Mariarita Sciumè

Effects of first- and second-generation tyrosine kinase inhibitor therapy on glucose and lipid metabolism in chronic myeloid leukemia patients: a real clinical problem?

Background Tyrosine kinase inhibitors (TKIs) have dramatically changed the prognosis of patients with chronic myeloid leukemia (CML). They have a distinct toxicity profile that includes glycometabolic alterations: i.e. diabetes mellitus (DM), impaired fasting glucose (IFG), and the metabolic syndrome (MS). The aim of this study was to evaluate the prevalence of these alterations in a cohort of CML-chronic phase patients treated with imatinib, dasatinib or nilotinib. Methods The study involved 168 consecutive CML-chronic phase patients with no history of DM/IFG or MS. Anthropometric and metabolic parameters were assessed, and DM/IFG and MS were diagnosed based on the criteria of the American Diabetes Association and the National Cholesterol Education Program-Adult Treatment Panel III, respectively. Results The nilotinib group had significantly higher levels of fasting plasma glucose, insulin, C-peptide, insulin resistance, and total and LDL cholesterol than the imatinib and dasatinib groups. DM/IFG were identified in 25% of the imatinib- and dasatinib-treated patients, and 33% of those in the nilotinib cohort (p = 0.39 vs imatinib and p = 0.69 vs dasatinib). A diagnosis of MS was made in 42.4% of the imatinib-treated patients, 37.5% of the dasatinib-treated patients, and 36.1% of the nilotinib-treated patients (p = 0.46 vs imatinib and p = 0.34 vs dasatinib). Conclusions Treatment with nilotinib does not seem to induce DM/IFG or the MS to a significantly higher extent than imatinib or dasatinib, though it causes a worse glycometabolic profile. These findings suggest the need for a close monitoring of glucose and lipid metabolism and a multidisciplinary approach in patients treated with nilotinib.

Lenalidomide in the Treatment of Chronic Lymphocytic Leukemia

The application of nucleoside analogue-based chemotherapy and immunotherapy with rituximab or alemtuzumab has increased both response rate and survival in patients with Chronic Lymphocytic Leukemia (CLL). However, because none of these therapies is curative, sequential therapeutic regimens are required. The majority of patients with relapsed or refractory CLL carry poor prognostic factors and show shorter overall survival and resistance to standard treatment. Numerous drugs have recently been approved for CLL therapy and many novel agents are under clinical investigation. The role of the tumor microenvironment and of immune dysfunction in CLL have allowed to enlarge the therapeutic armamentarium for CLL patients. This article will provide a comprehensive summary regarding mechanism of action, efficacy and safety of lenalidomide in CLL patients. Relevant clinical trials using lenalidomide alone or in combinations are discussed. Lenalidomide shows good activity also in relapsed/refractory or treatment-naive CLL patients. Definitive data from ongoing studies are needed to validate overall and progression-free survival. The toxicity profile might limit lenalidomide use because it can result in serious side effects, but largely controlled by gradual dose escalation. Further understanding of the exact mechanism of action in CLL will allow more efficacious use of lenalidomide alone or in combination regimens.

Marked eosinophilia as initial presentation of breast implant-associated anaplastic large cell lymphoma

Nicola Orofino, Francesca Guidotti, Daniele Cattaneo, Mariarita Sciumè, Umberto Gianelli, Agostino Cortelezzi and Alessandra Iurlo Oncohematology Division, IRCCS Ca’ Granda – Maggiore Policlinico Hospital Foundation, University of Milan, Milan, Italy; Hematopathology Service, Division of Pathology, Department of Pathophysiology and Transplantation, University of Milan and IRCCS Ca’ Granda – Maggiore Policlinico Hospital Foundation, Milan, Italy; Oncohematology Unit of the Elderly, IRCCS Ca’ Granda – Maggiore Policlinico Hospital Foundation, Milan, Italy

Low-dose alemtuzumab in refractory/relapsed chronic lymphocytic leukemia: Genetic profile and long-term outcome from a single center experience

Relapsed/refractory chronic lymphocytic leukemia (CLL) represents a clinical challenge, in particular when high risk gene mutations occur. In this setting, alemtuzumab was recognized to be effective. This retrospective study evaluates long‐term efficacy and tolerability of low‐dose alemtuzumab in relapsed/refractory CLL and correlates clinical outcome with biological feature. Sixty‐two consecutive patients (median age 68 years) were evaluated; alemtuzumab was administered 30 mg weekly for up to 18 weeks. Among the patients included in the analysis, 37% were fludarabine‐refractory, 33.3% carried a TP53 disruption, 14.8% a NOTCH1 mutation and 9% a SF3B1 mutation. Overall response rate (ORR) was 61.3% (complete remission 25.8%). After a median follow‐up of 43 months, overall survival (OS) and progression free survival (PFS) were 43.1 and 15 months, respectively; while ORR was 77.8% for patients carrying TP53 disruptions (OS 33.8 months) and 43.5% for fludarabine‐refractory patients (OS 30 months). Noteworthy, long‐term survivors (OS ≥ 36 months) were 54.8%. None of the biological poor risk factors negatively impacted on ORR, PFS and OS. Grade ≥3 cytopenia occurred in 24.2% patients, 6.5% experienced a grade ≥3 non‐CMV infection and no grade ≥3 CMV‐event occurred. In conclusion, low dose‐alemtuzumab is safe and effective in relapsed/refractory CLL, also in a long‐term follow‐up and high‐risk genetic subgroups. Am. J. Hematol. 90:970–974, 2015.

