Alessandro Bonini

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 outcome of invasive fungal diseases after allogeneic stem cell transplantation: A prospective study of the gruppo italiano trapianto midollo osseo (GITMO)

Epidemiologic investigation of invasive fungal diseases (IFDs) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be useful to identify subpopulations who might benefit from targeted treatment strategies. The Gruppo Italiano Trapianto Midollo Osseo (GITMO) prospectively registered data on 1858 consecutive patients undergoing allo-HSCT between 2008 and 2010. Logistic regression analysis was performed to identify risk factors for proven/probable IFD (PP-IFD) during the early (days 0 to 40), late (days 41 to 100), and very late (days 101 to 365) phases after allo-HSCT and to evaluate the impact of PP-IFDs on 1-year overall survival. The cumulative incidence of PP-IFDs was 5.1% at 40 days, 6.7% at 100 days, and 8.8% at 12 months post-transplantation. Multivariate analysis identified the following variables as associated with PP-IFDs: transplant from an unrelated volunteer donor or cord blood, active acute leukemia at the time of transplantation, and an IFD before transplantation in the early phase; transplant from an unrelated volunteer donor or cord blood and grade II-IV acute graft-versus-host disease (GVHD) in the late phase; and grade II-IV acute GVHD and extensive chronic GVHD in the very late phase. The risk for PP-IFD was significantly higher when acute GVHD was followed by chronic GVHD and when acute GVHD occurred in patients undergoing transplantation with grafts from other than matched related donors. The presence of PP-IFD was an independent factor in long-term survival (hazard ratio, 2.90; 95% confidence interval, 2.32 to 3.62; P < .0001). Our findings indicate that tailored prevention strategies may be useful in subpopulations at differing levels of risk for PP-IFDs.

High-dose busulfan and cyclophosphamide are an effective conditioning regimen for allogeneic bone marrow transplantation in chemosensitive multiple myeloma

The present clinical trial was undertaken to investigate the toxicity and antimyeloma activity of busulfan (BU) and cyclophosphamide (CY) at the maximum tolerated doses of, respectively, 16 mg/kg and 200 mg/kg (BU-CY 4) as conditioning therapy for allogeneic bone marrow transplantation (BMT) in 19 consecutive patients with multiple myeloma (MM). Twelve (63%) had failed to respond to prior chemotherapy, while the remaining 37% had chemosensitive disease. No life-threatening or fatal regimen-related complications were observed. The incidence of veno-occlusive disease of the liver was zero according to Jones’ criteria and 21% according to McDonald’s system. Transplant-related mortality was 37%. Using stringent criteria, the frequency of complete remission (CR) was 42% among all patients and 53% among those who could be evaluated. With a median follow-up of 21 months for all patients and 66 months for survivors, the actuarial probability of survival and event-free survival at 4 years from BMT was 26% (95% CI: 7–46) and 21% (95% CI: 3–39), respectively. A more favorable outcome of transplantation was observed in the subgroup of patients with chemosensitive disease who had a transplant-related mortality of 14%, an overall CR rate of 86% (95% CI: 49–97) and a 4-year projected probability of event-free survival of 57% (95% CI: 20–93). Four of these patients are currently alive in continuous CR after 54, 66, 80 and 94 months, respectively. It is concluded that BU-CY 4 as conditioning for allogeneic transplantation for MM is associated with acceptable morbidity and relatively low mortality. This regimen exerts substantial antimyeloma activity, resulting in a high CR rate and durable responses, especially in patients with chemosensitive disease. Long-lasting remission and probable cure is possible following allogeneic stem cell transplantation for MM.

Gemtuzumab Ozogamicin for Relapsed and Refractory Acute Myeloid Leukemia and Myeloid Sarcomas

Antibody-targeted chemotherapy is a promising approach in patients with hematological malignancies. In particular, gemtuzumab ozogamicin (GO, formerly CMA-676), an anti-CD33 antibody linked to calicheamicin, has been approved for the treatment of elderly patients with acute myeloid leukemia (AML) in relapse. Nevertheless, no data are until now available concerning the possible efficacy of GO for myeloid sarcomas (MS). We treated with GO 24 AML patients, in 5 cases presenting with myeloid sarcomas of the skin or bones. The overall complete response rate was 21%. The median duration of response was 6 months. Four out of the 5 patients with myeloid sarcoma showed a regression of the masses, in two cases also obtaining a clearance of marrow blasts. The most common adverse events included thrombocytopenia, neutropenia, infections, elevation of bilirubin and hepatic transaminases. Notably, severe bleeding occurred in 5 cases (21%). VOD was documented in 1 case. We conclude that GO is effective as a single agent in AML and myeloid sarcomas. Further data are required to clarify the possible correlation between GO administration and occurrence of bleeding.

