• lymphoproliferative disorders
• monoclonal antibodies

Article highlights

• Immunotherapy has been shown to offer a remarkable clinical benefit in many pediatric and adult patients with r/r B-cell malignancies, including ALL, NHL and CLL;

• After years of exclusive use of naked mAbs (e.g. rituximab), novel approaches of antibody-mediated or cell-mediated immunotherapy now rely on the use of either BiTEs (e.g. blinatumomab), or ADC (e.g. inotuzumab) or genetically modified patient’s T lymphocytes (i.e. CAR T cells);

• After the initial exciting results reported in patients with advanced disease, nowadays, these innovative strategies of immunotherapy are being tested as standard-of-care therapy for first relapse or even in front-line protocols. In particular, these therapies may either act as a stand-alone treatment or serve as a useful drug capable of bridging patients to allo-HSCT in better clinical conditions and negative MRD status;

• The most relevant side effects of BiTEs and CAR T cells are CRS and neurotoxicity, which, in some cases, may be life-threatening or even fatal and may lead to treatment discontinuation in a significant proportion of patients. By contrast, reduction of the risk of developing VOD/SOS will potentially improve the safety of inotuzumab;

• Future studies aimed at dissecting the role of all the variables influencing response to immunotherapy in B-cell malignancies and at fully elucidating both the strategies of immune-evasion and the pathophysiological mechanisms responsible for acute toxicity will contribute to optimize the role of these innovative therapeutic approaches.

Declaration of interest

F Locatelli is the responsible investigator for Italy of two Amgen-sponsored clinical trials using blinatumomab in pediatric patients. He has been a member of Amgen’s Scientific Advisory Boards for blinatumomab and received honoraria from Amgen as a Speaker. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.