Archibald G. Prentice

Itraconazole Prevents Invasive Fungal Infections in Neutropenic Patients Treated for Hematologic Malignancies: Evidence From a Meta-Analysis of 3,597 Patients

PURPOSE Efficacy of antifungal prophylaxis has not yet been convincingly proven in numerous trials of various antifungals. New evidence and the anti-Aspergillus efficacy of itraconazole prompted a new look at the data for the prevention of invasive fungal infections. PATIENTS AND METHODS Randomized, controlled studies with itraconazole for antifungal prophylaxis in neutropenic patients with hematologic malignancies were identified from electronic databases and hand searching. RESULTS Thirteen randomized trials included 3,597 patients who were assessable for invasive fungal infections. Itraconazole reduced the incidence of invasive fungal infection (mean relative risk reduction, 40% +/- 13%; P =.002), the incidence of invasive yeast infections (mean, 53% +/- 19%; P =.004) and the mortality from invasive fungal infections (mean, 35% +/- 17%; P =.04) significantly. The incidence of invasive Aspergillus infections was only reduced in trials using the itraconazole cyclodextrine solution (mean, 48% +/- 21%; P =.02) and not itraconazole capsules (mean, 75% +/- 73% increase; P =.3). The overall mortality was not changed. Adverse effects were rare, hypokalemia was noted in three studies, and a higher rate of drug discontinuation was found in trials that compared itraconazole cyclodextrine solution to a control without cyclodextrine. The effect of prophylaxis was clearly associated with a higher bioavailable dose of itraconazole. CONCLUSION Antifungal prophylaxis with itraconazole effectively prevents proven invasive fungal infections and-shown for the first time for antifungal prophylaxis-reduces mortality from these infections and the rate of invasive Aspergillus infections in neutropenic patients with hematologic malignancies. Adequate doses of the oral cyclodextrine solution (at least 400 mg/d) or i.v. formulations (200 mg/d) of itraconazole are necessary for these effects.

Prognostic factor analysis of the survival of elderly patients with AML in the MRC AML11 and LRF AML14 trials

This analysis, of 2483 patients with acute myeloid leukaemia (AML) aged 60+ years entered into two UK trials, was performed to determine the baseline parameters related to survival and to develop a risk index. The Medical Research Council (MRC) AML11 trial (n = 1071) was used to develop the index; this was validated using data from the Leukaemia Research fund (LRF) AML14 trial on 1137 intensively (AML14I) and 275 non‐intensively (AML14NI) treated patients. In AML11, cytogenetic group, age, white blood count, performance status and type of AML (de novo, secondary) were all highly significantly related to prognosis in multivariate analysis. The regression coefficients were used to define good, standard and poor risk groups, with 1‐year survival of 53%, 43% and 16% respectively (P < 0·0001). The risk index showed very good discrimination in both AML14I and AML14NI (both P < 0·0001), thereby providing validation, although survival in all groups was very poor in AML14NI. The risk factors for survival in older AML patients were similar to those in younger ones and discrimination of patient groups with relatively good to very poor prognosis was possible. These risk groups apply to both intensively and non‐intensively treated patients. Randomized trials of intensive versus non‐intensive therapy are needed to determine which types of patient should be given which type of treatment.

Attempts to Optimize Induction and Consolidation Treatment in Acute Myeloid Leukemia: Results of the MRC AML12 Trial

