ABSTRACT
Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2023-505160-12-00; Registered on October 30, 2023.
Subject(s)
Interferon alpha-2 , Interferon-alpha , Polyethylene Glycols , Recombinant Proteins , Thrombocythemia, Essential , Adult , Aged , Female , Humans , Male , Middle Aged , Interferon alpha-2/therapeutic use , Interferon alpha-2/adverse effects , Interferon-alpha/therapeutic use , Interferon-alpha/adverse effects , Polyethylene Glycols/therapeutic use , Polyethylene Glycols/adverse effects , Polyethylene Glycols/administration & dosage , Prospective Studies , Recombinant Proteins/therapeutic use , Recombinant Proteins/adverse effects , Recombinant Proteins/administration & dosage , Thrombocythemia, Essential/drug therapy , Treatment Outcome , Multicenter Studies as Topic , Clinical Trials, Phase III as TopicSubject(s)
Neoplasms , Refugees , Humans , Moldova/epidemiology , Romania , Neoplasms/epidemiology , Neoplasms/therapyABSTRACT
Introduction: Natural killer (NK) cells are key anti-tumor effectors of the innate immunity. Phenotypic differences allow us to discriminate in between three functional stages of maturation, named immature, mature and hypermature that are distinctive in terms of receptor expression, cytokine secretion, cytotoxic properties and organ trafficking. NKs display an impressive repertoire of highly polymorphic germline encoded receptors that can be either activating, triggering the effector's function, or inhibitory, limiting the immune response. In our study, we have investigated peripheral blood NK cells of acute myeloid leukemia (AML) patients. Methods: The Killer Immunoglobulin-like receptors (KIRs) and the HLA-C genotypes were assessed, as HLA-C molecules are cognate antigens for inhibitory KIRs. Results: The AA mainly inhibitory KIR haplotype was found in a higher proportion in AML, while a striking low frequency of the 2DS3 characterized the mainly activating Bx haplotype. Flow cytometry immunophenotyping evidenced a lower overall count of NK cells in AML versus healthy controls, with lower percentages of the immature and mature subpopulations, but with a markedly increase of the hypermature NKs. The analysis of the KIR2DL1, KIR2DL2, KIR2DL3, KIR3DL1, and NKG2A inhibitory receptors surface expression revealed a remarkable heterogeneity. However, an overall trend for a higher expression in AML patients could be noticed in all maturation subpopulations. Some of the AML patients with complex karyotypes or displaying a FLT3 gene mutation proved to be extreme outliers in terms of NK cells percentages or inhibitory receptors expression. Discussion: We conclude that while the genetic background investigation in AML offers important pieces of information regarding susceptibility to disease or prognosis, it is flow cytometry that is able to offer details of finesse in terms of NK numbers and phenotypes, necessary for an adequate individual evaluation of these patients.
ABSTRACT
Acute Myeloid Leukaemia (AML) is a neoplasia characterised by rapid proliferation and an increased rate of relapses. The AML blasts display features of antigen-presenting cells (APC), and thus can directly modulate the anti-tumour T cell responses. The bone marrow of a group consisting of 30 newly diagnosed patients and four healthy donors (HD) was investigated for the expression of HLA-DR, several molecules involved in MHC-II antigen-presentation and MHC-II groove editing, like HLA-DM, CD74 and CLIP, as well as a set of immune checkpoint ligands, like ICOS-L, B7.2, PD-L2 and B7-H3. The patients were further characterised for their genetic anomalies and distributed to favourable, intermediate and adverse ELN risk categories. We were able to show that while 23% of our patients displayed a low level of HLA-DR surface expression, all patients displayed higher HLA-DM and CD74 expression compared to HD. However, a higher CLIP expression was noticed only in the HLA-DR low patients. The co-inhibitory PD-L2 and B7-H3 molecules were increased in the cases with normal HLA-DR expression; oppositely, the co-stimulatory ICOS-L and the dual function B7.2 were significantly increased in the cases with HLA-DR low expression. Furthermore, no favourable ELN risk cases were found within the HLA-DR low group. All in all, these data show that the AML with low versus normal HLA-DR expression display different profiles of MHC class II machinery molecules and B7 ligands, which are correlated with distinct ELN stratification. Furthermore, as our study included healthy individuals, it offers valuable information about the expression levels that should be considered as normal for these markers known to cause differences in peptide repertoires, reflected further in distinct T-cells polarisation pathways.
