Efficacy of biosimilar granulocyte colony-stimulating factor versus originator granulocyte colony-stimulating factor in peripheral blood stem cell mobilization in de novo multiple myeloma patients.

BACKGROUND AIMS: Filgrastim and lenograstim are the standard granulocyte colony-stimulating factor (G-CSF) agents for peripheral blood stem cell mobilization (PBSC) in patients who undergo autologous stem cell transplantation. METHODS: To assess whether biosimilars are effective, we conducted a single-center, prospective study that included 40 consecutive de novo multiple myeloma patients who received cyclophosphamide 4 g/m(2) per day plus biosimilar filgrastim G-CSF to mobilize PBSC. These patients were compared with a group of 37 patients matched for age, diagnosis, previous chemotherapy and mobilization who had been treated with originator G-CSF. The mean number of CD34+ cells/µL in the peripheral blood was 199.6 ± 207.4 in the biosimilar and 192.8 ± 154.7 in the originator group (P = 0.87). The median number of CD34+ cells/kg recipient collected was 11.5 ± 5.8 and 12.3 ± 5.3 in the biosimilar and originator groups, respectively (P = 0.51). The mobilization failure rate was 2.5% and 2.7% in the biosimilar filgrastim and originator filgrastim cohorts (P = NS), respectively. RESULTS: Twenty-nine patients in the biosimilar group and 28 patients in the originator group underwent autologous transplantation. There were no statistically significant differences between the biosimilar and originator G-CSF cohorts in terms of hematopoietic recovery parameters and transplant-related toxicities. CONCLUSIONS: The efficacy of biosimilar G-CSF appears to be equivalent to the reference G-CSF.

The cancer stem cell hypothesis: a guide to potential molecular targets.

Common cancer theories hold that tumor is an uncontrolled somatic cell proliferation caused by the progressive addition of random mutations in critical genes that control cell growth. Nevertheless, various contradictions related to the mutation theory have been reported previously. These events may be elucidated by the persistence of residual tumor cells, called Cancer Stem Cells (CSCs) responsible for tumorigenesis, tumor maintenance, tumor spread, and tumor relapse. Herein, we summarize the current understanding of CSCs, with a focus on the possibility to identify specific markers of CSCs, and discuss the clinical application of targeting CSCs for cancer treatment.

Potential New Therapies "ROS-Based" in CLL: An Innovative Paradigm in the Induction of Tumor Cell Apoptosis.

Chronic lymphocytic leukemia, in spite of recent advancements, is still an incurable disease; the majority of patients eventually acquire resistance to treatment through relapses. In all subtypes of chronic lymphocytic leukemia, the disruption of normal B-cell homeostasis is thought to be mostly caused by the absence of apoptosis. Consequently, apoptosis induction is crucial to the management of this illness. Damaged biological components can accumulate as a result of the oxidation of intracellular lipids, proteins, and DNA by reactive oxygen species. It is possible that cancer cells are more susceptible to apoptosis because of their increased production of reactive oxygen species. An excess of reactive oxygen species can lead to oxidative stress, which can harm biological elements like DNA and trigger apoptotic pathways that cause planned cell death. In order to upset the balance of oxidative stress in cells, recent therapeutic treatments in chronic lymphocytic leukemia have focused on either producing reactive oxygen species or inhibiting it. Examples include targets created in the field of nanomedicine, natural extracts and nutraceuticals, tailored therapy using biomarkers, and metabolic targets. Current developments in the complex connection between apoptosis, particularly ferroptosis and its involvement in epigenomics and alterations, have created a new paradigm.

Monoclonal antibodies: potential new therapeutic treatment against multiple myeloma.

