Antonio Spadea

Cardiovascular Events and Intensity of Treatment in Polycythemia Vera

BACKGROUNDnCurrent treatment recommendations for patients with polycythemia vera call for maintaining a hematocrit of less than 45%, but this therapeutic strategy has not been tested in a randomized clinical trial.nnnMETHODSnWe randomly assigned 365 adults with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both to receive either more intensive treatment (target hematocrit, <45%) (low-hematocrit group) or less intensive treatment (target hematocrit, 45 to 50%) (high-hematocrit group). The primary composite end point was the time until death from cardiovascular causes or major thrombotic events. The secondary end points were cardiovascular events, cardiovascular hospitalizations, incidence of cancer, progression to myelofibrosis, myelodysplasia or leukemic transformation, and hemorrhage. An intention-to-treat analysis was performed.nnnRESULTSnAfter a median follow-up of 31 months, the primary end point was recorded in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the high-hematocrit group (9.8%) (hazard ratio in the high-hematocrit group, 3.91; 95% confidence interval [CI], 1.45 to 10.53; P=0.007). The primary end point plus superficial-vein thrombosis occurred in 4.4% of patients in the low-hematocrit group, as compared with 10.9% in the high-hematocrit group (hazard ratio, 2.69; 95% CI, 1.19 to 6.12; P=0.02). Progression to myelofibrosis, myelodysplasia or leukemic transformation, and bleeding were observed in 6, 2, and 2 patients, respectively, in the low-hematocrit group, as compared with 2, 1, and 5 patients, respectively, in the high-hematocrit group. There was no significant between-group difference in the rate of adverse events.nnnCONCLUSIONSnIn patients with polycythemia vera, those with a hematocrit target of less than 45% had a significantly lower rate of cardiovascular death and major thrombosis than did those with a hematocrit target of 45 to 50%. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT01645124, and EudraCT number, 2007-006694-91.).

Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: an Italian multicenter study.

The objective of this study was to evaluate the clinical features, prognostic factors, and efficacy of treatments in patients with blastic plasmacytoid dendritic cell neoplasm with a leukemic presentation at onset of the disease. In order to do this, a retrospective multicenter study was performed from 2005-2011 in 28 Italian hematology divisions in which 43 cases were collected. Forty-one patients received an induction therapy, consisting of an acute myeloid leukemia-type regimen in 26 patients (60%) and acute lymphoid leukemia/lymphoma-type regimen in 15 patients (35%). Six patients (14%) underwent allogeneic hematopoietic stem cell transplantation. Seventeen patients (41%) achieved a complete remission: seven after acute myeloid leukemia-type treatment and 10 after an acute lymphoid leukemia/lymphoma-type regimen, with a significant advantage for acute lymphoid leukemia/lymphoma-type chemotherapy (P=0.02). Relapse occurred in six of the 17 patients (35%) who achieved complete remission, more frequently after acute lymphoid leukemia/lymphoma-type chemotherapy. The median overall survival was 8.7 months (range, 0.2-32.9). The patients treated with an acute myeloid leukemia-type regimen had an overall survival of 7.1 months (range, 0.2-19.5), whereas that of the patients receiving acute lymphoid leukemia/lymphoma-type chemotherapy was 12.3 months (range, 1-32.9) (P=0.02). The median overall survival of the allogeneic hematopoietic stem cell transplant recipients was 22.7 months (range, 12-32.9), and these patients had a significant survival advantage compared to the non-transplanted patients (median 7.1 months, 0.2-21.3; P=0.03). In conclusion, blastic plasmacytoid dendritic cell neoplasm with bone-marrow involvement is an aggressive subtype of high-risk acute leukemia. The rarity of this disease does not enable prospective clinical trials to identify the better therapeutic strategy, which, at present, is based on clinicians experience.

