Annamaria Petrungaro

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.

Venetoclax for the treatment of chronic lymphocytic leukemia

ABSTRACT 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.

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.

Decreased Plasma Levels of IL-33 Could Contribute to the Altered Function of Th2 Lymphocytes in Patients with Polycythemia Vera and Essential Thrombocythemia

To the Editor: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPNs) primarily characterized by erythrocytosis and thrombocytosis, respectively (1). In addition, quality of life is adversely affected by a spectrum of disease complications including pruritus. Interleukin-33 (IL-33) is a cytokine from the IL-1 family, which has been linked to important diseases, including asthma, rheumatoid arthritis, ulcerative colitis, metabolic, neurologic, and cardiovascular diseases. IL-33 drives cytokine production in type 2 innate lymphoid cells (ILCs), T-helper (Th)2 lymphocytes, mast cells, basophils, eosinophils, invariant natural killer T (iNKT), and natural killer (NK) cells (2). In a previous work, we found a significant decrease of IL-33 plasma levels in patients affected by multiple myeloma, with a negative correlation between levels of IL-33 and stage (3). In the present study, we analyzed the plasma levels of IL33 in patients with PV and ET. In the same subjects, we also performed analysis of the JAK2V617F mutation, and evaluated a possible relationship between interleukin levels and thrombotic complications or with pruritus. Our population consisted of 65 patients with ET (29 M, 36 F; mean age = 66 ± 9 years) and 41 patients with PV (26 M, 15 F; mean age = 68 ± 12 years). Thirty-three patients (17 ET, 16 PV) had thrombotic symptoms in the past. All patients had not received aspirin or any treatment for ET or PV over the last 7 days. The study was conducted according to the principles of the Declaration of Helsinki. Informed written consent was obtained after potential risks were explained to the subjects. Plasma levels from 63 sexand age-matched normal subjects (35 M, 28 F; mean age = 64 ± 11 years) were also included in this study as controls. None of the patients or control subjects had symptoms or laboratory signs of active infections, inflam-

Severe dermatologic adverse reactions after exposure to lenalidomide in multiple myeloma patients with a positive HLA-DRB1*1501 and HLA-DQB1*0602

elucidated. It has been reported that the activation of Fas through Fas ligand (FasL) is an important primary step leading to keratinocyte apoptosis. CD94/NKG2C might be also involved in triggering cytotoxic lymphocytes in patients with SJS. Chung et al. showed that secretory 15-kDa granulysin, not granzyme B, or perforin, is a key molecule responsible for the disseminated keratinocyte death, with a significant correlation of granulysin levels in blister fluids with clinical severity. Moreover, various cytokines (TNF-a, interferon-g, IL-4, IL-6, IL-12, IL-13 and IL-18) may also contribute to epidermal cell death as well as to some of the constitutional symptoms [4]. Finally, special attention has focused recently on genetic susceptibility. Increasing data have in fact revealed that the genetic predisposition plays important roles in drug hypersensitivity. There was a correlation for SJS with HLA-B∗44, DRB1∗07 and with the MHC ancestral 57.1 haplotype, and its constituents, in Caucasian subjects [5]. References

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.

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.

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.

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.

Pomalidomide in multiple myeloma

The recent introduction of novel agents (thalidomide, lenalidomide, and bortezomib) has impacted favorably on the survival of multiple myeloma (MM) patients. However, prognosis is poor for those who relapse or are refractory (RR) to lenalidomide and bortezomib [1]. Pomalidomide, a third-generation IMiD, was approved in 2013 by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in combination with low-dose dexamethasone for MM patients who have received at least two prior therapies, including both lenalidomide and bortezomib, and whose disease progressed after the last treatment. Herein, we review the current knowledge regarding the clinical use of pomalidomide in MM (Tables 1 and 2).