Despite recent treatments, such as bortezomib, thalidomide, and lenalidomide, therapy of multiple myeloma (MM) is limited, and MM remains an incurable disease associated with high mortality. The outcome of patients treated with cytotoxic therapy has not been satisfactory. Therefore, new therapies are needed for relapsed MM. A new anticancer strategy is the use of monoclonal antibodies (MoAbs) that represent the best available combination of tumor cytotoxicity, environmental signal privation, and immune system redirection. Clinical results in patients with relapsed/refractory MM suggest that MoAbs are likely to operate synergistically with traditional therapies (dexamethasone), immune modulators (thalidomide, lenalidomide), and other novel therapies (bortezomib); in addition, MoAbs have shown the ability to overcome resistance to these therapies. It remains to be defined how MoAb therapy can most fruitfully be incorporated into the current therapeutic paradigms that have achieved significant survival earnings in patients with MM. This will require careful consideration of the optimal sequence of treatments and their clinical position as either short-term induction therapy, frontline therapy in patients ineligible for ASCT, or long-term maintenance treatment.

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.

Stevens-Johnson syndrome after lenalidomide therapy for multiple myeloma: a case report and a review of treatment options.

Stevens- Johnson syndrome (SJS) is a severe and life-threatening condition. Although allopurinol, an antihyperuricemia drug, is the drug most commonly associated with SJS, more than 100 different causative drugs have been reported. Among hematologic drugs recently introduced into the market, drugs such as rituximab, imatinib, and bortezomib are reported. Here, we describe a patient with SJS while receiving lenalidomide in combination with prednisolone for treatment-naïve multiple myeloma. Although SJS has been reported rarely as an adverse reaction to Lenalidomide, this drug should be considered in the etiology of SJS, and the increased number of prescriptions of Lenalidomide for the therapy of multiple myeloma has to stress the awareness of its potentially serious side-effects.

Increase of novel biomarkers for oxidative stress in patients with plasma cell disorders and in multiple myeloma patients with bone lesions.

OBJECTIVES: Protein oxidation plays a key role in the pathogenesis of oncological diseases. In this study, we analyzed the oxidative stress in untreated multiple myeloma (MM) patients and in patients affected by monoclonal gammopathy of uncertain significance (MGUS). METHODS: We evaluated serum levels of advanced oxidation protein products (AOPPs), advanced glycation end products (AGEs), and protein nitrosylation in patients with monoclonal gammopathy and in control subjects. RESULTS: Serum levels of AOPPs and S-nitrosylated proteins were significantly increased in MM patients in comparison to controls and to MGUS subjects. Moreover, in MM patients the levels of AOPPs, AGEs and S-nitrosylated proteins were significantly higher in patients with bone lesions compared with those without lytic bone lesions. CONCLUSIONS: MM is closely associated with oxidative stress and further investigation might provide an insight to understand a putative causal link between oxidative stress and MM disease onset and progression or MM complications.

Imatinib mesylate therapy induces reduction in neutrophil gelatinase-associated lipocalin serum levels and increase in leptin concentrations in chronic myeloid leukemia patients in molecular remission.

The aim of the present study was to determine serum levels of neutrophil gelatinase-associated lipocalin (NGAL) and leptin in patients with chronic myeloid leukemia (CML) at diagnosis and after imatinib therapy when patients achieved a complete molecular remission. The study was conducted on 22 patients with CML in the chronic phase and 10 healthy subjects. The median serum NGAL levels in CML patients at diagnosis were significantly higher compared to age-matched controls. After imatinib therapy, all patients achieved complete molecular remission and NGAL levels decreased and were found significantly lower with respect to the baseline. No significant correlations were found between NGAL levels and other disease parameters. Before imatinib therapy, the median blood leptin levels were not significantly different from those of controls. After therapy with imatinib, all patients in molecular remission presented an increase in leptin levels. Future research is eagerly awaited as it may demonstrate the real role of NGAL and leptin in the onset and progression of CML.

Novel therapeutic strategies in multiple myeloma: role of the heat shock protein inhibitors.