Melphalan treatment in patients with myelofibrosis with myeloid metaplasia

Summary. Between January 1985 and December 1992, 104 consecutive patients with symptomatic myelofibrosis with myeloid metaplasia (MMM) [splenic enlargement >u200a5u2003cm and/or transfusional requirement or Hbu2003<u200310u2003g/dl and/or white blood cell (WBC) count >u200a20u2003×u2003109/l and/or platelets >u200a1·0u2003×u2003109/l] received low‐dose Melphalan (2·5u2003mg/3 times/week) to evaluate the efficacy and toxicity of this approach. Among 99 evaluable patients, 66 (66·7%) achieved a response after a median time of 6·7u2003months: 26 (26·3%) had a normalization of all clinical and haematological parameters (complete response, CR) and 40 (40·4%) showed an improvement >u200a50% (partial response, PR). Thirty‐three patients (33·3%) were resistant. Reversible haematological toxicity was the most common complication. Median durations of CR and PR were 28·4 and 26u2003months respectively: median survival of CRu2003+u2003PR patients was 71·2u2003months (95%CI: 33·8–108·7) versus 36·5u2003months (95%CI: 24·5–48·5) for the non‐responders (log‐rank test, P =u200a0·002). In the multivariate analysis, the following variables were significantly associated with a shorter survival: anaemia [hazard risk (HR)u2003=u20032·7], WBC count >u200a20u2003×u2003109/l (HRu2003=u20032·4) and not achieving any type of response, either partial or complete (HRu2003=u20033·9). In conclusion, Melphalan could be a promising first‐line option for MMM patients with clinical or haematological symptoms requiring treatment.

Idarubicin (4-demethoxydaunorubicin) as single agent for remission induction of previously untreated acute promyelocytic leukemia : a pilot study of the Italian cooperative group GIMEMA

Abstract: Because of the reported high sensitivity of acute promyelocytic leukemia to daunorubicin, we treated 27 consecutive, newly diagnosed, acute promyelocytic leukemia (APL) patients with the new anthracycline idarubicin (IDA) as induction therapy. IDA dosage ranged from 0.25 to 0.30 mg/kg/day and the drug was administered as single agent during a single induction course of 6 days. A total of 22/27 patients (81%) achieved complete remission, 4 (15%) died during induction and 1 patient was resistant to IDA. Extrahematological toxicity was acceptable. A total of 13/22 patients having achieved CR are still alive and in first CR after a median follow‐up of 12 months. As for the treatment ot the coagulopathy present in APL: 17/27 (63%) received tranexamic acid (6 g/daily) in continuous infusion for total of 7 d. None of the patients treated with tranexamic acid experienced thromboembolic complications. In conclusion, this multicentric pilot study confirms the antileukemic potency of IDA and the high sensitivity of APL to anthracycline derivatives.

Multidrug resistant Pseudomonas aeruginosa bloodstream infection in adult patients with hematologic malignancies

We read with interest the article by Caselli et al. [1][1] who described a 9-year retrospective series of Pseudomonas aeruginosa (PA) bacteremia cases from 12 Italian pediatric hematology oncology centers and reported a total of 127 patients with Pseudomonas aeruginosa bloodstream infections (BSIs

Current epidemiology and antimicrobial resistance data for bacterial bloodstream infections in patients with hematologic malignancies: an Italian multicentre prospective survey

A prospective cohort study was conducted in nine hematology wards at tertiary care centres or at university hospitals located throughout Italy from January 2009 to December 2012. All of the cases of bacterial bloodstream infection (BBSI) occurring in adult patients with hematologic malignancies were included. A total of 668 bacterial isolates were recovered in 575 BBSI episodes. Overall, the susceptibility rates of Gram-negative bacteria were 59.1% to ceftazidime, 20.1% to ciprofloxacin, 79.1% to meropenem, 85.2% to amikacin, 69.2% to gentamicin and 69.8% to piperacillin/tazobactam. Resistance to third-generation cephalosporins was found in 98/265 (36.9%) of Enterobacteriaceae isolates. Among Klebsiella pneumoniae strains, 15/43 (34.9%) were resistant to carbapenems. Of 66 Pseudomonas aeruginosa isolates, 46 (69.7%) were multidrug resistant. Overall, the susceptibility rates of Gram-positive bacteria were 97.4% to vancomycin and 94.2% to teicoplanin. Among the monomicrobial cases of BBSI, the 21-day mortality rate was significantly higher for those caused by Gram-negative bacteria compared to those caused by Gram-positive bacteria (47/278, 16.9% vs. 12/212, 5.6%; p < 0.001). Among Gram-negative bacteria, the mortality rate was significantly higher for BBSI caused by K. pneumoniae, P. aeruginosa, and Acinetobacter baumannii. Our results confirm the recently reported shift of prevalence from Gram-positive to Gram-negative bacteria as causative agents of BBSIs among patients with hematologic malignancies and highlight a worrisome increasing frequency in antimicrobial resistance among Gram-negative bacteria.

