PHARMACOTHERAPY

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)

Management of immune thrombocytopenia in multiple sclerosis patients treated with alemtuzumab: a Belgian consensus

SUMMARY

Alemtuzumab (Lemtrada®) is a humanised monoclonal antibody indicated for the treatment of adult patients with relapsing/remitting multiple sclerosis with active disease defined by clinical or imaging features. Alemtuzumab demonstrated superior efficacy over active comparator in both treatment naive patients and those with inadequate response to prior therapy. Alemtuzumab is associated with a consistent and manageable safety and tolerability profile. Treatment with alemtuzumab for multiple sclerosis increases the risk for autoimmune adverse events including immune thrombocytopenia. Complete blood counts with differential should be obtained prior to initiation of treatment and at monthly intervals thereafter for 48 months after the last infusion. After this period of time, testing should be performed based on clinical findings suggestive of immune thrombocytopenia. If immune thrombocytopenia onset is confirmed, appropriate medical intervention should be promptly initiated, including immediate referral to a specialist. This paper presents the consensus of Belgian multiple sclerosis specialists and haematologists to guide the treating physician with practical recommendations.

(BELG J HEMATOL 2018;9(3):118–23)

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)

Venetoclax, the first available bcl-2 antagonist for chronic lymphocytic leukaemia

SUMMARY

Venetoclax, the first-in-class bcl-2 antagonist, has demonstrated deep and durable remissions as a single agent in relapse/refractory chronic lymphocytic leukaemia patients with a 17p deletion or chronic lymphocytic leukaemia refractory to B-cell receptor inhibitors or progressive after B-cell receptor inhibitor discontinuation. As reimbursement of venetoclax by the Belgian national public health insurance has been provided, this review describes mechanism of action, dosage and administration, efficacy and tolerability. As venetoclax can rapidly reduce the chronic lymphocytic leukaemia load, precautions to avoid tumour lysis syndrome depending on risk assessment is a sine qua non. Despite the convenience afforded by this oral, once daily formulation, treating physicians and patients must be aware of drug adherence and drug-drug interactions which can challenge treatment benefits and risks.

(BELG J HEMATOL 2017;8(7):265–71)

Ixazomib: the first oral proteasome inhibitor for the treatment of multiple myeloma

SUMMARY

The ubiquitin-proteasome system is a major pathway for the degradation of most intracellular proteins and therefore plays an essential regulatory role in cellular processes including cell cycle progression, proliferation, differentiation and apoptosis. The recognition of its importance in tumorigenesis has led to the development of agents that target this pathway as cancer therapeutics. Bortezomib is the first proteasome inhibitor approved for clinical use and has a profound impact on the survival of patients with multiple myeloma. Ixazomib is a promising second generation proteasome inhibitor.

(BELG J HEMATOL 2017;8(6):229–31)

CNS prophylaxis in aggressive non-Hodgkin’s lymphoma

SUMMARY

Although it doesn’t occur frequently, central nervous system relapse in aggressive non-Hodgkin lymphoma carries a very dismal prognosis. Indications for the use of prophylactic strategies are clear-cut in Burkitt and lymphoblastic lymphoma. However, this remains subject to much debate in other types of aggressive non-Hodgkin lymphoma, like diffuse large B-cell lymphoma. Available strategies consist of intrathecal administration of chemotherapy, the systemic use of high-dose central nervous system-penetrating cytotoxic agents or a combination of both. Nevertheless, all known methods entail a certain risk for toxicity in patients. Hence, great effort has been put in the search for risk factors and scores to identify high-risk patients who have benefit from central nervous system-prophylaxis and to exclude those who do not. This article aims to provide an overview of existing strategies, pharmacological properties and side effects of available cytotoxic agents, as well as an update on the current guidelines for the implementation of central nervous system prophylaxis in different types of non-Hodgkin lymphoma. However, due to lack of qualitative prospective data, a golden standard in this field is still lacking.

(BELG J HEMATOL 2017;8(6):232–8)