Iron overload and malignancies in patients with haemoglobinopathies: A single center experience.

Thalassemias and sickle cell disease are a group of inherited blood disorders caused by alterations of the synthesis or of the structure of hemoglobin chains. It results in variable outcomes ranging from severe anemia to clinically asymptomatic individuals. Hemolysis and transfusions therapies lead to iron overload and, thus, to an high production of reactive oxygen species (ROS). Recently, it was found an increasing frequency of tumors in patients with hemoglobinopathies and it was underlined the probable role of iron overload in the carcinogenesis. Here, we describe five patients with hemoglobinopathies affected by different types of cancers and we discuss the role of ROS in the carcinogenesis.

Efficacy of eculizumab in severe ADAMTS13-deficient thrombotic thrombocytopenic purpura (TTP) refractory to standard therapies.

Thrombotic thrombocytopenic purpura (TTP) is a rare microangiopathic hemolytic anemia (MAHA) defined by mechanical hemolytic anemia, severe thrombocytopenia, and systemic visceral ischemia due to systemic platelet-rich microthrombi. Forty percent of patients with autoimmune TTP experience one or multiple relapses. Patients with refractory TTP are currently managed by corticosteroids, twice-daily PEX, and the anti-CD20 monoclonal antibody rituximab. Herein, we report two cases of severe TTP, refractory to those standard agents. On the basis of the fact that in cases of severe TTP the classical complement pathway is activated, and that the alternative pathway is also involved, both patients underwent eculizumab (anti-C5 monoclonal antibody) therapy. We observed prompt hematological and organ system responses to the eculizumab and the recovery of plasma ADAMTS-13 activity in both cases. Moreover, the fact that both patients discontinued eculizumab, maintaining the response, emphasizes the possibility of its usefulness for limited treatment periods. In conclusion, the diagnostic and therapeutic algorithm in TTP appears complicated by increasing evidence of complement involvement and the eculizumab seems to be a potential agent for refractory patients.

Venetoclax for the treatment of chronic lymphocytic leukemia.

INTRODUCTION: Venetoclax, an orally bioavailable inhibitor of BCL-2, was approved in 2016 by the United States Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL) patients with 17p deletion [del(17p)], who have received at least one prior therapy. Areas covered: We focus on the mechanism of action of venetoclax and on the clinical trial data that led to the approval of venetoclax for CLL patients. We also review the studies in which this drug has being explored in combination with other anti-CLL drugs. Expert opinion: Data from early clinical trials have shown that venetoclax, as a single agent, is highly effective for relapsed/refractory CLL patients, including those cases with high-risk features. Furthermore, venetoclax seems to be an appropriate option for patients who progress on B-cell receptor (BCR) pathway kinase inhibitors. Venetoclax is also safe, with the most common serious adverse events being neutropenia. The risk of tumor lysis syndrome (TLS) can be reduced by a slow dose ramp-up, careful monitoring, and adequate prophylaxis. Ongoing trials will further clarify the safety and efficacy of venetoclax in combination with other drugs in both relapsed/refractory and untreated CLL patients.

Ponatinib-Induced Graft-versus-Host Disease/Graft-versus-Leukemia Effect in a Patient with Philadelphia-Positive Acute Lymphoblastic Leukemia without the T315I Mutation Relapsing after Allogeneic Transplant.

We describe the case of a patient with Philadelphia-positive acute lymphoblastic leukemia treated with dasatinib plus steroids as first-line therapy, who achieved a major molecular response (MMR) before undergoing matched, unrelated donor allogeneic stem cell transplant. Eleven months after the transplant, she experienced molecular relapse. Mutational screening showed negativity for the T315I mutation, The patient underwent a salvage chemotherapy regimen with clofarabine + cyclophosphamide + steroids and ponatinib (clofarabine 70 mg i.v., days 1-5, cyclophosphamide 700 mg i.v., days 1-5, and ponatinib 45 mg p.o., daily starting at day 15). We observed a rapid decrease in minimal residual disease on molecular assessment with an MMR of P190-BCR-ABL/ABL = 0.01% confirmed by bone marrow revaluations at days +23, +59, +108, and +191 after the first day of salvage chemotherapy. After starting ponatinib, the patient experienced skin graft-versus-host disease, suggesting that the efficacy of ponatinib could be related not only to the direct antileukemic effect but also to its ability to promote an indirect graft-versus-leukemia effect. Ponatinib treatment was well tolerated and considered safe with easily manageable side effects.

