PHARMACOTHERAPY

Ibrutinib and atrial fibrillation: A Belgian expert consensus paper

SUMMARY

Over the last decade, the oral Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib induced a paradigm shift in the treatment of patients with chronic lymphocytic leukaemia (CLL), mantle cell lymphoma (MCL), and Waldenströms macroglobulinemia (WM). In clinical trials and in real-world studies, ibrutinib proved to be an effective agent with an overall favourable safety and tolerability profile. However, compared with standard chemo-immunotherapy (CIT), ibrutinib was associated with a higher incidence of atrial fibrillation (AF). The patho-physiological mechanisms underlying this increased AF incidence are not completely understood, but it is thought to be related to off-target inhibitory effects of ibrutinib on the Tec protein tyrosine kinase (TEC) in cardiac cells. The prevalence of AF in patients treated with ibrutinib is highest during the first three months of therapy, which warrants an increased vigilance during this treatment phase. However, AF in patients treated with ibrutinib is generally well manageable without ibrutinib discontinuation. Prior to the start of ibrutinib treatment, identification and addressing modifiable risk factors for AF is a first important step. The threshold for haematologists to consult a cardiologist or a cardio-oncologist should be low and a close collaboration between both specialties is warranted. Unnecessary ibrutinib interruptions should be avoided, and uncomplicated AF is not a valid reason to discontinue or interrupt ibrutinib. If anticoagulation is required, direct oral anticoagulants are preferred. In this paper, a panel of haematology and cardiology specialists have provided practical guidance on how to evaluate patients prior to ibrutinib treatment and monitor during ibrutinib therapy. Furthermore, they have provided practical guidance on how to manage AF in ibrutinib-treated patients.

(BELG J HEMATOL 2021;12(4):155-64)

CAR-T cells: new developments and implications in multiple myeloma

SUMMARY

Despite significant progress in management of multiple myeloma (MM), prognosis of patients who fail standard treatment options is dismal. Therefore, refractory MM remains an unmet medical need. CAR-T cells are a form of cellular immunotherapy redirecting autologous T cells against tumour antigens after in vitro manufacturing. B-cell maturation antigen (BCMA) is the most promising target antigen for the development of CAR-T cell therapy for MM. In this review, we briefly go through the basics of CAR-T cell therapy applied to MM. We present the results on efficacy and safety of two recently developed CAR-T cell products: idecabtagene vicleucel (ide-cel or bb2121) and ciltacabtagene autoleucel (cilta-cel or JNJ-4528) and put them in perspective with what is published for approved CD19-CAR-T cells.

(BELG J HEMATOL 2020;12(3):128-31)

CAR-T cells: New developments and implications in lymphoma

SUMMARY

Recently, the use of chimeric antigen receptor modified T cells or CAR-T cells has emerged in the therapeutic arsenal of several hematological pathologies, including lymphoma. These CAR-T cells are the product of extensive research on understanding the mechanisms of tumour immunity and are the product of cellular engineering. By combining the specific recognition of an antibody and the activation pathways of a cytotoxic cell, CAR-T cells allow promising clinical results, but they also see the occurrence of side effects that are more specific to these treatments, which it is essential to manage in a multidisciplinary team. Different CAR-T cells are currently available, particularly in diffuse large cell B lymphoma. The trials that have enabled their use differ on many points, including patient selection, the manufacture of the CAR or the pre-therapeutic conditioning. In the future, the use of this expensive therapy could be extended to other lymphomas and new generations of CAR-T cells could emerge.

(BELG J HEMATOL 2020;12(2):77-84)

Caplacizumab, a game changer in the treatment of acquired thrombotic thrombocytopenic purpura

SUMMARY

Acquired or immune-mediated thrombotic thrombocytopenic purpura (aTTP) is a life-threatening auto-immune disorder caused by a functional deficiency of the von Willebrand factor-cleaving protease ADAMTS13, leading to thrombotic microangiopathy. The introduction of plasma-exchange has reduced mortality from over 90% to 10–20%. However, over the last two decades the treatment outcomes have not changed substantially. Caplacizumab, a humanised nanobody directed to the A1 domain of VWF, inhibits this lethal thrombotic cascade and is therefore essential for symptom control and prevention of irreversible end-organ damage. Both TITAN and HERCULES trials demonstrated that treatment with caplacizumab significantly reduced mean duration of hospitalisation and number of days of plasma-exchange. Moreover, no deaths were observed in caplacizumab-treated patients. Therefore, we can state that caplacizumab has changed the treatment paradigm of aTTP.