Despite advances in understanding the molecular pathogenesis of multiple myeloma and promising new therapies, almost all patients eventually relapse with resistant disease. There is therefore a strong rationale for combining novel therapies that target intrinsic molecular pathways mediating multiple myeloma cell resistance. One such protein family is the heat shock proteins (HSP), especially the HSP90 family. Heat shock protein inhibitors have been identified as promising cancer treatments as, while they only inhibit a single biologic function, the chaperone-protein association, their effect is widespread as it results in the destruction of numerous client proteins. This article reviews the preclinical and clinical data, which support the testing of HSP90 inhibitors as cancer drugs and update the reader on the current status of the ongoing clinical trials of HSP90 inhibitors in multiple myeloma.

Endoscopic mucosal resection of a large inflammatory fibroid polyp (Vanek's tumor): a case report.

Vanek's Tumor (inflammatory fibroid polyp) is a rare benign mesenchymal lesion occurring throughout the digestive tract. Classical Vanek's tumor ("gastric") contains concentric formations of proliferating spindle cells, which are CD34 positive. Atypical-inflammatory pseudotumor-like Vanek's tumor ("intestinal") lacks concentric formations and is CD34 negative. A 70-years-old man patient presented during hematochemical routine tests, sideropenic anemia and leukopiastrinosis. The patient performed osteomyelitis biopsy and esophagogastroduodenoscopy (EGD) showing a gastric wall with nodular appearance and, in antrum pre-pyloric, a polypoid pedunculated lesion, measuring approximately 3 cm in diameter, surrounded by hyperemic mucosa. The lesion then was removed by en bloc endoscopic mucosal resection (EMR) and histo-morphological, immune-cytochemical and biomolecular evaluations were performed. The data were compatible with a benign polyp fibroid inflammatory (Vanek's Tumor). The results of this study suggest that endoscopic mucosal resection is a safe and efficacy solution for the resection of these gastrointestinal polyps and the two morphological patterns of Vanek's tumor more probably represent only variants of one type of tumor than two different lesions. BRAF mutations were not shown growth PDGFRA wild-type Vanek's tumor.

Epigenetic therapy in myelodysplastic syndromes.

The wide spectrum of clonal hematopoietic disorders that fall under the broad diagnostic category of myelodysplastic syndromes (MDS) consist of a family of bone marrow malignancies - with ineffective, inadequate, and dysplastic hematopoiesis, and with an increased risk of life-threatening infections, bleeding, and progression to acute myeloid leukemia (AML) - that are characterized by a deep heterogeneity on the clinical, biologic and prognostic level. The intrinsic complexity of this group of disorders and the frequent association with one or more comorbidities have limited for many years the number of effective treatment options available: most patients are, indeed, still managed by supportive care measures, with just a minority of them being eligible for allogeneic stem cell transplantation, which is still the only potentially curative modality. In the last two decades, the progressively better understanding of MDS biology has shown how an abnormal epigenetic modulation might play a crucial part in the pathogenesis and in the process of biologic evolution of these disorders. Moreover, pharmacological agents that target the so-called epigenome have shown a significant clinical activity for diverse hematologic malignancies, including MDS. The aim of this review is to highlight recent developments within the context of current knowledge of MDS and its altered epigenetic regulation and to recall the experimental steps that have brought to the clinical development and application of epigenetic modifiers, such as azacytidine and decitabine, trying to explain the biologic rationale for their use in this setting.

Bisphosphonates induce apoptosis of circulating endothelial cells in multiple myeloma patients and in subjects with bisphosphonate-induced osteonecrosis of the jaws.

