Bulletin Du Cancer最新文献

L’arsenal thérapeutique du cancer du sein s’est enrichi de nouveaux anticorps drogues-conjugués dont l’utilisation est en large expansion dans l’ensemble des sous-types moléculaires connus. Ils représentent une classe thérapeutique innovante dont le principe repose sur la combinaison d’un agent cytotoxique à un anticorps monoclonal via une molécule de liaison, et dont l’objectif est de délivrer une chimiothérapie préférentiellement aux cellules exprimant l’antigène cible, et ainsi améliorer l’index thérapeutique. Le trastuzumab-emtansine a été le premier anticorps drogues-conjugués utilisé dans les cancers du sein HER2-surepxrimé. Plus récemment, le trastuzumab-deruxtecan et le sacituzumab-govitecan ont démontré une efficacité en survie sans progression et en survie globale dans les cancers du sein HER2-surexprimé et HER2-faibles pour le premier, et HER2-non surexprimé pour le second (incluant HER2-faible). De nombreux autres anticorps drogues-conjugués sont en cours de développement dans le cancer du sein. Bien qu’initialement développés avec l’intention d’élargir l’index thérapeutique et de limiter les toxicités, la gestion des effets indésirables liés aux anticorps drogues-conjugués reste un défi en clinique. L’objectif de cet article de synthèse est de rapporter les profils de toxicité de ces drogues déjà utilisées en pratique clinique courante ou en développement à travers les résultats observés dans les différentes études.

Therapeutic options for breast cancer have recently been enriched by new antibody-drug conjugates (ADC), which are now being utilized across all known molecular subtypes. ADCs represent a groundbreaking class of therapies that combine a cytotoxic agent with a monoclonal antibody via a combination molecule (linker). The primary objective is to selectively deliver chemotherapy to cells expressing the target antigen, thereby enhancing the therapeutic index. Trastuzumab-emtansine marked the pioneering use of this approach for HER2-overexpressed breast cancer. More recently, trastuzumab-deruxtecan and sacituzumab-govitecan have demonstrated efficacy in progression-free survival and overall survival in HER2-overexpressed and HER2-low breast cancer for the former, and HER2-non-overexpressed (including HER-low) for the latter. Numerous other ADCs are currently under development in breast cancer. While ADCs were initially designed to widen the therapeutic index and mitigate toxicities, managing ADC-related adverse events in the clinical setting remains a challenge. This review article aims to provide an overview of the toxicity profiles of these drugs already in current clinical practice or under development, drawing from results observed in various studies.

Diverses hémopathies malignes peuvent entraîner des complications rénales. La plus fréquente d’entre elles à atteindre le rein est le myélome multiple. Cependant un nombre croissant de maladies rénales sont associées avec d’autres gammapathies monoclonales. Il est reconnu que des clones en petite abondance peuvent être responsables de dommages d’organe sévère. C’est ainsi qu’est apparu le concept de gammapathie monoclonale de signification rénale (MGRS). Bien que l’hémopathie chez ces patients corresponde davantage à une gammapathie monoclonale de signification indéterminée (MGUS) qu’à un myélome multiple, le diagnostic d’une complication rénale change la prise en charge thérapeutique. La préservation et la restauration de la fonction rénale sont possibles avec un traitement ciblant le clone responsable. Dans cet article, nous prenons comme exemple la glomérulopathie immunotactoïde et fibrillaire, deux entités distinctes aux étiologies différentes et par conséquent ayant une prise en charge propre. La glomérulopathie immunotactoïde est le plus souvent associée à une gammapathie monoclonale ou une leucémie lymphoïde chronique. Les dépôts sur la biopsie rénale sont monotypiques, et le traitement repose donc sur le ciblage du clone. La glomérulonéphrite fibrillaire, quant à elle, est plutôt causée par des maladies auto-immunes ou des cancers solides. Les dépôts sur la biopsie rénale sont dans la majorité des cas polyclonaux. Il existe un marqueur spécifique en immunohistochimie, le DNAJB9, et le traitement est moins bien codifié.

Various hematologic malignancies can lead to renal complications. The most common of these hemopathies to affect the kidney is multiple myeloma, however an increasing number of kidney diseases are associated with other monoclonal gammopathies. It is recognized that clones in small abundance can be responsible for severe organ damage, thus the concept of monoclonal gammopathy of renal significance (MGRS) has emerged. Although the hemopathy in these patients is more consistent with monoclonal gammopathy of undetermined significance (MGUS) than with multiple myeloma, the diagnosis of a renal complication changes the therapeutic management. Preservation and restoration of renal function is possible with treatment targeting the responsible clone. In this article, we take as an example immunotactoid and fibrillary glomerulopathies, two distinct entities with different etiologies and consequently different management. Immunotactoid glomerulopathy is most often associated with monoclonal gammopathy or chronic lymphocytic leukemia, the deposits on renal biopsy are monotypic, and treatment is therefore based on clone targeting. Fibrillary glomerulonephritis, on the other hand, is caused by autoimmune diseases or solid cancers. Deposits on renal biopsy are in the vast majority polyclonal. There is a specific immunohistochemical marker, DNAJB9, and treatment is less well established.

Chimeric antigen receptor T (CAR-T)-cell, an adaptive immune therapy is approved for patients with acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Its use and subsequent toxicities are expected to rise in the coming years. The main toxicities are cytokine release syndrome, hemophagocytic lymphohistiocytosis and immune effector cell associated neurotoxicity syndrome. Cytokine release syndrome is observed in up to 40% of patients. Almost 20% of patient suffer from acute kidney injury after CAR-T cell infusion. Associated factors are high-grade cytokine release syndrome, a prior autologous or allogeneic stem cell transplantation andrequirement of intensive care unit. Several mechanisms may contribute to the occurrence of acute kidney injury after CAR-T infusion: hypoperfusion during cytokine release syndrome, cytokine injury, T cell infiltration, tumor lysis syndrome and sepsis-induced injury. Kidney injury is associated with substantial increase in morbi-mortality.

Introduction

The number of cancer patients receiving long-term hemodialysis (HD) is increasing, and HD could jeopardize treatments’ safety and efficacy. Therefore, managing anticancer drugs is critical in this frail population. In addition, evidence of HD safety or risk is regularly released both for cytotoxic chemotherapy (CT) or hormone therapy (HT) as well as new therapies with molecularly targeted therapies (MTT), immune checkpoint inhibitors (ICI), and a summary of current knowledge is needed.

Methods

We aimed to synthesize available data on cancer treatments in HD patients using PubMed database, FDA labels, summary of product characteristics (SmPC), FDA and EMA approval documents, guidelines and finally case reports for which relevant pharmacokinetic (PK) data is available.

Results

For CT, recently proposed guidelines were balanced by the publication of particular toxic reports following them. SmPC was helpful in some cases, but no data was found for most CTs. MTT, both oral and monoclonal antibodies, were rarely modified by HD. However, HD patients have particular frailty that could require dose adaptation despite no substantial PK modification. Similarly, exposure to ICIs is unlikely to be modified by HD since immunoglobulins are not dialyzable. For HT, PK characteristics and HD impact were more heterogeneous and were reviewed molecule by molecule.

Conclusions

We summarized current knowledge on HD and cancer treatments. Data remains scarce, and the latest guidelines rely on few clinical data. There is a need to collect both retrospective and prospective data to better characterize the safety and relevant dose and schedule adaptations whenever needed in this situation to reinforce future guidelines.