[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate the effects of a non-standard, intermittent imatinib treatment in elderly patients with Philadelphia-positive chronic myeloid leukaemia and to answer the question on which dose should be used once a stable optimal response has been achieved. Seventy-six patients aged ⩾65 years in optimal and stable response with ⩾2 years of standard imatinib treatment were enrolled in a study testing a regimen of intermittent imatinib (INTERIM; 1-month on and 1-month off). With a minimum follow-up of 6 years, 16/76 patients (21%) have lost complete cytogenetic response (CCyR) and major molecular response (MMR), and 16 patients (21%) have lost MMR only. All these patients were given imatinib again, the same dose, on the standard schedule and achieved again CCyR and MMR or an even deeper molecular response. The probability of remaining on INTERIM at 6 years was 48% (95% confidence interval 35-59%). Nine patients died in remission. No progressions were recorded. Side effects of continuous treatment were reduced by 50%. In optimal and stable responders, a policy of intermittent imatinib treatment is feasible, is successful in about 50% of patients and is safe, as all the patients who relapsed could be brought back to optimal response.
Blood Cancer Journal 09/2015; 5(9):e347. DOI:10.1038/bcj.2015.75 · 3.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several factors are predictive of treatment-free remission (TFR) in chronic myeloid leukemia (CML) but few data exist on the role of natural killer (NK) cells and their killer- immunoglobin-like receptors (KIRs). KIR and HLA genotypes were investigated in 36 CML patients who discontinued tyrosine kinase inhibitor (TKI) treatment after achieving deep molecular response (MR(4.5)). Cumulative TFR was significantly higher in patients homozygous for KIR A haplotype (85.7% vs 45.5%; p=0.029). Younger age, Bx haplotype and the combination KIR3DS1/KIR3DL1present/HLA-Bw4 present were significantly associated with relapse. KIR genotypes could prove useful in identifying patients that are likely to maintain MR(4.5) after discontinuing TKI treatment.
[Show abstract][Hide abstract] ABSTRACT: Chronic Myeloid Leukemia (CML) is characterized by a balanced translocation juxtaposing the Abelson (ABL) and breakpoint cluster region (BCR) genes. The resulting BCR-ABL1 oncogene leads to increased proliferation and survival of leukemic cells. Successful treatment of CML has been accompanied by steady improvements in our capacity to accurately and sensitively monitor therapy response. Currently, measurement of BCR-ABL1 mRNA transcript levels by real-time quantitative PCR (RQ-PCR) defines critical response endpoints. An antibody-based technique for BCR-ABL1 protein recognition could be an attractive alternative to RQ-PCR. To date, there have been no studies evaluating whether flow-cytometry based assays could be of clinical utility in evaluating residual disease in CML patients. Here we describe a flow-cytometry assay that detects the presence of BCR-ABL1 fusion proteins in CML lysates to determine the applicability, reliability, and specificity of this method for both diagnosis and monitoring of CML patients for initial response to therapy. We show that: i) CML can be properly diagnosed at onset, (ii) follow-up assessments show detectable fusion protein (i.e. relative mean fluorescent intensity, rMFI%>1) when BCR-ABL1IS transcripts are between 1-10%, and (iii) rMFI% levels predict CCyR as defined by FISH analysis. Overall, the FCBA assay is a rapid technique, fully translatable to the routine management of CML patients.