Bisphosphonates (BPs) are the current standard of care for bone lesions in patients with multiple myeloma (MM) but they are associated with a number of side effects such as osteonecrosis of the jaw. The exact mechanisms of osteonecrosis are not elucidated, and its physiopathology is based on several hypotheses such as a decrease in bone remodeling or an inhibitory effect on angiogenesis. The aim of our study was to investigate the mechanism involved in the pathogenesis of osteonecrosis. We examined the apoptosis of circulating endothelial progenitor cells in MM subjects before and after BP treatment and in osteonecrosis patients using a flow-cytometric analysis. Our data showed an increase in endothelial cell apoptosis in MM patients after BP administration and in osteonecrosis subjects. Our study seems in agreement with the hypothesis that BPs can inhibit angiogenesis interfering with endothelial cell proliferation and survival, leading to loss of blood vessels and avascular necrosis.

Absence of the V617F JAK2 mutation in the lymphoid compartment in a patient with essential thrombocythemia and B-chronic lymphocytic leukemia and in two relatives with lymphoproliferative disorders.

BACKGROUND: Myeloproliferative neoplasms likely involve both myeloid and lymphoid lineages. Nevertheless, the coincidence of chronic myeloproliferative and lymphoproliferative diseases in the same patient is a rare phenomenon. METHODS: We report a case of a patient having essential thrombocythemia (ET) and B-chronic lymphocytic leukemia (B-CLL). In this patient and in 2 relatives with lymphoproliferative disorders, we searched for JAK2(V617F) mutation in lymphocytes. RESULTS: In the patient with ET and B-CLL, we identified homozygous JAK2(V617F) mutation in the granulocytic compartment. Both relatives were heterozygous for JAK2(V617F) mutation, whereas no mutation signal could be detected in the lymphoid compartment of all 3 patients. CONCLUSION: Our results seem to confirm that CLL cases are negative for JAK2(V617F) mutation in B- and T-lymphocyte populations.Presence of JAK2(V617F) mutation in subjects without myeloproliferative diseases could indicate an increased risk of a future myeloproliferative neoplasm development.

JAK2 V617F-positive latent essential thrombocythemia and splanchnic vein thrombosis: the role of bone marrow biopsy for the diagnosis of myeloproliferative disease.

BACKGROUND: Splanchnic vein thrombosis (SVT) is a severe complication of essential thrombocythemia (ET). No clear explanation has been given for the occurrence of thrombosis in this unusual site in patients with ET, but the existence of a specific association between unexplained SVT and the JAK2 mutation has been reported. METHODS AND RESULTS: The present study describes SVT (portal and splenic vein thrombosis) in a young woman as the first presenting symptom of latent ET. Extensive screening for thrombophilia was negative. Our patient in fact did not fulfill the WHO diagnostic criteria for myeloproliferative disease (MPD), while she had splenomegaly and developed features suggestive of latent ET during follow-up. CONCLUSIONS: In these patients with SVT, the detection of JAK2(V617F) mutation is diagnostic for masked MPD as could be documented by bone marrow histopathology. The presence of JAK2(V617F) mutation should be considered per se a prothrombotic state for cerebral, coronary and peripheral microvascular disturbances and for SVT but not for deep vein thrombosis. Anticoagulation is the treatment of choice for all SVT and proper treatment of the MPD is recommended in patients with SVT associated with the JAK2(V617F) mutation.

Telomerase and telomere biology in hematological diseases: A new therapeutic target.

Telomeres are structures confined at the ends of eukaryotic chromosomes. With each cell division, telomeric repeats are lost because DNA polymerases are incapable to fully duplicate the very ends of linear chromosomes. Loss of repeats causes cell senescence, and apoptosis. Telomerase neutralizes loss of telomeric sequences by adding telomere repeats at the 3' telomeric overhang. Telomere biology is frequently associated with human cancer and dysfunctional telomeres have been proved to participate to genetic instability. This review covers the information on telomerase expression and genetic alterations in the most relevant types of hematological diseases. Telomere erosion hampers the capability of hematopoietic stem cells to effectively replicate, clinically resulting in bone marrow failure. Furthermore, telomerase mutations are genetic risk factors for the occurrence of some hematologic cancers. New discoveries in telomere structure and telomerase functions have led to an increasing interest in targeting telomeres and telomerase in anti-cancer therapy.