Luana Fianchi

Invasive aspergillosis in patients with acute myeloid leukemia: a SEIFEM-2008 registry study.

Background The aim of this study was to evaluate prognostic factors, treatments and outcome of invasive aspergillosis in patients with acute myeloid leukemia based on data collected in a registry. Design and Methods The registry, which was activated in 2004 and closed in 2007, collected data on patients with acute myeloid leukemia, admitted to 21 hematologic divisions in tertiary care centers or university hospitals in Italy, who developed proven or probable invasive aspergillosis. Results One hundred and forty cases of invasive aspergillosis were collected, with most cases occurring during the period of post-induction aplasia, the highest risk phase in acute myeloid leukemia. The mortality rate attributable to invasive aspergillosis was 27%, confirming previous reports of a downward trend in this rate. Univariate and multivariate analyses revealed that the stage of acute myeloid leukemia and the duration of, and recovery from, neutropenia were independent prognostic factors. We analyzed outcomes after treatment with the three most frequently used drugs (liposomal amphotericin B, caspofungin, voriconazole). No differences emerged in survival at day 120 or in the overall response rate which was 71%, ranging from 61% with caspofungin to 84% with voriconazole. Conclusions Our series confirms the downward trend in mortality rates reported in previous series, with all new drugs providing similar survival and response rates. Recovery from neutropenia and disease stage are crucial prognostic factors. Efficacious antifungal drugs bridge the period of maximum risk due to poor hematologic and immunological reconstitution.

Incidence and clinical impact of extended-spectrum-β-lactamase (ESBL) production and fluoroquinolone resistance in bloodstream infections caused by Escherichia coli in patients with hematological malignancies.

OBJECTIVES To identify risk factors for mortality in patients suffering from hematological malignancies with concurrent bacteremia caused by Escherichia coli. Particular attention was focused on defining the impact of extended-spectrum-beta-lactamase (ESBL) production and fluoroquinolone resistance by the bacterial isolates on mortality. MATERIALS AND METHODS A retrospective eight-year cohort study design was employed. The outcome measured was death within 30 days of the first positive blood culture. Survivor and non-survivor subgroups were compared to identify predictors of mortality. RESULTS A total of 62 episodes of bacteremia caused by E. coli were analyzed. The overall incidences of ESBL production and fluoroquinolone resistance were 41.9% and 62.9%, respectively. The overall 30-day mortality rate was 20.9% (13/62). In a multivariate analysis, significant predictors of mortality were inadequate initial antimicrobial therapy (OR=14.96, 95% CI 1.95-114.51; P=0.009), infection caused by ESBL-producing isolates (OR=8.84, 95% CI 1.48-52.91; P=0.01), and prolonged neutropenia (OR=8.10, 95% CI 1.29-50.57; P=0.02). CONCLUSIONS Sound knowledge of the local distribution of pathogens and their susceptibility patterns and prompt initiation of effective antimicrobial treatment are essential in patients suffering from hematological malignancies with BSIs caused by E. coli.

Pneumocystis carinii pneumonia in patients with malignant haematological diseases: 10 years' experience of infection in GIMEMA centres

Summary. A retrospective survey was conducted over a 10‐year period (1990–99) among 52 haematology divisions in order to evaluate the clinical and laboratory characteristics and outcome of patients with proven Pneumocystis carinii pneumonia (PCP) complicating haematological diseases. The study included 55 patients (18 with non‐Hodgkins lymphoma, 10 with acute lymphoblastic leukaemia, eight with acute myeloid leukaemia, five with chronic myeloid leukaemia, four with chronic lymphocytic leukaemia, four with multiple myeloma, three with myelodysplastic syndrome, two with myelofibrosis and one with thalassemia) who developed PCP. Among these, 18 (33%) underwent stem cell transplantation; only two received an oral prophylaxis with trimethroprim/sulphamethoxazole. Twelve patients (22%) developed PCP despite protective isolation in a laminar airflow room. The most frequent symptoms were: fever (86%), dyspnoea (78%), non‐productive cough (71%), thoracic pain (14%) and chills (5%); a severe hypoxaemia was present in 39 patients (71%). Chest radiography or computerized tomography showed interstitial infiltrates in 34 patients (62%), alveolar infiltrates in 12 patients (22%), and alveolar–interstitial infiltrates in nine patients (16%). Bronchoalveolar lavage was diagnostic in 47/48 patients, induced sputum in 9/18 patients and lung biopsy in 3/8 patients. The diagnosis was made in two patients at autopsy. All patients except one started a specific treatment (52 patients trimethroprim/sulphamethoxazole, one pentamidine and one dapsone). Sixteen patients (29%) died of PCP within 30 d of diagnosis. Multivariate analysis showed that prolonged steroid treatment (P < 0·006) and a radiological picture of diffuse lung involvement (P < 0·003) were negative diagnostic factors.

