Toxicities of novel therapies for hematologic malignancies

ABSTRACT

Introduction: Over the last decade targeted therapies have transformed the treatment landscape for hematologic malignancies with >70 new or extended approvals by the FDA since 2010. Since many of these drugs are registered for multiple entities and >1/3 were approved in the last two years, treatment options in hematology are rapidly expanding. Despite the justified excitement around the often previously unseen emerging therapeutic potential, distinct side-effect profiles require vigilance and adequate management by patients and caregivers.

Areas covered: This review provides a summary of the unique toxicity profiles of therapies for hematologic malignancies during the last decade with a focus on clinical implications and applicability. Due to the already wide implementation in common practice or an immense potential thereof selected treatments such as immune checkpoint inhibitors, various monoclonal antibodies, tyrosine kinase inhibitors and CAR T-cell therapies are discussed in detail. Challenges and potential strategies to assess and manage real-world toxicity after drug approval are addressed.

Expert opinion: The rapidly expanding therapeutic landscape of hematologic malignancies comes with a broad spectrum of side effects which are distinct from conventional hematotoxicity and require alertness.

KEYWORDS:

• CAR T-cell therapy
• checkpoint inhibition
• hematologic malignancies
• side effect
• targeted therapy
• toxicity management

Article Highlights

• Novel agents often approved on the basis of phase II trials with scarce data on toxicities are rapidly changing the treatment of hematologic malignancies

• The side effect profiles of these drugs change with larger and more heterogeneous patient groups treated outside clinical trials

• Underlying mechanisms or biomarkers for the development of toxicities with novel therapeutics as well as potential long-term toxicities remain poorly understood

• Checkpoint inhibition generally is well tolerable, with mostly low-grade irAEs and rare potentially life-threatening affection of lung, heart or liver. Treatment delay/discontinuation and corticosteroid treatment usually results in full recovery.

• Even though having transformed first-line treatment for diseases like CLL or WM, BTKis show a distinct toxicity profile, which is mostly well manageable. Physicians should be aware of bleeding, cardiovascular side effects such as hypertension or atrial fibrillation and opportunistic infections, which can be life-threatening.

• CAR T-cell treatment is improving the outcome of patients with r/r malignancies and AEs like CRS and ICANS are frequently seen, although mostly °1-2. Further investigation is needed to improve the treatment of patients with CRS and ICANS °3-4 and therefore even further improve the outcome of these patients.

• The management of toxicities emerging from novel therapeutics should follow guidelines and locally established interdisciplinary algorithms

• Data regarding the efficacy of different strategies to mitigate relevant toxicities need to be generated, ideally in collaborative multicenter analyses or even within prospective interventional clinical trials.

Declaration of interest

F Simon and J Garcia Borrega have received travel grants from Gilead. PJ Bröckelmann has received research funding from Bristol-Myers Squibb, Merck Sharpe & Dohme and Takeda, honoraria from Bristol-Myers Squibb and Takeda and has served in an advisory role for Takeda. 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.