Pre-chemotherapy risk factors for invasive fungal diseases: prospective analysis of 1,192 patients with newly diagnosed acute myeloid leukemia (SEIFEM 2010-a multicenter study)

Correct definition of the level of risk of invasive fungal infections is the first step in improving the targeting of preventive strategies. We investigated the potential relationship between pre-hospitalization exposure to sources of fungi and the development of invasive fungal infections in adult patients with newly diagnosed acute myeloid leukemia after their first course of chemotherapy. From January 2010 to April 2012, all consecutive acute myeloid leukemia patients in 33 Italian centers were prospectively registered. Upon first admission, information about possible pre-chemotherapy risk factors and environmental exposure was collected. We recorded data regarding comorbid conditions, employment, hygienic habits, working and living environment, personal habits, hobbies, and pets. All invasive fungal infections occurring within 30 days after the first course of chemotherapy were recorded. Of the 1,192 patients enrolled in this study, 881 received intensive chemotherapy and were included in the present analysis. Of these, 214 developed an invasive fungal infection, including 77 proven/probable cases (8.7%). Of these 77 cases, 54 were proven/probable invasive mold infections (6.1%) and 23 were proven yeast infections (2.6%). Upon univariate analysis, a significant association was found between invasive mold infections and age, performance status, diabetes, chronic obstructive pulmonary disease, smoking, cocaine use, job, hobbies, and a recent house renovation. Higher body weight resulted in a reduced risk of invasive mold infections. Multivariate analysis confirmed the role of performance status, job, body weight, chronic obstructive pulmonary disease, and house renovation. In conclusion, several hospital-independent variables could potentially influence the onset of invasive mold infections in patients with acute myeloid leukemia. Investigation of these factors upon first admission may help to define a patient’s risk category and improve targeted prophylactic strategies.

Long‐term evaluation of 164 patients with essential thrombocythaemia treated with pipobroman: occurrence of leukaemic evolution

Summary. Essential thrombocythaemia (ET) is usually considered an indolent disease, but it may progress during its natural course into acute leukaemia (AL); however, an influence of myelosuppressive agents in the blastic transformation of ET cannot be excluded. We performed a retrospective study to assess the incidence of AL in ET patients treated with pipobroman (PB) as first‐line therapy. One hundred and sixty‐four patients with ET were managed with PB at a dose of 1u2003mg/kg/d until a stable platelet count below 400u2003×u2003109/l was achieved. Maintenance therapy was given at a planned dose ranging between 0·2 and 1u2003mg/kg/d according to platelet count, in all cases, with a median daily dose of 25u2003mg (range 7–75u2003mg/d). The median treatment time was 100u2003months (range 25–243u2003months). The patients were evaluated for the occurrence of AL and/or secondary malignancies and survival end‐points. AL was observed in nine patients (5·5%) after a median treatment time of 153u2003months (range 79–227u2003months). The overall survival (OS) and the event‐free survival (EFS) at 120u2003months were 95% and 97%, whereas at 180u2003months, they were 84% and 76% respectively. In conclusion, this retrospective analysis shows a low incidence of AL in a large group of patients consecutively treated with PB as first‐line chemotherapy. Therefore, an investigation of the role of myelosuppressive agents in the blastic transformation of ET would be of interest.

