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.

Allogeneic transplantation improves the overall and progression-free survival of Hodgkin lymphoma patients relapsing after autologous transplantation: a retrospective study based on the time of HLA typing and donor availability.

Hodgkin lymphoma relapsing after autologous transplantation (autoSCT) has a dismal outcome. Allogeneic transplantation (alloSCT) using reduced intensity conditioning (RIC) is a salvage option, but its effectiveness is still unclear. To evaluate the role of RIC alloSCT, we designed a retrospective study based on the commitment of attending physicians to perform a salvage alloSCT; thus, only Hodgkin lymphoma patients having human leukocyte antigen-typing immediately after the failed autoSCT were included. Of 185 patients, 122 found an identical sibling (55%), a matched unrelated (32%) or a haploidentical sibling (13%) donor; 63 patients did not find any donor. Clinical features of both groups did not differ. Two-year progression-free (PFS) and overall survival (OS) were better in the donor group (39.3% vs 14.2%, and 66% vs 42%, respectively, P < .001) with a median follow-up of 48 months. In multivariable analysis, having a donor was significant for better PFS and OS (P < .001). Patients allografted in complete remission showed a better PFS and OS. This is the largest study comparing RIC alloSCT versus conventional treatment after a failed autoSCT, indicating a survival benefit for patients having a donor.

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).

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.

Postoperative patient blood management: transfusion appropriateness in cancer patients.

BACKGROUND: While patient blood management (PBM) principles are not specific to cancer patients, their application contains the pathophysiological premises that could also benefit this patient population. In this study, we assessed the effects of implementing a PBM bundle for cancer patients in the postoperative period. MATERIALS AND METHODS: The Azienda USL-IRCCS of Reggio Emilia implemented a two-step PBM bundle for the postoperative period of cancer patients hospitalised in the semi-intensive post-surgery (SIPO) ward. Step 1 included seminars and lessons specifically targeting SIPO personnel; Step 2 introduced Points of Care (POCs) for the continuous monitoring of haemoglobin (Radical7, Masimo Corp, Irvine, CA, USA). We conducted 3 audits on 600 cancer patients recruited between 2014 and 2017: Audit 1 on 200 patients before the application of our PBM bundle; Audit 2 after Step 1 on 200 patients; Audit 3 after Step 2 on 200 patients monitored with POCs. Red blood cell (RBC) transfusion appropriateness in the postoperative period was evaluated using the Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) recommendations. RESULTS: RBC transfusion appropriateness in the postoperative period of cancer patients rose from 38% to 75% after seminars, and reached 79% after the introduction of POC. The mean number of RBC units each patient received remained unchanged after training sessions (1.8 units/patient) while the introduction of POCs saw a simultaneous decrease in the number of prescribed units (1.3 units/patient). DISCUSSION: Our PBM bundle positively impacted RBC transfusion appropriateness in postsurgical cancer patients, both in terms of quality and quantity. A structured PBM programme specifically dedicated to surgical oncology should cover the entire perioperative period and might further improve transfusion appropriateness in these patients. The publication of guidelines on the management of anaemia in surgical oncology should be a priority.

Patient Blood Management: transfusion appropriateness in the post-operative period.

BACKGROUND: Within the context of Patient Blood Management (PBM) policy for the peri-operative period, the transfusion medicine unit of our institution adopted a series of strategies to support and enhance red blood cell (RBC) transfusion best practices. This study aimed to evaluate the appropriateness of RBC transfusion therapy in the post-operative period, before and after starting a multifactorial PBM policy. MATERIALS AND METHODS: A 2-phase observational study was conducted on patients who underwent major surgery. The study was designed as follows: 3 months of preliminary audit, followed by multifactorial PBM policy, and a final audit. The policy comprised seminars, teaching lessons, periodic consultations and the insertion of Points of Care. RBC transfusion appropriateness was evaluated in both audits. RESULTS: The preliminary audit, performed on 168 patients, showed that 37.7% of the patients were appropriately transfused. The final audit, performed on 205 patients, indicated a significant increase of RBC transfusion appropriateness to 65.4%. DISCUSSION: In our experience, our multifactorial PBM policy improved the RBC transfusion appropriateness in the post-operative period. We believe that our multifactorial PBM policy, which comprises the insertion of Points of Care, supported the healthcare workers in the transfusion decision-making process. This enhancement of transfusion appropriateness implies clinical and managerial advantages, such as reduced transfusion-related risks, optimisation of health care resources, and reduction in costs.

