[Show abstract][Hide abstract] ABSTRACT: The primary objective of this study was to investigate whether the presence of comorbidities was associated with a lower health-related quality of life (HRQOL) in elderly patients with chronic myeloid leukemia (CML). A sample of 174 CML patients aged 60 years or above was analyzed. HRQOL was assessed with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). A number of pre-selected sociodemographic and disease-related factors were considered as potential confounding factors for the association between comorbidity and HRQOL. Mean age of the 174 patients analyzed was 70 years (range 60-87 years) and 55 % were male. Overall, 111 patients (64 %) reported at least one comorbidity. Analysis stratified by age group category showed a greater proportion of patients with comorbidities in the older sub-group population (≥70 years) compared to younger patients (60 to 69 years). Differences in HRQOL outcomes between patients with no comorbidity at all and those with two or more comorbid conditions were at least twice the magnitude of a clinically meaningful difference in all the physical and mental health scales of the SF-36. In multivariate analysis, after adjusting for key confounding factors, the following scales were significantly lower in those with comorbidity: general health (p < 0.001), bodily pain (p < 0.001), physical functioning (p = 0.002), and vitality (p = 0.002). Assessing comorbidity in elderly patients with CML is important to facilitate identification of those most in need of HRQOL improvements.
Full-text · Article · Nov 2015 · Annals of Hematology
[Show abstract][Hide abstract] ABSTRACT: Nilotinib (NIL) is approved for the first-line treatment of CML based on the results of the ENESTnd study that demonstrated a higher efficacy compared to imatinib (IM). However, there are concerns on the vascular toxicity of NIL, disclosed by an increased rate of cardiovascular adverse events (CVAEs) with respect to imatinib. For this reason, we investigated the CVAEs in 2 studies of the GIMEMA CML WP that included NIL as first-line treatment of CML: the GIMEMA CML 0307 trial (73 pts; NIL
400 mg BID), and the GIMEMA CML 0408 trial (123 pts; 3-months alternating regime of NIL 400 mg BID and IM 400 mg QD). The median age at CML diagnosis of all 196 pts was 55 (18-84) years; 59 (30%) pts were ≥65 years; 52% were males; cardiovascular risk factors (CVRF: hypertension, dyslipidemia, diabetes, BMI ≥30, and prior ischemic disease) were present in 74 (38%) pts (median 1, range 1-4). There were no significant differences between the pts characteristics in the 2 studies. The
median f-up was 61 months. Nineteen CVAEs occurred in 17 (8.6%) pts: 7 acute myocardial infarctions (MI); 5 PAODs; 2 carotid stenosis, 2 aortic atherosclerosis, 1 stroke, 1 unstable angina, and 1 stable angina (1 patient had 1 PAOD, 1 stroke, and 1 MI). In pts with CVAEs, the median age at CML diagnosis was 67 (43-84 years), and the median interval from CML
diagnosis to CVAE was 38(1-76) months. Out of the 17 pts with CVAEs, 53% were males; 70% were ≥65 years at CML diagnosis; 76% had at least 1 CVRF, and 65% were treated with NIL alone. All pts but one (who died at 90 years for congestive heart failure post MI) are alive. Treatment of CVAEs included coronary angioplasty in 5 pts, lower limb amputation in 2 pts, and peripheral vascular surgery in 2 pts; all other pts received medical treatment; 12/17 pts permanently discontinued NIL. In univariate analysis, the occurrence of CVAEs was associated with age≥65 years (12/59[20%] vs 5/137[3.6%]; p=0.0004), the presence of at least one CVRF (13/74[18%] vs 4/122[3.3%]; p=0.001), and the monotherapy with NIL (11/73[15%] vs 6/123[4.8%]; p=0.018). CVAEs occurred at a significant rate in pts treated with NIL-based regimes, and in particularly in pts ≥65 years and/or with CVRF. Noteworthy, the alternating schedule of NIL and IM resulted in a lower incidence of CVAEs compared to NIL monotherapy. Thus, considering the morbidity associated to CVAEs, the risk/benefit ratio of NIL monotherapy should be
carefully evaluated in selected groups of patients.
[Show abstract][Hide abstract] ABSTRACT: Background: The treatment-free remission (TFR) is an emerging treatment goal in CML and a sustained deep molecular response (DMR, MR4 or better) is a pre-requisite to achieve TFR. The 5-year update from the ENESTnd trial showed a superiority of NIL over IM in terms of achievement of DMR, but differences concerning the stability of DMR have not
been reported yet. Independent studies are important to confirm and to extend the results of company-sponsored trials.
Aims: To assess the efficacy of NIL as first-line treatment in terms of achievement of DMR and stability of DMR.
Methods: Phase 3b study conducted by the GIMEMA CML WP (NCT01535391). Primary endpoint: MR4 at 24 months. Key secondary endpoints: kinetics of molecular response and stability of DMR. Starting NIL dose: 300 mg BID (dose escalation to 400 mg BID for ELN 2009 suboptimal response or failure). Molecular response assessed in GIMEMA standardized molecular laboratories (Labnet network): MR4 and MR4.5, according to EUTOS 2015 definitions; sustained MR4 or MR4.5, MR4 or MR4.5 for at least 1 year with at least 3 evaluable analysis. All the analysis were performed according to the ITT principle. Results: 130 CML patients in early chronic phase have been enrolled: median age, 50 (18-85) years; high risk patients, 22% (Sokal), 6% (Euro) and 8% (EUTOS); CCA in Ph+ cells at baseline, 5%; median follow-up, 29 (24-37) months. At the last contact the patients still on treatment with NIL were 100/130, 77%, while 30/130 patients, 23%, permanently interrupted the study drug: 3% progression, 5% failure or suboptimal response, 8% adverse events, 1% TFR, 5% other reasons. At 3 months, 80% of patients had BCR-ABL transcript levels <10%; at 6 months, 78% of patients had BCR-ABL transcript levels <1%. The major molecular response rates at 12 and 24 months were 57% and 65%, respectively. The rates of MR4 at 6, 12, 18 and 24 months were 12%, 28, 31% and 46%, respectively. Seventy-six patients (58%) achieved a MR4 at least once; the patients with a sustained MR4 were 39/76 (51%, or 30% of the total). The rates of MR4.5 at 6, 12, 18 and 24 months were 2%, 7%, 11% and 17%, respectively. Eleven patients (8%) achieved a sustained MR4.5. All the patients are still alive.
Conclusions: After 2 to 3 years of treatment, 30% and 8% of all the enrolled patients were in stable MR 4.0 and in stable MR4.5, respectively. It is likely that a longer treatment time is required to bring more patients to treatment free remission.
[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.
Full-text · Article · Sep 2015 · Blood Cancer Journal
[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.
Full-text · Article · Aug 2015 · Experimental hematology
[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.
[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.
Full-text · Article · Jun 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
[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.
No preview · Article · Mar 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
[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.
Full-text · Article · Oct 2014 · Annals of Oncology
[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.
No preview · Article · Jun 2014 · Journal of Antimicrobial Chemotherapy
[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.
No preview · Article · Apr 2014 · Journal of Clinical Oncology
[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.