(BELG J HEMATOL 2020;11(3):120–7)

The role of direct oral anticoagulants in the management of cancer-associated thrombosis

Cancer patients are at an increased risk of venous thromboembolism (VTE). The current standard initial treatment of an acute episode of VTE in cancer patients consists of the administration of three to six months of subcutaneous low molecular weight heparin (LMWH) at a dose adjusted to the body weight. The efficacy and safety profile of LMWHs are well established, but a drawback of these agents is that they require daily subcutaneous administration. In addition, they are mainly cleared through the kidneys, and their use in patients with severe renal insufficiency may require dose reduction or monitoring of the anti-Xa activity. To address the issues with LMWH, several direct oral anticoagulants (DOAC) have been developed for the treatment of VTE. In contrast to LMWHs and vitamin K antagonist, DOACs directly interfere with thrombin or activated factor X (FXa). DOACs have now become standard treatment options in the general management of VTE, but until recently, there were no results of clinical trials specifically assessing the role of DOACs in the treatment of cancer-associated thrombosis. Recently, the Hokusai VTE cancer study and preliminary data from the Select-D trial demonstrated that DOACs are non-inferior to LMWH in preventing recurrent VTE. However, both studies also show that this comes at the cost of an increased rate of both major and clinically-relevant non-major bleeding. Especially in the subgroup of patients with gastrointestinal cancer, the benefit in VTE recurrence with the DOAC seems to be outbalanced by a significantly increased bleeding risk. Based on the available results, DOACs might represent an interesting alternative for LMWH in certain subgroups of patients, but with an important list of exceptions. It seems reasonable not to use DOACs in patients with a high bleeding risk, and especially in patients with gastrointestinal cancer, DOACs should not be the first-line choice. In summary, while LMWHs are currently the standard of care in the acute management of cancer-associated thrombosis, the advent of DOACs is welcomed for patients at a low bleeding risk who are in need of long-term anticoagulation.

(BELG J HEMATOL 2019;10(4):169–76)

Emerging pharmaceuticals: Mutant isocitrate dehydrogenase (mIDH) inhibitors

Alterations in genes involved in cellular metabolism and epigenetic regulation are common in myeloid malignancies. In approximately 20% of acute myeloid leukaemia patients and 5% of patients suffering from myelodysplastic syndromes, recurring mutations in isocitrate dehydrogenase (IDH) are found. Wild-type IDH catalyses the oxidative decarboxylation of isocitrate, thereby contributing to histone demethylation, DNA modification and cellular adaptation to hypoxia. Mutant IDH has neomorphic activity and reduces α-ketoglutarate to 2-hydroxyglutarate. High levels of 2-hydroxyglutarate are associated with hypermethylation, altered gene expression and differentiation block of haematopoietic progenitor cells. There is no prognostic significance of mutant IDH using standard treatment approaches. However, new oral treatments specifically targeting mutant IDH have shown promising results in inducing responses and are well tolerated. Novel combinations with drugs with non-overlapping mechanisms are underway and may address the clonal heterogeneity of myeloid malignancies. For now, only enasidenib and ivosidinib are FDA approved, but the field of mutant IDH inhibitors is rapidly moving.

(BELG J HEMATOL 2019;10(2):80–4)

Vaccine response in patients receiving anti-B-cell targeted therapy

SUMMARY

Infection prevention is of major importance in patients with haematological malignancies, who are immunocompromised because of disease-related and therapy-related factors. However, in patients receiving anti-B-cell therapies, such as rituximab or ibrutinib (an irreversible BTK inhibitor), measures for infection prevention are hardly studied. In this review we considered vaccine response in patients receiving rituximab treatment and we investigated if an adequate vaccine response can be achieved in patients treated with ibrutinib. For rituximab, no protective titers are obtained in patients with haematological malignancies, but in rheumatoid arthritis 30–50% of patients achieve protective titres. Vaccine response following ibrutinib seems low but it is insufficiently studied to make evidence based recommendations.

(BELG J HEMATOL 2018;9(3):113–7)