Silvia Maria Trisolini

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.

ADAMTS‐13 activity and autoantibodies classes and subclasses as prognostic predictors in acquired thrombotic thrombocytopenic purpura

Summary.  Background:  Thrombotic thrombocytopenic purpura (TTP) is a rare life‐threatening disease. Of surviving patients, 45% develops an exacerbation or a late recurrence. Severe ADAMTS‐13 deficiency, both during the acute episode and remission, is a well‐established predictor of recurrence. The predictive value of anti‐ADAMTS‐13 antibodies, their inhibitory activity and Ig class subtype for disease recurrence is still to be established.

How long can we give interleukin-2? Clinical and immunological evaluation of AML patients after 10 or more years of IL2 administration

We have treated 20 patients, affected by acute myelogenous leukemia in advanced phase of the disease, with intravenous high-dose recombinant interleukin-2 (IL2) as induction treatment, achieving a complete remission (CR) in 11/20 of patients (55%). All CR patients were planned to receive a maintenance program with lower subcutaneous doses of IL2 until relapse. Currently, 5/11 patients are alive in continuous complete remission with a minimum follow-up of 9 years from IL2 induction. In the aim to investigate the treatments side-effects during or after prolonged IL2 therapy, we decided to submit these patients to a clinical and immunological evaluation. Four patients have been evaluated as one, who independently stopped IL2 after 6 years, refused the check-up. No organ-specific treatment sequelae that may decrease the quality of life or may be life-threatening were found, concerning renal, liver and cardiovascular function. Endocrine abnormalities were detected in three patients, the most serious being a severe hypothyroidism, which prompted cessation of IL2 maintenance after 6 years and required thyroid supplementation treatment. Immunological studies were carried out prior to the last IL2 cycle and showed high levels of CD3-positive T cells expressing the IL2 receptor alpha chain (CD25), both in the peripheral blood and in the bone marrow. Our study shows that low-dose IL2 can be given for a prolonged period of time without serious organ-specific late sequelae and with a good quality of life.

A PDGFRB-positive acute myeloid malignancy with a new t(5;12)(q33;p13.3) involving the ERC1 gene.

A PDGFRB -positive acute myeloid malignancy with a new t(5;12)(q33;p13.3) involving the ERC1 gene

Prospective cytomegalovirus monitoring during first-line chemotherapy in patients with acute myeloid leukemia

Little is known about the incidence and clinical impact of cytomegalovirus (CMV) infection in patients with acute myeloid leukemia at the time of diagnosis and during chemotherapy. The aims of the present study were to assess prospectively the incidence of active CMV infection in 69 consecutive patients with acute myeloid leukemia and to describe the outcomes of treatment. pp65 antigenemia was monitored at diagnosis, post‐induction and post‐consolidation chemotherapy, and whenever CMV reactivation was suspected. Patients with pp65 antigenemia received pre‐emptive anti‐CMV treatment. Fifty‐nine patients achieved complete remission. Baseline CMV serology results were available for 56 of the 59 patients: 52 patients (93%) were IgG positive. The overall incidence of pp65 antigenemia in patients in complete remission after chemotherapy was 35% (21/59): 9 patients after induction and 12 post‐consolidation. Sixteen of the 21 pp65‐positive patients received anti‐CMV treatment: 15 as pre‐emptive therapy and 1 for interstitial CMV pneumonitis. Five patients received no anti‐CMV treatment and did not develop CMV disease. Patients with pp65 antigenemia had more hospital admissions (2.57 vs. 2.16; P = 0.009), while patients with >10 pp65‐positive cells had more clinical complications (8/9 vs. 2/12; P = 0.002). In conclusion, patients with acute myeloid leukemia receiving chemotherapy should be monitored for active CMV infection. CMV reactivation in these patients was associated with an increased number of hospital admissions, and high levels of pp65 antigenemia were associated with more clinical complications. Controlled studies are needed to assess the relevance of pre‐emptive anti‐CMV therapy in patients with acute myeloid leukemia receiving chemotherapy. J. Med. Virol. 82: 1201–1207, 2010.