Incidence and susceptibility to therapy-related myeloid neoplasms

Therapy-related myeloid neoplasms (t-MN) include acute myeloid leukemias and myelodysplastic syndromes arising in patients who have been treated with chemotherapy, radiation therapy, immunosuppressive agents or after documented exposure to environmental carcinogen. t-MN are defined according to the primary treatment and the corresponding genetic and molecular lesions. Chromosome(s) 7 and/or 5 monosomies or deletions are typical of alkylating agent-induced AML, while balanced translocations involving chromosome bands 11q23 and 21q22 are associated to preceeding therapy with DNA-topoisomerase II inhibitors. Antimetabolites, and in particular the immunosuppressive agents azathioprine and fludarabine, have also been recently associated to t-MN. Leukemias developing after benzene exposure are similar to t-MN and are characterized by chromosomal aberrations, which have been also observed among otherwise healthy benzene-exposed workers. Individual predisposing factors, including polymorphisms of detoxification and DNA-repair enzymes have been identified. Two genetic variants in key metabolizing enzymes, myeloperoxidase and NAD(P)H:quinone oxidoreductase, have been shown to influence susceptibility to benzene hematotoxicity. Combination of polymorphisms impairing detoxification and DNA repair may significantly increase therapy-related myeloid neoplasm risk. Among hematological malignancies, long-term survivors of Hodgkins lymphoma are exposed to an increased t-MN risk, particularly when receiving MOPP-based and escalated-BEACOPP regimens, and when alkylators are combined to radiotherapy. Patients with lymphoma are at highest risk if total body irradiation followed by autologous stem cell transplantation is used as rescue or consolidation. The addition of granulocyte-colony stimulating factor (G-CSF) and radiotherapy plays a significant role in t-MN following treatment of childhood acute lymphoblastic leukemia. In solid tumors, treatment for breast cancer and germ-cell tumors has been associated with a 1-5% lifetime risk of t-MN.

The role of Gemtuzumab Ozogamicin in the treatment of acute myeloid leukemia patients.

Gemtuzumab Ozogamicin (GO) is an antibody-targeted chemotherapy agent consisting of the humanized murine CD33 antibody (clone P67.6) to which the calicheamicin-g1 derivative is attached via a hydrolysable bifunctional linker. GO is able to induce apoptosis in vitro in CD33-expressing cells and it has been approved in USA and in Europe as monotherapy for the treatment of elderly patients (older than 60 years) with relapsed acute myeloid leukemia (AML). GO administered as a single agent has resulted in overall response rates of about 30% in previously relapsed adults AML patients (including also with incomplete platelet recovery). Preliminary data indicate a potential role for GO also as a component of induction or consolidation regimens in adults and children. As for adverse events, veno-occlusive syndrome characterizes its tolerability profile, but GO is comparatively well tolerated by most patients.

Factors associated with mortality in bacteremic patients with hematologic malignancies

We conducted a retrospective cohort study to identify risk factors for mortality in a large cohort of hematologic patients with bacteremia. From 2000 through 2005, bacteremia was diagnosed in 217 patients with hematologic malignancies. The infections were caused only by Gram-positive organisms in 57.1% (124/217) cases and only by Gram-negative bacteria in 37.8% (82/217); the remaining 5.1% (11/217) were polymicrobial. The overall 30-day mortality rate was 20.3% (44/217). In multivariate analysis, significant predictors of mortality were prolonged neutropenia (P < 0.001), acute renal failure (P = 0.002), nosocomial bacteremia (P = 0.009), age >55 years (P = 0.007), and monomicrobial bacteremia due to antibiotic-resistant Gram-negative bacteria (P = 0.009). Reducing fatal outcomes associated with bacteremia in patients with hematologic malignancies is a challenge, and the emergence of resistance to the antimicrobials widely used in this setting is of great concern. Future infection trends must be carefully monitored and treatment guidelines adjusted accordingly.

Zygomycosis in Italy: a Survey of FIMUA-ECMM (Federazione Italiana di Micopatologia Umana ed Animale and European Confederation of Medical Mycology)