PURPOSE To optimize treatment for younger patients with acute myeloid leukemia and high-risk myelodysplastic syndrome by comparing induction options and the number of consolidation courses and whether consolidation should include transplantation. PATIENTS AND METHODS We randomly assigned 1,658 patients younger than age 60 years to receive mitoxantrone/cytarabine/etoposide versus cytarabine/daunorubicin/etoposide and subsequently 1,193 patients to daunorubicin/cytarabine/thioguanine (DAT) where the cytarabine dose was standard (S-DAT) versus double the standard dose (H-DAT). Patients in this randomization were randomly assigned to all-trans-retinoic acid or not. In consolidation, 992 patients were randomly assigned between a total of four courses versus five courses, and 324 patients who were not good risk were randomly assigned to transplantation or chemotherapy as the final course. RESULTS Complete remission (CR) was achieved in 74% of patients and CR without recovery was achieved in an additional 11%; overall survival (OS) at 8 years was 38%. No differences in CR, relapse-free survival, relapse, or OS were seen between any of the induction randomizations except for a reduction in relapse risk (RR) on the mitoxantrone arm, which was offset by increased myelosuppression and deaths in CR. The addition of a fifth course did not improve OS and may be detrimental in older patients. Although transplantation reduced RR, it did not improve OS for the intermediate-risk group but was probably of benefit in high-risk patients. CONCLUSION Several chemotherapy schedules achieved similar remission rates and OS. Four courses of chemotherapy are adequate, but the addition of transplantation as a final course does not improve OS. New agents are required to enhance conventional chemotherapy.

The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome : the results of the LRF AML14 trial

The acute myeloid leukaemia (AML)14 trial addressed four therapeutic questions in patients predominantly aged over 60 years with AML and High Risk Myelodysplastic Syndrome: (i) Daunorubicin 50 mg/m2 vs. 35 mg/m2; (ii) Cytarabine 200 mg/m2 vs. 400 mg/m2 in two courses of DA induction; (iii) for part of the trial, patients allocated Daunorubicin 35 mg/m2 were also randomized to receive, or not, the multidrug resistance modulator PSC‐833 in a 1:1:1 randomization; and (iv) a total of three versus four courses of treatment. A total of 1273 patients were recruited. The response rate was 62% (complete remission 54%, complete remission without platelet/neutrophil recovery 8%); 5‐year survival was 12%. No benefits were observed in either dose escalation randomization, or from a fourth course of treatment. There was a trend for inferior response in the PSC‐833 arm due to deaths in induction. Multivariable analysis identified cytogenetics, presenting white blood count, age and secondary disease as the main predictors of outcome. Although patients with high Pgp expression and function had worse response and survival, this was not an independent prognostic factor, and was not modified by PSC‐833. In conclusion, these four interventions have not improved outcomes in older patients. New agents need to be explored and novel trial designs are required to maximise prospects of achieving timely progress.

The impact on outcome of the addition of all-trans retinoic acid to intensive chemotherapy in younger patients with nonacute promyelocytic acute myeloid leukemia: overall results and results in genotypic subgroups defined by mutations in NPM1,FLT3, and CEBPA

We investigated the benefit of adding all-trans retinoic acid (ATRA) to chemotherapy for younger patients with nonacute promyelocytic acute myeloid leukemia and high-risk myelodysplastic syndrome, and considered interactions between treatment and molecular markers. Overall, 1075 patients less than 60 years of age were randomized to receive or not receive ATRA in addition to daunorubicin/Ara-C/thioguanine chemotherapy with Ara-C at standard or double standard dose. There were data on FLT3 internal tandem duplications and NPM1 mutations (n = 592), CEBPA mutations (n = 423), and MN1 expression (n = 195). The complete remission rate was 68% with complete remission with incomplete count recovery in an additional 16%; 8-year overall survival was 32%. There was no significant treatment effect for any outcome, with no significant interactions between treatment and demographics, or cytarabine randomization. Importantly, there were no interactions by FLT3/internal tandem duplications, NPM1, or CEBPA mutation. There was a suggestion that ATRA reduced relapse in patients with lower MN1 levels, but no significant effect on overall survival. Results were consistent when restricted to patients with normal karyotype. ATRA has no overall effect on treatment outcomes in this group of patients. The study did not identify any subgroup of patients likely to derive a significant survival benefit from the addition of ATRA to chemotherapy.

