Updated guidelines for managing fungal diseases in hematology patients

Many prospective open or comparative studies have been published over the last few years on antifungals. As invasive fungal disease remains an important cause of morbidity and mortality in high-risk hematology patients, the correct use of antifungal drugs, either as prophylaxis, empirical treatment in neutropenic patients or for therapy of overt disease, is of the utmost importance. Several international or national groups, including the Infectious Diseases Society of America and the European Conference on Infections in Leukaemia, have elaborated practice guidelines to improve the correct usage of antifungals. This article summarizes these guidelines, which have very similar recommendations, and comments on their evidence base.     

Secondary osteosarcoma arising after treatment for childhood hematologic malignancies

Abstract

Secondary osteosarcoma arising after the treatment of hematologic malignancies other than Hodgkin's lymphoma is rare. We report two cases of secondary osteosarcoma arising after treatment for childhood hematologic malignancies (non-Hodgkin's lymphoma and lymphoblastic leukemia). A 10-year-old boy, at the age of 3, was diagnosed with non-Hodgkin's lymphoma. He received chemotherapy, radiation, and bone-marrow transplantation and then was in complete remission. At 6 years, he complained of increasing pain of the right thigh and was diagnosed with osteoblastic osteosarcoma. A 26-year-old man, at the age of 6, was diagnosed as having acute lymphoblastic leukemia (ALL). He received chemotherapy, radiation, and peripheral blood stem cell transplantation (PBSCT). At 11 years after PBSCT, he visited with the complaint of left lumbar swelling. He was diagnosed with chondroblastic osteosarcoma. In both cases alkaline phosphatase (ALP) had already increased prior to the onset of the symptom. We should rule out secondary osteosarcoma at the abnormal elevation of ALP during clinical follow-up of patients after treatment of childhood hematologic malignancies.     

急性淋巴细胞白血病(ALL)复发患儿化疗后合并侵袭性真菌感染一例(英文)

真菌感染在血液系统疾病尤其是血液系统恶性疾病中十分常见。血液系统恶性疾病伴肺部真菌感染多表现为发热、咳嗽及肺部影像学改变。但是,肺部的X线及CT等影像学改变多无特异性。本例病例中,急性淋巴细胞白血病患儿在强化疗后出现粒细胞缺乏伴发热,经强有力的抗生素治疗无效。患儿给予经验性抗真菌治疗,最后予威凡片剂治疗后好转。患儿在抗真菌治疗的同时行小剂量化疗,最终患儿白血病治愈,肺部侵袭性真菌感染控制。     

The 32nd Annual Meeting of German Society of Immunology

The use of unmodified asparaginases (ASP) in the management of pediatric and adult acute lymphoblastic leukemia (ALL) is well established. Despite its well-proven clinical efficacy, the use of unmodified Escherichia coli ASP (EC-ASP) has been limited by frequent toxicities, especially the development of hypersensitivity reactions and neutralizing antibodies, and by the need for frequent administration. To overcome these limitations, EC-ASP enzyme was covalently linked to monomethoxypolyethylene glycol (PEG), forming the pegylated ASP (PEG-ASP) (Oncaspar^®). PEG-ASP has a prolonged half-life and is associated with decreased immunogenicity when compared with EC-ASP. Clinical trials have demonstrated the efficacy, safety and tolerability of PEG-ASP administered intramuscularly, subcutaneously or intravenously as part of multi-agent chemotherapy regimens in the management of newly diagnosed and relapsed pediatric and adult ALL. Here we discuss the pharmacology, pharmacokinetics, clinical trial results and potential side effects of PEG-ASP.     

Imatinib mesylate for the treatment of chronic myeloid leukemia

Chronic myeloid leukemia (CML) is the first human malignancy for which the promise of targeted therapy has come true. CML is invariably associated with a specific genetic lesion – the t(9;22) chromosomal translocation. As a consequence of this translocation, a BCR-ABL fusion gene is formed on the 22q- derivative (traditionally known as the Philadelphia chromosome) and the deregulated tyrosine kinase activity of the protein encoded by this gene has been shown to be both necessary and sufficient for initiation and maintenance of the disease. Imatinib mesylate, an orally available tyrosine kinase inhibitor that targets Bcr-Abl, entered clinical evaluation in 1998. Its efficacy surpassed almost everyone’s predictions, and the observation of high response rates and favorable toxicity profile associated with imatinib therapy led to its approval as first-line treatment for all newly diagnosed CML patients over an exceptionally short period of time. The 6-year results of the Phase III trial have recently been reported and confirm durability of responses and declining incidence of adverse events over time, although, at present, occurrence of unexpected side effects in the long term cannot be excluded. Although imatinib does not ‘cure’ CML and has to be administered chronically to patients, it has revolutionized both outcome and quality of life of CML patients.     