PLoS ONE 06/2015; 10(6):e0130360. DOI:10.1371/journal.pone.0130360 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: For almost 10 years imatinib has been the therapeutic standard of chronic myeloid leukemia. The introduction of other tyrosine-kinase inhibitors (TKIs) raised a debate on treatment optimization. The debate is still heated: some studies have protocol restrictions or limited follow-up; in other studies some relevant data are missing. The aim of this report is to provide a comprehensive, long-term, intention-to-treat, analysis of 559 newly diagnosed, chronic phase, patients treated frontline with imatinib. With a minimum follow-up of 66 months, 65% of patients were still on imatinib, 19% were on alternative treatment, 12% died, and 4% were lost to follow-up. The prognostic value of BCR-ABL1 ratio at 3 months (lower than or equal to 10% in 81% of patients) was confirmed. The prognostic value of complete cytogenetic response and major molecular response at 1 year was confirmed. The 6-year overall survival was 89%, but since 50% of deaths occurred in remission, the 6-year cumulative incidence of leukemia-related death was 5%. The long-term outcome of first-line imatinib was excellent, also due to second-line treatment with other TKIs, but all responses and outcomes were inferior in high-risk patients, suggesting that to optimize treatment results, a specific risk-adapted treatment is needed for such patients.Leukemia accepted article preview online, 19 June 2015. doi:10.1038/leu.2015.152.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2015; 29(9). DOI:10.1038/leu.2015.152 · 10.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated the influence of molecular status on disease characteristics and clinical outcome in young patients (⩽40 years) with World Health Organization (WHO)-defined essential thrombocythemia (ET) or early/prefibrotic primary myelofibrosis (early-PMF). Overall, 217 patients with ET (no. 197) and early-PMF (no. 20) were included in the analysis. Median follow-up time was 10.2 years. The cumulative incidence of thrombosis, hemorrhages and disease evolution into myelofibrosis/acute leukemia were 16.6, 8.6 and 3% at 15 years, respectively. No differences were detectable between ET and early-PMF patients, although the latter cohort showed a trend for worse combined-event free survival (EFS). Mutation frequency were 61% for JAK2V617F, 25% for CALR and 1% for MPLW515K and were comparable across WHO diagnosis; however, JAK2V617F allele burden was higher in the early-PMF group. Compared to JAK2V617F positive patients, CALR-mutated patients displayed higher platelet count and lower hemoglobin level. CALR mutations significantly correlated with lower thrombotic risk (9.1 vs 21.7%, P=0.04), longer survival (100 vs 96%, P=0.05) and better combined-EFS (86 vs 71% P=0.02). However, non-type 1/type 2 CALR mutations ('minor' mutations) and abnormal karyotype were found to correlate with increased risk of disease evolution. At last contact, 6 patients had died; in 5 cases, the causes of death were related to the hematological disease and occurred at a median age of 64 years (range: 53-68). Twenty-eight patients (13%) were unmutated for JAK2, CALR and MPL: no event was registered in these 'triple-negative' patients.Leukemia accepted article preview online, 24 March 2015. doi:10.1038/leu.2015.87.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 03/2015; 29(6). DOI:10.1038/leu.2015.87 · 10.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
The incidence of chronic myeloid leukemia (CML) increases with age, but it is unclear how the characteristics of the disease vary with age. In children, where CML is very rare, it presents with more aggressive features, including huge splenomegaly, higher cell count and higher blast cell percentage.
Patients and methods:
To investigate if after childhood the disease maintains or loses these characteristics of aggressiveness, we analyzed 2784 adult patients, at least 18 years old, registered by GIMEMA CML WP over a 40-year period.
Young adults (YAs: 18-29 years old) significantly differed from adults (30-59 years old) and elderly patients (at least 60 years old) particularly for the frequency of splenomegaly (71%, 63% and 55%, P < 0.001), and the greater spleen size (median value: 4.5, 3.0 and 1.0 cm, P < 0.001). According to the EUTOS score, that is age-independent, high-risk patients were more frequent among YAs, than among adult and elderly patients (18%, 9% and 6%, P < 0.001). In tyrosine kinase inhibitors-treated patients, the rates of complete cytogenetic and major molecular response were lower in YAs, and the probability of transformation was higher (16%, 5% and 7%, P = 0.011).
The characteristics of CML or the host response to leukemia differ with age. The knowledge of these differences and of their causes may help to refine the treatment and to improve the outcome.
Clinical trial numbers:
NCT00510926, NCT00514488, NCT00769327, NCT00481052.
Annals of Oncology 10/2014; 26(1). DOI:10.1093/annonc/mdu490 · 7.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives:
To investigate the incidence, treatment and outcome of breakthrough invasive fungal infections (IFIs) in adult acute myeloid leukaemia (AML) patients after posaconazole prophylaxis.
From January 2010 to April 2012, all consecutive patients with newly diagnosed AML were prospectively registered at 33 participating Italian centres. All cases of IFIs occurring within 30 days after the end of the first induction chemotherapy were recorded. The strategy of antifungal treatment (empirical, pre-emptive or targeted) and the drugs used were analysed. ClinicalTrials.gov code: NCT01315925.