The use and efficacy of empirical versus pre-emptive therapy in the management of fungal infections: the HEMA e-Chart Project

Background Neutropenic patients with persistent fever despite antibiotic therapy are managed with empirical or pre-emptive antifungal therapy. The aim of the present study was to evaluate the current clinical use and efficacy of these two approaches in patients with high risk hematologic conditions. Design and Methods An electronic medical record system, the “Hema e-Chart”, was designed and implemented to collect information prospectively on infectious complications, particularly on invasive fungal diseases, in patients with hematologic malignancies treated with chemotherapy and/or autologous or allogenic hemopoietic stem cell transplantation. The patients were enrolled from Hematology units distributed widely across Italy. Results Three hundred and ninety-seven adults with hematologic malignancies treated with chemotherapy with persistent fever and suspected invasive fungal disease were evaluable for the study (190 treated had been treated with empirical antifungal therapy and 207 with preemptive antifungal therapy). There was a significantly lower incidence of proven/probable invasive fungal diseases in patients treated with empirical antifungal therapy (n=14, 7.4%) than in patients treated with pre-emptive therapy (n=49, 23.7%) (P<0.001). The rate of deaths attributable to invasive fungal diseases was significantly lower in subjects treated with empirical antifungal therapy (1 case; 7.1%) than in subjects treated with pre-emptive therapy (11 cases; 22.5%) (P=0.002). Conclusions These data indicate that empirical antifungal treatment decreased the incidence of invasive fungal disease and of attributable mortality with respect to a pre-emptive antifungal approach in neutropenic febrile patients with hematologic malignancies. (ClinicalTrials.gov Identifier: NCT01069887)

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.

Efficacy of caspofungin as secondary prophylaxis in patients undergoing allogeneic stem cell transplantation with prior pulmonary and/or systemic fungal infection

Transplanted patients with a history of invasive fungal infection (IFI) are at high risk of developing relapse and fatal complications. Eighteen patients affected by hematological malignancies and a previous IFI were submitted to allogeneic stem cell transplantation, using Caspofungin as a secondary prophylaxis. Patients had a probable or proven fungal infection and 16 had a pulmonary localization. No side effects were recorded during treatment with Caspofungin. Compared to pre-transplant evaluation, stability or improvement of the previous IFI was observed in 16 of the 18 patients at day 30, in 13 of the 15 evaluable patients at day 180 and in 11 of the 11 evaluable patients at day 360 post transplant. In particular, all the six patients with a proven fungal infection were alive, with a stable or improved IFI after 1 year from transplant. At a maximum follow-up of 31 months, eight patients died for disease progression or transplant-related complications, but only two had evidence of fungal progression. Secondary prophylaxis with Caspofungin may represent a suitable approach to limit IFI relapse or progression, allowing patients with hematological malignancies to adhere to the planned therapeutic program.

Multicentre phase III trial on fludarabine, cytarabine (Ara-C), and idarubicin versus idarubicin, Ara-C and etoposide for induction treatment of younger, newly diagnosed acute myeloid leukaemia patients.

Fludarabine plus cytarabine (Ara‐C) and idarubicin (FLAI) is an effective and well‐tolerated induction regimen for the treatment of acute myeloid leukaemia (AML). This phase III trial compared the efficacy and toxicity of FLAI versus idarubicin plus Ara‐C and etoposide (ICE) in 112 newly diagnosed AML patients <60 years. Fifty‐seven patients received FLAI, as the first induction–remission course, and 55 patients received ICE. Post‐induction treatment consisted of high‐dose Ara‐C (HDAC). After HDAC, patients in complete remission (CR) received a second consolidation course (mitoxantrone, etoposide, Ara‐C) and autologous stem cell transplantation (auto‐SCT) or allogeneic (allo)‐SCT, according to the age, disease risk and donor availability. After a single induction course, CR rate was 74% in the FLAI arm and 51% in the ICE arm (P = 0·01), while death during induction was 2% and 9% respectively. Both haematological (P = 0·002) and non‐haematological (P = 0·0001) toxicities, especially gastrointestinal (i.e. nausea, vomiting, mucositis and diarrhoea), were significantly lower in FLAI arm. In both arms, relapses were more frequent in patients who were not submitted to allo‐SCT. After a median follow‐up of 17 months, 30% and 38% of the patients are in continuous CR in FLAI and ICE arm respectively. Our prospective randomised study confirmed the anti‐leukaemic effect and the low toxic profile of FLAI as induction treatment for newly diagnosed AML patients.