Oxidative status in treatment-naïve essential thrombocythemia: a pilot study in a single center

Oxidative stress (OS), due to pro‐oxidant species [reactive oxygen species (ROS)] excess not counterbalanced by endogenous antioxidant molecules [e.g., reduced glutathione (GSH)], is involved in the pathogenesis of human cancers, but few data are available on essential thrombocythemia (ET). This study aims to investigate OS in ET off‐therapy patients. Thirty ET treatment‐naïve patients were compared with 26 age‐matched and gender‐matched controls. Serum ROS, urinary 8‐hydroxydeoxyguanosine, full blood GSH levels, and reduced/oxidized GSH ratio (GSH/GSSG) were measured. Data were adjusted for gender, age, JAK2 mutational status, smoking, dyslipidemia, or hypercholesterolemia requiring drug therapy, antiplatelet therapy, treatment with acetylsalicylic acid, high‐sensitive C‐reactive protein levels, and absolute monocyte count. ROS and GSH levels were increased in both patients and controls. Patients showed increased GSSG (p = 0.05), reduced GSH/GSSG ratio (p = 0.08), and similar 8‐hydroxydeoxyguanosine levels when compared with controls. No differences in OS parameters were found between JAK2‐positive and JAK2‐negative patients. Confounding factors did not modify the results. Our study suggests an OS condition in a cohort of treatment‐naïve ET patients, not associated with JAK2 mutational status or with chronic inflammation situation. GSH/GSSG ratio, altered in ET patients because of increased GSSG levels, showed the presence of higher GSH levels in ET than controls as a possible compensatory mechanism of an excess of pro‐oxidant production. Copyright

Biological and molecular characterization of a rare case of cutaneous Richter syndrome.

Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia in a high‐grade lymphoma usually presenting nodal and bone marrow involvement. Richter syndrome can be localized at extranodal sites including the gastrointestinal tract, lungs, and skin. Cutaneous RS is an extremely rare disease apparently showing a less aggressive course than common presentations. While nodal RS has been extensively investigated in literature, pathogenesis and prognosis of cutaneous RS are still partially unknown, even if a role of Epstein‐Barr virus infection and p53 disruption has been suggested. Herein, we characterized the histopathological, immunohistochemical features and cytogenetics and molecular alterations of a case of cutaneous RS developed after 8 years chronic lymphocytic leukemia history. Moreover, we reviewed the literature reports concerning cutaneous RS and made a focus on biological patterns and prognostic implications.

Early Detection of Pulmonary Hypertension in Primary Myelofibrosis: The role of Echocardiography, Cardiopulmonary Exercise Testing and Biomarkers

of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2016 [Epub ahead of print]. [5] Ostronoff F, Othus M, Lazenby M, et al. Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report. J Clin Oncol. 2015;33:1157–1164. [6] Guolo F, Minetto P, Clavio M, et al. High feasibility and antileukemic efficacy of fludarabine, cytarabine, and idarubicin (FLAI) induction followed by risk-oriented consolidation: a critical review of a 10-year, single-center experience in younger, non M3 AML patients. Am J Hematol. 2016;91:755–762.

Treating chronic lymphocytic leukemia with obinutuzumab: safety and efficacy considerations

ABSTRACT Introduction: Obinutuzumab is a novel glycoengineered type II anti-CD20 monoclonal antibody (MoAb) with a higher affinity for CD20 epitope. It was approved by the United States Food and Drug Administration (FDA) in November 2013 for use in combination with chlorambucil for previously untreated chronic lymphocytic leukemia (CLL). Areas covered: This article evaluates the safety of obinutuzumab in CLL patients, also addressing pharmacokinetics/pharmacodynamics (PK/PD), clinical use and efficacy. Moreover, a comparison with other anti-CD20 MoAb is performed. The principal available studies on obinutuzumab are reviewed, focusing on CLL. A PubMed literature search (August 2002 to September 2015) was conducted using the terms obinutuzumab, GA101, anti-CD20 antibody, and CLL. Expert opinion: Obinutuzumab, a third-generation anti-CD20 MoAb, is a safe and effective treatment for elderly patients who are un-fit for fludarabine-based regimen. Its use, proven in the CLL11 study and the results of many ongoing trials evaluating other obinutuzumab-based regimen can lead obinutuzumab to be a candidate to replace rituximab as the first-line treatment option.