Scedosporiosis in patients with acute leukemia: a retrospective multicenter report.

We retrospectively analyzed 542 proven/probable mould infections registered, in the course of 2 studies, in 8,633 patients with acute leukemia, focusing on scedosporiosis. We aimed to define scedosporiosis incidence and mortality rate over a 15-year period. Only 5 cases of scedosporiosis were identified, all of them involving patients with acute myeloid leukemia (AML). We also reviewed all cases of Scedosporium spp. infections in acute leukemia reported to date in the international literature. The 52 cases analyzed confirmed that acute myeloid leukemia is the category with the highest risk of scedosporiosis. Clinical features of scedosporiosis were extremely variable and closely related to patient immune status. Infection disseminated to multiple sites in a very high percentage of patients and outcome was confirmed to be very poor. In our surveys all patients died, in spite of Amphotericin B compounds or voriconazole administration. Our review of literature found scedosporiosis attributable mortality rate (AMR) to be 77%. In conclusion, scedosporiosis, although extremely rare, represents a big problem for clinicians because of its aggressive clinical presentation and the lack of an effective therapy. New drugs with in vitro activity against Scedosporium spp (voriconazole, posaconazole) should be considered. However, their clinical activity should be more widely demonstrated.

Galactomannan detection in Geotrichum capitatum invasive infections: report of 2 new cases and review of diagnostic options.

We report 2 cases of Geotrichum capitatum infection in leukemia patients for which Aspergillus galactomannan (GM) assay was positive. The diagnostic options of G. capitatum infections in hematologic patients were reviewed. Although the pathogen was isolated from blood in 77% of cases, diagnostic difficulties remain and GM assay may have a role.

Incidence of bacterial and fungal infections in newly diagnosed acute myeloid leukaemia patients younger than 65 yr treated with induction regimens including fludarabine: retrospective analysis of 224 cases.

OBJECTIVES: Infections are the major cause of morbidity and mortality in patients with acute myeloid leukaemia (AML). They primarily occur during the first course of induction chemotherapy and may increase the risk of leukaemia relapse, due to a significant delay in consolidation therapy. The intensification of induction chemotherapy and the use of non-conventional drugs such as fludarabine are considered responsible for the increased risk of infections. METHODS: In this study, we retrospectively analysed the infections occurred in 224 newly diagnosed AML patients

The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the incidence and outcome of invasive fungal infections (IFI) in patients with hematologic malignancies. DESIGN AND METHODS: This was a retrospective cohort study of patients admitted between 1999 and 2003 to 18 hematology wards in Italy. Each participating center provided information on all patients with newly diagnosed hematologic malignancies admitted during the survery period and on all episodes of IFI experienced by these patients. RESULTS: The cohort was formed of 11,802 patients with hematologic malignacies: acute leukemia (myeloid 3012, lymphoid 1173), chronic leukemia (myeloid 596, lymphoid 1104), lymphoma (Hodgkin's 844, non-Hodgkin's 3457), or multiple myeloma (1616). There were 538 proven or probable IFI (4.6%); 373 (69%) occurred in patients with acute myeloid leukemia. Over half (346/538) were caused by molds (2.9%), in most cases Aspergillus spp. (310/346). The 192 yeast infections (1.6%) included 175 cases of candidemia. Overall and IFI-attributable mortality rates were 2% (209/11802) and 39% (209/538), respectively. The highest IFI-attributable mortality rates were associated with zygomycosis (64%) followed by fusariosis (53%), aspergillosis (42%), and candidemia (33%). INTERPRETATION AND CONCLUSIONS: Patients with hematologic malignancies are currently at higher risk of IFI caused by molds than by yeasts, and the incidence of IFI is highest among patients with acute myeloid leukemia. Aspergillus spp are still the most common pathogens, followed by Candida spp. Other agents are rare. The attributable mortality rate for aspergillosis has dropped from 60-70% to approximately 40%. Candidemia-related mortality remains within the 30-40% range reported in literature although the incidence has decreased.

