Clara Minotti

Clinically Driven Diagnostic Antifungal Approach in Neutropenic Patients: A Prospective Feasibility Study

PURPOSE Preemptive strategies in neutropenic patients based on serum galactomannan (GM) -guided triggering of diagnostic work-up may be time-consuming and expensive when applied to the entire population. We have assessed the feasibility of a clinically driven diagnostic strategy without GM screening. PATIENTS AND METHODS Patients with neutropenic fever underwent a baseline diagnostic work-up (BDWU; three blood cultures and other examinations as indicated). An intensive diagnostic work-up (IDWU; GM for 3 days, chest computed tomography and other examinations as indicated) was reserved for patients with 4 days of persisting or relapsing fever or with other clinical findings possibly related to an invasive fungal diseaser (IFD). Antifungal therapy was administered to patients diagnosed with IFD and empirically (negative IDWU) only to those with persisting neutropenic fever and worsening clinical conditions. RESULTS Of 220 neutropenia episodes, fever occurred in 159 cases and recurred in 28 cases. Overall, 49 IFDs were diagnosed (two by BDWU and 47 by IDWU) during 48 episodes (21.8%). Diagnostic-driven therapy was administered to 48 patients with IFDs; one patient with zygomycosis died without treatment. Only one patient received empirical therapy. IDWU was required in 40% of neutropenia episodes, and only 1.4 mean blood samples per neutropenia episode were tested for GM. Our strategy allowed a 43% reduction in antifungal treatments compared with a standard empirical approach. At 3-month follow-up, 63% of patients with IFD survived, and no undetected IFDs were found. CONCLUSION A clinically driven diagnostic approach in selected neutropenia episodes offered effective antifungal control and reduced the exposure to unnecessary antifungal treatment.

Posaconazole prophylaxis during front-line chemotherapy of acute myeloid leukemia: a single-center, real-life experience

Background Posaconazole is effective as primary antifungal prophylaxis of invasive fungal diseases in patients with acute myeloid leukemia. Design and Methods The impact of primary antifungal prophylaxis administered during front-line chemotherapy for acute myeloid leukemia was evaluated by comparing 58 patients who received oral amphotericin B (control group) to 99 patients who received oral posaconazole (posaconazole group). The primary endpoint was the incidence of proven/probable invasive fungal diseases. Secondary endpoints included incidence of invasive aspergillosis, survival at 4 and 12 months after the diagnosis of acute myeloid leukemia and costs. Results Proven/probable invasive fungal diseases were documented in 51.7% of patients in the control group and in 23.2% in the posaconazole group (P=0.0002). Invasive aspergillosis was documented in 43% of patients in the control group and in 15% in the posaconazole group (P=0.002). No survival difference was observed in patients aged over 60 years. In patients aged 60 years or less, a statistically significant survival advantage was observed at 4 months, but no longer at 12 months, in the posaconazole group (P=0.03). It was calculated that in the posaconazole group there was a mean 50% cost reduction for the antifungal drugs. Conclusions Primary antifungal prophylaxis with posaconazole during front-line chemotherapy was effective in preventing invasive fungal diseases in a “real-life” scenario of patients with acute myeloid leukemia, resulted in an early but transitory survival advantage in younger patients and was economically advantageous.

Increased BMI correlates with higher risk of disease relapse and differentiation syndrome in patients with acute promyelocytic leukemia treated with the AIDA protocols

We investigated whether body mass index (BMI) correlates with distinct outcomes in newly diagnosed acute promyelocytic leukemia (APL). The study population included 144 patients with newly diagnosed and genetically confirmed APL consecutively treated at a single institution. All patients received All-trans retinoic acid and idarubicin according to the GIMEMA protocols AIDA-0493 and AIDA-2000. Outcome estimates according to the BMI were carried out together with multivariable analysis for the risk of relapse and differentiation syndrome. Fifty-four (37.5%) were under/normal weight (BMI < 25), whereas 90 (62.5%) patients were overweight/obese (BMI ≥ 25). An increased BMI was associated with older age (P < .0001) and male sex (P = .02). BMI was the most powerful predictor of differentiation syndrome in multivariable analysis (odds ratio = 7.24; 95% CI, 1.50-34; P = .014). After a median follow-up of 6 years, the estimated cumulative incidence of relapse at 5 years was 31.6% (95% CI, 22.7%-43.8%) in overweight/obese and 11.2% (95% CI, 5.3%-23.8%) in underweight/normal weight patients (P = .029). Multivariable analysis showed that BMI was an independent predictor of relapse (hazard ratio = 2.45, 95% CI, 1.00-5.99, in overweight/obese vs under/normal weight patients, P = .049). An increased BMI at diagnosis is associated with a higher risk of developing differentiation syndrome and disease relapse in APL patients treated with AIDA protocols.

High levels of antiphospholipid antibodies are associated with cytomegalovirus infection in unrelated bone marrow and cord blood allogeneic stem cell transplantation

Antiphospholipid antibodies (APA) are a family of autoimmune and alloimmune immunoglobulins recognizing protein–phospholipid complexes in in vitro laboratory test systems. These antibodies have been associated with several conditions (malignancies, autoimmune diseases, infections, use of drugs); moreover, a syndrome capable of inducing thromboembolic disease has recently been associated with the presence of these antibodies. The aim of this prospective study was to investigate the levels of APA in subjects affected by haematological malignancies undergoing allogeneic haematopoietic stem cell transplantation (ASCT). Between March 1996 and December 1997, 32 patients undergoing ASCT were studied prospectively until day +180 from transplant. The mean values of IgG and IgM anticardiolipin antibodies (ACA) increased in recipients of stem cells from anunrelated donor, and a statistically significant difference inACA IgG mean value between unrelated and related transplanted patients was demonstrated between days +95 and +180. All of the subjects who received stem cells from an unrelated donor had APA levels higher than the mean normal value +3 SD vs. 35% of those receiving stem cells from a related donor (P < 0·01). The reason for such a difference may be a result of the different incidence in documented cytomegalovirus (CMV) infection in the two groups (83% vs. 23%; P < 0·01), as indicated by the significant correlation between APA positivity and CMV infection (P < 0·05). No relationship was found between APA, conditioning regimen and acute or chronic graft vs. host disease (GVHD). Moreover, we did not observe any thromboembolic disorder or veno occlusive disease (VOD).