In total, 1192 patients with newly diagnosed AML were enrolled in the study, of whom 510 received posaconazole prophylaxis and were included in the present analysis. Of these patients, 140 (27%) needed systemic antifungal treatment. Among the 127 evaluable cases, an empirical approach was utilized in 102 patients (80%), a pre-emptive approach in 19 patients (15%) and targeted therapy in 6 patients (5%). Only five patients died of IFIs (three in the empirical group and two in the targeted group; 4%). A critical review of IFI diagnoses at 30 days demonstrated that among the patients treated empirically, ∼30% were not affected by IFIs but rather only by fever of unidentified origin. A comparison between the empirical and the pre-emptive groups showed no significant differences regarding the attributable and overall mortalities.
This study confirms that posaconazole prophylaxis reduces the incidence of breakthrough IFIs and does not modify the efficacy of subsequent systemic antifungal treatment, regardless of the approach (empirical or pre-emptive) or the antifungal drug used.
[Show abstract][Hide abstract] ABSTRACT: Empiric antibiotic monotherapy is considered the standard of treatment for febrile neutropenic patients with cancer, but this approach may be inadequate because of the increasing prevalence of infections caused by multidrug resistant (MDR) bacteria.
In this multicenter, open-label, randomized, superiority trial, adult, febrile, high-risk neutropenic patients (FhrNPs) with hematologic malignancies were randomly assigned to receive piperacillin/tazobactam (4.5 g intravenously every 8 hours) with or without tigecycline (50 mg intravenously every 12 hours; loading dose 100 mg). The primary end point was resolution of febrile episode without modifications of the initial allocated treatment.
Three hundred ninety FhrNPs were enrolled (combination/monotherapy, 187/203) and were included in the intention-to-treat analysis (ITTA). The ITTA revealed a successful outcome in 67.9% v 44.3% of patients who had received combination therapy and monotherapy, respectively (127/187 v 90/203; absolute difference in risk (adr), 23.6%; 95% CI, 14% to 33%; P < .001). The combination regimen proved better than monotherapy in bacteremias (adr, 32.8%; 95% CI, 19% to 46%; P < .001) and in clinically documented infections (adr, 36%; 95% CI, 9% to 64%; P < .01). Mortality and number of adverse effects were limited and similar in the two groups.
The combination of piperacillin/tazobactam and tigecycline is safe, well tolerated, and more effective than piperacillin/tazobactam alone in febrile, high-risk, neutropenic hematologic patients with cancer. In epidemiologic settings characterized by a high prevalence of infections because of MDR microorganisms, this combination could be considered as one of the first-line empiric antibiotic therapies.
[Show abstract][Hide abstract] ABSTRACT: Background In essential thrombocythemia (ET) patients, history of thrombosis and age over 60 y are validated risk factors for occurrence of thrombosis during the follow-up. Leukocytosis, JAK2 V617F mutation, cardiovascular (CV) general risk factors, and male gender are candidate risk factors for thrombosis. The thrombocytosis, a constitutive abnormality in ET, is associated with both thrombotic and hemorrhagic complications.
[Show abstract][Hide abstract] ABSTRACT: We report a study of an alternative treatment schedule of imatinib (IM) in chronic myeloid leukemia (CML). Seventy-six Philadelphia-positive (Ph+) - BCR-ABL - positive patients aged 65 years or older, who had been treated with IM for more than two years and who were in stable complete cytogenetic response (CCgR) and in major molecular response (MMR), were enrolled in a single-arm study to test the effects of a policy of intermittent imatinib (INTERIM) therapy, one month on and one month off. With a minimum follow-up of four years, 13 patients (17%) lost CCgR and MMR, and 14 (18 %) lost MMR only. All these patients resumed continuous imatinib, and all - but one (lost to follow-up) regained CCgR and MMR. No patients progressed to accelerated or blastic phase, or developed clonal chromosomal abnormalities in Ph+ cells, or BCR-ABL mutations. In elderly Ph+ CML patients carefully selected for a stable CCgR (lasting > 2 years), the policy of intermittent imatinib treatment affected the markers of residual disease, but not the clinical outcomes (overall and progression-free survival). ClinicalTrials.gov number: NCT 00858806.