Invasive fungal infections in patients with acute myeloid leukemia and in those submitted to allogeneic hemopoietic stem cell transplant: who is at highest risk?

To the Editor: Invasive fungal infections (IFIs) are a growing cause of morbidity and mortality in patients with acute myeloid leukemia (AMLs) and in recipients of allogeneic hemopoietic stem cell transplantation (allo-HSCTs) (1–6). It is widely debated if either allo-HSCTs or AMLs are to be considered at higher risk, but no data comparing the two categories of patients have been reported in literature so far. This cohort study has been conducted from January 1999 to December 2003 in hematology wards located throughout Italy. The study was aimed at evaluating the incidence and mortality for IFIs in adult AMLs and in patients submitted to all types of allo-HSCT procedures; a comparison between the two categories of patients was carried out. EORTC ⁄MSG consensus criteria were used to define IFIs (7). Only infections that were classified as ‘proven’ or ‘probable’ were included in the data analysis. Overall and IFI-attributable mortality rates (IFI-AMR) were estimated. IFI-AMR was defined as a progression of sepsis-related symptoms or of the involved organ failure in the absence of other morbid condition thought to cause death. Outcome was assessed on the 150th day after IFI diagnosis. During the 5-yr study, 1596 new patients received intensive chemotherapy for AML and 679 were submitted to allo-HSCT procedures in the nine participating centers. Proven or probable IFIs were documented in 270 AMLs (174 moulds and 96 yeasts) (incidence 16.9%) and in 56 allo-HSCTs (43 moulds and 13 yeasts) (incidence 8.2%). All yeast infections were sustained by Candida spp. Conversely, mould infections were mostly caused by Aspergillus spp (96% in AML and 91% in HSCT); only a few cases due to rare agents were observed. Significant differences emerged from the comparison of IFI incidence rates in AMLs and allo-HSCTs. The overall mortality rate for fungal infection was 5.9% in AMLs and 5.7% in allo-HSCTs, with an IFI-AMR of 34.8% and 69.6% respectively (Table 1). Furthermore, we separately analyzed mould and yeast infections. In yeast infections, the incidence was higher in AMLs (P-value <0.001), while differences in AMR were not statistically significant (P-value 0.105). As for moulds, significant differences in both incidence rate and AMR were found in AMLs and allo-HSCTs (P-value <0.001). Data about mortality rate became more impressive after having compared AML patients treated with chemotherapy (174 pts) to those treated with allo-HSCT (21 pts). Mortality reached 90.5% in transplanted patients (RR 2.58, CI95% 2.02–3.3, P-value <0.001). IFIs appeared both during the early and late phase after allo-HSCT. Interestingly in moulds infections only, AMR resulted higher for those infections occurring within 100 d from transplant (AMR 85% in early vs. 56% in late aspergillosis, P-value 0.04); it means that patients receiving allo-HSCT continue to be at risk for IFIs even after 100 d, but risk of mortality decreases during the post-engraftment phase.

A prospective survey of febrile events in hematological malignancies

The Hema e-Chart prospectively collected data on febrile events (FEs) in hematological malignancy patients (HMs). The aim of the study was to assess the number, causes and outcome of HM-related FEs. Data were collected in a computerized registry that systematically approached the study and the evolution of FEs developing in a cohort of adult HMs who were admitted to 19 hematology departments in Italy from March 2007 to December 2008. A total of 869 FEs in 3,197 patients with newly diagnosed HMs were recorded. Fever of unidentified origin (FUO) was observed in 386 cases (44.4%). The other causes of FE were identified as noninfectious in 48 cases (5.5%) and infectious in 435 cases (50.1%). Bacteria were the most common cause of infectious FEs (301 cases), followed by fungi (95 cases), and viruses (7 cases). Mixed agents were isolated in 32 episodes. The attributable mortality rate was 6.7% (58 FEs). No deaths were observed in viral infection or in the noninfectious groups, while 25 deaths were due to FUO, 16 to bacterial infections, 14 to fungal infections, and three to mixed infections. The Hema e-Chart provided a complete system for the epidemiological study of infectious complications in HMs.