Risk of infection in patients with lymphoma receiving rituximab: systematic review and meta-analysis

BackgroundThe addition of Rituximab (R) to standard chemotherapy (C) has been reported to improve the end of treatment outcome in patients affected by CD-20 positive malignant lymphomas (CD20+ ML). Nevertheless, given the profound and prolonged immunosuppression produced by R there are concerns that severe infections may arise. A systematic review and meta-analysis were performed to determine whether or not the addition of R to C may increase the risk of severe infections in adults undergoing induction therapy for CD20+ ML.MethodsOnly randomised controlled trials comparing R-C to C standard alone in adult patients with CD20+ ML were included. Meta-analysis was performed on overall incidence of severe infection, risk of dying as the consequence of infection, risk of febrile neutropenia, risk of severe leucopenia, risk of severe granulocytopenia and overall response assuming a fixed effect model. Heterogeneity was investigated, if present and I2 >20%, according to several predefined baseline characteristics of the study populations.ResultsSeveral relevant results have emerged. First, the addition of R to standard C does not increase the overall risk of severe infections (RR = 1.00; 95% CI 0.87 to 1.14) nor does it increase the risk of dying as a consequence of infection (RR = 1.60; 95% CI 0.68 to 3.75). Second, we confirmed that the addition of R to standard C increases the proportion of overall response (RR = 1.12; 95% CI 1.09 to 1.15), but it also increases the risk of severe leucopenia (RR = 1.24; 95% CI 1.12 to 1.37) and granulocytopenia (RR = 1.07; 95% CI 1.02 to 1.12).ConclusionsR-C is superior to standard C in terms of overall response and it does not increase the overall incidence of severe infection. However, data on special groups of patients (for example, HIV positive subjects and HBV carriers) are lacking. In our opinion more studies are needed to explore the potential effect of R on silent and chronic viral infections.

Infections in patients taking Rituximab for hematologic malignancies: two-year cohort study

BackgroundRituximab (R) is a chimeric human-murine anti-CD20 monoclonal antibody used to treat B-cell lymphomas. Despite R remarkable activity against malignant cells, there are concerns that R may facilitate the occurrence of infections. This study is aimed to define risk factors for infections, and the potential interaction with time since therapy, in patients undergoing R containing regimens.MethodsThe study has been designed as a multiple failure events historical cohort including all patients who received a R contain regimen at London Royal Free Hospital between May 2007 and April 2009.ResultOne-hundred-eighty-one infections occurred among the 113 enrolled patients (overall incidence rate 3.30 per 1000 person-days). Multivariate analysis showed that lymphocyte counts at nadir, graft versus host disease, HIV sero-status and the type of malignancy were all independently associated with the risk of infection. In addition the analysis of the interaction with the time since the start of therapy provided evidence that different risk factors may increase risk of infections in different times.ConclusionThis study provides preliminary data to describe the association between several patients’ baseline characteristics and infections during therapy with R.

Clinico-pathologic characteristics of patients with hepatic lymphoma diagnosed using image-guided liver biopsy techniques

Abstract Primary hepatic lymphoma is a rare presentation of a common disease. Diagnosis is difficult due to the risks of liver biopsy. We report the clinico-pathologic features of this presentation and specifically the utility of image-guided biopsy as a safe method of diagnosis. We retrospectively studied patients diagnosed with ‘hepatic lymphoma’ at a single center. Twenty-two patients fulfilled the criteria. Median age was 53 years (range 29–87). Nine patients were human immunodeficiency virus (HIV)-positive. The most frequent mode of presentation was with B-symptoms (15/22). All procedures were successful at obtaining diagnostic material with no complications. Six patients had synchronous bone marrow involvement. Nineteen patients received chemotherapy (10 had dose reductions) with an overall response rate of 74%. After a median follow-up of 19 months, 12 patients had died; the median overall survival (OS) was 4 months. Grade 3 or 4 aspartate transaminase (AST) abnormality was associated with very poor outcome. The OS of patients with hepatic lymphoma is poor. However, a response to modern induction therapies may predict a better outcome. The optimal dose adjustment of chemotherapy in this setting is unclear. In patients without readily accessible tissue, an image-guided core biopsy of hepatic lesions is a safe procedure with high diagnostic yield.

Patients undergoing high dose chemotherapy for primary CNS lymphoma should receive prophylactic thiamine to prevent Wernike’s encephalopathy

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