[Show abstract][Hide abstract] ABSTRACT: Health-related quality of life (HRQOL) is an important goal of therapy for chronic myeloid leukemia (CML) patients treated with current molecular-targeted therapies. The main objective of this study was to investigate factors associated with long-term HRQOL outcomes of CML patients receiving imatinib. Analysis was performed on 422 CML patients recruited in an observational multicenter study. HRQOL was assessed with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Key socio-demographic and clinical data were investigated for their association with HRQOL outcomes. Chronic fatigue and social support were also investigated. Univariate and multivariate linear regression analyses were used to identify independent factors associated with HRQOL outcomes. Fatigue was the only variable showing an independent and consistent association across all physical and mental HRQOL outcomes (P<0.01). Differences, between patients reporting low versus high fatigue levels were more than eight and seven times the magnitude of a clinically meaningful difference, respectively for the role physical (Δ=70 points) and the role emotional scale (Δ=63 points) of the SF-36. Fatigue did not occur as an isolated symptom and was most highly correlated with musculoskeletal pain (|r|=.511; P0.001) and muscular cramps (|r|=.448; P0.001). Chronic fatigue is the major factor limiting HRQOL of CML patients receiving imatinib.Leukemia accepted article preview online, 18 February 2013; doi:10.1038/leu.2013.51.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2013; 27(7). DOI:10.1038/leu.2013.51 · 10.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. To analyze the efficacy of antifungal prophylaxis (AFP) with posaconazole and itraconazole in a real-life setting of patients with acute myeloid leukemia (AML) during the first induction of remission.Methods. From January 2010 to June 2011, all patients with newly diagnosed AML were consecutively registered and prospectively monitored at 30 Italian hematological centers. Our analysis focused on adult patients who received intensive chemotherapy and a mold-active AFP for at least 5 days. To determine the efficacy of prophylaxis, invasive fungal disease (IFD) incidence, IFD-attributable mortality, and overall survival were evaluated.Results. In total, 515 patients were included in the present analysis. Posaconazole was the most frequently prescribed drug (260 patients [50%]) followed by fluconazole (148 [29%]) and itraconazole (93 [18%]). When comparing the groups taking posaconazole and itraconazole, there were no significant differences in the baseline clinical characteristics, whereas there were significant differences in the percentage of breakthrough IFDs (18.9% with posaconazole and 38.7% with itraconazole, P < .001). The same trend was observed when only proven/probable mold infections were considered (posaconazole, 2.7% vs itraconazole, 10.7%, P = .02). There were no significant differences in the IFD-associated mortality rate, while posaconazole prophylaxis had a significant impact on overall survival at day 90 (P = .002).Conclusions. During the last years, the use of posaconazole prophylaxis in high-risk patients has significantly increased. Although our study was not randomized, it demonstrates in a real-life setting that posaconazole prophylaxis confers an advantage in terms of both breakthrough IFDs and overall survival compared to itraconazole prophylaxis.Clinical Trials Registration. NCT01315925.
[Show abstract][Hide abstract] ABSTRACT: There have been few reports of a response to dasatinib or nilotinib after failure of two prior sequential tyrosine kinase inhibitors. We report the outcome of 82 chronic phase patients who received nilotinib or dasatinib as third alternative tyrosine kinase inhibitor therapy. Thirty-four patients failed to respond to nilotinib and were started on dasatinib as third tyrosine kinase Inhibitor line therapy while 48 patients were switched to nilotinib after dasatinib failure. Overall, we obtained a cytogenetic response in 32/82 patients and major molecular response in 13 patients; disease progression occurred in 12 patients. At last follow-up, 70 patients (85.4%) were alive with a median overall survival of 46 months. Our results show that third line tyrosine kinase inhibitor therapy in chronic myeloid leukemia patients after failure of two prior sequential tyrosine kinase inhibitors may induce a response that, in some instances, could prolong overall survival and affect event-free survival.
[Show abstract][Hide abstract] ABSTRACT: The main objective of this study was to investigate whether patients with chronic myeloid leukemia (CML) in treatment with long-term therapy imatinib have a different health-related quality-of-life (HRQOL) profile compared with the general population. In total, 448 CML patients were enrolled, and the SF-36 Health Survey was used to compare generic HRQOL profiles. Symptoms were also assessed. HRQOL comparisons were adjusted for key possible confounders. The median age of patients was 57 years and the median time of imatinib treatment was 5 years (range 3-9 years). The largest HRQOL differences were found in younger patients. In particular, patients aged between 18 and 39 years had marked impairments in role limitations because of physical and emotional problems, respectively: -22.6 (P < .001), -22.3 (P < .001). Patients with CML age 60 or older had a HRQOL profile very similar to that reported by the general population. Women had a worse profile than men when each were compared with their peers in the general population. Fatigue was the most frequently reported symptom. The HRQOL of CML patients is comparable with that of population norms in many areas, however, younger and female patients seem to report the major limitations.