Journal: Expert review of hematology
Recombinant IFN-α (rIFN-α) induces complete hematologic remissions in patients with myeloproliferative neoplasms (MPNs), but its use has been limited by side effects owing to the relatively high doses used. Now, low-dose rIFN-α is stressed, starting relatively early in the course of the MPNs. In polycythemia vera, this has resulted in a significant clinical, hematologic, morphologic and molecular response manifested by reduction in the JAK2(V617F) allele burden, sustained even after discontinuation of recombinant IFN. In essential thrombocythemia, platelet count reduction is prompt and durable without treatment for varying periods. In hypercellular primary myelofibrosis, rIFN-α has restored normal blood counts, reduced splenomegaly and induced morphologic marrow remissions. This article highlights our current use of rIFN-α in MPNs.
Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin’s lymphoma. It can follow a heterogeneous clinical course but generally patients relapse early after standard immunochemotherapy regimens and develop resistance to subsequent therapies. For younger patients, intensive approaches followed by autologous stem cell transplantation offer excellent long-term disease control but with the possible exception of an allogenic stem cell transplant, MCL is an incurable condition. As MCL principally affects older individuals, the majority of patients are not candidates for such intensive approaches. Ibrutinib is an orally active, Bruton’s tyrosine kinase inhibitor. It inhibits signaling pathways downstream of Bruton’s tyrosine kinase that appear critical for the proliferation and survival of MCL. As a single agent it has shown extremely promising activity in relapsed and refractory MCL patients with an excellent side-effect profile. The exact role for ibrutinib in the treatment of MCL is yet to be established; however, it is likely to fundamentally change the way we treat this disease.
The recent discovery of mutations of the gene calreticulin has allowed raising the proportion of patients with essential thrombocythemia and primary myelofibrosis with known mutational abnormality up to 85-90%. Knowledge of the mechanisms by which mutated calreticulin underlie a myeloproliferative neoplasm as well as the clinical and therapeutic implications is just at the very beginning, and exciting times await research in this field.
A major advance in the management of febrile neutropenia (FN) has been the stratification of the population of adult patients with FN for the risk of complications and death. Using validated reliable predictive instruments, such as the Multinational Association for Supportive Care in Cancer score, it is possible to identify a population of ‘low-risk’ patients, who can benefit from simplified and less expensive therapeutic approaches (e.g., orally administered antimicrobial therapy and early home return). Prevention of FN by the use of granulopoietic colony-stimulating factor (G-CSF) has been successfully applied to patients at ‘high risk’ of developing FN. In addition to the aggressiveness of chemotherapy, which usually defines the ‘high-risk’ status, the role of a series of factors that increase both the risk of FN and the complications rate has been recognized and should probably be taken into consideration when selecting patients for G-CSF prophylaxis. The cost of the G-CSF is the major limiting factor for their broad use; further efforts should be made to match the cost issue with the need of protecting from the development of FN most patients treated with chemotherapy for cancer.
Incompatibility of red cell and platelet antigens can lead to maternal alloimmunization causing hemolytic disease of the fetus & newborn and fetal neonatal alloimmune thrombocytopenia respectively. As the molecular background of these polymorphisms emerged, prenatal testing using initially fetal DNA obtained from invasively obtained amniotic fluid or chorionic villus was implemented. This evolved into testing using maternal plasma as source of fetal DNA, and this is in routine use as a safe non-invasive diagnostic that has no risk to the fetus of alloimmunization or spontaneous miscarriage. These tests were initially applied to high risk pregnancies, but has been applied on a mass scale, to screen fetuses in D-negative pregnant populations as national screening programs. Fetal neonatal alloimmune thrombocytopenia management has had comparatively small take up in non-invasive testing for causative fetal platelet alleles (e.g., HPA-1A), but mass scale genotyping of mothers to identify at risk HPA-1b1b pregnancies and their treatment with prophylactic anti-HPA-1A is being considered in at least one country (Norway).
A deficiency in ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin type-1 repeats, member 13) is associated with thrombotic thrombocytopenic purpura (TTP). Congenital TTP is caused by a defect in the ADAMTS13 gene resulting in decreased or absent enzyme activity; acquired TTP results from autoantibodies that either inhibit the activity or increase the clearance of ADAMTS13. Despite major progress in recent years in our understanding of the disease, many aspects around the pathophysiology of TTP are still unclear. Newer studies expanded the TTP field from ADAMTS13 and inhibitory antibodies to immune complexes, cloned autoantibodies and a possible involvement of other proteases. Additionally, several new treatment strategies supplementing plasma- exchange and infusion are under investigation for a better and more specific treatment of TTP patients. In this review, we discuss the recent insights in TTP pathophysiology and describe upcoming therapeutic opportunities.