Subject(s)
HLA-DR Antigens/metabolism , Immune Checkpoint Proteins/metabolism , Leukemia, Myeloid, Acute/immunology , Plasma Cells/immunology , T-Lymphocytes/immunology , Adult , Aged , Antigen Presentation , Antigens, Differentiation, B-Lymphocyte/metabolism , B7 Antigens/metabolism , B7-2 Antigen/metabolism , B7-H1 Antigen/metabolism , Female , Gene Expression Regulation, Neoplastic , HLA-D Antigens/metabolism , Histocompatibility Antigens Class II/metabolism , Humans , Immune Checkpoint Proteins/genetics , Male , Middle Aged , Transcriptome , Tumor MicroenvironmentABSTRACT
Blastic plasmacytoid dendritic cell neoplasms (BPDCNs) are extremely rare and aggressive hematological malignancies that derive from precursors of plasmacytoid dendritic cells (pDC) and frequently involve skin lesions and bone marrow infiltration. They mostly affect the elderly population and the prognosis is poor with the therapeutic choices currently available. Diagnosis is made with the help of tools such as immunohistochemistry and flow cytometry. Here, we present a particular case of BPDCN with a positive FLT3-D835 mutation and we discuss the possible impact this may have on the evolution of the disease and response to treatment.
ABSTRACT
Background: Therapy for acute lymphoblastic leukemia (ALL) are currently initially efficient, but even if a high percentage of patients have an initial complete remission (CR), most of them relapse. Recent data shows that immunotherapy with either bispecific T-cell engagers (BiTEs) of chimeric antigen receptor (CAR) T cells can eliminate residual chemotherapy-resistant B-ALL cells. Objective: The objective of the manuscript is to present improvements in the clinical outcome for chemotherapy-resistant ALL in the real-life setting, by describing Romania's experience with bispecific antibodies for B-cell ALL. Methods: We present the role of novel therapies for relapsed B-cell ALL, including the drugs under investigation in phase I-III clinical trials, as a potential bridge to transplant. Blinatumomab is presented in a critical review, presenting both the advantages of this drug, as well as its limitations. Results: Bispecific antibodies are discussed, describing the clinical trials that resulted in its approval by the FDA and EMA. The real-life setting for relapsed B-cell ALL is described and we present the patients treated with blinatumomab in Romania. Conclusion: In the current manuscript, we present blinatumomab as a therapeutic alternative in the bridge-to-transplant setting for refractory or relapsed ALL, to gain a better understanding of the available therapies and evidence-based data for these patients in 2019.
Subject(s)
Antibodies, Bispecific/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Drug Resistance, Neoplasm/immunology , Immunotherapy, Adoptive , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Drug Resistance, Neoplasm/drug effects , Humans , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapyABSTRACT
Bone marrow (BM) sections were examined in 128 untreated adult patients with newly diagnosed acute lymphoblastic leukemia (ALL), seen in our institution over a 19-year period. BM biopsy was performed in order to assess the incidence, degree and prognostic significance of histological data of the disease. BM features studied were reticular fibrosis, total cellularity, residual hematopoiesis, mitotic activity, and blastic infiltration. T-cell lineage ALL were diagnosed in 23% of the cases, while B-cell lineage ALL represented 70% of the cases. There were 7% of non-T-non-B-cell lineage ALL. The percentage of BM leukemic cells was related to cellularity (P=0.02), while it was related to the disappearance of normal cell lines (P<0.0001). BM cellularity was related to the percentage of circulating leukemic cells at diagnosis (P=0.006). Residual hematopoiesis was related to a higher initial granulocyte count (P=0.04) and lower percentage of circulating blasts (P=0.04). The degree of fibrosis was inversely related to that of BM cellularity (P=0.04). All patients, but four, received standard ALL induction chemotherapy according to different successive protocols. In this whole cohort of patients, complete remission (CR) rate was 78%. Median disease-free survival (DFS) and median overall survival (OS) were 13.7 months and 20.2 months, respectively. In univariate analysis, CR rate was positively affected by mitotic activity (P=0.01) and residual hematopoiesis (P=0.008). OS was positively influenced by a higher leukemic cell mitotic activity (P=0.03) and the persistence of more than two residual normal cell lines in BM (P=0.04). Patients presenting with both of those characteristics had better outcome than patients who did not, as well as, in terms of CR (P=0.03), or DFS (P=0.002), or OS (P=0.003). T-cell lineage ALL and L3 ALL did not significantly influence those results. Our findings did not confirm that among marrow features, reticular fibrosis has any prognostic value. A multivariate analysis of both clinical and histological data was performed to test their prognostic relevance. In a model including age, immunophenotype, Philadelphia chromosome status, mitotic index, and level of normal residual hematopoiesis, the only significant predictor of CR achievement were the persistence of normal residual hematopoietic cell lines (P=0.01) and the mitotic activity of leukemic cells (P=0.002). Philadelphia chromosome status (P=0.03) and age (P<0.0001) were of prognostic value, respectively for DFS and OS. We conclude that some characteristics of BM biopsy afford not only descriptive but also prognostic information for predicting the outcome. The persistence of normal residual hematopoiesis and intense leukemic cells mitotic activity were both factors of favorable outcome, while BM fibrosis did not display any prognostic value.