Should patients with acute myeloid leukemia treated with venetoclax-based regimens receive antifungal prophylaxis?

Invasive fungal disease (IFD) is a major complication in patients with acute myeloid leukemia (AML) receiving intensive induction chemotherapy, and the use of anti-mold prophylaxis is considered standard of care. On the other hand, the use of anti-mold prophylaxis in AML patients receiving less-intensive venetoclax-based regimens is not well established, basically because the incidence of IFD may not be high enough to justify primary antifungal prophylaxis. Furthermore, dose adjustments in venetoclax are needed because of drug interactions with azoles. Finally, the use of azoles is associated with toxicity, including liver, gastrointestinal and cardiac (QT prolongation) toxicity. In a setting of low incidence of invasive fungal disease, the number needed to harm would be higher than the number needed to treat. In this paper we review the risk factors for IFD in AML patients receiving intensive chemotherapeutic regimens, the incidence and risk factors for IFD in patients receiving hypomethylating agents alone, and in patients receiving less-intensive venetoclax-based regimens. We also discuss potential problems with the concomitant use of azoles, and present our perspective on how to manage AML patients receiving venetoclax-based regimens without primary antifungal prophylaxis.

BCL-2 Inhibition as Treatment for Chronic Lymphocytic Leukemia.

OPINION STATEMENT: At the end of the 1990s, with the advent of imatinib for chronic myeloid leukemia and rituximab for B cell lymphoproliferative diseases with CD20 expression, there was a great conceptual evolution in the treatment of onco-hematological diseases. Researchers from around the world and the pharmaceutical industry began to focus their efforts on the so-called target therapy used alone or associated with classic chemotherapeutic drugs. In chronic lymphocytic leukemia, the development of second-generation anti-CD20 antibodies, biosimilars, PI3K (phosphatidylinositol 3-kinases) inhibitors, BTK (Bruton's tyrosine kinase) inhibitors, and anti-bcl 2 drugs represented mainly by venetoclax brought new, broader, and more effective opportunities in the treatment of this disease. This breakthrough occurred mainly regarding patients with alteration in 17p or mutation of the p53 gene for whom selecting the new drugs that act on B cell signaling (BTK and PI3K inhibitors) in the first line is mandatory. In fit patients with immunoglobulin heavy chain mutation, it is still acceptable to use the chemotherapy regimen with fludarabine, cyclophosphamide, and rituximab (FCR) and, in those who do not fit or are not IgVH-mutated, bendamustine-rituximab regimen. However, the first-line use of ibrutinib or venetoclax associated with immunotherapy within the concepts of infinite (ibrutinib) or finite (venetoclax) treatment has been increasingly used. In the second line, venetoclax, ibrutinib, and idelalisib have become the preferred treatments. I believe that a process of instruction and decision shared with patients considering the risks-benefits-cost and access to treatments should guide the choices within these concepts. Another fundamental aspect to discuss is the objective of the treatment for chronic lymphocytic leukemia (CLL) for a specific patient: the increase progression-free survival and overall survival and/or the achievement of minimal residual disease. CLL is the most common leukemia in adults with a median age at diagnosis of 72 years. The clinical course is heterogeneous, and outcomes are influenced by individual clinical presentation and disease biology. Molecular and genomic factors, including fluorescence in situ hybridization (FISH) testing, karyotype, and immunoglobulin heavy chain variable region gene (IGHV) mutational status, are important to treatment decisions and to predict the clinical course. However, despite disease biology, the presence of active disease is the most important criteria to initiate treatment. In the past decade, target therapies that inhibit B cell receptor signaling pathways and, more recently, BCL2 antagonists have emerged as a new treatment paradigm: chemo-free with fixed duration therapy. Bruton's tyrosine kinase inhibitors (BTK) are a class of oral medications approved for frontline and relapsed disease, effective for achieving lasting response and disease control with a good safety profile. BTK inhibitors are an attractive option for high-risk patients who are not candidates for an intensive regimen. However, it is a continuous therapy, and drug resistance or severe adverse events could lead to treatment suspension. BCL2 antagonists are an attractive alternative to BTK inhibitors. Anti-apoptotic BCL2 is associated with tumor genesis and chemotherapy resistance. The BCl2, an anti-apoptotic protein located in the mitochondrial membrane, is a major contributor to the pathogenesis of lymphoid malignancies and is overexpressed in CLL cells promoting clonal cell survival. Venetoclax is a potent and selective member of the BH3 mimetic drugs and a physiologic antagonist of BCL2. Venetoclax has demonstrated quick and durable responses in naïve and relapsed or refractory CLL (r/r CLL) patients, including high-risk patients. Furthermore, it has shown deeper responses, achieving a higher incidence of negative minimal residual disease (MRD) with a fixed duration therapy. In the past decade, there was a remarkable progress in CLL treatment. However, neither of the new target therapies is considered curative or free of toxicity. This article will focus on the treatment approach of CLL patients with BCl2 antagonists. Treatment strategy (combined versus monotherapy; continuous versus limited duration therapy), toxicity profile, and future directions will be exposed in this review.