The role of all-trans-retinoic acid (ATRA) treatment in newly-diagnosed acute promyelocytic leukemia patients aged >60 years

BACKGROUNDnTo evaluate the role and toxicity of ATRA therapy in newly-diagnosed APL patients aged > 60 yrs, the outcome of 16 consecutive elderly APL patients observed between January 1990 and June 1996 were analyzed.nnnPATIENTS AND METHODSnTheir median age was 65.5 yrs (range 60-81 years), the male/female ratio was 7:9, and molecular biology analysis showed a PML/RARa rearrangement in all patients. Seven patients had a concomitant cardiovascular disease. ATRA 45 mg/sqm/day was given to all patients, and in 11 was associated with idarubicin (AIDA protocol); in two patients ATRA was associated with mitoxantrone + ara-C, while the remaining three patients received ATRA alone.nnnRESULTSnFourteen patients (87.5%) achieved CR, and two patients (12.5%) died during induction. Despite the high CR rate, eight episodes of severe cardiovascular complication were observed in seven patients, three of whom had previously had cardiovascular disease; in addition, three patients had sepsis (two bacterial and one fungal). As of 31 March 1997, 9 of 14 patients were still in first CR after a 19-month (range 7-64 months) median follow-up since attainment of the CR. One patient died in CR of a fungal complication and four patients relapsed after 8, 9, 23 and 35 months following CR: two of them achieved a second CR lasting seven and +15 months with ATRA alone. Of the nine patients still in first CR, only three have received the planned consolidation therapy and five have been in CR for more than 24 months (+25, +33, +34, +38, +63).nnnCONCLUSIONSnDespite the fact that most of these patients received shorter consolidation treatments than do younger patients, the good results achieved in them might be considered an indication for modifying treatment schedules in order to reduce severe toxicity and improve protocol compliance.

Imatinib in very elderly patients with chronic myeloid leukemia in chronic phase: a retrospective study

BackgroundA large number of chronic myeloid leukemia (CML) patients are treated with imatinib mesylate outside of clinical trials, which may not be representative of common clinical practice. The age of CML patients enrolled within controlled clinical studies is lower with respect to patients included in population-based registries.Patients and MethodsTo describe the safety and tolerability of imatinib in very elderly CML patients in chronic phase, 211 chronic-phase CML patients aged >75xa0years were retrospectively analyzed using data collected from 31 institutions in Italy.ResultsThe median age at imatinib start was 78.6xa0years [interquartile range (IR) 76.3–81.4], median time from diagnosis to imatinib start was 1.2xa0months (IR 0.5–3.7). The starting dose of imatinib was 400xa0mg/day in 144 patients (68.2xa0%), >400xa0mg/day in 4 patients (2.0xa0%), and <400xa0mg/day in 63 patients (29.8xa0%); overall, 94 patients (44.5xa0%) needed a dose reduction and 27 (12.7xa0%) discontinued imatinib for toxicity. Grade 3–4 hematologic and extrahematologic toxicities were observed in 40 (18.9xa0%) and 45 (21.3xa0%) patients, respectively. After a median observation of 29.8xa0months (IR 13.0–55.6), 203/211 patients had at least 6xa0months of observation on imatinib or discontinued before and were evaluable for response and outcome; of them, 183 patients (90.2xa0%) achieved a complete hematologic response (CHR). Among these 183 patients in CHR, 14 refused any other karyotypic or molecular evaluation, 24 achieved CHR only, and 145 (71.4xa0%) achieved a cytogenetic response (CyR) of any grade, which was complete (CCyR) in 129 (63.5xa0%). Among the 129 patients with CCyR, 95 (46.7xa0%) achieved a major molecular response (MMolR). By multivariate regression analysis, late chronic phase (pxa0=xa00.001) and grade 3–4 extrahematologic toxicity (pxa0=xa00.007) maintained a negative independent prognostic impact for CCyR, while late chronic phase (pxa0=xa00.026), grade 3–4 extrahematologic toxicity (pxa0=xa00.007), and lower initial dose of imatinib (pxa0=xa00.044) maintained a negative independent prognostic impact for MMolR. The 2-year and 4-year overall survival were 92.6xa0% (95xa0% CI 88.7–96.5) and 78.0xa0% (95xa0% CI 71.2–84.8), respectively.ConclusionsResults from this large cohort of patients show that no upper age limit should be applied for the administration of imatinib to patients with chronic-phase CML; the very elderly, including those with concomitant severe diseases, should be offered this treatment. The role of a reduced starting dose of imatinib warrants further studies.