Early hemorrhagic death before starting therapy in acute promyelocytic leukemia: association with high WBC count, late diagnosis and delayed treatment initiation

Early death is one of the major causes of failure in acute promyelocytic leukemia (APL), it occurs in approximately 5–10% of newly diagnosed cases and is most frequently due to severe intracranial or pulmonary bleeding. In the present single center study, we reviewed the clinical and biological

As compared to kaolin clotting time, silica clotting time is a specific and sensitive automated method for detecting lupus anticoagulant

Lupus anticoagulants (LAs) are antiphospholipid antibodies capable of interfering with the coagulation system and modifying in vitro the phospholipid-dependent clotting tests. Colloidal silica was used as activator to perform an activated partial thromboplastin time (aPTT) in 73 plasma samples with pathologically elevated kaolin clotting time (KCT) values using a photooptical automated coagulometer. Samples were incubated for 5 min with micronized silica, and after recalcification, the clotting times were measured. Pathologically prolonged results were confirmed by a confirmation and a neutralization test adding platelet-poor normal plasma (PPNP) and natural phospholipids, respectively. Silica clotting time (SCT) was abnormally elevated in 72/73 (98.6%) (mean ratio 1.71 +/- 0.28) KCT positive samples and normalized (mean ratio 1.03 +/- 0.16) after adding natural phospholipids to test plasma. The values expressed as SCT and KCT ratios were significantly correlated (r = .92; P < .001). SCT was normal in 40 healthy subjects utilised as controls (mean ratio 0.99 +/- 12). Sensitivity, specificity and diagnostic accuracy of SCT were 98.6%, 100% and 97.6%, respectively. Our data suggest that SCT is a sensitive test for detecting LA with a prolonged KCT in automated photooptical coagulometers. This peculiarity makes it particularly useful, in combination with diluted Russel viper venom time (dRVVT), for large-scale screening tests on LA.

Efficacy of prolonged therapy with combined arsenic trioxide and ATRA for relapse of acute promyelocytic leukemia

Front-line treatment combining All-trans retinoic acid (ATRA) and chemotherapy is curative in approximately 80% of patients with acute promyelocytic leukemia (APL). As for patients who relapse after this approach, current guidelines recommend the administration of arsenic trioxide (ATO) with or

Invasive fungal diseases during first induction chemotherapy affect complete remission achievement and long-term survival of patients with acute myeloid leukemia

We retrospectively evaluated, in a logistic-regression-model, the role of proven/probable invasive fungal diseases (PP-IFD), occurring during first induction chemotherapy, on the achievement of complete remission (CR) and overall survival (OS) in 198 acute myeloid leukemia (AML) patients. A PP-IFD was documented in 34 (17.2%) patients. Younger age, good performance status at AML diagnosis and no development of a PP-IFD (OR 4.09, 95% CI 1.71-9.81, p<0.0001) were independent factors associated to CR achievement. Younger age, good performance status, favorable genetic risk and no development of PP-IFD (HR 1.86, 95% CI 1.20-2.88, p=0.005) were independent factors associated to OS at 3 years.

Aberrant phenotypic expression of CD15 and CD56 identifies poor prognostic acute promyelocytic leukemia patients

Limited information is available on the relationship between expression of some additional aberrant phenotypic features and outcome of acute promyelocytic leukemia (APL) patients. Here, we set out to assess the frequency of CD15 and CD56 expression, and their prognostic value in a large series of APL patients. One hundred and fourteen adult patients consecutively diagnosed with PML/RARα-positive APL and homogeneously treated with the AIDA induction schedule at a single institution were included in the study. Twelve (10.5%) and 9 (8%) of the 114 patients expressed CD15 and CD56, respectively. CD15 expression identified a subset of patients with a classic morphologic subtype (92%), a prevalent association with a bcr1 expression (67%) with an unexpectedly higher frequency of relapses (42% vs 20% for the CD15- patients, p=0.03) and a low overall survival (OS) (median OS at 5 years 58% vs 85% for the CD15- patients, p=0.01). CD56 expression was detected only in patients with a classic morphologic subtype, a prevalent bcr3 expression (67%), high incidence of differentiation syndrome (55%), higher frequency of relapse (34% vs 20% for the CD56- population, p=0.04) and a low OS (60% vs 85% for the CD56- population p=0.02). We hereby confirm the negative prognostic value of CD56 and we show that the same applies also to cases expressing CD15. These aberrant markers may be considered for the refinement of risk-adapted therapeutic strategies in APL patients.

Pregnancy in acute promyelocytic leukaemia after front-line therapy with arsenic trioxide and all-trans retinoic acid.

JF, JC and KR treated the patient, analysed the data and wrote the manuscript. LB analysed the data and wrote the manuscript. VD and BS contributed to the immune reconstitution data, were involved in the design of the immune reconstitution study, analysed the data and helped to draft the manuscript. AP and GJM treated the patient and helped to draft the manuscript. All authors read and approved the final manuscript.