Effects of intravenous analgesia with combined dezocine and butorphanol on postoperative cognitive function in elderly patients.

The aim of this study was to observe the analgesic effects of the combination of dezocine and butorphanol on postoperative cognitive function in elderly patients. Forty elderly patients undergoing upper abdominal surgeries or thoracotomies with general anesthesia were randomly divided into the dezocine and butorphanol group or the butorphanol group (20 patients per group). A visual analog scale was used to evaluate analgesia and the degree of malignant vomiting. The Ramsay scoring method was used to evaluate sedation. The Mini-Mental State Examination (MMSE) was used to evaluate cognitive function. Forty-eight hours after the operation, the pain score of the dezocine and butorphanol group (means ± SD, 1.75 ± 0.44) was lower than that of the butorphanol group (2.25 ± 0.79; P < 0.05), and the nausea and vomiting score of the dezocine and butorphanol group (0) was lower than that of the butorphanol group (0.70 ± 1.30; P < 0.05). Six hours after the operation, the sedative score of the butorphanol group (3.75 ± 0.79) was higher than that of the dezocine and butorphanol group (2.15 ± 0.75; P < 0.05). Compared to 1 day before the operation, the MMSE scores of both groups decreased 6 h after the operation, and the MMSE score of the butorphanol group (15.00 ± 2.00) was lower than that of the dezocine and butorphanol group (20.95 ± 1.54; P < 0.05). Dezocine and butorphanol analgesia had transient effects on postoperative cognitive function in elderly patients, and the effect of the combination was superior than butorphanol only.

Clinical report on transarterial neoadjuvant chemotherapy of malignant fibrous histiocytoma in soft tissue.

PURPOSE: To review the experience in transarterial neoadjuvant chemotherapy of malignant fibrous histiocytoma (MFH) in soft tissue and to analyze the factors related to prognosis of MFH in soft tissue. METHODS: Between September 1999 and December 2011, 101 cases of MFH in soft tissue patients treated by transarterial administration of Cisplatin, Adriamycin and Norcantharidin were divided into primary group and recurrent group, and the clinical documents were reviewed. Nine factors that might affect prognosis such as age, sex, tumor size, tumor site, tumor infiltration depth, recurrence if any, pathological type, histologic grade and histologic response of chemotherapy were analyzed statistically. RESULTS: The 5-year relapse-free survival rate and the overall survival rate were 70.5 and 75.0 %, respectively, in the primary group; 56.1 and 57.9 %, respectively, in the recurrent group. Univariate analysis (log-rank test) showed that the factors affecting the prognosis were age (P = 0.03), tumor size (P = 0.01), pelvic tumor (P = 0.02), recurrence if any (P = 0.004), histologic grade (P = 0.01), and histologic response to chemotherapy (P = 0.007). Multivariate analysis showed that the major factors affecting prognosis were pelvic tumor (P = 0.01), tumor size (P = 0.002), histologic grade (P = 0.002), recurrence if any (P = 0.0004), and histologic response to chemotherapy (P = 0.008). CONCLUSION: Transarterial neoadjuvant chemotherapy can significantly increase the curative efficacy of chemotherapy and survival rate in MFH treatment.