Choosing first-line therapy for chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) exhibits a highly variable natural history, but the addition of genomic risk stratification to traditional clinical staging systems has begun to explain the heterogeneous clinical course. Overall response to treatment has significantly improved over the past three decades and for the first time, a survival benefit has been demonstrated with the use of monoclonal antibodies in combination with cytotoxic chemotherapy. Newer therapeutic strategies have abrogated the adverse prognosis associated with some higher risk features, but other genetic subgroups remain at high risk for rapid disease progression and early mortality. Patients at advanced age or with significant comorbidity constitute a large proportion of the CLL population and present unique clinical challenges. This article will discuss the evolution of contemporary therapeutic approaches to the initial treatment of CLL, and highlight the ways in which risk-adapted therapeutic strategies are improving clinical outcomes.     

IGHV3‐21 gene usage is associated with high TCL1 expression in chronic lymphocytic leukemia

T‐cell leukemia/lymphoma protein 1 (TCL1) was recently shown to display an expression pattern in chronic lymphocytic leukemia (CLL) corresponding to molecular subtypes, where poor‐risk patients demonstrated higher expression levels. Here, we examined the mRNA expression pattern of TCL1 in 144 patients with CLL, including 67 immunoglobulin heavy‐chain variable (IGHV) mutated, 58 IGHV unmutated and 19 patients with IGHV3‐21 usage. A higher TCL1 expression level was detected in patients with CLL with unmutated vs. mutated IGHV genes (P < 0.001), whereas no difference was demonstrated within the IGHV3‐21 cohort (i.e., mutated vs. unmutated and stereotyped vs. non‐stereotyped complementarity determining region 3). The IGHV3‐21 subgroup displayed high TCL1 mRNA expression, differing significantly from other IGHV mutated cases (P < 0.001), although 11/19 had mutated IGHV genes. Furthermore, high TCL1 expression levels were associated with significantly shorter overall survival (P < 0.001). Altogether, we show that TCL1 mRNA expression may predict clinical outcome in CLL and that the IGHV3‐21 subset, regardless of mutational status, displays high TCL1 expression.     

Anti‐leukemic activity of valproic acid and imatinib mesylate on human Ph+ ALL and CML cells in vitro

The armamentarium of anti‐leukemic drugs has increased substantially since anti‐leukemic activities were recently found for a variety of non‐classical cytostatic drugs, among them the histone deacetylase (HDAC) inhibitor valproic acid (VPA). This study investigated the effect of VPA on proliferation and apoptosis of human Philadelphia chromosome‐positive (Ph+) acute lymphatic (ALL) and chronic myeloid leukemia (CML) cells and on colony formation of human chronic‐phase CML progenitor cells. Strong anti‐proliferative and pro‐apoptotic effects of VPA were observed on human ALL and CML cell lines at concentrations achievable in vivo. These effects were most pronounced in ALL cell lines as well as in primary ALL cells. Notably, VPA revealed enhanced activity with imatinib mesylate, nilotinib, the farnesyl transferase inhibitor SCH66336, interferon‐alpha and cytosine arabinoside. VPA inhibited the growth of colony‐forming cells from 12 Ph+ chronic‐phase CML patients but also of those from normal healthy controls in a dose‐dependent fashion. HDAC‐inhibiting activity of VPA was confirmed on ALL and CML cells. In conclusion, VPA, whether alone or in combination with other non‐classical anti‐leukemic compounds, exerts significant anti‐leukemic effects on human ALL and CML cells.     

Cytogenetics of pediatric acute myeloid leukemia

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease accounting for 15–20% of all childhood acute leukemias, while it is responsible for more than half of the leukemic deaths in these patients. This article focuses on the significance of cytogenetic analysis in pediatric AML supporting the importance of cytogenetic analysis in the pathogenesis, diagnosis, prognosis, follow‐up and treatment selection in childhood AML. It reviews in detail the types and frequencies of most common chromosomal aberrations, their molecular background, their correlation with French American British (FAB) subtypes and age distribution and their prognostic relevance. It also summarizes some less frequent or rare chromosome aberrations in which the prognostic classification has not been determined yet owning to the small number of patients and the variable treatment modalities used in different study groups. Furthermore, it discusses the association of specific chromosome rearrangements with prenatal exposure to carcinogenic agents or therapeutic agents and highlights the ongoing and future research on pediatric AML in the evolving field of Cytogenetics.