Clinical relevance of hypogammaglobulinemia, clinical and biologic variables on the infection risk and outcome of patients with stage A chronic lymphocytic leukemia.

The prognostic effect of hypogammaglobulinemia (HGG), clinical and biologic characteristics on the infection risk and outcome has been retrospectively analyzed in 899 patients with stage A chronic lymphocytic leukemia (CLL). Low levels of IgG were recorded in 19.9% of patients at presentation, low levels of IgM and/or IgA in 10.4% and an additional 20% of patients developed HGG during the course of the disease. Before the start of any treatment, 160 (12.9%) patients experienced at least one grade ≥3 infection requiring a systemic anti-infective treatment and/or hospitalization. While IgG levels at diagnosis were not associated with an increased risk of grade ≥3 infection or with an adverse outcome, a significantly increased rate of grade ≥3 infections was recorded in patients with unmutated IGHV (p=0.011) and unfavorable FISH aberrations (p=0.009). Late onset HGG, more frequently recorded in patients with Rai stage I-II (p=0.001) and unmutated IGHV (p=0.001), was also associated with a higher rate of severe infections (p=0.002). These data indicate that, stage A patients with clinical and biologic characteristics of a more aggressive disease develop more frequently late onset HGG, grade ≥3 infections and require a closer clinical monitoring.

Lenalidomide and low-dose dexamethasone (Rd) versus bortezomib, melphalan, prednisone (VMP) in elderly newly diagnosed multiple myeloma patients: A comparison of two prospective trials.

There are currently no direct head-to-head clinical trials evaluating bortezomib-melphalan-prednisone (VMP) versus lenalidomide and low-dose dexamethasone (Rd). VMP (257 cases) and Rd (222 cases) arms of two randomized phase III trials were employed to assess the treatment influence on outcome in untreated elderly MM patients. Progression free survival (PFS) and overall survival (OS) were the primary and secondary end-points, respectively, and were investigated according to treatments administered over a 60-months follow-up period. While VMP significantly reduced the disease progression rate between enrolment and 12 months of follow-up, no difference between the two schedules was found between 12 and 32 months. After 32 months, Rd-treated patients had a lower incidence of disease progression. A statistically significant higher OS rate was seen in the VMP arm, which was maintained after data adjustment for potential confounders. Both approaches showed acceptable toxicity profiles. The profound tumor reduction by VMP over Rd justifies the initial higher PFS rate in favor of the bortezomib schedule, while the Rd regimen overcomes this evident initial drawback in reducing the tumor burden by long-term drug administration, gaining a subsequent improved disease control. VMP is associated with a significant reduced risk of death. This study may help physicians make a more informed therapy choice.

Health-related quality of life and burden of fatigue in patients with primary immune thrombocytopenia by phase of disease.

The main objective of this study was to compare health-related quality of life (HRQOL) of primary immune thrombocytopenia (pITP) patients with that of general population, overall, and by patient group (i.e., newly diagnosed, persistent, and chronic patients). Fatigue was also investigated as a secondary objective. Overall, 424 adult patients were enrolled in a multicenter observational study and the control group consisted of a representative sample from the general population. Propensity score matching plus further multivariate linear regression adjustment was used to compare HRQOL outcomes between pITP patients and general population. Mean age of patients was 54 years. Of those with HRQOL assessment, 99 patients (23.6%) were newly diagnosed, 53 (12.6%) were persistent, and 268 (63.8%) were chronic pITP patients. Comparison by patient group versus their respective peers in the general population revealed greater impairments in persistent pITP patients. Persistent pITP patients reported clinically meaningful impairments in physical functioning (-15; 95% CI -24.1 to -5.8; P = 0.002), social functioning (-15.3; 95% CI -25.5 to -5.1; P = 0.004), role physical (-28.4; 95% CI -43.1 to -13.7; P < 0.001), role emotional (-23.9; 95% CI -40.1 to -7.7; P = 0.004), and mental health scales (-11.3; 95% CI -21.2 to -1.4; P = 0.026) of the SF-36 questionnaire. Higher fatigue severity was associated with lower physical and mental HRQOL outcomes. Our findings suggest that the burden of the disease and treatment might depend on the disease phase and that persistent pITP patients are the most vulnerable subgroup. Am. J. Hematol. 91:995-1001, 2016. © 2016 Wiley Periodicals, Inc.