Despite lack of knowledge in the field, several studies have underlined the role of endothelium dysfunction and platelet activation as significant players in the development and progression of chronic obstructive pulmonary disease (COPD). Indeed, endothelium plays a crucial role in vascular homeostasis and impairment, due to the inflammation process enhanced by smoking. Chronic inflammation and endothelial dysfunction have been proved to drive platelet activity. Consequently, thrombotic risk is enhanced in COPD, and might explain the higher percentage of cardiovascular death in such patients. Areas covered: This review aims to clarify the role of endothelium function and platelet hyper-activity as the pathophysiological mechanisms of the increased thrombotic risk in COPD. Expert commentary: In COPD patients, chronic inflammation does not impact only on lung parenchyma, but potentially involves all systems, including the endothelium of blood vessels. Impaired endothelium has several consequences, such as reduced vasodilatation capacity, enhanced blood coagulation, and increased platelet activation resulting in higher risk of thrombosis in COPD patients. Endothelium dysfunction and platelet activation are potential targets of therapy in patients with COPD aiming to reduce their risk of cardiovascular events.
Introduction: Real-world effectiveness of hemato-oncology pharmaceuticals may not necessarily mimic clinical trial efficacy results, mainly due to demographic and clinical practice variability. The aim of this review was to systematically assess the availability of real-world evidence (RWE) and the transferability of clinical trial (CT) efficacy results to real life, for novel agents recently approved to manage lymphomas, leukemias and multiple myeloma. This is the largest cross-indication review comparing RWE to CT results, aspiring to inform clinical practice and decision making when funding hemato-oncology pharmaceuticals. Areas Covered: The review methodology focused on identifying all novel agents that entered EU landscape between 2012 and 2016 by using European Medicines Agency (EMA) database, while conducting a systematic PubMed literature review of RWE in the specific hematological malignancies, in order to compare RWE versus CT efficacy endpoints. Expert Opinion: In total, 18 international non-proprietary names (INNs) that received EMA approval for any indication were included and the registrational efficacy results are presented. Eight (44%) INNs proved to have relevant RWE generated in at least one approved indication. The analysis of findings revealed high variability in terms of RWE availability and transferability of CT results to relevant real-life experience among the disease areas investigated.
Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and is an aggressive malignancy with heterogeneous outcomes. Diverse methods for DLBCL outcomes assessment ranging from clinical to genomic have been developed with variable predictive and prognostic success. Areas covered: The authors provide an overview of the various methods currently used to estimate prognosis in DLBCL patients. Models incorporating cell of origin, genomic features, sociodemographic factors, treatment effectiveness measures, and machine learning are described. Expert opinion: The clinical and genetic heterogeneity of DLBCL presents distinct challenges in predicting response to therapy and overall prognosis. Successful integration of predictive and prognostic tools in clinical trials and in a standard clinical workflow for DLBCL will likely require a combination of methods incorporating clinical, sociodemographic, and molecular factors with the aid of machine learning and high-dimensional data analysis.
Objectives: Iron overload might lead to bone loss in transfusion-dependent beta-thalassemia (TDT) patients. To investigate the role of iron chelation therapy (ICT) on bone mineral density (BMD) of TDT patients suffering from iron overload, the authors compared the efficacy of five different iron chelation regimens through assessing serum ferritin and BMD. Methods: In 256 consecutive TDT patients, BMD was measured by dual-energy X-ray absorptiometry in lumbar spine and femoral neck regions. Treatment outcome of five iron chelation regimens including Deferoxamine (DFO), Deferiprone (DFP), Deferasirox (DFX), and combination therapy was evaluated to compare the mean differences of serum ferritin and BMD indices pre- and post-treatment during 12-months follow-up period. Results: No significant difference was observed in DXA characteristics and serum ferritin level changes between ICT groups, but combination of DFO and DFX had the best outcome in improving bone mass through assessing each group individually. Conclusion: Combination therapy with DFX and DFO had the highest impact on reducing serum ferritin, however insignificant, and improving bone loss in both lumbar spine and femoral neck in comparison with other regimens. A randomized prospective clinical trial is advised to accurately assess the efficacy of iron chelation regimens on BMD measurements of TDT patients.