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.

Case-control study of multidrug resistance phenotype and response to induction treatment including or not fludarabine in newly diagnosed acute myeloid leukaemia patients.

One hundred and six patients aged /= 6) vs. 75% among the MDR-Pgp-negative (neg(ve)) ones (MFI < 6) (P = 0.16). Conversely, in the controls, the CR rate was 44% among the MDR-Pgp-pos(ve) patients vs. 67% among the MDR-Pgp-neg(ve) ones (P = 0.02). The 4-year disease-free survival (DFS) and overall survival (OS) of MDR-Pgp-pos(ve) cases were significantly longer than those of MDR-Pgp-pos(ve) controls (DFS, 28.1% vs. 6.5%, P = 0.004; OS, 33.5% vs. 9.6%, P = 0.01). This difference was not found among the MDR-Pgp-neg(ve) patients. By univariate (P = 0.007) and multivariate (P = 0.007) analysis, the MDR-Pgp-pos(ve) phenotype was negatively correlated with CR and it emerged as the most important independent negative prognostic factor, after cytogenetics. Our study confirms the prognostic impact of the MDR phenotype in AML and strongly suggests fludarabine-based induction treatments as a promising strategy for MDR-Pgp-pos(ve) AML patients. In this setting of patients, large prospective randomised studies should be planned.

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.

Autologous transplantation of granulocyte colony-stimulating factor-primed bone marrow is effective in supporting myeloablative chemotherapy in patients with hematologic malignancies and poor peripheral blood stem cell mobilization.

We assessed the hematopoietic recovery and transplantation-related mortality (TRM) of patients who had failed peripheral blood stem cell mobilization and subsequently received high-dose chemotherapy supported by granulocyte colony-stimulating factor (G-CSF)-primed bone marrow (BM). Studied were 86 heavily pretreated consecutive patients with acute leukemia (n = 21), refractory/relapsed non-Hodgkin lymphoma (n = 41) and Hodgkin disease (n = 17), and multiple myeloma (n = 7). There were 78 patients who showed insufficient mobilization of CD34+ cells (< 10 cells/microL), whereas 8 patients collected less than 1 x 106 CD34+ cells/kg. BM was primed in vivo for 3 days with 15 to 16 microg/kg of subcutaneous G-CSF. Median numbers of nucleated cells, colony-forming unit cells (CFU-Cs), and CD34+ cells per kilogram harvested were 3.5 x 10(8), 3.72 x 10(4), and 0.82 x 10(6), respectively. Following myeloablative chemotherapy, median times to achieve a granulocyte count higher than 0.5 x 10(9)/L and an unsupported platelet count higher than 20 and 50 x 10(9)/L were 13 (range, 8-24), 15 (range, 12-75), and 22 (range, 12-180) days, respectively, for lymphoma/myeloma patients and 23 (range, 13-53), 52 (range, 40-120), and 90 (range, 46-207) days, respectively, for leukemia patients. Median times to hospital discharge after transplantation were 17 (range, 12-40) and 27 (range, 14-39) days for lymphoma/myeloma and acute leukemia patients, respectively. TRM was 4.6%, whereas 15 patients died of disease. G-CSF-primed BM induces effective multilineage hematopoietic recovery after high-dose chemotherapy and can be safely used in patients with poor stem cell mobilization.