Thrombotic thrombocytopenic purpura in the first trimester and successful pregnancy

Dear Editor, Thrombotic thrombocytopenic purpura (TTP) is a rare complication of pregnancy with a poor prognosis and a high fetal mortality when presenting early during gestation. Few cases of TTP (10%) occur during the first trimester [1, 2], the majority occurring at the time of delivery or during post-partum period [4, 6]. Until the effectiveness of plasma infusion and plasma exchange was recognized, TTP was associated with a mortality rate of 95% and, in case of pregnancy-related TTP, the maternal survival was rare and the fetal mortality rate approached 80% [9]. Fetal death is secondary to placental infarction due to thrombotic occlusion of the decidual arterioles [8]. Currently, plasma infusion and plasmapheresis have improved maternal and fetal survival rates [10]. At present, it is well known that termination of pregnancy is rarely needed and that the fetal survival rate could be improved by effective maternal therapy [14]. When TTP occurs during the first trimester of pregnancy and delivery of a viable infant is not an option, plasma exchange treatment is urgently indicated and may allow the pregnancy to continue [13]. There are some reports showing that prolonged courses of plasma exchange, beginning as early as 6 weeks of gestation, may achieve and maintain a remission of TTP allowing delivery of a healthy, full-term infant [1]. When plasma exchange fails to induce remission, therapeutic abortion may be considered, although the response of TTP to termination of pregnancy is uncertain. We have previously reported a case of a successful pregnancy in a young female who developed a severe TTP relapse at 18 weeks of gestation [5]. In the present study, we describe a case of a first pregnancy concomitant to a severe TTP diagnosed in the first trimester with maternal survival and delivery of a healthy child. In August 2004, a 26-year-old nulliparous woman at 9 weeks of gestation presenting macrohematuria and ecchymoses was admitted to our institution. Laboratory data showed thrombotic microangiopathy, with anemia (7.5 g/dl), thrombocytopenia (platelets 6×10/l), numerous schistocytes (60%) in the peripheral blood smears, elevated levels of lactic dehydrogenase (1,472 IU/l range 70–190) and bilirubin (total 3.4 mg/dl, normal value 0.4–1.1, indirect 3 mg/dl, normal value 0.1–0.4), reticulocytosis (250×10/l), and negative direct/indirect Coombs’ test. Renal function was normal. Bone marrow aspirate showed a normal bone marrow cytomorphology. Thrombophilic screening showed normal levels of antithrombin (AT), absence of lupus anticoagulant (LAC), normal levels of C and S proteins, and no mutations of Leiden Factor V and prothrombin gene, while a heterozygous mutation of MTHFR C677T, with normal plasma homocysteine concentrations, was found. Serologic examinations were negative for anti-extractable nuclear antibodies and anticardiolipin antibodies. Unfortunately, ADAMTS-13 levels and inhibitor were not determined during the acute event. On the basis of the symptoms and laboratory tests, a clinical diagnosis of TTP was made and the patient was treated with intravenous methylprednisolone (2 mg/kg/die to 120 mg/die) and daily plasmapheresis, with plasma replacement of 30 ml/kg/die, in combination with continuous infusion of fresh frozen plasma (FFP) (10 ml/kg/die). Folic acid (15 mg/die) support was given. The initial response was Ann Hematol (2009) 88:287–289 DOI 10.1007/s00277-008-0579-4

Pregnancy complications in acquired thrombotic thrombocytopenic purpura: a case-control study

BackgroundPregnant women with a history of acquired thrombotic thrombocytopenic purpura (TTP) are considered at risk for disease recurrence and might be at risk for miscarriage, similar to other autoimmune disorders. However, the exact entity of these risks and their causes are unknown. The aim of this study was to evaluate risk factors associated with adverse pregnancy outcome, in terms of both gravidic TTP and miscarriage, in women affected by previous acquired TTP.MethodsWe conducted a nested case–control study in women with a history of acquired TTP enrolled in the Milan TTP registry from 1994 to October 2012, with strict inclusion criteria to reduce referral and selection bias.ResultsFifteen out of 254 women with acquired TTP were included, namely four cases with gravidic TTP, five with miscarriage, and six controls with uncomplicated pregnancy. In the cases, ADAMTS13 activity levels in the first trimester were moderately-to-severely reduced (median levels <3% in gravidic TTP and median levels 20% [range 14-40%] in the women with miscarriage) and anti-ADAMTS13 antibodies were invariably present, while in the control group ADAMTS13 activity levels were normal (median 90%, range 40-129%), with absence of detectable anti-ADAMTS13 antibodies. Reduced levels of ADAMTS13 activity (<25%) in the first trimester were associated with an over 2.9-fold increased risk for gravidic TTP and with an over 1.2-fold increased risk for miscarriage (lower boundary of the confidence interval of the odds ratio). In addition, the presence of anti-ADAMTS13 antibodies during pregnancy was associated with an over 6.6-fold increased risk for gravidic TTP and with an over 4.1-fold increased risk for miscarriage.ConclusionsADAMTS13 activity evaluation and detection of anti-ADAMTS13 antibody could help to predict the risk of complications in pregnant women with a history of acquired TTP.