Evaluation of interleukin-23 plasma levels in patients with polycythemia vera and essential thrombocythemia.

Essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis share the same acquired genetic lesion, JAK2V617F. It is believed that cytokines participate in the activation of JAK2V617F. In this study, we analyzed the plasma levels of interleukin (IL)-23, IL-10 and IL-22 in patients with PV and ET. In the same subjects we also performed analysis of the JAK2(V617F) mutation, and evaluated a possible relationship between interleukin levels and thrombotic complications or with the symptom pruritus. Plasma levels of IL-23 were significantly increased in all patients with MPN in comparison to controls. Moreover, there was a significant difference between the levels of IL-23 in patients affected by PV and those measured in controls (8.57±3.69pg/mL vs. 6.55±4.125pg/mL; p<0.03). No difference was found between IL-23 levels in ET patients and controls. No statistically significant differences were found between the levels of IL-23, Il-22 or IL-10 in PV or ET subjects with or without thrombosis, in patients with or without pruritus, or according the JAK2V617F burden. In PV patients the JAK2 burden and Hb levels correlated with occurrence of pruritus. Our study seems to point out a possible involvement of IL-23 in the pathogenesis of PV.

Circulating microRNAs: new biomarkers in diagnosis, prognosis and treatment of cancer (review).

MicroRNAs (miRNAs) are small non-coding, endogenous, single-stranded RNAs. MiRNAs have been implicated in different areas such as the immune response, neural development, DNA repair, apoptosis, oxidative stress response and cancer. However, while the majority of miRNAs are found intracellularly, a significant number of miRNAs have been observed outside of cells, including various body fluids. Circulating miRNAs function as 'extracellular communication RNAs' that play an important role in cell proliferation and differentiation. MiRNA regulation is essential to many cellular processes, and escape from this regulatory network seems to be a common characteristic of several disease processes and malignant transformation. The interest in circulating miRNAs reflects in fact their central role in regulation of gene expression and the implication of miRNA-specific aberrant expression in the pathogenesis of cancer, cardiac, metabolic, neurologic, immune-related diseases as well as others. In our review we aimed to summarize the data related to the action of cellular miRNAs on the onset of various diseases, thus bringing together some of the latest information available on the role of circulating miRNAs. Additionally, the role of circulating miRNAs could be particularly relevant in the context of neoplastic diseases. At least 79 miRNAs have been reported as plasma or serum miRNA biomarkers of solid and hematologic tumors. Circulating miRNA profiling could improve the diagnosis of cancer, and could predict outcome for cancer patients, while the profiling of alterations in circulating miRNA that may signal a predisposition to cancer, could also be a therapeutic target in these patients.

Increased serum levels of neutrophil gelatinase-associated lipocalin in patients with essential thrombocythemia and polycythemia vera.

Neutrophil gelatinaase-associated lipocalin (NGAL) is a glycoprotein bound with matrix metalloproteinase-9 (MMP-9) in human neutrophils, and elevated tissue NGAL expression has been documented in different infectious and inflammatory conditions. Recent evidence suggests that NGAL expression is induced in many types of human cancer. Moreover, NGAL is required for BCR-ABL-induced tumorigenesis. The aim of the present study was to measure serum levels of NGAL in patients with essential thrombocythemia (ET) and polycythemia vera (PV). We also evaluated NGAL levels in patients with ET and PV with and without thrombotic events, to explore a possible correlation of NGAL with platelet and leukocyte activation, and in patients with sepsis. Serum NGAL levels in the study population were significantly higher than in healthy adults and in subjects with sepsis. A correlation between NGAL and the number of white cells and neutrophils was found in patients with PV and ET. NGAL serum levels were not different depending on the presence or not of the JAK2 mutation, and a mutant allele dosage effect was not observed for NGAL levels. Patients with PV and ET with thrombosis did not have significantly higher levels of NGAL. We were unable to demonstrate a significant association between serum NGAL levels and CD11b or CD62 expression. In conclusion, our study reports evidence demonstrating that increased levels of NGAL appear to be a characteristic of patients with PV and ET.