Abstract The aims of the study were to analyze the clinical and epidemiological characteristics and treatments for patients who developed zygomycosis enrolled in italy during the european Confederation of medical mycology survey. This prospective multicenter study was performed between 2004 and 2007 at 49 italian Departments. 60 cases of zygomycosis were enrolled: the median age was 59.5 years (range 1-87), with a prevalence of males (70%). The majority of cases were immunocompromised patients (42 cases, 70%), mainly hematological malignancies (37). Among non-immunocompromised (18 cases, 30%), the main category was represented by patients with penetrating trauma (7/18, 39%). The most common sites of infection were sinus (35%) with/without CNS involvement, lung alone (25%), skin (20%), but in 11 cases (18%) dissemination was observed. According to EORTC criteria, the diagnosis of zygomycosis was proven in 46 patients (77%) and in most of them it was made in vivo (40/46 patients, 87%); in the remaining 14 cases (23%) the diagnosis was probable. 51 patients received antifungal therapy and in 30 of them surgical debridement was also performed. The most commonly used antifungal drug was liposomal amphotericin b (L- AmB), administered in 44 patients: 36 of these patients (82%) responded to therapy. Altogether an attributable mortality rate of 32% (19/60) was registered, which was reduced to 18% in patients treated with L-AmB (8/44). Zygomycosis is a rare and aggressive filamentous fungal infection, still associated with a high mortality rate. This study indicates an inversion of this trend, with a better prognosis and significantly lower mortality than that reported in the literature. It is possible that new extensive, aggressive diagnostic and therapeutic procedures, such as the use of L-AmB and surgery, have improved the prognosis of these patients.

Current therapeutic approaches to fungal infections in immunocompromised hematological patients.

Invasive fungal infections are significant causes of morbidity and mortality in patients with hematological malignancies. Patients with acute myeloid leukemia and those who have undergone allogeneic hematopoietic stem cell transplantation are at especially high risk. Various fungal agents are responsible for this complication, but Aspergillus spp. and Candida spp. are the most frequently isolated micro-organisms; less commonly, infections could be caused by Zygomycetes or other rare molds or yeasts. Several new systemically-administered antifungal agents have been approved for clinical use since 2001; these agents include liposomal amphotericin B, voriconazole, caspofungin, and posaconazole, and they represent a major advance in antifungal therapy and have improved the prognosis of patients with hematological malignancies. This review focuses on therapeutic aspects of the management of fungal infections in hematological patients.

Therapy-related myeloid neoplasms

Purpose of review The purpose of this review is to update knowledge on therapy-related myeloid neoplasms (t-MN), taking into account the new 2008 WHO classification, new genome-wide approaches for the definition of susceptibility towards t-MN and the introduction of new more aggressive treatments in cancer patients. Recent findings t-MN are an increasing matter in cancer survivors treated with chemoradiotherapy. One of the major concerns in hematologic malignancies is childhood acute lymphoblastic leukemia, in which the leukemogenic role of extended etoposide/teniposide treatment, concomitant intensive antimetabolite and asparaginase, granulocyte colony-stimulating factor (G-CSF) and prophylactic cranial radiotherapy use have been established. In high-risk Hodgkin lymphoma, 3% t-MN have been observed at 10-year follow-up with the escalated bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone (BEACOPP) schedule, versus 0.4% with doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD). In lymphoproliferative diseases the new drugs fludarabine and lenalidomide may increase the risk of second tumors, when associated to other cytotoxic therapies. Among solid tumors, breast cancer is most frequently associated to t-MN. The risk is correlated to higher chemotherapy doses, radiotherapy, use of G-CSF, but also independent from treatment, suggesting a genetic predisposition to both diseases. Radiotherapy plays a role also in female pelvic tumors and in testicular cancer, when associated to cisplatin. Summary The risk of t-MN is not negligible, although below 2% in most series. This is particularly significant for younger cancer patients and during the first 5 years after the primary malignancies. Efforts should be maximized to identify susceptibility factors to identify patients at risk, in whom more leukemogenic drugs and schedules should be avoided.

Fungal CNS infections in patients with hematologic malignancy

Various fungal agents can cause CNS infections. CNS fungal infections may present as a mass (i.e., brain abscess) typically in the course of aspergillosis or zygomycosis, or may primarily involve the meninges (i.e., meningitis), as can be observed in patients with candidiasis or cryptococcosis. Most commonly, fungal brain abscesses are due to aspergillosis. CNS aspergillosis is observed particularly in acute leukemia and allogeneic hemopoietic stem cell transplantation patients. Usually, aspergillosis is localized in the lungs and secondarily spreads to the brain; only in few cases does it develop as solitary localization of CNS. In these conditions, diagnosis is very difficult because signs and symptoms can be completely aspecific. Diagnosis can often be performed only through aggressive procedures (i.e., stereotactic puncture). Zygomycetes are the second most frequent cause of brain abscesses. CNS involvement is higher than in the course of invasive aspergillosis, and this fungal complication is also characterized by a high mortality rate. In vitro and in vivo studies demonstrated that only posaconazole and lipid formulations of amphotericin B present some possibility of success in the treatment of zygomycosis, but the pharmacologic approach should always be associated with surgery. Among molds, other agents (i.e., Fusarium and Scedosporium) may also be responsible for fungal abscess. More rarely during the course of a hematologic malignancy, a meningeal candidiasis or cryptococcosis may be observed. This review mainly focuses on the epidemiology, clinical manifestations, diagnosis and management strategies of all cases of CNS fungal infections in hematologic patients.