Thrombotic thrombocytopenic purpura during pregnancy versus imitator of preeclampsia.

Thrombotic thrombocytopenic purpura (TTP) is a severe disorder affecting the microcirculation of multiple organs due to a systemic endothelial cell injury secondary to a deficiency in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) activity. TTP is a rare complication of pregnancy with a poor prognosis and high fetal mortality, especially when it occurs during the first trimester. Recent data have supported that effective treatment of TTP is plasma therapy. Unfortunately a major problem remains in the delay in diagnosis due to confounding factors between other “imitators of preeclampsia.” Rapid and readily available laboratory testing to quickly diagnose TTP is desperately needed to improve care and to save mother and future child life.

Independent prognostic impact of CD15 on complete remission achievement in patients with acute myeloid leukemia.

The prognostic role of CD15 in acute myeloid leukemia (AML) has been tested in different studies with conflicting results. To address this issue, we retrospectively evaluated a cohort of 460 AML patients of all ages with the exclusion of acute promyelocytic leukemia (M/F 243/217, median age 50.6 years [range 0.9‐81.2]) intensively treated at our institute between January 1999 and December 2010. CD15 positivity was found in 171 of 406 evaluable patients (42.1%). Complete remission (CR) was achieved by 334 patients (72.6%), while 82 (17.8%) were resistant and 44 (9.6%) died during induction: the median CR duration was 15.5 months (range 0.6‐176.0), with 2‐year disease‐free survival rate of 45.1% (95% confidence interval 39.6‐50.6). The median overall survival was 14.4 months (range 0.3‐177.0), with 2‐year overall survival rate of 42.2% (95% confidence interval 37.5‐46.9). At univariate analysis for CR achievement, age < 60 years (P < .001), World Health Organization classification (P = .045), low‐risk karyotype (P < .001), no high‐risk karyotype (P = .006), positivity for AML‐ETO (P = .004)/CBFβ‐MYH11 (P = .003)/CD15 (P = .006)/CD11b (P = .013), negativity for FLT3‐ITD (P = .001), Hb > 8 g/dL (P = .020), and white blood cell < 50 × 109/L (P = .034) had a favorable impact. At a multivariate logistic regression model, CD15 positivity (P = .002), age < 60 years (P = .008), white blood cell < 50 × 109/L (P = .017), and low‐risk/no high‐risk karyotype (P = .026/P = .025) retained an independent prognostic role on CR achievement. The baseline assessment of CD15 positivity appears to have a role in the risk evaluation for CR achievement in AML patients undergoing intensive chemotherapy and should be assessed in prospective studies together with other clinical and biologic features already reported.

Complete Remission Obtained with Azacitidine in a Patient with Concomitant Therapy Related Myeloid Neoplasm and Pulmonary Mucormycosis

Mucormycosis is the third cause of invasive mycosis after candidiasis and aspergillosis in AML patients, representing a poor prognostic factor associated with a high rate of fatal outcome. We report a case of a patient with AML and a concomitant pulmonary mucormycosis at diagnosis, who obtained a complete remission both of her AML and of the fungal infection. The incidence of the infection at the onset of leukemia is extremely unusual, and, to our knowledge, the sporadic cases reported in the literature are included in heterogeneous series retrospectively examined. In our case, Liposomal Amphotericin B as single agent appeared incapable of controlling the infection, so anti-infective therapy was intensified with posaconazole and simultaneously antileukemic treatment with 5-azacitidine was started, with the understanding that the only antifungal treatment would not have been able to keep the infection under control for a long time if not associated with a reversal of neutropenia related to the disease. We observed a progressive improvement of the general conditions, a healing of pneumonia and a complete remission of the leukemic disease, suggesting that a careful utilization of the new compounds available today, in terms of both antifungal and antileukemic treatment, may offer a curative chance a patient who would have otherwise been considered unfit for a potentially curative therapeutic strategy.